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TABLE OF CONTENTS

54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. A1. Pituitary Hormones (Page 1) Corticosteroids (Page 9) Oestrogens, Anti-Oestrogens, Progestogens, Anti-Progestogens (Page 15) Oral Contraceptives (Page 23) Androgens, Anabolic Steroids, Anti-Androgens (Page 25) Thyroid Hormones, Antithyroid Drugs (Page 30) Insulin, Glucagon and Oral Hypoglycaemic Agents (Page 36) Parathyroid Hormone, Calcitonin and Vitamin D, Drugs Used to Treat Osteoporosis (Page 47) Sulfonamides and Trimethoprim. Fluoroquinolones (Page 53) Beta-Lactam Antibiotics (Page 62) Tetracyclines, Chloramphenicol, Macrolide Antibiotics (Page 74) Clindamycin, Polymixins, Vancomycin (Page 74) Aminoglycosides (Page 74) Antituberculotic Drugs. Anti-Leprosy Drugs (Page 87) Antifungal Drugs (Page 95) Antiviral Drugs (Page 102) Antiseptics and Disinfectants (Page 114) Antiprotozoal Drugs (Page 122) Antihelminthic Drugs (Page 140) Drugs Used in the Chemotherapy of Neoplastic Diseases: Alkylating Agents, Antimetabolites (Page 147) Drugs Used in the Chemotherapy of Neoplastic Diseases: Alkaloids, Antibiotics, Hormonal Agents (Page 147) Immunosuppressants and Immunomodulators (Page 159) Drugs Used in the Intoxicated Patient: Decontamination, Facilitation of Toxicant Elimination, Antidote Administration, Supportive Treatment (Page 160) Drug Intoxications: Mechanisms, Symptoms, Treatment (Page 161) Drugs, 3rd Semester (Page 162)

54. PITUITARY HORMONES


Overview
pituitary hormones are synthesized and secreted by the pituitary gland (hypophysis) the pituitary gland consists of 2 lobes LOBE ANTERIOR LOBE DESCRIPTION - consists of endocrine cells synthesizing and storing hormones - secretion of hormones from these cells is regulated by regulatory hormones secreted by the hypothalamus and/or by blood-borne end-products of the peripheral cells that these hormones stimulate - consists of terminal axons of neurons whose cell bodies reside in the hypothalamus - the cell bodies in the hypothalamus synthesize hormones which then are transported to the terminal axons of the posterior lobe for storage - secretion of hormones from these terminal axons is regulated by nervous signals originating from peripheral receptors

POSTERIOR LOBE

ANTERIOR LOBE HORMONES


Relevant Drugs
5 (6) categories 1) GROWTH HORMONE - growth hormone (GH, somatropin) acts on GH receptors (GHRs) found exclusively in the liver - stimulation of GHRs causes synthesis and secretion of insulin-like growth factor 1 (IGF-1) by the liver - IGF-1 acts on IGF-1 receptors (IGF-1Rs) found in most cells, thus inducing growth and/or division of the stimulated cells - consequences of IGF-1 stimulation include TISSUE MUSCLE CONSEQUENCE - increased protein uptake - increased protein anabolism - decreased protein catabolism - increased deliberation of free fatty acids - increased beta-oxidation

ADIPOSE TISSUE

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MUSCLE AND ADIPOSE TISSUE

- decreased glucose uptake - decreased glycolysis - increased osteoblast activity - decreased osteoclast activity

BONE

regulation of GH secretion is done by 2 mechanisms REGULATION STIMULATION MEDIATOR - growth hormone-releasing hormone (GHRH) - dopamine (through action on D2 receptors) - IGF-1

INHIBITION

1 type DRUG NAME SOMATROPIN DESCRIPTION General information - recombinant GH - administered subcutaneously Medical uses - treatment of turners syndrome (dwarfism)

2) ADRENOCORTICOTROPHIC HORMONE - adrenocorticothropic hormone (ACTH) acts on ACTH receptors (ACTHRs) exclusively found in zona fasciculata and zona reticularis of the adrenal cortex (see 55) - consequences of ACTH stimulation include TISSUE ZONA FASCICULATA CONSEQUENCE - increased glucocorticoid synthesis and secretion (see 55) - increased sex hormone synthesis and secretion (see 55)

ZONA RETICULARIS

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regulation of ACTH secretion is done by 2 mechanisms REGULATION STIMULATION MEDIATOR - corticotropin-releasing hormone (CRH) - ADH (through action on V3 receptors, see below) - glucocorticoids (mainly hydrocortisone)

INHIBITION

1 type DRUG NAME TETRACOSACTIDE DESCRIPTION General information - synthetic analogue of ACTH - administered intramuscularly Medical uses - diagnosis of adrenocortical insufficiency

3) PROLACTIN - prolactin (PRL) acts on PRL receptors (PRLRs) exclusively found in the mammary glands of the breasts - consequences of PRL stimulation include TISSUE MAMMARY GLAND CONSEQUENCE - increased milk production (together with oestrogens, see 56) - upregulation of oestrogen receptors (see 56)

regulation of PRL secretion is done by 2 mechanisms REGULATION STIMULATION MEDIATOR - prolactin-releasing hormone (PRH) - dopamine (through action on D2 receptors) -3-

INHIBITION

1 group A) D2 RECEPTOR ANTAGONISTS - D2 receptor antagonists inhibit the inhibitory action of dopamine on PRL secretion, thus facilitating PRL secretion and following increased milk production - see 41

4) THYROID-STIMULATING HORMONE - thyroid-stimulating hormone (TSH) acts on TSH receptors (TSHRs) exclusively found in the follicles of the thyroid gland - consequences of TSH stimulation include TISSUE THYROID FOLLICLES CONSEQUENCE - increased secretion of thyroid hormones (tetraiodotyronine and triiodothyronine, see 59)

regulation of TSH secretion is done by 2 mechanisms REGULATION STIMULATION MEDIATOR - thyrotropin-releasing hormone (TRH) - thyroxine - triiodothyronine

INHIBITION

not used clinically

5) FOLLICLE-STIMULATING HORMONE AND LUTENIZING HORMONE - follicle-stimulating hormone (FSH) and lutenizing hormone (LH) act on FSH receptors (FSHRs) and LH receptors (LHRs), respectively, exclusively found in the gonads (see 56/57/58) - consequences of FSH and LH stimulation may be divided in 2 groups A) FSH STIMULATION - consequences include TISSUE OVA CONSEQUENCE - development of the primordial follicles to yield mature follicles -4-

- oestrogen synthesis and secretion by the mature follicles TESTES - maturation of spermatozoa (spermatogenesis, together with testosterone, see 58)

B) LH STIMULATION - consequences include TISSUE OVA CONSEQUENCE - rupture of the mature follicles and following ovulation - progesterone synthesis and secretion by the remnants of the ruptured follicles (corpus luteum) - testosterone synthesis and secretion

TESTES

regulation of FSH and LH secretion is done by 2 mechanisms REGULATION STIMULATION MEDIATOR - gonadotropin-releasing hormone (GnRH) - estrogen - progesterone - testosterone

INHIBITION

1 group A) ORAL CONTRACEPTIVES - oral contraceptives inhibit the release of FSH and LH from the anterior pituitary, thus preventing ovulation and following prevention of pregnancy - see 57

POSTERIOR LOBE HORMONES


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Relevant Drugs
2 categories 1) ANTIDIURETIC HORMONE - antidiuretic hormone (ADH, vasopressin) acts on ADH receptors (ADHRs) found in several tissues - there are 3 types of ADH receptors RECEPTOR TYPE V1 DESCRIPTION Location - vascular smooth muscle Consequence - vasoconstriction V2 Location - distal tubules and collecting ducts of the kidney Consequence - insertion of aquaporins in the luminal surface of the distal tubules and collecting ducts of the kidney and following sodium extretion and water reabsorption V3 Location - pituitary gland Consequence - ACTH secretion

regulation of ADH secretion is done by 1 mechanism REGULATION STIMULATION MEDIATOR - stimulation of osmoreceptors in the hypothalamic capillaries by high blood osmolality - stimulation of baroreceptors in the carotid bodies by low blood pressure

3 types DRUG NAME -6DESCRIPTION

VASOPRESSIN

General information - ADH itself - non-selective ADH-receptor agonist - administered IV, intramuscularly and/or subcutaneously Medical uses - treatment of hemorrhagic esophageal varices - treatment of diabetes insipidus

TERLIPRESSIN

General information - synthetic ADH analogue - selective V1 receptor agonist Medical uses - treatment of hemorrhagic esophageal varices

DESMOPRESSIN

General information - synthetic ADH analogue - selective V2 receptor agonist - administered nasally Medical uses - treatment of diabetes insipidus

2) OXYTOCIN - oxytocin acts on oxytocin receptors exclusively found in the smooth muscle cells of the uterus and surrounding the mammary glands of the breasts - consequences of oxytocin stimulation include TISSUE UTERUS CONSEQUENCE - very strong rhythmic contractions leading to labor - ejection of milk

MAMMARY GLANDS

regulation of oxytocin secretion is done by 1 mechanism REGULATION STIMULATION -7MEDIATOR - extreme distension of the uterus (end of

pregnancy) - suckling of the nipples (breast feeding)

2 groups A) OXYTOCIN RECEPTOR AGONISTS - oxytocin receptor agonists (oxytocic drugs) stimulate oxytocin receptors, thus facilitating contractions of the uterus and following induction of labor - see 35 B) OXYTOCIN RECEPTOR ANTAGONISTS - oxytocin receptor antagonists (tocolytic drugs) inhibit the action of oxytocin on oxytocin receptors, thus inhibiting contractions of the uterus and following prevention of labor - see 35

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55. CORTICOSTEROIDS
Overview
corticosteroids are steroid hormones synthesized and secreted by the adrenal cortex the adrenal cortex consists of 3 layers (listed from outermost to innermost) LAYER ZONA GLOMERULOSA ZONA FASCICULATA DESCRIPTION - synthesize mineralocorticoids (primarily aldosterone) - synthesize glucocorticoids (primarily hydrocortisone (cortisol)) - synthesize and store sex hormones (primarily testosterone and oestradiol)

ZONA RETICULARIS

all the corticosteroids are steroid hormones synthesized from cholesterol in a complex meshwork GLUCOCORTICOIDS SEX HORMONES

MINERALOCORTICOIDS CHOLESTEROL PREGNONELONE 3-dehydrogenase PROGESTERONE 21-hydroxylase 11-DEOXYCORTICOSTERONE 11- hydroxylase CORTICOSTERONE ALDOSTERONE

17-HYDROXYPREGNONELONE 3-dehydrogenase 17-HYDROXYPROGESTERONE 21-hydroxylase 11-DEOXYCORTISOL 11- hydroxylase HYDROCORTISONE

DEHYDROEPIANDROSTERONE 3-dehydrogenase ANDROSTENEDIONE 17-dehydrogenase TESTOSTERONE aromatase OESTRADIOL OESTRIOL OESTRONE

though this meshwork might seem overly complex to memorize, please notice that the enzymes in each row (see above) essentially are the same (!)

MINERALOCORTICOIDS
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Overview
mineralocorticoids are synthesized by the zona glomerulosa of the adrenal cortex the main mineralocorticoid is aldosterone aldosterone acts on aldosterone receptors exclusively found in the late distal tubule of the kidney nephrons consequences of aldosterone stimulation, see 24 regulation of aldosterone secretion is done by the renin angiotensin aldosterone system (see 24)

Relevant Drugs
3 groups 1) ALDOSTERONE RECEPTOR AGONISTS - aldosterone receptor agonists agonizes aldosterone receptors, thus causing increased water/sodium retention and increased potassium/hydrogen ion excretion - 2 types DRUG NAME ALDOSTERONE DESCRIPTION General information - not used clinically General information - administered orally Medical uses - treatment of hypoadrenocorticism (addisons disease)

FLUDROCORTISONE

2) ALDOSTERONE RECEPTOR ANTAGONISTS - potassium-sparing diuretics - aldosterone receptor antagonists antagonize the action of aldosterone on aldosterone receptors, thus causing decreased water/sodium retention and decreased potassium/hydrogen ion excretion - see 25 3) CORTICOSTEROID SYNTHESIS INHIBITORS - corticosteroid synthesis inhibitors inhibit enzymes responsible corticosteroid synthesis (see above), thus causing decreased synthesis of aldosterone, hydrocortisone and sex hormones - 2 types DRUG NAME TRILOSTANE DESCRIPTION General information - 3-dehydrogenase inhibitor - 10 -

Medical uses - treatment of hyperaldosteronism (cushings syndrome) - treatment of hypercortisolism (conns syndrome) METYRAPONE General information - 11-hydroxylase inhibitor - same as trilostane (see above)

GLUCOCORTICOIDS
Overview
glucocorticoids are synthesized by the zona fasciculata of the adrenal cortex the main glucocorticoid is hydrocortisone (cortisol) hydrocortisone acts on glucocorticoid receptors found in most cells hydrocortisone also has a strong action on aldosterone receptors (see above) consequences of hydrocortisone stimulation include CONSEQUENCE CARBOHYDRATE METABOLISM DESCRIPTION - decreased glucose uptake - decreased glycolysis - increased gluconeogenesis - increased deliberation of free fatty acids from adipose tissue - increased beta-oxidation - decreased protein uptake - decreased protein synthesis - increased protein catabolism - decreased calcium absorption from the GI tract - decreased osteoblast activity - increased osteoclast activity - increased calcium excretion by the kidneys - decreased synthesis of COX-2 (see 51/52) - decreased synthesis of eicosanoids (due to decreased COX-2 synthesis, see 35) - decreased edema, pain and fever (due to decreased eicosanoid synthesis)

FAT METABOLISM

PROTEIN METABOLISM

CALCIUM HOMEOSTASIS

IMMUNE DEFENSE SYSTEM

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- decreased synthesis of nitric oxide synthase - decreased vasodilation (due to decreased nitric oxide synthase synthesis) - decreased synthesis of GM-CSF - decreased proliferation of granulocytes and monocytes/macrophages in the bone marrow (due to decreased GM-CSF synthesis) - decreased synthesis of TNF-gamma - decreased synthesis of VCAM-1 and ICAM-1 cell adhesion molecules (due to decreased TNF-gamma synthesis) - decreased migration of granulocytes and monocytes/macrophages (due to decreased VCAM-1/ICAM-1 synthesis) - decreased activation of helper T-cells - decreased secretion of IL-2 from helper Tcells (due to decreased activation of T-helper cells) - decreased activation of cytotoxic T-cells (due to decreased IL-2 secretion from helper Tcells) - decreased activation of fibroblasts - decreased deposition of collagen and glycosaminoglycans (due to decreased activation of fiboblasts) - decreased wound healing and fibrosis (due to decreased deposition of collagen/glycosaminoglycans) - decreased activation of mast cells - decreased secretion of histamine (due to decreased activation of mast cells) - decreased bronchoconstriction (due to decreased histamine release) - decreased synthesis of complement factors by the liver

regulation of hydrocortisone secretion is done by ACTH (see 54)

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Relevant Drugs
1 group 1) GLUCOCORTICOID RECEPTOR AGONISTS - 6 types DRUG NAME HYDROCORTISONE DESCRIPTION General information - cortisol itself - administered orally, IV, intramuscularly, intra-articularly, by inhalation, and/or dermally Medical uses - treatment of adrenal hypofunction (addisons disease) Side effects - cushings syndrome-like syndrome (due to negative feedback on the anterior lobe of the pituitary gland, see 54) - hyperglycemia (due to altered carbohydrate metabolism) - diabetes (due to hyperglycemia) - inhibition of growth in children (due to altered protein metabolism and altered calcium homeostasis) - osteoporosis in adults (due to altered calcium homeostasis) - increased susceptibility to infections (due to immunosuppression) - generalized edema (due to sodium/water retention by action on aldosterone receptors) - adrenal hypofunction (if withdrawn rapidly) CORTISONE General information - pro-drug - activated to hydrocortisone in the body - same as hydrocortisone (see above) Medical uses - treatment of adrenal hypofunction (addisons disease) - treatment of inflammations (including exophthalmus of hyperthyroidism, see 59) - treatment of hypersensitivity reactions - 13 -

(including asthma, see 36) Side effects - same as hydrocortisone (see above) PREDNISOLONE General information - synthetic hydrocortisone derivative - same as hydrocortisone (see above) Medical uses - treatment of inflammations - treatment of hypersensitivity reactions (including asthma, see 36) Side effects - same as hydrocortisone (see above) PREDNISONE General information - pro-drug - activated to prednisolone in the body - same as prednisolone (see above) General information - same as prednisolone (see above) General information same as prednisolone (see above)

BETAMETHASONE

DEXAMETHASONE

SEX HORMONES
Overview
sex hormones are synthesized by the zona reticularis of the adrenal cortex the main sex hormones of the zona reticularis are testosterone and oestrogens however, the zona reticularis only maintains a basal level of testosterone and oestrogens in childhood and menopause, with the gonads synthesizing the bulk of the testosterone and oestrogens in puberty and adulthood (see 56/57/58) regulation of sex hormone secretion by the zona reticularis is done by ACTH (see 54)

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56. OESTROGENS, ANTI-OESTROGENS, PROGESTOGENS, ANTI-PROGESTOGENS


Overview
oestrogens and progestogens are the female sex hormones they are steroid hormones synthesized and secreted by 4 different tissues TISSUE OVA PLACENTA ADRENAL CORTEX DESCRIPTION - during puberty and adulthood - during pregnancy - only a small basal output - only significant during childhood and menopause - see 55 - only a small basal output - in males

TESTIS

like all other steroid hormones, oestrogens and progestogens are synthesized from cholesterol (see 55)

OESTROGENS
Overview
there are 3 main types of endogenous oestrogens (listed from least to most potent) TYPE OESTRONE OESTRIOL OESTRADIOL DESCRIPTION

oestrogens act on oestrogen receptors found in most tissues, but with a high prevalence in the ovaries, uterus, vagina and breasts oestrogens also have a weak action on aldosterone receptors (see 55) consequences of oestrogen stimulation may be divided in 2 groups 1) SEXUAL CONSEQUENCES - 15 -

include CONSEQUNECE DEVELOPMENT OF PRIMARY SEXUAL CHARACTERISTICS DEVELOPMENT OF SECONDARY SEXUAL CHARACTERISTICS REGULATION OF THE MENSTRUAL CYCLE DESCRIPTION - development of the ova, uterus and vagina

- redistribution of fat to the breasts and hips

- proliferation of the endometrium of the uterus (endometrial proliferative phase) - upregulation of progestogen receptors in the ova, uterus and anterior lobe of the pituitary gland - inhibition of FSH and LH secretion of by the anterior lobe of the pituitary gland (, thus inhibiting menstruation, see 54) - development of the mammary glands (together with progestogens, see below) - increased milk production (together with prolactin, see 54) - weak rhythmic contractions of the uterus (see 35)

REGULATION OF PREGNANCY

2) NON-SEXUAL CONSEQUENCES - include TISSUE LIVER CONSEQUENCE - increased synthesis of coagulation factors - increased synthesis of antithrombin III and plasminogen - increased synthesis of HDL cholesterol - decreased synthesis of LDL cholesterol BONE - increased osteoblast activity - decreased osteoclast activity

regulation of oestrogen secretion is done by LH (see 54)

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Relevant Drugs
2 groups 1) NATURAL OESTROGENS - 2 types DRUG NAME ESTRADIOL DESCRIPTION General information - oestradiol - administered orally, subcutaneously and/or dermally Medical uses - treatment of primary hypogonadism - treatment of secondary hypogonadism (menopause) - treatment of post-menopausal osteoporosis Side effects - thrombosis/embolism (due to increased synthesis of coagulation factors) - breast cancer - nausea/vomiting - hypertension (due to sodium/water retention by action on aldosterone receptors) - generalized edema (due to sodium/water retention) ESTRIOL General information - oestriol - administered orally and/or vaginally - same as estradiol (see above)

2) SYNTHETIC OESTROGENS - 2 types DRUG NAME ETHINYLESTRADIOL DESCRIPTION General information - synthetic oestrogen derivative - administered orally, intramuscularly, subcutaneously and/or dermally Medical uses - same as estradiol (see above) - 17 -

- prevention of pregnancy (oral contraceptive, then administered coherently with a progestogen, see 57)

MESTRANOL

General information - same as ethinylestradiol (see above)

ANTI-OESTROGENS
Overview
anti-oestrogens are drugs that either inhibit the action of oestrogen on oestrogen receptors or inhibit the synthesis of oestrogen

Relevant Drugs
2 categories 1) OESTROGEN RECEPTOR ANTAGONISTS - oestrogen receptor antagonists antagonize the action of oestrogen on oestrogen receptors - oestrogen receptor antagonists also have an oestrogen receptor agonist action to a varying degree in different tissues - 2 types

DRUG NAME TAMOXIFEN

DESCRIPTION General information - oestrogen receptor antagonist in the breasts, thus inhibiting the increased risk of breast cancer associated with oestrogen - oestrogen receptor agonist everywhere else Medical uses - treatment of breast cancer (oestrogen receptor antagonist action) - treatment of post-menopausal osteoporosis (oestrogen receptor agonist action)

CLOMIPHENE

General information - oestrogen receptor antagonist in the anterior lobe of the pituitary gland, thus inhibiting negative feedback of oestrogen on the anterior lobe of the pituitary gland - oestrogen receptor agonist everywhere else

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Medical uses - treatment of anovulation (oestrogen receptor antagonist action)

2) OESTROGEN SYNTHESIS INHIBITORS - oestrogen synthesis inhibitors inhibit aromatase (see 55), thus inhibiting synthesis of oestrogens - 2 types DRUG NAME ANASTRAZOLE DESCRIPTION Medcal uses - treatment of breast cancer Medical uses - same as anastrazole (see above)

FORMESTANE

PROGESTOGENS
Overview
the main endogenous progestogen is progesterone progesterone acts on progestogen receptors primarily found in the ova and uterus progesterone also has a weak action on aldosterone receptors (see 55) consequences of progesterone stimulation may be divided in 2 groups 1) SEXUAL CONSEQUENCES - include CONSEQUENCE REGULATION OF THE MENSTRUAL CYCLE DESCRIPTION - secretion by the endometrium of the uterus (endometrial secretory phase) - downregulation of estrogen receptors in the ova and uterus - development of the mammary glands (together with oestrogens, see above) - strong rhythmic contractions of the uterus (see 35)

REGULATION OF PREGNANCY

2) NON-SEXUAL CONSEQUENCES - include - 19 -

CONSEQUENCE LIVER

DESCRIPTION - increased synthesis of LDL cholesterol - decreased synthesis of HDL cholesterol

regulation of progesterone secretion is done by FSH (see 54)

Relevant Drugs
2 categories 1) PROGESTERONE AND PROGESTERONE DERIVATIVES - 2 types DRUG NAME HYDROXYPROGESTERONE DESCRIPTION General information - administered orally, intramuscularly, vaginally and/or rectally Medical uses - treatment of ectopic endometrial tissue (endometriosis) - treatment of endometrial hyperplasia - treatment of endometrial cancer Side effects - irregular menstrual cycles - irregular menstrual bleeding - irritability - depression - thrombosis/embolism (due to increased LDL cholesterol and decreased HDL cholesterol) - hypertension (due to sodium/water retention by action on aldosterone receptors) - generalized edema (due to sodium/water retention) MEDROXYPROGESTERONE General information - same as hydroxyprogesterone

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2) SYNTHETIC PROGESTOGENS - 5 types DRUG NAME NORETHISTERONE DESCRIPTION General information - also a weak testosterone receptor agonist - administered orally Medcal uses - same as hydroxyprogesterone (see above) - prevention of pregnancy (oral contraceptive, then administered alone or coherently with an oestrogen, see 57) Side effects - same as hydroxyprogesterone (see above) - increased muscular mass (due to action on testosterone receptors) - acne (due to action on testosterone receptors) ETHYNODIOL General information - same as norethisterone (see above) General information - administered orally Medical uses - same as norethisterone (see above) Side effects - same as hydroxyprogesterone (see above) DESOGESTREL General information - same as levonorgestrel (see above) General information - same as levonorgestrel (see above)

LEVONORGESTREL

GESTODENE

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ANTI-PROGESTOGENS
Overview
anti-progestogens are progestogen receptor antagonists, thus inhibiting the action of progesterone on progestogen receptors

Relevant Drugs
1 type DRUG NAME MIFEPRISTONE DESCRIPTION Medical uses - 1st trimester abortion (then administered coherently with misoprostol, see 37)

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57. ORAL CONTRACEPTIVES


Overview
oral contraceptives are drugs that inhibit FSH and LH release from the anterior lobe of the pituitary gland (see 54) this causes inhibition of development of primordial follicles to mature follicles of the ova, and inhibition of rupture of these mature follicles and following ovulation (see 54) , thus oral contraceptives prevent pregnancy oral contraceptives are administered orally (duh!)

Relevant Drugs
3 categories 1) COMBINED PILL - the combined pill is a combination of 1 oestrogen and 1 progestogen - oestrogens and progestogens inhibit FSH and LH release from the anterior lobe of the pituitary gland by negative feedback (see 54) - the combined pill is taken for 21 consecutive days, followed by a 7 day break to induce mestruation (without previous ovulation) - drugs combined in the combined pill may be divided in 2 groups A) SYNTHETIC OESTROGENS - any synthetic oestrogen may be used in the combined pill (see 56) B) SYNTHETIC PROGESTOGENS - any synthetic progestogen may be used in the combined pill (see 56) there are 3 groups of combined pills A) MONOPHASIC COMBINED PILL - the same ratio of the oestrogen and the progestogen is taken for all the 21 days B) BIPHASIC COMBINED PILL - the 21 days are divided in 2 periods, and 2 different ratios of the oestrogen and the progestogen are taken in these periods C) TRIPHASIC COMBINED PILL - the 21 days are divided in 3 periods, and 3 different ratios of the oestrogen and the progestogen are taken in these periods side effects of the combined pill include STEROID SIDE EFFECT

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OESTROGEN

- breast cancer - nausea/vomiting - irritability - depression - acne (if the progestogen also is a weak testosterone agonist) - increased muscle mass (if the progestogen is a weak testosterone agonist) - thrombosis/embolism - hypertension - generalized edema

PROGESTOGEN

OESTROGEN/PROGESTOGEN

2) PROGESTOGEN-ONLY PILL - the progestogen-only pill consists of only 1 progestogen (duh!) - progestogen alone also inhibit FSH and LH release from the anterior lobe of the pituitary gland by a negative feed back mechanism, though less efficiently than in combination with an oestrogen - the progestogen-only pill is taken continuously - 1 group A) SYNTHETIC PROGESTOGENS - any synthetic progestogen may be used in the progestogen-only pill (see 56) side effects of the progestogen-only pill are the same as the progestogen- and oestrogen/progestogen side effects of the combined pill (see above)

3) POSTCOITAL CONTRACEPTION PILL - emergency pill - the postcoital contraception pill is a modified progestogen-only pill or a modified combined pill with a much higher concentration of progestogen and/or oestrogen - it powerfully inhibits FSH and LH release from the anterior lobe of the pituitary gland, thus preventing pregnancy - the post-coital contraception pill is taken less than 72 hours after unprotected intercourse, and then repeated 12 hours later

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58. ANDROGENS, ANABOLIC STEROIDS, ANTIANDROGENS


Overview
androgens are the male sex hormones they are steroid hormones synthesized and secreted by 3 different tissues TISSUE TESTIS ADRENAL CORTEX DESCRIPTION - during puberty and adulthood - only a small basal output - only significant during childhood and andropause - see 55 - only a small basal output - in females

OVARIES

like all other steroid hormones, androgens are synthesized from cholesterol (see 55)

ANDROGENS
Overview
there are 3 main endogenous androgens (listed from least to most potent) TYPE DEHYDROEPIANDROSTERONE ANDROSTENEDIONE TESTOSTERONE DESCRIPTION - DHEA

however, both dehydroepiadrosterone and androstenedione is converted to testosterone in the liver , thus testosterone may be considered the only main endogenous androgen testosterone acts on androgen receptors found in most tissues testosterone also has a weak action on aldosterone receptors (see 55) testosterone is only a weak androgen receptor agonist (!) however, testosterone is converted to dihydrotestosterone (DHT) in peripheral tissues dihydrotestosterone is a strong androgen receptor agonist, thus the effects of testosterone is mediated by this metabolite - 25 -

conversion of testosterone to dihydrotestosterone is done in 1 step TESTOSTERONE 5-reductase DIHYDROTESTOSTERONE

consequences of dihydrotestosterone stimulation may be divided in 2 groups 1) SEXUAL CONSEQUENCES - include MECHANISM DEVELOPMENT OF PRIMARY SEXUAL CHARACTERISTICS DESCRIPTION - development of the testes and penis

DEVELOPMENT OF SECONDARY SEXUAL CHARACTERISTICS

- increased hair growth on the body (especially on the pubicand axillary regions, and on the face) - increased activity of the sebaceous glands (acne) - thickening of the skin (coarser skin) - hypertrophy of the vocal cords (deeper voice) - maturation of spermatozoa (together with FSH, see 54) - increased sexual drive, physical vigour and feeling of well-being

SPERMATOGENESIS

INCREASED LIBIDO

2) NON-SEXUAL CONSEQUENCES - include TISSUE MUSCLE CONSEQUENCE - increased protein uptake - increased protein anabolism - decreased protein catabolism - increased deliberation of free fatty acids

ADIPOSE TISSUE

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- increased beta-oxidation MUSCLE AND ADIPOSE TISSUE - decreased glucose uptake - decreased glycolysis - increased osteoblast activity - decreased osteoclast activity

BONE

, thus the non-sexual consequences of testosterone stimulation are the same as with GH (see 54)

regulation of testosterone secretion is done by LH (see 54)

Relevant Drugs
5 types DRUG NAME TESTOSTERONE DESCRIPTION General information - administered subcutaneously and/or dermally Medical uses - treatment of hypogonadism Side effects - infertility (due to negative feedback on the anterior lobe of the pituitary gland and following decreased FSH secretion) - hypertension (due to sodium/water retention by action on aldosterone receptors) - generalized edema (due to sodium/water retention) TESTOSTERONE ETHANATE General information - administered intramuscularly - same as testosterone (see above) General information - same as testosterone ethanate (see above) General information - administered orally - same as testosterone (see above)

TESTOSTERONE PROPIONATE

TESTOSTERONE UNDECANOATE

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METHYL TESTOSTERONE

General information - same as testosterone undecanoate (see above)

ANABOLIC STEROIDS
Overview
anabolic steroids are synthetic androgen analogues with decreased sexual consequences and increased non-sexual consequences (anabolic effects, see above)

Relevant Drugs
2 types DRUG NAME NANDROLONE DESCRIPTION General information - administered Medical uses - treatment of muscle wasting - treatment of aplastic anemias Side effects - same as androgens (see above) STANOZOLOL General information - same as nandrolone (see above)

anabolic steroids may also be abused as a performance enhancer in body builders however, to provide the desired anabolic consequences it needs to be taken in so high doses (5-25 times therapeutic dose) that the sexual consequences marginalize even the sexual consequences of normal androgens (see above) side effects of anabolic steroid abuse include SUBJECT MALES SIDE EFFECT - testicular atrophy (due to negative feedback on the anterior lobe of the pituitary gland and following decreased FSH secretion) - sterility (due to testicular atrophy) - gynecomastia - anovulation (due to negative feedback on the anterior - 28 -

FEMALES

lobe of the pituitary gland and following decreased FSH and LH secretion) - hisrutism - acne - coarser skin - deeper voice MALES AND FEMALES - aggressiveness - psychosis - sudden death (!)

ANTI-ANDROGENS
Overview
anti-androgens are drugs that either inhibit the action of dihydrotestosterone on androgen receptors or inhibit the synthesis of dihydrotestosterone

Relevant Drugs
2 categories 1) ANDROGEN RECEPTOR ANTAGONISTS - androgen receptor antagonists antagonize the action of dihydrotestosterone on androgen receptors - 1 type DRUG NAME FLUTAMIDE DESCRIPTION Medical uses - treatment of prostate cancer

2) DIHYDROTESTOSTERONE SYNTHESIS INHIBITORS - dihydrotestosterone synthesis inhibitors inhibit 5-reductase (see above), thus inhibiting synthesis of dihydrotestosterone - 1 type DRUG NAME FINASTERIDE DESCRIPTION Medcal uses - treatment of benign prostate hyperplasia - treatment of prostate cancer

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59. THYROID HORMONES, ANTITHYROID DRUGS


Overview
the thyroid gland synthesizes and secretes 3 hormones HORMONE TETRAIODOTHYRONINE DESCRIPTION - T4 - thyroxine - 2 diiodotyrosine molecules covalently bound to each other (see below) - T3 - 1 monoiodotyrosine- and 1 diiodotyrosine molecule covalently bound to each other (see below) - see 61

TRIIODOTHYRONINE

CALCITONIN

however, thyroid hormones in its strictest sense only encompass tetraiodothyronine and triiodothyronine, thus these are the hormones covered here thyroid hormones are synthesized from iodine and tyrosine in the follicular cells of the thyroid gland, and stored as thyroglobulin in the colloid of the thyroid follicles synthesis of thyroid hormones is done by oxidation of iodine to oxidized iodine (iodide) and oxidation of tyrosine to oxidized tyrosine this oxidation is done by the enzymatic action of thyroperoxidase and its coenzyme hydrogen peroxide (an oxidizing agent, see 70) then, iodide and oxidized tyrosine spontaneously join to form 2 different molecules MOLECULE MONOIODOTYROSINE DESCRIPTION - 1 iodide covalently bound to 1 tyrosine - 2 iodides covalently bound to 1 tyrosine

DIIODOTYROSINE

2 diiodotyrosine molecules covalently bound to each other will form tetraiodothyronine, while 1 monoiodotyrosine- and 1 diiodotyrosine molecule covalently bound to each other will form triiodotyronine (see above) however, tetraiodothyronine is converted to triiodothyronine in the peripheral tissues , thus triiodothyronine may be considered the only main endogenous thyroid hormone triiodothyronine acts on thyroid hormone receptors found in most cells consequences of triiodothyronine stimulation may be divided in 2 groups - 30 -

1) DIRECT METABOLIC CONSEQUENCES - include CONSEQUENCE CARBOHYDRATE METABOLISM DESCRIPTION - increased glucose uptake - increased glycolysis - increased gluconeogenesis - increased deliberation of free fatty acids from adipose tissue - increased beta-oxidation - increased synthesis of HDL cholesterol - decreased synthesis of LDL cholesterol PROTEIN METABOLISM - increased protein uptake - increased protein anabolism - decreased protein catabolism

FAT METABOLISM

2) INDIRECT METABOLIC CONSEQUENCES - include TISSUE CARDIOVASCULAR SYSTEM CONSEQUENCE - increased heart rate (positive chronotropic effect) - increased force of contraction (positive ionotropic effect) - increased myocardial excitability (positive bathmotropic effect) - increased AV conduction (positive dromotropic effect) - increased respiratory rate - increased food intake - increased hormone secretion - increased mental activity (cerebration)

RESPIRATORY SYSTEM GI SYSTEM ENDOCRINE SYSTEM CENTRAL NERVOUS SYSTEM - 31 -

- hyperactivity and/or somnolence

collectively the direct- and indirect metabolic consequences cause increased metabolic rate, increased heat production, increased growth and decreased weight regulation of thyroid hormone secretion is done by TSH (see 54)

Relevant Drugs
2 categories 1) THYROID HORMONES - thyroid hormones are used in treatment of hypothyroidism - 2 groups A) NATURAL THYROID HORMONES - 2 types

DRUG NAME THYROXINE

DESCRIPTION General information - tetraiodothyronine itself - administered orally Side effects - angina pectoris (due to postive chronotropic- and -ionotropic effect) - cardiac dysrhythmia (due to positive bathmotropic- and dromotropic effect) - cardiac failure (due to angina pectoris and cardiac dysrhythmias) - osteoporosis

TRIIODOTHYRONINE

General information - same as thyroxine

B) SYNTHETIC THYROID HORMONES - 2 types

DRUG NAME LEVOTHYROXINE

DESCRIPTION General information - synthetic tetraiodothyronine

- 32 -

- same as thyroxine LIOTHYRONINE General information - synthetic triiodothyronine - same as thyroxine

2) ANTITHYROID DRUGS - antithyroid drugs are used in treatment of hyperthyroidism (toxic goiter, basedow-graves disease) - 5 groups A) IODIDE - iodide inhibits synthesis of hydrogen peroxide, thus inhibiting oxidation of iodine and tyrosine and following inhibition of formation of thyroid hormones - 1 type DRUG NAME POTASSIUM IODIDE DESCRIPTION General information - lugol solution - administered orally Side effects - angioedema - rashes - conjunctivitis - fever

B) RADIOACTIVE IODINE - radioactive iodine is almost completely taken up by the thyroid follicles where it emits beta- and gamma-radiation, thus destroying parts of the thyroid gland - 1 type DRUG NAME RADIOIODINE DESCRIPTION General information - I131 - administered orally Side effects - hypothyroidism - teratogenesis

- 33 -

C) THIOUREYLENES - thioureylenes inhibit thyroperoxidase, thus inhibiting oxidation of iodine and tyrosine and following inhibition of formation of thyroid hormones - 4 types DRUG NAME METHIMAZOLE DESCRIPTION General information - administered orally - may cross the placental barrier Side effects - non-toxic goiter (due to absence of negative feedback on the anterior lobe of the pituitary gland, see 54) - exophthalmus (due to absence of negative feedback on the anterior lobe of the pituitary gland, see 54) - leukocytopenia - jaundice - rashes - nausea CARBIMAZOLE General information - pro-drug - converted to methimazole in the body - same as methimazole (see above) General information - same as methimazole (see above) General information - same as methimazole (see above)

THIOURACIL

METHYLTHIOURACIL

D) NON-SELECTIVE BETA ANTAGONISTS - non-selective beta antagonists inhibit the action of catecholamines on beta-adrenergic receptors, thus decreasing the tachycardia, dysrhythmia, tremor and agitation associated with hyperthyroidism - see 21 E) GLUCOCORTICOIDS

- 34 -

glucocorticoids suppress the immune defense system, thus preventing the exophthalmus associated with hyperthyroidism see 55

- 35 -

60. INSULIN, GLUCAGON AND ORAL HYPOGLYCAEMIC AGENTS


Overview
diabetes mellitus is an inability of the body to remove glucose from the blood stream, thus leading to chronic hyperglycemia there are 2 types of diabetes mellitus depending on the etiology of the chronic hyperglycemia TYPE DIABETES MELLITUS TYPE 1 DESCRIPTION - insulin-dependent diabetes mellitus (IDDM), juvenile diabetes mellitus - primarily occurs in children - caused by an inability of the beta-cells of the endocrine pancreas to secrete insulin (see below), thus leading to decreased stimulation of the insulindependent glucose transporters and following decreased removal of glucose from the blood stream - non-insulin dependent diabetes mellitus (NIDDM), adult-onset diabetes mellitus, obesity-related diabetes mellitus - primarily occurs in adults (primarily if obese) - caused by decreased responsiveness of the insulindependent glucose transporters to insulin, and following decreased removal of glucose from the blood stream

DIABETES MELLITUS TYPE 2

ENDOCRINE PANCREATIC HORMONES


Overview
the pancreas is a multifunctional organ primarily consumed with the digestion and metabolism of macronutrients it consists of 2 parts PART EXOCRINE PANCREAS DESCRIPTION - consists of pancreatic acini - secretes digestive enzymes into the gastrointestinal tract - consists of langerhans islets - secretes regulatory hormones into the blood stream

ENDOCRINE PANCREAS

- 36 -

the endocrine pancreas contains of 4 different types of endocrine cells, each synthesizing and secreting distinct hormones CELL TYPE ALPHA-CELLS DESCRIPTION - synthesize and secrete glucagon (see below) - regulate the metabolism of macronutrients - synthesize and secrete insulin (see below) - regulate the metabolism of macronutrients - synthesize and secrete somatostatin - regulate the endocrine pancreas (see above) - not discussed further here (!) - synthesize and secrete pancreatic polypeptide - regulate the exocrine pancreas (see above) - not discussed further here (!)

BETA-CELLS

GAMMA-CELLS

PP-CELLS

though all 4 hormones are true pancreatic hormones in its strictest sense, only insulin and glucagon have a direct effect on blood glucose , thus, in the context of diabetes mellitus, these 2 hormones are the only ones covered here

Relevant Drugs
2 categories 1) INSULIN - insulin acts on insulin-dependent glucose transporters (GLUT4) found exclusively in striated muscle, adipose tissue and liver - consequences of insulin stimulation include TISSUE STRIATED MUSCLE CONSEQUENCE Carbohydrate metabolism - increased glucose uptake - increased glycolysis Protein metabolism - increased amino acid uptake - increased protein anabolism - decreased protein catabolism ADIPOSE TISSUE Carbohydrate metabolism - increased glucose uptake - increased glycolysis

- 37 -

Fat metabolism - increased fatty acid uptake - increased fatty acid synthesis - decreased beta-oxidation LIVER Carbohydrate metabolism - increased glucose uptake - increased glycolysis - increased glycogenesis - decreased gluconeogenesis - decreased glycogenolysis

regulation of insulin secretion is done by 2 mechanisms REGULATION STIMULATION MEDIATOR - high blood glucose - high blood fatty acids - high blood amino acids - glucagons (see below) - growth hormone (see 54) - cortisol (see 55) - gastrointestinal hormones (gastrin, cholecystokinin, secretin, gastric inhibitory peptide) - acetylcholine (parasympathetic nervous system, see 14) - low blood glucose - somatostatin (see above) - catecholamines (sympathetic nervous system, see 18)

INHIBITION

3 groups A) SHORT/RAPIDLY ACTING INSULIN PREPARATIONS - 2-8 hours - 2 types DRUG NAME - 38 DESCRIPTION

INSULIN

General information - insulin itself - administered subcutaneously, intramuscularly and/or IV Medical uses - treatment of diabetes mellitus type 1 (then administered in conjunction with an intermediately acting- and/or a long/slowly acting insulin preparation, see below) - treatment of diabetes mellitus type 2 (then administered in conjunction with one or more oral hypoglycaemic agents, see below) Side effects - hypoglycemia - rebound hyperglycemia (due to hypoglycemia and following severe release of inhibitory mediators, see above)

INSULIN LISPRO

General information - recombinant insulin (reversation of an adjacent lysine and proline) - same as insulin (see above)

B) INTERMEDIATELY ACTING INSULIN PREPARATIONS - 18-24 hours - 2 types DRUG NAME INSULIN LENTE DESCRIPTION General information - insulin in conjunction with zinc - same as insulin (see above) General information - insulin in conjunction with zinc and protamine

INSULIN NPH

- 39 -

- same as insulin (see above)

C) LONG/SLOWLY ACTING INSULIN PREPARATIONS - 24-36 hours - 2 types DRUG NAME INSULIN GLARGINE DESCRIPTION General information - recombinant insulin (exchange of an aspargine with a glycine) - same as insulin (see above) General information - recombinant insulin (addition of a tetradecanoic acid to a lysine) - same as insulin (see above)

INSULIN DETEMIR

2) GLUCAGON - glucagon acts on receptors found exclusively in striated muscle (including the heart), adipose tissue and liver - consequences of glucagon stimulation are roughly the opposite of those of insulin (see above), and include TISSUE STRIATED MUSCLE CONSEQUENCE Carbohydrate metabolism - decreased glycolysis - decreased glycogenesis Protein metabolism - decreased protein anabolism - increased protein catabolism ADIPOSE TISSUE Carbohydrate metabolism - decreased glycolysis - decreased glycogenesis Fat metabolism - decreased fatty acid synthesis - increased beta-oxidation

- 40 -

LIVER

Carbohydrate metabolism - decreased glycolysis - decreased glycogenesis - increased glycogenolysis - increased gluconeogenesis Positive tropic effect - positive chronotropic effect - positive ionotropic effect - positive bathmotropic effect - positive dromotropic effect

HEART

regulation of glucagon secretion is done by 2 mechanisms REGULATION STIMULATION MEDIATOR - high blood amino acids - low blood glucose - low blood fatty acids - gastrointestinal hormones (gastrin, cholecystokinin, secretin, gastric inhibitory peptide) - acetylcholine (parasympathetic nervous system, see 14) - catecholamines (sympathetic nervous system, see 18) - high blood glucose - high blood fatty acids - insulin (see above) - somatostatin (see above)

INHIBITION

1 type DRUG NAME GLUCAGON DESCRIPTION General information - glucagon itself - administered subcutaneously, intramuscularly and/or IV

- 41 -

Medical uses - treatment of hypoglycemia (if unconscious) Side effects - hyperglycemia

ORAL HYPOGLYCAEMIC AGENTS


Overview
oral hypoglycaemic agents are drugs that decrease blood glucose however, their ability to decrease blood glucose is exponentially inferior to conventional insulin preparations (see above), thus they may only be used in the treatment of diabetes mellitus type 2

Relevant Drugs
2 categories 1) SULFONYLUREAS - sulfonylureas act on potassium channel-linked sulfonylurea receptors found exclusively on the beta-cells of the endocrine pancreas - stimulation of the sulfonylurea receptors causes opening of the potassium channels and following influx of potassium into the cytoplasm of the betacells - this causes depolarization of the beta-cells and following insulin secretion (see above) - 2 types DRUG NAME TOLBUTAMIDE DESCRIPTION General information - administered orally - may cross the placental barrier Medical uses - treatment of diabetes mellitus type 2 (the administered in conjunction with insulin (see above) and/or other oral hypoglycaemic agents (see below)) Side effects - hypoglycemia - weight gain (due to stimulation of the feeding - 42 -

center in the hypothalamus) - nausea, vomiting and/or diarrhea - bone marrow depression - hypersensitivity reactions leading to fever and/or skin rashes GLIBENCLAMIDE General information - same as tolbutamide (see above)

2) SULFONYLUREA-LIKE DRUGS - sulfonylurea-like drugs have the same mechanism of action as the sulfonylureas (see above) - they only differ from sulfonylureas by their chemical structure - 2 types DRUG NAME REPAGLINIDE DESCRIPTION General information - same as tolbutamide (see above) General information - same as tolbutamide (see above)

NATEGLINIDE

3) GLITAZONES - thiazolidinediones - glitazones act on peroxysome proliferator response receptor-gamma (PPARgamma) primarily found in adipose tissue (but also in striated muscle and liver) - consequences of PPAR-gamma activation include TISSUE STRIATED MUSCLE CONSEQUENCE Carbohydrate metabolism - increased glucose uptake - increased glycolysis Carbohydrate metabolism - increased glucose uptake - increased glycolysis

ADIPOSE TISSUE

- 43 -

Fat metabolism - increased fatty acid uptake - increased beta-oxidation LIVER Carbohydrate metabolism - increased glucose uptake - increased glycolysis - decreased gluconeogenesis

2 types DRUG NAME ROSIGLITAZONE DESCRIPTION General information - administered orally Medical uses - same as tolbutamide (see above) Side effects - weight gain (due to stimulation of the feeding center in the hypothalamus) - headache - nausea, vomiting and/or diarrhea - fluid retention - heart failure (due to fluid retention and following hemodilution) PIOGLITAZONE General information - same as rosiglitazone (see above)

4) BIGUANIDES - biguanides act on receptors not currently identified, and by mechanisms not completely elucidated - however, the consequences of biguanide stimulation include TISSUE STRIATED MUSCLE - 44 CONSEQUENCE Carbohydrate metabolism

- increased glucose uptake - increased glycolysis LIVER Carbohydrate metabolism - increased glucose uptake - increased glycolysis - decreased gluconeogenesis

1 type DRUG NAME METFORMIN DESCRIPTION General information - administered orally Medical uses - same as tolbutamide (see above) Side effects - nausea, vomiting and/or diarrhea - malabsorption - vitamin B12 deficiency (cobolamin deficiency (see 32), due to malabsorption) - lactic acidosis

5) ALPHA-GLUCOSIDASE INHIBITORS - alpha-glucosidase is found on the luminal surface of the enterocytes in the small intestine, and is responsible for the hydrolysis of oligosaccarides to yield monosaccarides - alpha-glucosidase inhibitors inhibit alpha-glucosidase, thus preventing the hydrolysis of the oligosaccarides and following inhibition of monosaccaride absorption by the enterocytes - 1 type DRUG NAME ACARBOSE DESCRIPTION General information - administered orally (but is not absorbed) Medical uses - same as tolbutamide (see - 45 -

above) Side effects - epigastric pain - diarrhea

- 46 -

61. PARATHYROID HORMONE, CALCITONIN AND VITAMIN D, DRUGS USED TO TREAT OSTEOPOROSIS
Overview
bone consists of 2 components COMPONENT OSTEOID DESCRIPTION - organic - primarily composed of type I collagen - inorganic - composed of calcium and phosphate

HYDROXYAPATITE

remodeling of bone is done by 2 types of cells CELL TYPE OSTEOBLAST DESCRIPTION - anabolic - synthesizes osteoid and hydroxyapatite - catabolic - resorbs osteoid and hydroxypatite

OSTEOCLAST

regulation of bone remodeling is done indirectly through regulation of plasma calcium- and phosphate homeostasis there are 6 hormones regulating plasma calcium- and -phosphate homeostasis 1) VITAMIN D - vitamin D is a steroid pro-hormone - there are 2 types of vitamin D ORIGIN VITAMIN D3 CONSEQUENCE - cholecalciferol - endogenous - synthesized in the skin from 7-dehydrocholesterol by UV radiation (!) - ergocalciferol - exogenous - found in plants

VITAMIN D2

- 47 -

vitamin D is activated in the liver and kidneys in 2 steps

VITAMIN D (CHOLECALCIFEROL/ERGOCALCIFEROL) in the liver 25-HYDROXYVITAMIN D (CALCIFEDIOL/ ERGOFEDIOL) in the kidneys 1,25-DIHYDROVITAMIN D (CALCITRIOL/ ERGOTRIOL) regulation of vitamin D activation is done by 2 mechanisms REGULATION STIMULATION MEDIATOR - PTH (see below) - low plasma phosphate - calcitriol (1,25-dihydrovitamin D3)

INHIBITION

consequences of vitamin D stimulation include TISSUE GI TRACT CONSEQUENCE - increased absorption of calcium - increased absorption of phosphate (secondarily to calcium) - decreased osteoblast activity - increased osteoclast activity - increased reabsorption of calcium - increased reabsorption of phosphate (secondarily to calcium)

BONE

KIDNEYS

, thus collectively vitamin D promotes bone resorption, increases plasma calcium, and increases plasma phosphate

2) PARATHYROID HORMONE - parathyroid hormone (parathormone, PTH) is synthesized and stored by the parathyroid gland - regulation of PTH secretion is done by 1 mechanism - 48 -

REGULATION STIMULATION

MEDIATOR - low plasma calcium

consequences of PTH stimulation include TISSUE GI TRACT CONSEQUENCE - increased absorption of calcium - increased absorption of phosphate (secondarily to calcium) - decreased osteoblast activity - increased osteoclast activity - increased reabsorption of calcium - increased EXCRETION of phosphate

BONE

KIDNEYS

, thus collectively PTH promotes bone resorption, increases plasma calcium, and decreases plasma phosphate PTH also stimulates activation of vitamin D (see above)

3) GLUCOCORTICOIDS - glucocorticoids decrease calcium (and phosphate secondarily) absorption by the GI tract, decrease osteoblast activity, increase osteoclast activity, and increase calcium (and phosphate secondarily) excretion by the kidneys - , thus collectively glucocorticoids promote bone resorption, decrease plasma calcium, and decrease plasma phosphate - see 55 4) OESTROGENS - oestrogens increase osteoblast activity, and decrease osteoclast activity - , thus collectively oestrogens promote bone synthesis - see 56 5) ANDROGENS - androgens increase osteoblast activity, and decrease osteoclast activity - , thus collectively androgens promote bone synthesis - see 58 6) CALCITONIN - calcitonin is synthesized and stored in the parafollicular cells of the thyroid gland - 49 -

regulation of calcitonin secretion is done by 1 mechanism REGULATION STIMULATION MEDIATOR - HIGH plasma calcium

consequences of calcitonin stimulation include TISSUE GI TRACT CONSEQUENCE - DECREASED absorption of calcium - DECREASED absorption of phosphate (secondarily to calcium) - INCREASED osteoblast activity - DECREASED osteoclast activity - DECREASED reabsorption of calcium - DECREASED reabsorption of phosphate (secondarily to calcium)

BONE

KIDNEYS

, thus collectively calcitonin promotes bone synthesis, decreases plasma calcium, and decreases plasma phosphate

Relevant Drugs
5 categories 1) CALCIUM SALTS - 3 types DRUG NAME HYDROXYAPATITE DESCRIPTION General information - administered orally Medical uses - treatment of hypocalcemia (due to malabsorption and/or hypoparathyroidism) - treatment of osteoporosis Side effects - cardiac dysrhythmias - gastrointestinal disturbances CALCIUM LACTATE - 50 General information

- same as hydroxyapatite (see above) CALCIUM GLUCONATE General information - administered orally and/or IV - same as hydroxyapatite (see above)

2) VITAMIN D - 1 type DRUG NAME ERGOCALCIFEROL DESCRIPTION General information - vitamin D2 - found in plants - administered orally Medical uses - treatment of hypo-D-vitaminosis (due to malabsorption) - treatment of hypocalcemia (due to hypoparathyroidism) Side effects - hypercalcemia - fatigue (due to hypercalcemia) - constipation (due to hypercalcemia) - polyuria (due to hypercalcemia) - polydipsia (due to polyuria) - hypercalcuria (if chronic hypercalcemia) - urolithiasis (due to hypercalcuria) - renal failure (due to urolithiasis) CALCITRIOL General information - 1,25-dihydrovitamin D3 - same as ergocalciferol (see above) Medical uses - treatment of hypo-D-vitaminosis (due to liver disease) - treatment of hypocalcemia (due to hypoparathyroidism) Side effects - same as ergocalciferol (see above) - 51 -

3) OESTROGEN RECEPTOR AGONISTS - oestrogen receptor agonists act on oestrogen receptors, thus causing increased osteoblast activity and decreased osteoclast activity and following promotion of bone synthesis - see 56 4) OESTROGEN RECEPTOR ANTAGONISTS - oestrogen receptor antagonists have an oestrogen receptor agonist action to a varying degree in different tissues (including bone), thus also causing promotion of bone synthesis - see 56 5) CALCITONIN - 2 types DRUG NAME CALCITONIN DESCRIPTION General information - administered subcutaneously, intramuscularly and/or nasally Medical uses - treatment of hypercalcemia (due to neoplasias) - treatment of postmenopausal osteoporosis Side effects - nausea/vomiting SALCATONIN General information - synthetic calcitonin analogue - same as calcitonin (see above)

- 52 -

62. SULFONAMIDES AND TRIMETHOPRIM. FLUOROQUINOLONES


FOLATE ANTAGONISTS
Overview
folate (dihydrofolate, FH2, folic acid, vitamin B9) is a cofactor (methyl-group donor) in the synthesis of purines and pyrimidines used for DNA and RNA synthesis (see 32) humans are not able to synthesize folate themselves, and exclusively rely on absorption of folate from the GI tract bacteria, on the other hand, are not able to absorb it through their bacterial cell envelope, and exclusively rely on synthesizing folate themselves however, folate is only active in the tetrahydrofolate (FH4) form, thus both humans and bacteria need to activate folate to utilize it synthesis and activation of folate is done in 3 steps

PARA-AMINOBENZOIC ACID (PABA) + PTERIDINE PYROPHOSPHATE dihydropteroate synthetase DIHYDROPTEROATE + GLUTAMATE dihydrofolate synthetase DIHYDROFOLATE (FH2) dihydrofolate reductase TETRAHYDROFOLATE (FH4)

Relevant Drugs
3 categories 1) SULFONAMIDES - sulfonamides are synthetic structural analogues of PABA and act by displacing PABA from its binding site on dihydropteroate synthetase, thus inhibiting bacterial synthesis of folate - this leads to an inability of the bacteria to synthesize DNA and RNA and following inability for them to divide - however, bacteria are still able to survive without dividing, thus sulfonamides are only bacteriostatic - since humans do not synthesize their own folate, sulfonamides leave DNA and RNA synthesis in human cells untouched - bacteria may develop resistance to sulfonamides by plasmid transfer and/or chromosomal mutations - this resistance may occur by 3 separate mechanisms MECHANISM DECREASED UPTAKE - 53 DESCRIPTION - due to decreased

permeability of the bacterial cell envelope to sulfonamides DECREASED AFFINITY - due to structural alterations of dihydropteroate synthetase - due to increased synthesis of PABA

INCREASED DISPLACEMENT

3 groups A) SHORT-ACTING SULFONAMIDES - 4-6 hours - 2 types DRUG NAME SULFADIAZINE DESCRIPTION General information - administered orally and/or IV - may cross the blood-brain barrier - may cross the placental barrier Medical uses - treatment of cystitis due to escherichia and/or proteus infection - treatment of chlamydia, trachoma and/or lymphogranuloma venerum due to chlamydia infection Side effects - headache - nausea and vomiting - hepatitis - bone marrow depression leading to thrombocytopenia and/or granulocytopenia - methemoglobinemia - hemolytic anemia (if glucose-6-phosphate deficiency) - kernicterus (in infants) - urolitihasis (crystalluria, - 54 -

due to poor solubility in the low pH of the renal tubules and following crystal formation) - hypersensitivity reactions leading to skin rashes and/or angioedema SULFADIMIDINE General information - same as sulfadiazine (see above)

B) INTERMEDIATELY-ACTING SULFONAMIDES - 8-12 hours - 2 types DRUG NAME SULFADOXIN DESCRIPTION General information - same as sulfadiazine (see above) General information - same as sulfadoxin (see above)

SULFAMETHOXAZOLE

C) LONG-ACTING SULFONAMIDES - 16-24 hours - 2 types DRUG NAME SULFAMETHOXYDIAZINE DESCRIPTION General information - same as sulfadiazine (see above) Medical uses - same as sulfadiazine (see above) Side effects - same as sulfadiazine, except for urolithiasis (due to higher solubility at low pH, see above) - hypersensitivity reactions - 55 -

leading to skin rashes, angioedema and/or stevensjohnson syndrome SULFAMETHOXYPYRAZINE General information - same as sulfamethoxydiazine (see above)

2) DIHYDROFOLATE REDUCTASE INHIBITORS - dihydrofolate reductase inhibitors are structural analogues of folate and act by competitively inhibiting dihydrofolate reductase, thus inhibiting the activation of folate - this leads an inability of the bacteria to synthesize DNA and RNA and following inability for them to divide, thus dihydrofolate reductase inhibitors are bacteriostatic - since humans need to activate folate as well, dihydrofolate reductase inhibitors also affect DNA and RNA synthesis in human cells (!) - however, dihydrofolate reductase inhibitors have a much stronger affinity for bacterial dihydrofolate reductase, thus affecting human cells to a much smaller extent - bacteria may develop resistance to dihydrofolate reductase inhibitors by 1 mechanism MECHANISM DECREASED AFFINITY DESCRIPTION - due to structural alterations of dihydrofolate reductase

2 types DRUG NAME PYRIMETHAMINE DESCRIPTION General information - administered orally - may cross the blood-brain barrier Medical uses - treatment of malaria due to plasmodium falciparum and/or plasmodium malariae infection (see 71, then administered in conjunction with dapsone (see 67) - treatment of malaria due to plasmodium vivax and/or plasmodium ovale infection - 56 -

(see 71, then administered in conjunction with dapsone (see 67) - treatment of malaria due to plasmodium falciparum infection (if resistant to 4aminoquinolines (see 71), then administered in conjunction with mefloquine (see 71)) Side effects - nausea and vomiting - folate deficiency leading to macrocytic hyperchromatic anemia, leukocytopenia and/or thrombocytopenia - hypersensitivity reactions leading to skin rashes TRIMETHOPRIM General information - same as pyrimethamine (see above) Medical uses - treatment of cystitis due to escherichia and/or proteus infection - treatment of pneumonia due to streptococcus and/or haemophilus infection Side effects - same as pyrimethamine (see above)

3) COMBINATIONS - sulfonamides and dihydrofolate reductase inhibitors are often combined due to both of them potentiating each other in inhibition of folate synthesis and activation - together they exhibit increased antibacterial spectrum and decreased probability of resistance in bacteria than either of them alone - 2 types DRUG NAME PYRIMETHAMINE-SULFADIAZINE DESCRIPTION General information - this particular combination is

- 57 -

chosen due to similar pharmacokinetics of the 2 active compounds - administered orally and/or IV - may cross the blood-brain barrier Medical uses - treatment of toxoplasmosis due to toxoplasma infection (see 71) - treatment of malaria due to plasmodium falciparum and/or plasmodium malariae infection (see 71) - treatment of malaria due to plasmodium vivax and/or plasmodium ovale infection (see 71, then administered in conjunction with an 8aminoquinoline (see 71)) Side effects - same as short-acting sulfonamides and dihydrofolate reductase inhibitors combined (see above) TRIMETHOPRIMSULFAMETHOXAZOLE General information - co-trimoxazole - same as pyrimethaminesulfadiazine (see above) Medical uses - treatment of bacillary dysentery due to shigella infection - treatment of typhoid fever due to salmonella infection - treatment of gonorrhea due to neisseria infection - treatment of cystitis due to escherichia and/or proteus infection - treatment of pneumonia due to streptococcus, haemophilus and/or legionella infection - treatment of pneumonia due - 58 -

to pneumocystis infection Side effects - same as intermediately-acting sulfonamides and dihydrofolate reductase inhibitors combined (see above)

DNA TOPOISOMERASE II INHIBITORS


Overview
during bacterial (eukaryotic) DNA replication, both DNA strands are simultaneously replicated by DNA polymerase III of the eukaryotic replisome complex due to the double-helical supercoiled conformation of the DNA, this would normally result in 2 hypercoiled inseparable intertwined chromosomes DNA topoisomerases are enzymes of the eukaryotic replisome complex that are capable of cutting and religating DNA during DNA replication without changing the primary structure of the DNA there are 2 types of DNA topoisomerases in bacteria (eukaryotes) TYPE DNA TOPOISOMERASE I DESCRIPTION - cuts 1 of the DNA strands at the beginning of replication, thus causing supercoil relaxation (preventing hypercoil formation) - DNA gyrase - cuts both the DNA strands at the end of replication, thus causing separation of the 2 chromosomes

DNA TOPOISOMERASE II

Relevant Drugs
1 category 1) FLUOROQUINOLONES - fluoroquinolones bind to DNA topoisomerase II and prevent it from religating the DNA strands after cutting them, thus causing fragmentation of the bacterial chromosomes - bacteria are not able to survive with fragmented chromosomes, thus fluoroquinolones are bacteriocidal - bacteria may develop resistance to fluoroquinolones by chromosomal mutations - this resistance may occur by 3 different mechanisms MECHANISM DECREASED UPTAKE - 59 DESCRIPTION - due to decreased number of porins in

the outer cell membrane - only in gram bacteria (only gram bacteria have outer cell membrane) DECREASED AFFINITY - due to structural alterations of DNA topoisomerase II - due to increased energy-dependent transport of the fluoroquinolones out of the cytoplasm through the inner cell membrane

INCREASED EXCRETION

3 types DRUG NAME CIPROFLOXACIN DESCRIPTION General information - administered orally and/or IV - may not cross the blood-brain barrier Medical uses - treatment of bacillary dysentery due to shigella infection - treatment of pneumonia due to enterobacter, proteus, klebsiella, haemophilus, legionella and/or pseudomonas infection - treatment of cystitis due to escherichia, enterobacter, proteus and/or klebsiella infection - treatment of chlamydia, trachoma and/or lymphogranuloma venerum due to chlamydia infection - treatment of gonorrhea due to neisseria infection - treatment of tuberculosis due to mycobacterium infection (if resistant to first-choice antituberculotic drugs, see 67) Side effects - headache, vertigo and nausea - diarrhea - phototoxicity leading to skin rashes - urolitihasis (crystalluria, due to poor solubility in the low pH of the renal - 60 -

tubules and following crystal formation) - articular cartilage erosion (arthropathy, in infants, children and teenagers) NORFLOXACIN General information - administered orally - may not cross the blood-brain barrier Medical uses - treatment of cystitis due to escherichia, enterobacter, proteus and/or klebsiella infection Side effects - same as ciprofloxacin (see above) OFLOXACIN General information - administered orally and/or IV - may cross the blood-brain barrier Medical uses - treatment of chlamydia, trachoma and/or lymphogranuloma venerum due to chlamydia infection - treatment of gonorrhea due to neisseria infection - treatment of leprosy due to mycobacterium infection (if resistant to first-choice anti-leprosy drugs, see 67) Side effects - same as ciprofloxacin (see above)

- 61 -

63. BETA-LACTAM ANTIBIOTICS


Overview
all bacteria (except mycoplasma) lack sterols stabilizing their inner cell membrane, thus rendering their inner cell membrane extremely vulnerable to osmotic pressure however, these bacteria have a cell wall (again, except mycoplasma) primarily consisting of peptidoglycan intimately surrounding the outside of their inner cell membrane this peptidoglycan protects and stabilizes the inner cell membrane, thus preventing the osmotic lysis of the bacteria the peptidoglycan consists of 2 parts PART DISACCARIDE BACKBONE DESCRIPTION - alternating molecules of N-acetyl glucosamine (NAG) and N-acetyl muramic acid (NAM) - tetra- or pentapeptides of varying composition extending from both sides of the disaccaride backbone - covalently linked to oligopeptide side-chains of adjacent disaccaride backbones

OLIGOPEPTIDE SIDE-CHAINS

gram + bacteria have more than 40 concentric lamellae of peptidoglycan, while gram bacteria have only 1-2 lamellae synthesis and remodeling of peptidoglycan is primarily done by 3 groups of enzymes residing within the peptidoglycan layer (penicillin-binding proteins, PBPs) ENZYME NAG-NAM POLYMERASE DESCRIPTION - covalently links alternating NAG and NAM molecules to produce the disaccaride backbone - covalently links the oligopeptide side-chains of adjacent disaccaride backbones - lysozyme - degrades parts of the disaccaride backbone during remodeling of peptidoglycan - is rapidly inactivated by autolysin inhibitors (lysozyme inhibitors) upon completed remodeling

TRANSPEPTIDASE

AUTOLYSIN

the penicillin-binding proteins are only active during bacterial cell division, due to the immediate need of additional peptidoglycan in the 2 newly formed cells beta-lactam antibiotics are substances that contain a beta-lactam ring in their chemical structure - 62 -

a beta-lactam ring is a 4-membered hydrocarbon ring where 1 of the carbons has been exchanged with a nitrogen, and the 2 hydrogens of the carbon adjacent to the nitrogen have been exchanged with a double-bonded oxygen beta-lactam antibiotics inhibit both transpeptidase and autolysin inhibitors, thus causing failure of linkage of oligopeptide side-chains of adjacent disaccaride backbones and increased degradation disaccaride backbones this leads to decreased protection and stability of the inner cell membrane and following osmotic lysis of the bacteria , thus the beta-lactam antibiotics are bacteriocidal however, beta-lactam antibiotics are only active in actively proliferating bacteria, due to the penicillin-binding proteins only being active during bacterial cell division bacteria may develop resistance to beta-lactam antibiotics in 2 ways 1) NATURAL RESISTANCE - due to the structure of the bacterial cell envelope - 2 mechanisms MECHANISM NO PEPTIDOGLYCAN DESCRIPTION - in mycoplasma - does penicillin-binding proteins for the betalactam antibiotics to attack - in gram - bacteria - prohibits uptake of larger beta-lactam antibiotics - only smaller beta-lactam antibiotics may pass through porins of the outer cell membrane

OUTER CELL MEMBRANE

2) ACQUIRED RESISTANCE - due to plasmid transfer and/or chromosomal mutations - 3 mechanisms MECHANISM DECREASED UPTAKE DESCRIPTION - due to decreased number of porins in the outer cell membrane - limits uptake of even the smaller beta-lactam antibiotics - only in gram bacteria (only gram bacteria have outer cell membrane) - due to structural alterations of the penicillinbinding proteins - due to the presence of beta-lactamases (penicillinases) - beta-lactamases cleave the beta-lactam ring between the nitrogen and the oxygen-bound carbon, - 63 -

DECREASED AFFINITY

INCREASED INACTIVATION

thus inactivating the beta-lactam antibiotics - most gram bacteria (and many gram + bacteria) have beta-lactamases

Relevant Drugs
5 categories 1) PENICILLINS - consist of 2 parts PART 6-AMINOPENICILLANIC ACID DESCRIPTION - includes the beta-lactam ring - is the same in all penicillins - covalently bound to the 6aminopenicillanic acid - differs between different penicillins - gives the different penicillins different properties

R SIDE-CHAIN

4 groups A) NARROW-SPECTRUM PENICILLINS - natural penicillins - found the penicillium fungus - all the penicillins of the other groups are semi-synthetic derivatives of the natural penicillins by substitution of the R side-chain - are sensitive to beta-lactamase - 2 types DRUG NAME PENICILLIN G DESCRIPTION General information - benzylpenicillin - administered orally, intramuscularly and/or IV - may cross the placental barrier - may cross the blood-brain barrier (but only if the meninges are inflamed (!))

- 64 -

Medical Uses - treatment of folliculitis, cellulitis and/or impetigo due to staphylococcus and/or streptococcus infection - treatment of arthritis and/or osteomyelitis due to staphylococcus infection - treatment of pharyngitis due to streptococcus infection - treatment of pneumonia due to streptococcus infection - treatment of endocarditis due to streptococcus infection - treatment of meningitis due to streptococcus, listeria and/or neisseria infection - treatment of gas gangrene due to clostridium infection - treatment of anthrax due to bacillus infection infection - treatment of gonorrhea due to neisseria infection - treatment of syphilis due to treponema infection Side effects - hypersensitivity reactions leading to fever, skin rashes, angioedema and/or anaphylactic shock - seizures (if high doses) PENICILLIN V General information - phenoxymethylpenicillin - same as penicillin g (see above)

B) BROAD-SPECTRUM PENICILLINS - are sensitive to beta-lactamase - 2 types

- 65 -

DRUG NAME AMPICILLIN

DESCRIPTION General information - administered orally - same as penicillin g (see above) Medical uses - treatment of meningitis due to listeria infection - treatment of pneumonia due to haemophilus infection - treatment of cystitis due to escherichia and/or proteus infection - treatment of enteric fever due to salmonella infection - treatment of gonorrhea due to neisseria infection - treatment of syphilis due to treponema infection Side effects - same as penicillin g (see above) - diarrhea (due to gastrointestinal overgrowth by broad-spectrum penicillin-resistant bacteria)

AMOXICILLIN

General information - same as ampicillin (see above)

C) EXTENDED-SPECTRUM PENICILLINS - are sensitive to beta-lactamase - 2 types DRUG NAME CARBENICILLIN DESCRIPTION General information - administered intramuscularly and/or IV - same as penicillin g (see above)

- 66 -

Medical uses - treatment of meningitis due to pseudomonas infection - treatment of endocarditis due to pseudomonas infection - treatment of pneumonia due to pseudomonas and/or haemophilus infection - treatment of cystitis due to pseudomonas, escherichia and/or proteus infection Side effects - same as penicillin g (see above) - hemorrhagic diathesis (due to platelet dysfunction) PIPERACILLIN General information - same as carbenicillin (see above)

D) BETA-LACTAMASE RESISTANT PENICILLINS - are not sensitive to beta-lactamase - 2 types DRUG NAME FLUCLOXACILLIN DESCRIPTION General information - same as carbenicillin (see above) Medical uses - treatment of folliculitis, cellulitis and/or impetigo due to staphylococcus infection (if beta-lactamase producing) - treatment of arthritis and/or osteomyelitis due to staphylococcus infection (if beta-lactamase producing) Side effects - same as penicillin g (see above) - 67 -

- nephrotoxicity METHICILLIN General information - same as flucloxacillin (see above)

2) CEPHALOSPORINS - consist of 2 parts PART 7-AMINOCEPHALOSPORANIC ACID DESCRIPTION - includes the beta-lactam ring - is the same in all cephalosporins - covalently bound to opposite sides of the 7aminocephalosporanic acid - differ between different cephalosporins - give the different cephalosporins different properties

R1- AND R2 SIDE-CHAINS

found in the cephalosporium fungus all cephalosporins in clinical use are semi-synthetic derivatives of the natural cephalosporins by substitution of the R side-chains they are more resistant to beta-lactamases than penicillins (except for betalactamase resistant penicillins) 4 groups (listed from most gram + antibacterial action and least gram antibacterial action to least gram + antibacterial action and most gram antibacterial action) A) FIRST-GENERATION CEPHALOSPORINS - 2 types DRUG NAME CEPHALEXIN DESCRIPTION General information - administered orally - may not cross the bloodbrain barrier Medical uses - treatment of folliculitis, - 68 -

cellulitis and/or impetigo due to staphylococcus and/or streptococcus infection - treatment of pharyngitis due to streptococcus infection Side effects - hypersensitivity reactions leading to fever, skin rashes, angioedema and/or anaphylactic shock - consecutive hypersensitivity to penicillins (due to crossreactivity) - diarrhea (due to gastrointestinal overgrowth by cephalosporin-resistant bacteria) CEPHALOTHIN General information - administered intramuscularly and/or IV - may not cross the bloodbrain barrier Medical uses - same as cephalexin (see above) Side effects - hypersensitivity reactions leading to fever, skin rashes, angioedema and/or anaphylactic shock - consecutive hypersensitivity to penicillins (due to crossreactivity)

B) SECOND-GENERATION CEPHALOSPORINS - 3 types DRUG NAME - 69 DESCRIPTION

CEFACLOR

General information - same as cephalexin (see above) Medical uses - treatment of pharyngitis due to streptococcus infection - treatment of pneumonia due to streptococcus, enterobacter, klebsiella, proteus and/or haemophilus infection Side effects - same as cephalexin (see above)

CEFUROXIME

General information - same as cephalothin (see above) Medical uses - same as cefaclor (see above) Side effects - same as cephalothin ( see above)

CEFOXITIN

General information - same as cefuroxime (see above)

C) THIRD-GENERATION CEPHALOSPORINS - 3 types DRUG NAME CEFOTAXIME DESCRIPTION General information - administered intramuscularly and/or IV - may cross the blood-brain barrier Medical uses - 70 -

- treatment of pharyngitis due to streptococcus infection - treatment of meningitis due to streptococcus, haemophilus and/or neisseria infection - treatment of gonorrhea due to neisseria infection Side effects - same as cephalothin ( see above) CEFTAZIDIME General information - same as cefotaxime (see above) General information - same as cefotaxime (see above)

CEFTRIAXONE

D) FOURTH-GENERATION CEPHALOSPORINS - 2 types DRUG NAME CEFEPIME DESCRIPTION General information - same as cephalothin ( see above) Medical uses - treatment of pneumonia due to streptococcus, enterobacter, klebsiella, proteus, haemophilus and/or pseudomonas infection Side effects - same as cephalothin ( see above) CEFPIROM General information - same as cefepim ( see above)

- 71 -

Side effects - same as cephalothin ( see above)

3) CARBAPENEMS - synthetic beta-lactam antibiotics - resistant to most beta-lactamases - 1 type DRUG NAME IMIPENEM DESCRIPTION General information - administered IV - may cross the blood-brain barrier (but only if the meninges are inflamed (!)) Medical uses - treatment of folliculitis, cellulitis and/or impetigo due to staphylococcus and/or streptococcus infection (if beta-lactamase producing) - treatment of pneumonia due to enterobacter, proteus, klebsiella, haemophilus, legionella and/or pseudomonas infection - treatment of cystitis due to escherichia, enterobacter, proteus and/or klebsiella infection Side effects - nausea and vomiting - diarrhea (due to gastrointestinal overgrowth by carbapenem-resistant bacteria) - eosinophilia - neutropenia - seizures (if high doses)

4) MONOBACTAMS - synthetic beta-lactam antibiotics - 72 -

resistant to most beta-lactamases 1 type DRUG NAME AZTREONAM DESCRIPTION General information - administered intramuscularly and/or IV - may cross the blood-brain barrier Medical uses - treatment of meningitis due to neisseria infection - treatment of pneumonia due to haemophilus and/or pseudomonas infection Side effects - hypersensitivity reactions leading to fever, skin rashes, angioedema and/or anaphylactic shock

5) BETA-LACTAMASE INHIBITORS - like all the other beta-lactam antibiotics, beta-lactamase inhibitors contain a beta-lactam ring - however, they are nearly devoid of antibacterial action - they augment the action of beta-lactam antibiotics by binding to bacterial beta-lactamases and following inhibit them - they are administered in conjunction with other beta-lactamase sensitive betalactam antibiotics - 2 types DRUG NAME TAZOBACTAM SULBACTAM DESCRIPTION

- 73 -

64. TETRACYCLINES, CHLORAMPHENICOL, MACROLIDE ANTIBIOTICS 65. CLINDAMYCIN, POLYMIXINS, VANCOMYCIN 66. AMINOGLYCOSIDES
PEPTIDOGLYCAN ANTAGONISTS
Overview
see 63

Relevant Drugs
2 categories 1) BETA-LACTAM ANTIBIOTICS - beta-lactam antibiotics inhibit peptidoglycan synthesis by inhibition of transpeptidase and facilitate peptidoglycan degradation by inhibition of autolysin inhibitors, thus causing cell lysis - see 63 2) GLYCOPEPTIDE ANTIBIOTICS - glycopeptide antibiotics inhibit NAG-NAM polymerase (see 63), thus causing failure of disaccaride backbone synthesis of the peptidoglycan - this leads to decreased protection and stability of the inner cell membrane and following osmotic lysis of the bacteria - , thus glycopeptide antibiotics are bacteriocidal (except against streptococci in which they are bacteriostatic) - bacteria may develop resistance to glycopeptide antibiotics by plasmid transfer - this resistance may occur by 1 mechanism MECHANISM DECREASED UPTAKE DESCRIPTION - due to decreased number of porins in the outer cell membrane - only in gram bacteria (only gram bacteria have outer cell membrane)

1 type DRUG NAME VANCOMYCIN DESCRIPTION General information - administered IV - may penetrate the blood-brain barrier (but

- 74 -

only if the meninges are inflamed (!)) Medical uses - treatment of folliculitis, cellulitis and/or impetigo due to staphylococcus infection (if resistant to beta-lactamase resistant penicillins, methicillin-resistant staphylococcus aureus, MRSA) - treatment of arthritis and/or osteomyelitis due to staphylococcus infection (if resistant to beta-lactamase resistant penicillins, methicillin-resistant staphylococcus aureus, MRSA) - treatment of pseudomembranous colitis due to clostridium infection (then administered orally) Side effects - hypersensitivity reactions leading to fever, skin rashes, angioedema, diffuse erythema (red man syndrome) and/or anaphylactic shock - deafness (due to cochlear nerve damage, if renal failure)

INHIBITORS OF mRNA TRANSLATION


Overview
mRNAs are translated to proteins on ribosomes in both bacteria and human cells both bacterial- and human ribosomes have 3 binding sites for aminoacyl-tRNAs BINDING SITE A SITE DESCRIPTION - aminoacyl site, access site - the site of entry of the presently coded aminoacyl-tRNA - peptidyl site, parking site - the site of residence of the previously coded aminoacyl-tRNA - exit site - the site of exit of the penultimately coded tRNA

P SITE

E SITE

translation of mRNAs are done in 4 steps in both bacteria and human cells

- 75 -

STEP ASSEMBLY

DESCRIPTION - assembly of the 2 ribosomal subunits, the mRNA, and the initiation codon-coded aminoacyl-tRNA to the P site - attachment of the presently coded aminoacyl-tRNA to the A site - conjugation of the previously coded amino acid with the presently coded amino acid - catalyzed by the peptidyl transferase action of the larger subunit - accompanied by detachment of the previously coded amino acid from its tRNA (, thus all previously coded amino acids will be directly connected to the presently coded aminoacyl-tRNA) - movement of the ribosome along the mRNA to the next codon - accompanied by movement of the currently coded aminoacyltRNA to the P site (, thus becoming the next previously coded aminoacyl-tRNA), and movement of the previously coded tRNA to the E site (, thus exiting the ribosome-mRNA complex)

ATTACHMENT

CONJUGATION

TRANSLOCATION

though both the binding sites of aminoacyl-tRNA and the mechanism of translation is the same in both bacteria and human cells, both the primary-, secondary- and tertiary structure of the bacterial ribosome (70S) and its subunits (30S and 50S) differ from the human ribosome (80S) and its subunits (40S and 60S) , thus inhibitors of mRNA translation leave human cells more or less untouched however, bacterial ribosomes are very similar to the mitochondrial ribosomes of human cells (!) , thus inhibitors of mRNA translation may affect mRNA translation by mitochondrial ribosomes of human cells

Relevant Drugs
5 categories 1) AMINOGLYCOSIDES - aminoglycosides enter the bacterial cytoplasm through oxygen-dependent permeases of the inner cell membrane where they bind to free 30S subunits - aminoglycosides block the assembly of the ribosome-mRNA complex, thus leading to complete inhibition of protein synthesis - , thus aminoglycosides are bacteriocidal - bacteria may develop resistance to aminoglycosides by plasmid transfer and/or chromosomal mutations - this resistance may occur by 3 separate mechanisms MECHANISM DECREASED UPTAKE DESCRIPTION - due to absence of oxygendependent permeases

- 76 -

- only in anaerobic bacteria (only aerobic bacteria have oxygendependent permeases) DECREASED AFFINITY - due to structural alterations of the 30S subunit - due to the presence of aminoglycoside-inactivating enzymes - the aminoglycoside-inactivating enzymes modify the aminoglycoides, thus inactivating them - these enymes include acetyltransferases, nucleotidyltransferases and phosphotransferases

INCREASED INACTIVATION

2 groups A) STREPTOMYCES-DERIVED AMINOGLYCOSIDES - found in the streptomyces bacterium - 2 types DRUG NAME STREPTOMYCIN DESCRIPTION General information - administered intramuscularly and/or IV - may cross the placental barrier - may not cross the blood-brain barrier Medical uses - treatment of pneumonia due to enterobacter, proteus, klebsiella and/or pseudomonas infection - treatment of cystitis due to escherichia, enterobacter, proteus and/or klebsiella infection - treatment of tularemia due to francisella infection - treatment of cholera gravis due to vibrio infection - treatment of the bubonic plague due to yersinia infection - 77 -

- treatment of tuberculosis due to mycobacterium infection (if resistant to first-choice antituberculotic drugs, see 67) Side effects - vertigo (due to vestibular nerve damage) - deafness (due to cochlear nerve damage) - nephrotoxicity TOBRAMYCIN General information - same as streptomycin, except for treatment of tuberculosis (see above)

B) MICROMONOSPORA-DERIVED AMINOGLYCOSIDES - found in the micromonospora bacterium - 2 types DRUG NAME GENTAMICIN DESCRIPTION General information - same as streptomycin, except for treatment of tuberculosis (see above) General information - same as streptomycin, except for treatment of tuberculosis (see above)

NETILMICIN

2) TETRACYCLINES - tetracyclines enter the bacterial cytoplasm through permeases of the inner cell membrane where they bind to the 30S subunit of assembled ribosome-mRNA complexes - tetracyclines block the attachment of the presently coded aminoacyl-tRNA to the A site of the ribosome-mRNA complex, thus leading to inhibition of protein synthesis - inhibition of protein synthesis would normally lead to death of the bacteria, but due to the inhibition occuring after assembly of the ribosome-mRNA complexes, some bacterial proteins are still being randomly translated - , thus tetracyclines are bacteriostatic - bacteria may develop resistance to tetracyclines by plasmid transfer and/or chromosomal mutations - this resistance may occur by 3 separate mechanisms MECHANISM - 78 DESCRIPTION

DECREASED UPTAKE

- due to decreased number of permeases in the inner cell membrane - due to structural alterations of the 30S subunit - due to increased magnesiumdependent transport of the tetracyclines out of the cytoplasm through the inner cell membrane

DECREASED AFFINITY

INCREASED EXCRETION

4 types DRUG NAME TETRACYCLINE DESCRIPTION General information - administered orally and/or IV - may cross the placental barrier - may not cross the blood-brain barrier Medical uses - treatment of pneumonia due to haemophilus infection - treatment of cholera gravis due to vibrio infection - treatment of chlamydia, trachoma and/or lymphogranuloma venerum due to chlamydia infection - treatment of syphilis due to treponema infection - treatment of lyme disease due to borrelia infection - treatment of rocky mountain spotted fever due to rickettsia infection - treatment of malaria due to plasmodium falciparum and/or plasmodium malariae infection (see 71) - treatment of malaria due to plasmodium vivax and/or plasmodium ovale infection (see 71, then administered in conjunction with an 8-aminoquinoline (see 71))

- 79 -

Side effects - phototoxicity - pseudotumor cerebri (benign intracranial hypertension) - diarrhea (due to gastrointestinal overgrowth by tetracycline-resistant bacteria) - gastric pain (due to irritation of the gastric mucosa) - discoloration and hypoplasia of teeth (due to deposition in teeth, primarily occurs in children) - bone deformities (due to deposition in bone, primarily occurs in children) - hepatic failure and death (if pregnant) OXYTETRACYCLINE General information - same as tetracycline (see above) General information - same as tetracycline (see above) General information - administered orally, intramuscularly and/or IV - may cross the placental barrier - may cross the blood-brain barrier Medical uses - same as tetracycline (see above) Side effects - same as tetracycline, except for phototoxicity (see above) - nausea and vomiting - vertigo

DOXYCYCLINE

MINOCYCLINE

3) CHLORAMPHENICOL - found in the streptomyces bacterium (as with streptomyces-derived aminoglycosides, see above)

- 80 -

chloramphenicol enters the bacterial cytoplasm through permeases of the inner cell membrane where it binds to the 50S subunit of assembled ribosome-mRNA complexes here it blocks conjugation of the previously coded aminoacyl-tRNA with the presently coded aminoacly-tRNA, thus leading to inhibition of protein synthesis inhibition of protein synthesis would normally lead to death of the bacteria, but due to the inhibition occuring after assembly of the ribosome-mRNA complexes, some bacterial proteins are still being randomly translated , thus chloramphenicol is bacteriostatic (but is bacteriocidal in haemophilus influenzae) bacteria may develop resistance to chloramphenicol by plasmid transfer and/or chromosomal mutations this resistance may occur by 2 separate mechanisms MECHANISM DECREASED UPTAKE DESCRIPTION - due to decreased number of permeases in the inner cell membrane - due to the presence of acetyl-CoA transferase - acetyl-CoA transferase modifies chloramphenicol thus inactivating it

INCREASED INACTIVATION

1 type DRUG NAME CHLORAMPHENICOL DESCRIPTION General information - administered orally and/or IV - may cross the blood-brain barrier Medical uses - treatment of meningitis due to streptococcus, neisseria and/or haemophilus infection - treatment of pneumonia due to haemophilus infection - treatment of typhoid fever due to salmonella infection Side effects - hypersensitivity reactions leading to fever, skin rashes, and/or angioedema - diarrhea (due to gastrointestinal overgrowth by chloramphenicol- 81 -

resistant bacteria) - bone marrow depression leading to pancytopenia and death - hemolytic anemia (if glucose-6phosphate dehydrogenase deficiency) - vomiting, diarrhea, flaccid paralysis, hypothermia, ash-gray cyanosis (gray baby syndrome) and death (due to inhibition of mitochondrial protein synthesis and following decreased aerobe glycolysis, in neonates)

4) MACROLIDES - macrolides enter the bacterial cytoplasm through permeases of the inner cell membrane where they bind to the 50S subunit of assembled ribosome-mRNA complexes - macrolides block the translocation of the ribosome along the mRNA to the next codon, thus leading to inhibition of protein synthesis - inhibition of protein synthesis would normally lead to death of the bacteria, but due to the inhibition occuring after assembly of the ribosome-mRNA complexes, some bacterial proteins are still being randomly synthesized - , thus macrolides are bacteriostatic (but may be bacteriocidal in some bacteria and in high doses) - bacteria may develop resistance to macrolides by plasmid transfer and/or chromosomal mutations - this resistance may occur by 3 separate mechanisms MECHANISM DECREASED UPTAKE DESCRIPTION - due to decreased number of permeases in the inner cell membrane - due to structural alterations of the 50S subunit - due to the presence of erythromycin esterase - erythromycin esterase modifies the macrolides, thus inactivating them

DECREASED AFFINITY

INCREASED INACTIVATION

macrolides are naturally found in the streptomyces bacterium 3 types DRUG NAME ERYTHROMYCIN DESCRIPTION General information

- 82 -

- administered orally and/or IV - may not cross the blood-brain barrier Medical uses - treatment of diphtheria due to corynebacterium infection - treatment of pneumonia due to legionella infection - treatment of chlamydia, trachoma and lymphogranuloma venerum due to chlamydia infection - treatment of syphilis due to treponema infection - treatment of pneuminitis due to mycoplasma infection - treatment of non-gonococcal urethritis due to ureaplasma infection Side effects - hypersensitivity reactions leading to fever, skin rashes and/or angioedema - diarrhea (due to gastrointestinal overgrowth by macrolide-resistant bacteria) - gastric pain (due to irritation of the gastric mucosa) - cholestatic jaundice - transient deafness (due to cochlear nerve damage) CLARITHROMYCIN General information - same as erythromycin (see above) Medical uses - treatment of folliculitis, cellulitis and/or impetigo due to staphylococcus and/or streptococcus infection - treatment of arthritis and/or osteomyelitis due to staphylococcus infection - treatment of pharyngitis due to streptococcus infection - treatment of pneumonia due to streptococcus, haemophilus and/or legionella infection - 83 -

- treatment of chlamydia, trachoma and lymphogranuloma venerum due to chlamydia infection Side effects - hypersensitivity reactions leading to fever, skin rashes and/or angioedema - diarrhea (due to gastrointestinal overgrowth by macrolide-resistant bacteria) AZITHROMYCIN General information - same as erythromycin (see above) Medical uses - treatment of pneumonia due to haemophilus infection - treatment of chlamydia, trachoma and lymphogranuloma venerum due to chlamydia infection - treatment of leprosy due to mycobacterium infection (if resistant to first-choice anti-leprosy drugs, see 67) Side effects - same as clarithromycin (see above)

5) LINCOSAMIDES - lincosamides have the same mechanism of entry, mechanism of action, and bacterial mechanisms of resistance as the macrolides (see above) - 1 type DRUG NAME CLINDAMYCIN DESCRIPTION General information - administered orally - may not pentrate the blood-brain barrier Medical uses - treatment of folliculitis, cellulitis and/or impetigo due to staphylococcus and/or streptococcus infection - treatment of arthritis and/or - 84 -

osteomyelitis due to staphylococcus infection (if beta-lactamase producing) - intra-abdominal sepsis due to bacteroides infection Side effects - hypersensitivity reactions leading to fever, skin rashes and/or angioedema - diarrhea (due to gastrointestinal overgrowth by lincosamide-resistant bacteria) - pseudomembranous colitis (due to gastrointestinal overgrowth by clostridium difficile)

DETERGENTS
Relevant Drugs
1 category 1) POLYMIXINS - polymixins are detergents that dissolve lipoprotein membranes - , thus polymixins are bacteriocidal - however, they are not able to transverse the peptidoglycan layer, thus they are only effective against the outer cell membrane of gram bacteria (only gram bacteria have outer cell membrane) - 2 types DRUG NAME POLYMIXIN B DESCRIPTION General information - administered orally (by not absorbed from the GI tract (!)) Medical uses - treatment of gastrointestinal overgrowth by gram bacteria Side effects - neurotoxicity - nephrotoxicity POLYMIXIN D General information - colistin - same as polymixin b (see above)

- 85 -

- 86 -

67. ANTITUBERCULOTIC DRUGS. ANTI-LEPROSY DRUGS


Overview
myobacteria are a genus of gram + bacteria with 4 very characteristic molecules embedded in their bacterial envelope that are not found in any other bacterial MOLECULE MYCOLIC ACID ACTION - resistance against MAC-mediated cell lysis - resistance against phagolysosomal oxidative burst in macrophages - resistance against most antibiotics - anchorage of the mycolic acid to the peptidoglycan - inhibition of INF-gamma mediated activation of macrophages - stimulation of TNF-alpha production of macrophages (leads to flu-like symptoms) - cytotoxicity - inhibition of polymorphonuclear leukocyte (neutrophil) migration - cytotoxicity

ARABINOGALACTAN

LIPOARABINOMANNAN (LAM)

CORD FACTOR

these molecules render the mycobacteria resistant to the host immune defense system, thus giving them the ability to both survive and divide within phagolysosomes of macrophages (!) the molecules also render the mycobacteria resistant to most antibiotics the intracellular nature of mycobacteria, in addition to their resistance against most antibiotics, make mycobacterial infections very hard to treat

ANTITUBERCULOTIC DRUGS
Overview
tuberculosis is a chronic persistent systemic inflammation caused by mycobacterium tuberculosis mycobacterium tuberculosis is an airborn bacteria entering the airways in droplet nuclei leading to formation of primary caseating granuomatic lesions in the lungs form here, mycobacterium tuberculosis may spread by the pulmonary veins to cause secondary caseating granulomatic lesions in virtually any tissue of the body

- 87 -

Relevant Drugs
2 categories 1) FIRST-CHOICE ANTITUBERCULOTIC DRUGS - first-choice antituberculotic drugs are the preferred drugs administered against mycobacterium tuberculosis infections - 4 types DRUG NAME ISONIAZID DESCRIPTION General information - inhibits mycolic acid synthesis, thus rendering the mycobacteria susceptible to oxidative burst in the phagolysosomes of macrophages - is bacteriostatic in resting mycobacteria and bacteriocidal in dividing mycobacteria (only dividing mycobacteria synthesize new mycolic acid) - is only active against mycobacteria (only mycobacteria synthesize mycolic acid) - bacteria may develop resistance by decreased uptake - administered orally - may cross the blood-brain barrier Side effects - hypersensitivity reactions leading to fever and/or skin rashes - arthritis - vasculitis - hepatotoxicity - central- and/or peripheral neuropathies (if vitamin B6 deficiency) - hemolytic anemia (if glucose-6-phosphate dehydrogenase deficiency) ETHAMBUTOL General information - binds to arabinogalactan and following inhibits anchorage of mycolic acid to the peptidoglycan, thus rendering the mycobacteria susceptible to oxidative burst in the phagolysosomes of macrophages - is bacteriostatic in resting mycobacteria and bacteriocidal in dividing mycobacteria (only dividing mycobacteria synthesize new arabinogalactan) - is only active against mycobacteria (only mycobacteria synthesize arabinogalactan)

- 88 -

- bacteria may develop resistance by decreased affinity - administered orally - may cross the blood-brain barrier Side effects - optic neuritis leading to red-green color blindness PYRAZINAMIDE General information - prodrug - activated by pyrazinamidase - pyrazinamidase is only active at low pH - , thus pyrazinamide is only active in the phagolysosomes of macrophages - pyrazinamidase is an enzyme only present in mycobacteria - , thus pyrazinamide is only effective against mycobacteria - inhibits prokaryotic fatty acid synthetase, thus inhibiting bacterial fatty acid synthesis - , thus is bacteriostatic - bacteria may develop resistance by decreased activation (decreased pyrazinamidase activity) - administered orally - may cross the blood-brain barrier Side effects - nausea and/or vomiting - gout - hepatotoxicity (if high doses) RIFAMPICIN General information - rifampin - inhibits prokaryotic RNA polymerase, thus completely inhibiting bacterial protein synthesis - , thus is bacteriocidal - is active against mycobacteria as well as most gram + bacteria and several gram bacteria - bacteria may develop resistance by decreased affinity - administered orally - may cross the blood-brain barrier - 89 -

Medical uses - treatment of tuberculosis due to mycobacterium tuberculosis infection - treatment of paucibacillary leprosy due to mycobacterium leprae infection (see below, then administeted in conjunction with dapsone (see below)) - treatment of multibacillary leprosy due to mycobacterium leprae infection (see below, then administered in conjunction with dapsone and clofazimine (see below)) Side effects - hypersensitivity reactions leading to fever and/or skin rashes - light-brown discoloration of all body secretions - nausea and/or vomiting - hepatotoxicity

first-choice antituberculotic drugs are never used alone, but in combinations with each other due to high incidence of resistance in the mycobacteria the use of first-choice antituberculotic drug combinations are divided in 2 phases PHASES PRIMARY PHASE DESCRIPTION Duration - 2 months Combination - isoniazid - rifampicin - pyrazinamide - ethambutol (if high level of resistance is suspected) SECONDARY PHASE Duration - 4 months Combination - isoniazid - rifampicin

- 90 -

2) SECOND-CHOICE ANTITUBERCULOTIC DRUGS - second-choice antituberculotic drugs are drugs administered against mycobacterium tuberculosis infections if the mycobacteria exhibit resistance to the first-choice antituberculotic drugs (see above) - 4 types DRUG NAME CAPREOMYCIN DESCRIPTION General information - administered intramuscularly - is only active against mycobacteria Side effects - deafness (due to cochlear nerve damage) - nephrotoxicity CYCLOSERINE General information - administered orally - may cross the blood-brain barrier - is active against mycobacteria as well as several gram bacteria Side effects - headache - depression - schizophrenia - convulsions CIPROFLOXACIN General information - a fluoroquinolone (see 62) General information - a streptomyces-derived aminoglycoside (see 66)

STREPTOMYCIN

ANTI-LEPROSY DRUGS
Overview
leprosy (hansen disease) is a systemic infection primarily affecting skin and peripheral nerves caused by mycobacterium leprae leprosy may be divided in 2 types according to the severity of mycobacterium leprae infection

- 91 -

TYPE PAUCIBACILLARY LEPROSY

DESCRIPTION - tuberculoid leprosy - due to moderate mycobacterium leprae infection - lepromatous leprosy - due to severe mycobacterium leprae infection

MULTIBACILLARY LEPROSY

Relevant Drugs
2 categories 1) FIRST-CHOICE ANTI-LEPROSY DRUGS - first-choice anti-leprosy drugs are the preferred drugs administered against mycobacterium leprae infections - 3 types DRUG NAME DAPSONE DESCRIPTION General information - chemically related to sulfonamides (see 62) - inhibits dihydropteroate synthetase (see 62), thus inhibiting folate synthesis and following inhibition of bacterial DNA- and RNA synthesis - , thus is bacteriostatic - bacteria may develop resistance by increased displacement (increased PABA synthesis) - administered orally Medical uses - treatment of paucibacillary leprosy (then administered in conjunction with rifampicin, see below) - treatment of multibacillary leprosy (then administered in conjunction with rifampiciin and clofazimine, see below) - treatment of malaria due to plasmodium falciparum and/or plasmodium malariae infection (see 71, then administered in conjunction with pyrimethamine (see 62)) - treatment of malaria due to plasmodium vivax and/or plasmodium ovale infection (see 71, then administered in conjunction - 92 -

with pyrimethamine (see 62)) Side effects - hypersensitivity reactions leading to fever and/or skin rashes - nausea and vomiting - hemolysis - methemoglobinemia - peripheral neuropathies CLOFAZIMINE General information - a complex dye - mechanism of action is unknown - administered orally Medical uses - treatment of multibacillary leprosy (then administered in conjunction with dapsone (see above) and rifampicin (see below)) Side effects - red discoloration of skin and urine - dark blue discoloration of leprous skin lesions - headache - vertigo - nausea and vomiting RIFAMPICIN General information - a first-choice antituberculotic drug (see above)

like first-choice antituberculotic drugs, first-choice anti-leprosy drugs are never used alone, but in combinations with each other due to high incidence of resistance in the mycobacteria the administration of first-choice anti-leprosy drug combinations are divided in 2 according to the type of leprosy TYPE PAUCIBACILLARY LEPROSY DESCRIPTION Duration - 6 months Combination - 93 -

- dapsone - rifampicin

MULTIBACILLARY LEPROSY

Duration - 2 years Combination - dapsone - rifampicin - clofazimine

2) SECOND-CHOICE ANTI-LEPROSY DRUGS - second-choice anti-leprosy drugs are drugs administered against mycobacterium leprae infections if the mycobacteria exhibit resistance to the first-choice anti-leprosy drugs (see above) - 2 types DRUG NAME OFLOXACIN DESCRIPTION General information - a fluoroquinolone (see 67) General information - a macrolide (see 64)

AZITHROMYCIN

- 94 -

68. ANTIFUNGAL DRUGS


Overview
fungi are a diverse kingdom of unicellular- and multicellular eukaryotic organisms that replicate either by simple mitosis or by spore formation fungal cells consist of 4 parts (listed from innermost to outermost) PART CYTOPLASM DESCRIPTION - contains membrane-bound organelles including a nucleus-bound genetic material (in opposition to bacterial cytoplasm that neither contains membrane-bound organelles nor a nucleus) - consists of a lipoprotein membrane containing ergosterol that stabilizes the lipoprotein membrane (in opposition to human cell membranes that contain cholesterol, and bacterial cell membranes that do not contain any sterols whatsoever (except mycoplasma)) - composed of beta-D-glucan and chitin (in opposition to bacterial cell walls that are composed of peptidoglycan, and human cells that do not have a cell wall whatsoever) - a polysaccaride coat - present only in some fungal species

CELL MEMBRANE

CELL WALL

CAPSULE

ergosteriol of the fungal cell membrane is synthesized from squalene by an extremely complicated biochemical pathway too vast to cover here however, this pathway is extremely important pharmacologically (!) fungal infections (mycoses) occur in subjects with a decreased defense against fungal colonization, including decreased immune defense system and decreased normal bacterial flora fungal infections may be divided in 2 groups 1) SUPERFICIAL FUNGAL INFECTIONS - local fungal infections - 2 groups DRUG NAME CANDIDIASIS DESCRIPTION General information - caused by candida albicans Affected Sites - 95 -

- dermal candidiasis - oral candidiasis - vaginal candidiasis DERMATOMYCOSIS General information - dermatophytosis - caused by epidermopyhton, trichophyton and/or microsporium (collectively known as dermatophytes) Affected Sites - tinea corporis (affects any skin site except the ones listed immediately below) - tinea capitis (affects the scalp) - tinea cruris (affects the groin) - tinea pedis (affects the feet) - tinea unguium (affects the nails)

2) DEEP FUNGAL INFECTIONS - systemic fungal infections - may affect any internal tissue or -organ

Relevant Drugs
2 categories 1) NATURAL ANTIFUNGAL DRUGS - 2 groups A) MACROLIDES - macrolides used in treatment of fungal infections have a different mechanism of action than those used to treat bacterial infections (see 64) - they bind to ergosterol of the fungal cell membrane where insert themselves to form cell membrane pores - the cell membrane pores cause severe dysregulation of ion homeostasis, particularly potassium homeostasis, thus leading to disruption of several vital fungal metabolic pathways - , thus macrolides are fungicidal - the macrolides used in treatment of fungal infections are found in the streptomyces bacterium - 2 types DRUG NAME AMPHOTERICIN B DESCRIPTION General information - administered orally, dermally and/or IV

- 96 -

- may not cross the blood-brain barrier Medical uses - treatment of superficial fungal infections (then administered orally and/or dermally) - treatment of deep fungal infections (then administered IV) - treatment of mucocutaneous leischmaniasis due to leischmania protozoal infection (see 71) Side effects - headache - tinnitus - nausea and vomiting - acute drug-induced interstitial nephritis - hypokalemia and/or hypomagnesemia (due to acute drug-induced interstitial nephritis) - normocytic normochromatic anemia (due to acute drug-induced interstitial nephritis and following decreased erythropoietin synthesis and secretion) - drug induced hepatitis leading to hepatic failure - thrombocytopenia (due to drug induced hepatitis and following decreased thrombopoietin synthesis and secretion) - hypersensitivity reactions leading to fever and/or skin rashes NYSTATIN General information - administered orally and/or dermally Medical uses - treatment of superficial fungal infections Side effects - none ((!), does not enter the systemic circulation)

B) GRISEOFULVIN - griseofulvin is naturally found in the penicillium griseofulvum fungus - griseofulvin binds to microtubules in the fungal cytoplasm, thus inhibiting mitosis - 97 -

, thus griseofulvin is fungistatic 1 type DRUG NAME GRISEOFULVIN DESCRIPTION General information - keratinophilic - administered orally Medical uses - treatment of superficial fungal infections Side effects - headache - nausea, vomiting and/or diarrhea - photosensitivity - hypersensitivity reactions leading to fever and/or skin rashes

2) SYNTHETIC ANTIFUNGAL DRUGS - 4 groups A) ECHINOCANDINS - echinocandins are synthetic derivatives of echinocandin B normally found in the aspergillus nidulans fungus - echinocandins inhibit beta-D-glucan synthesis, thus inhibiting cell wall synthesis - this leads to decreased stability and protection of the fungal cell membrane and following osmotic lysis of the fungi - , thus echinocandins are fungicidal - 2 types DRUG NAME CASPOFUNGIN DESCRIPTION General information - administered IV Medical uses - treatment of deep fungal infections Side effects - headache - nausea, vomiting and/or diarrhea - hypersensitivity reactions leading to fever, skin rashes and/or pruritus MICAFUNGIN - 98 General information

- same as caspofungin (see above)

B) AZOLES - azoles inhibit ergosterol synthesis, thus leading to decreased stability of the fungal cell membrane - however, the fungi retain the protection of their cell wall - , thus azoles are fungistatic - 4 types DRUG NAME KETOCONAZOLE DESCRIPTION General information - administered orally - may cross the blood-brain barrier (but only if administered in high doses) Medical uses - treatment of superficial fungal infections - treatment of deep fungal infections Side effects - pruritus - nausea, vomiting and/or diarrhea - hepatotoxicity and death - gynecomastia (due to inhibition of testosterone synthesis from cholesterol, in males, if high doses) FLUCONAZOLE General information - administered orally and/or IV - may cross the blood-brain barrier Medical uses - treatment of deep fungal infections Side effects - headache - nausea - abdominal pain - hepatotoxicity - hypersensitivity reactions leading to fever, skin rashes and/or stevens-johnson syndrome ITRACONAZOLE - 99 General information

- administered orally and/or IV - may not pass the blood-brain barrier Medical uses - treatment of deep fungal infections Side effects - headache - vertigo - nausea, vomiting and/or diarrhea - hepatotoxicity - hypersensitivity reactions leading to fever, skin rashes and/or stevens-johnson syndrome MICONAZOLE General information - administered orally and/or dermally - may not cross the blood-brain barrier Medical uses - treatment of superficial fungal infections (then administered orally and/or dermally - treatment of deep fungal infections (then administered orally) Side effects - nausea, vomiting and/or diarrhea - cardiac dysrhythmias - hypersensitivity reactions leading to fever, skin rashes and/or pruritus

C) TERBINAFINE - terbinafine inhibits ergosterol synthesis, thus leading to decreased stability of the fungal cell membrane - however, the fungi retain the protection of their cell wall - , thus terbinafine is fungistatic - 1 type DRUG NAME TERBINAFINE DESCRIPTION General information - keratinophilic - administered orally and/or dermally Medical uses - 100 -

- treatment of superficial fungal infections (then administered orally and/or dermally - treatment of deep fungal infections (then administered orally) Side effects - headache - vertigo - nausea, vomiting and/or diarrhea - myalgias - arthralgias - hepatotoxicity - hypersenstitivity reactions leading to fever, pruritus and/or skin rashes

D) FLUCYTOSINE - flucytosine is a prodrug that is converted to 5-fluorouracil in fungi - human cells have little or no ablility to convert flucytosine to 5fluorouracil, thus leaving them more or less untouched - 5-fluorouracil is an antimetabolite that inhibits thymidylate synthetease, thus inhibiting DNA synthesis (see 73) - , thus flucytozine is fungistatic - 1 type DRUG NAME FLUCYTOSINE DESCRIPTION General information - administered orally and/or IV - administered in conjunction with amphotericin b (see above, due to high level of resistance) - may cross the blood-brain barrier Medical uses - treatment of deep fungal infections Side effects - nausea, vomiting and/or diarrhea - hepatotoxicity - bone marrow depression leading to anemia, neutropenia and thrombocytopenia - alopecia (hair loss)

- 101 -

69. ANTIVIRAL DRUGS


Overview
viridae are a kingdom of lifeless particles devoid of any metabolic activity, thus are incapable of growth and replication on their own to replicate they have to infect a host cell and utilize the host cells anabolic enzymes, thus they are obligate intracellular parasites extracellularly the viridae particles are known as virions virions consist of 3 parts (listed from innermost to outermost) PART CYTOPLASM DESCRIPTION - sparse cytoplasm originating from the host cell containing a naked viral genetic material and a few viral proteins specific for each separate virus that is encoded by the viral genome - protein coat consisting of capsomer subunits that is encoded by the viral genome - the cytoplasm and the capsid are collectively known as a nucleocapsid - lipoprotein membrane originating from the host cell containing embedded viral proteins specific for each separate virus that is encoded by the viral genome - present only in some viral species (in viridae that do not have an envelope, these viral proteins are embedded in the capsid instead)

CAPSID

ENVELOPE

the viral infective cycle of a host cell is divided in 5 phases 1) ENTRY - viridae may be divided in 2 types according to their mechanism of entry and exit (see below) TYPE ENVELOPED VIRUSES MECHANISM - the viral proteins embedded in the envelope bind to physiologic receptors of the host cell membrane - this induces fusion between the virion envelope and the host cell membrane, thus the nucleocapsid is

- 102 -

released into the host cell cytoplasm NON-ENVELOPED VIRUSES - the viral proteins embedded in the capsid bind to physiologic receptors of the host cell membrane - this induces the host cell to endocytose the virion, thus the nucleocapsid is released into the host cell cytoplasm

2) UNCOATING - release of the viral cytoplasm (including the viral genetic material and viral proteins) from the capsid into the host cell cytoplasm - mechanism of uncoating is unknown, or poorly understood at best 3) REPLICATION - viridae may be divided in 3 types according to their mechanism of replication TYPE DNA VIRUSES MECHANISM - the viral DNA enters the host cell nucleus where it induces its own viral DNA polymerase (DNA-dependent DNA polymerase) - this causes replication of new viral DNA molecules - the viral DNA also induces host cell RNA polymerase - this causes transcription of viral DNA into viral mRNA molecules - the viral mRNA molecules are exported into the host cell cytoplasm where they are translated on host cell ribosomes to yield viral pre-proteins - the viral pre-proteins are then spliced by viral proteases, thus forming functional viral proteins - the viral RNA enters the host cell nucleus where it induces its own viral reverse transcriptase (RNAdependent DNA polymerase) - this causes reverse transcription of the viral RNA into viral DNA molecules - the viral DNA molecules are then inserted into the host cell genome

RETROVIRAL RNA VIRUSES

- 103 -

- the inserted viral DNA molecules are then transcribed, translated and spliced in the same way as with DNA viruses (see above) RNA VIRUSES - the viral RNA stays in the host cell cytoplasm where in induces its own viral RNA polymerase (RNAdependent RNA polymerase) - this causes transcription of new viral RNA molecules - the new viral RNA molecules act both as new viral RNA genome and as viral mRNA molecules - the viral mRNA molecules are then translated and spliced in the same way as with DNA viruses (see above)

4) ASSEMBLY - assembly of capsomers into capsids and following importation of the viral genome and the viral proteins, thus yielding new nucleocapsids - mechanism of packaging is unknown, or poorly understood at best 5) EXIT - viridae are divided in the same 2 types in regards to their mechanism of exit as with their mechanism of entry (see above) TYPE ENVELOPED VIRUSES MECHANISM - the viral nucleocapsids bud from the host cell membrane, thus acquiring their respective envelopes - , thus the host cell survives the viral infection - the viral nucleocapsids induce lysis of the host cell, thus escaping the host cell cytoplasm - thus, the host cell dies as a result of the viral infection

NON-ENVELOPED VIRUSES

Relevant Drugs
4 categories 1) DRUGS USED AGAINST DNA VIRUSES - 104 -

2 groups A) INDIRECT VIRAL DNA POLYMERASE INHIBITORS - indirect viral DNA polymerase inhibitors are antimetabolite analogues of the normal guanosine nucleoside used in synthesis of DNA both by the host cell DNA polymerase and by the viral DNA polymerase - however, the guanosine analogues have much higher affinity for the viral DNA polymerase, thus being relatively specific for the replication of viral DNA - in the host cell, host cell enzymes phosphorylate the guanosine analogues 3 times, thus yielding activated guanosine triphosphate analogues (guanosine nucleotide analogues) - these guanosine triphosphate analogues are then incorporated into the elongating viral DNA - however, the guanosine triphosphate analogues lack the binding site (hydroxyl group) needed for the following nucleotide to be incorporated into the elongating viral DNA, thus causing termination of the elongation of the viral DNA (chain-termination) - DNA viruses may develop resistance by decreased affinity - 3 types DRUG NAME ACICLOVIR DESCRIPTION General information - administered orally, dermally and/or IV - may cross the blood-brain barrier Medical uses - treatment of herpes labialis, herpes genitalis and/or herpetic keratitis due to herpes simplex infection - treatment of varicella and/or zoster due to varicella-zoster virus infection Side effects - headache - nausea - urolitihasis (crystalluria) - encephalopathies PENCICLOVIR General information - administered dermally and/or IV - same as aciclovir (see above) General information - administered IV - may cross the blood-brain barrier

GANCICLOVIR

- 105 -

Medical uses - treatment of infectious mononucleosis-like syndrome due to cytomegalovirus infection - treatment of infectious mononucleosis due to epstein-barr virus infection Side effects - bone marrow depression leading to pancytopenia - carciongenicity - teratogenicity

B) DIRECT VIRAL DNA POLYMERASE INHIBITORS - direct viral DNA polymerase inhibitors are pyrophosphate analogues (diphosphate analogues) that competitively inhibit viral DNA polymerase by binding to its active site - this causes inhibition of replication of viral DNA - 1 type DRUG NAME FOSCARNET DESCRIPTION General information - administered IV Medical uses - treatment of infectious mononucleosis-like syndrome due to cytomegalovirus infection - treatment of - treatment of herpes labialis, herpes genitalis and/or herpetic keratitis due to herpes simplex infection (if aciclovirresistant) - treatment of varicella and/or zoster due to varicella-zoster virus infection (if aciclovir-resistant) Side effects - nephrotoxicity

2) DRUGS USED AGAINST RETROVIRAL RNA VIRUSES - 3 groups

- 106 -

A) INDIRECT VIRAL REVERSE TRANSCRIPTASE INHIBITORS - indirect viral reverse transcriptase inhibitors are antimetabolite analogues of the normal nucleosides used in synthesis of DNA both by the host cell DNA polymerase and by the viral reverse transcriptase - they have the same specificity for viral reverse transcriptase, mechanism of activation, mechanism of action and mechanism of resistance as with indirect viral DNA polymerase inhibitors (see above) - they are never used alone, but in combinations with one or more direct viral reverse transcriptase inhibitors (see below) and/or viral protease inhibitors (see below) due to high incidence of resistance in the viruses - 4 types DRUG NAME DIDANOSINE DESCRIPTION General information - adenosine antimetabolite analogue - administered orally - may cross the blood-brain barrier Medical Uses - treatment of acquired immunodeficiency syndrome (AIDS) due to human immunodeficiency virus (HIV) infection Side effects - headache - nausea, vomiting and/or diarrhea - buccal- and/or gingival ulcerations - skin rashes - lower extremity edema - peripheral neuropathies - pancreatitis ABACAVIR General information - guanosine antimetabolite analogue - administered orally - may cross the blood-brain barrier Medical Uses - treatment of AIDS due to HIV infection Side effects - nausea, vomiting and/or diarrhea - 107 -

- hypersensitivity reactions leading to fever, skin rashes and/or anaphylactic shock LAMIVUDINE General information - cytosine antimetabolite analogue - also inhibits viral DNA polymerase - administered orally - may cross the blood-brain barrier Medical uses - treatment of AIDS due to HIV infection - treatment of hepatitis due to hepatitis B virus infection Side effects - headache - nausea, vomiting and/or diarrhea ZIDOVUDINE General information - thymidine antimetabolite analogue - administered orally and/or IV - may cross the blood-brain barrier Medical uses - treatment of AIDS due to HIV infection - prevention of mother-to-infant HIV transmission Side effects - nausea, vomiting and/or diarrhea - skin rashes - myopathy - paresthesia - confusion, insomnia, anxiety and/or depression - bone marrow depression leading to anemia and/or neutropenia - flu-like syndrome leading to fever, headache, myalgias, arthraligas, rhinitis and/or pharyngitis

- 108 -

B) DIRECT VIRAL REVERSE TRANSCRIPTASE INHIBITORS - direct viral reverse transcriptase inhibitors competitively inhibit viral reverse transcriptase by binding to its active site - this causes inhibition of transcription of viral RNA into viral DNA - they are never used alone, but in combinations with one or more indirect viral reverse transcriptase inhibitors (see above) and/or viral protease inhibitors (see below) due to high incidence of resistance in the viruses - 2 types DRUG NAME NEVIRAPINE DESCRIPTION General information - administered orally - may cross the blood-brain barrier Medical uses - treatment of AIDS due to HIV infection - prevention of mother-to-infant HIV transmission Side effects - headache - hepatotoxicity - stevens-johnson syndrome and/or death - toxic epidermal necrolysis and/or death EFAVIRENZ General information - administered orally - may not cross the blood-brain barrier Medical uses - treatment of AIDS due to HIV infection Side effects - nausea, vomiting and/or diarrhea - skin rashes - vertigo, confusion and/or dysphoria

C) VIRAL PROTEASE INHIBITORS - 109 -

viral protease inhibitors bind to the cleavage sites on viral pre-proteins, thus in thus inhibiting splicing of viral pre-proteins into functional viral proteins by the viral protease they are never used alone, but in combinations with one or more indirect- and/or direct viral reverse transcriptase inhibitors (see above) due to high incidence of resistance in the viruses 4 types DRUG NAME SAQUINAVIR DESCRIPTION General information - administered orally - may penetrate the blood-brain barrier Medical uses - treatment of AIDS due to HIV infection Side effects - nausea, vomiting and/or diarrhea - diabetes mellitus type 2 - redistribution of fat to the neck, mamma and abdomen RITONAVIR General information - same as saquinavir (see above) Medical uses - same as saquinavir (see above) Side effects - same as saquinavir (see above) - labial-, palmar and plantar paresthesia AMPRENAVIR General information - same as saquinavir (see above) Medical uses - same as saquinavir (see above) Side effects - same as saquinavir (see above) - stevens-johnson syndrome

- 110 -

INDINAVIR

General information - administered orally - may not penetrate the blood-brain barrier Medical uses - same as saquinavir (see above) Side effects - same as saquinavir (see above) - urolithiasis

3) DRUGS USED AGAINST RNA VIRUSES - 3 groups A) VIRAL RNA-DEPENDENT RNA POLYMERASE INHIBITORS - viral RNA-dependent RNA polymerase inhibitors are antimetabolite analogues of the normal guanosine nucleoside used in synthesis of mRNA both by the host cell RNA polymerase and by the viral RNAdependent RNA polymerase - they have the same specificity for viral RNA-dependent RNA polymerase, mechanism of activation, mechanism of action and mechanism of resistance as with indirect viral DNA polymerase inhibitors (see above) - 1 type DRUG NAME RIBAVIRIN DESCRIPTION General information - also inhibits viral DNA polymerase - administered pulmonarily and/or IV Medical uses - treatment of influenza due to influenza A virus and/or influenza B virus infection - treatment of lassa fever due to lassa virus infection Side effects - hemolytic anemia

B) INHIBITORS OF VIRAL UNCOATING AND ASSEMBLY - inhibitors of uncoating and assembly inhibit key proteins required for the virus to perform these 2 phases of the viral infective cycle - 111 -

1 type DRUG NAME AMANTIDINE DESCRIPTION General information - inhibits the M2 protein of the influenza A virus - M2 is only present in the influenza A virus, thus amantidine may only be used against influenza A infections - administered orally and/or pulmonarily Medical uses - treatment of influenza due to influenza A virus infection Side effects - vertigo - insomnia - speech impairment

C) INHIBITORS OF VIRAL EXIT - inhibitors of exit inhibit key proteins required for the virus to perform this phase of the viral infective cycle - 1 type DRUG NAME ZANAMIVIR DESCRIPTION General information - inhibits neuraminidase of the influenza A and -B viruses - neuraminidase is only present in the influenza A and B viruses, thus zanamivir may only be used against influenza A and B infections Medical uses - treatment of influenza due to influenza A virus and/or influenza B virus infection Side effects - none (!)

- 112 -

4) IMMUNOMODULATORS - 1 group A) INTERFERONS - interferons are a group of cytokines that potentiate the immune defense system upon microbial infections - 1 type DRUG NAME INTERFERON-ALPHA2 DESCRIPTION General information - IFN-alpha2 - induces transcription of host cell enzymes that inhibit the ribosomal translation of viral mRNA into viral pre-proteins - administered IV - may not cross the blood-brain barrier Medical uses - treatment of kaposi sarcoma due to kaposi sarcoma herpesvirus infection - treatment of acquired immunodeficiency syndrome due to human immunodeficiency virus infection - treatment of hepatitis due to hepatitis B virus infection - treatment of hepatitis due to hepatitis C virus infection Side effects - skin rashes - flu-like syndrome leading to fever, headache, myalgias, arthraligas, rhinitis and/or pharyngitis - bone marrow depression leading to pancytopenia - alopecia (hair loss)

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70. ANTISEPTICS AND DISINFECTANTS


Overview
antimicrobial agents are compounds that inhibit the growth of and/or kill microbes antimicrobial agents may be divided in 2 groups 1) SELECTIVE ANTIMICROBIAL AGENTS - selective antimicrobial agents are compounds that inhibit the growth of and/or kill specific microbes - due to this specific antimicrobial action they are relatively harmless to human cells, thus are normally (but not necessarily) used against microbial invasions of deep tissues - the specific antimicrobial action is mediated specific biochemical mechanisms, thus the selective antimicrobial agents have a relatively slow onset - 5 types TYPE ANTIBIOTICS DESCRIPTION - used against specific bacteria - see 62, 63, 64, 65, 66 and 67 -used against specific viridae - see 69 - used against specific fungi - see 68 - used against specific protozoa - see 71 - used against specific helminths - see 72

ANTIVIRAL DRUGS

ANTIFUNGAL DRUGS

ANTIPROTOZOAL DRUGS ANTIHELMINTHIC DRUGS

2) NON-SELECTIVE ANTIMICROBIAL AGENTS - non-selective antimicrobial agents are compounds that inhibit the growth of and/or kill microbes in general - due to this general antimicrobial action they are relatively harmful to human cells, thus are normally (but not necessarily) used against microbial colonies of surface tissues and of inanimate objects - the general antimicrobial action is mediated by general chemical mechanisms, thus the non-selective antimicrobial agents have a relatively fast onset - 2 types TYPE - 114 DESCRIPTION

ANTISEPTICS

General information - used against microbial colonies of surface tissues in general Sites of application - mucous membranes - skin

DISINFECTANTS

General information - used against microbial colonies of inanimate objects (vehicles) in general Sites of application - ingestible vehicles (food and drinks) - non-ingestible vehicles (fomites)

most non-selective antimicrobial agents are antiseptics at lower concentrations and disinfectants at higher concentrations however, some non-selective antimicrobial agents are very expensive, thus are only used as antiseptics conversely, some non-selective antimicrobial agents are very harmful to human cells, thus are only used as disinfectants

Relevant Drugs
10 categories 1) HALOGENS - halogens are non-metallic elements with only 1 valence electron (found in group 17 of the periodic table) - 2 groups A) IODINE - iodine has an antimicrobial action by precipitation of proteins - 2 types DRUG NAME IODINE SOLUTION DESCRIPTION General information - dissolved in water - antiseptic General information - dissolved in ethanol - antiseptic

IODINE TINCTURE

- 115 -

B) CHLORIDE AND CHLORIDE DERIVATIVES - chloride and chloride derivatives have an antimicrobial action directly by chlorination of proteins and indirectly by deliberation of oxygen free radicals from water and following damage to cell membrane phospholipids and DNA - 4 types DRUG NAME CHLORIDE SOLUTION DESCRIPTION General information - dissolved in water - disinfectant General information - antiseptic General information - a phenol (see below) - antiseptic General information - an acid (see below) - antiseptic

CHLORHEXIDINE GLUCONATE

HEXACHLOROPHENE

CHLOROGENATE

2) HEAVY METALS - heavy metals are metallic elements with specific gravity above 4.0 (found between copper and bismuth in the periodic table) - heavy metals have an antimicrobial action by precipitation of proteins and disturbance of ionic gradients - 3 groups A) MERCURY DERIVATIVES - quicksilver derivatives - 3 types DRUG NAME MERBROMIN DESCRIPTION General information - antiseptic General information - antiseptic General information - antiseptic and

THIOMERSAL

NITROMERSOL

- 116 -

disinfectant

B) SILVER DERIVATIVES - 2 types DRUG NAME SILVER NITRATE DESCRIPTION General information - antiseptic General information - antiseptic

COLLOIDAL SILVER

C) ZINC DERIVATIVES - 1 type DRUG NAME ZINC OXIDE DESCRIPTION General information - antiseptic and disinfectant

3) ALCOHOLS - alcohols are linear molecules containing 1 hydroxyl group - they have an antimicrobial action by precipitation of proteins - 2 types DRUG NAME ETHANOL DESCRIPTION General information - antiseptic and disinfectant General information - rubbing alcohol - antiseptic and disinfectant

ISOPROPANOL

4) DIOLS - glycols - diols are linear molecules containing 2 hydroxyl groups - their antimicrobial action is the same as that of alcohols (see above) - 1 type DRUG NAME - 117 DESCRIPTION

PROPYLENE GLYCOL

General information - antiseptic

5) PHENOLS - phenols are aromatic molecules containing 1 hydroxyl group - their antimicrobial action is the same as that of alcohols (see above) - 2 types DRUG NAME RESORCINOL DESCRIPTION General information - antiseptic General information - antiseptic

THYMOL

6) ALDEHYDES - aldehydes are linear molecules containing an aldehyde group - they have an antimicrobial action by alkylation of molecules (including proteins) - 2 types DRUG NAME FORMALDEHYDE DESCRIPTION General information - formalin - disinfectant General information - disinfectant

GLUTARALDEHYDE

7) ACIDS - acids are molecules that donate hydrogen ions in solutions at neutral pH - they have an antimicrobial action by denaturation of proteins (by lowering extracellular- and intracellular pH) - 4 types DRUG NAME ACETATE DESCRIPTION General information - antiseptic General information - antiseptic

SALICYLATE

- 118 -

LACTATE

General information - antiseptic General information - disinfectant

BENZOATE

8) DYES - dyes are colored compounds that bind to subcellular components, thus staining them for light microscopic visualization - they have an antimicrobial action by chelation of DNA and disturbance of ionic gradients - 3 types DRUG NAME CARBOFUCHSIN DESCRIPTION General information - antiseptic General information - antiseptic General information - antiseptic

GENTIAN VIOLET

BRILLIANT GREEN

9) OXIDIZING AGENTS - oxidizing agents are electron-poor molecules that oxidize other molecules to gain electrons - they have an antimicrobial action by damaging cell membrane phospholipids and DNA - 2 types DRUG NAME HYDROGEN PEROXIDE DESCRIPTION General information - antiseptic and disinfectant General information - antiseptic and disinfectant

POTASSIUM PERMANGANATE

10) SURFACTANTS - surface-active agents

- 119 -

surfactants are molecules that are both hydrophilic and lipophilic (amphiphilic molecules) the surfactants consist of 2 parts PART HEAD DESCRIPTION - either positively charged (cationic) or negatively charged (anionic) - , thus is hydropilic - uncharged (nonionic) - , thus is lipophilic - are long unbranched alkyl chains

TAIL

2 groups A) CATIONIC SURFACTANTS - invert soaps - invert soaps are quaternary ammonium derivatives, thus have a positively charged head - they have an antimicrobial action by disruption of cell membranes - 2 types DRUG NAME BENZALKONIUM CHLORIDE DESCRIPTION General information - antiseptic General information - antiseptic

CETYLPYRIDINIUM CHLORIDE

B) ANIONIC SURFACTANTS - regular soaps - regular soaps are fatty acid derivatives, thus have a negatively charged head - they do not have any antimicrobial action whatsoever, but remove dirt (and by that also microbes) by micelle formation and simple friction - , thus they are used to partially remove microbial colonies of both surface tissues and inanimate objects - 2 types DRUG NAME SODIUM LAURETH SULFATE DESCRIPTION General information - antiseptic and disinfectant

- 120 -

SODIUM DODECYL SULFATE

General information - antiseptic and disinfectant

- 121 -

71. ANTIPROTOZOAL DRUGS


Overview
protozoa are a division of the protista kingdom consisting of unicellular eukaryotic organisms that replicate by simple mitosis, by complex mitosis, by spore formation, by meiosis and following fusion, or by all of the above (!) protozoal cells consist of 3 parts (listed from innermost to outermost) PART CYTOPLASM DESCRIPTION - contains membrane-bound organelles including a nucleus-bound genetic material - a lipoprotein membrane containing a cytostome (a primitive mouth with which the protozoa phagocytose nutrients) - protective coat of different structure and composition depending on the species - only in the cyst form of the protozoa (see below)

CELL MEMBRANE

PELLICLE

protozoa may exist in 2 common forms FORM TROPHOZOITE DESCRIPTION - the active motile form of the protozoa - the form of the protozoa in favorable environments - the inactive protected form of the protozoa - the form of the protozoa in unfavorable environments - surrounded by a protective pellicle (see above)

CYST

though these 2 forms are the common forms of the protozoa, many protozoal species may exist in a torrent of other forms as well depending on their mechanism of replication

ANTIMALARIAL DRUGS
Overview
malaria is an anemic, febrile illness caused by the plasmodium protozoa the plasmodium protozoa is transmitted to humans by the anopheles mosquito (vector)

- 122 -

the plasmodium protozoal infective cycle is divided in 11 phases, each of the phases characterized by a distinct form of the plasmodium protozoon FORM SPOROZOITE DESCRIPTION - the motile transmittable form of the plasmodium protozoa - they reside in the salivary glands of anopheles mosquitoes - here the sporozoites stay latent until an infected anopheles mosquito bites a human, thus transferring them to the human dermis - from the human dermis, they are carried by way of the blood stream to the liver where they infect the hepatocytes - the active form of the plasmodium protozoa within hepatocytes - they ingest intracellular structures of the host hepatocytes by phagocytosis, thus forming food vacuoles in the cytoplasm of the pre-erythrocytic trophozoites - the food vacuoles fuse with lysosomes, thus forming phagolysosomes - the contents of the phagolysosomes is degraded by lysosomal enzymes, thus providing the preerythrocytic trophozoites with carbohydrates, free fatty acids and amino acids - the mitotic form of the plasmodium protozoa within hepatocytes - they divide by exponential division of nuclei yielding thousands of nuclei within each preerythrocytic schizont - this is followed by invaginations of their cell membrane to form new cell membranes around each of the newly formed nuclei, thus forming thousands of pre-erythrocytic merozoites (see below) - they continue to divide until the host hepatocytes rupture, thus releasing them back into the blood stream - the mature form of the plasmodium protozoa originating from the hepatocytes - they are carried by the way of the blood stream to either reinfect new hepatocytes to form hypnozoites (see below) or infect RBCs to form erythrocytic trophozoites (see below)

PRE-ERYTHROCYTIC TROPHOZOITE

PRE-ERYTHROCYTIC SCHIZONT

PRE-ERYTHROCYTIC MEROZOITE

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HYPNOZOITE

- the dormant form of the plasmodium protozoa - they may lie dormant within hepatocytes for years before activating themselves, thus forming new pre-erythrocytic trophozoites (see above) - the active form of the plasmodium protozoa within RBCs - they phagocytose and degrade intracellular structures of the host RBCs by the same mechanism as the pre-erythrocytic trophozoites (see above) - the main source of proteins for the erythrocytic trophozoites is the globin part of hemoglobin - this leads to release of heme in their phagolysosomes which is extremely toxic to the erythrocytic trophozoites - however, the toxic heme is neutralized by the enzymatic action of haem polymerase within the phagolysosomes - the mitotic form of the plasmodium protozoa within RBCs - they divide by the same mechanism as with the pre-erythrocytic schizonts (see above), thus forming thousands of erythrocytic merozoites (see below) - as with the pre-erythrocytic schizonts, they continue to divide until the host RBCs rupture, thus releasing them back into the blood stream - the mature form of the plasmodium protozoa originating from the RBCs - they are carried by the way of the blood stream to reinfect new RBCs either to form new erythocytic schizonts (see above) or male/female gametocytes (see below) - the meiotic form of the plasmodium protozoa - they continue to divide until the host RBCs rupture, thus releasing them back into the blood stream - here they stay latent until a new anopheles mosquito bites the infected human, thus transferring them to the anopheles mosquito digestive system - the fused male and female gametocyte form (zygote form) of the plasmodium protozoa - 124 -

ERYTHROCYTIC TROPHOZOITE

ERYTHROCYTIC SCHIZONT

ERYTHROCYTIC MEROZOITE

MALE/FEMALE GAMETOCYTES

OOKINETE

- they immediately synthesize a protective pellicle around them to prevent them from being digested in the anopheles mosquito digestive system, thus forming oocysts (see below) OOCYST - the protected mitotic form of the plasmodium protozoa in the anopheles mosquito digestive system - they divide by the same mechanism as with the pre-erythrocytic schizonts (see above), thus forming thousands of new sporozoites (see above) -the new sporozoites disseminate throughout the anopheles mosquito (including the salivary glands of the anopheles mosquito), thus completing the plasmodium protozoal infective cycle

in other words: SPOROZOITE PRE-ERYTHROCYTIC TROPHOZOITE

HYPNOZOITE

PRE-ERYTHROCYTIC SCHIZONT PRE-ERYTHROCYTIC MERZOITE ERYTHROCYTIC TROPHOZOITE ERYTHROCYTIC SCHIZONT ERYTHROCYTIC MERZOITE MALE/FEMALE GAMETOCYTES OOKINETE OOCYST

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there are 4 species of plasmodium protozoa that may cause malaria (listed from most to least pathogenic) SPECIES PLASMODIUM FALCIPARUM DESCRIPTION - causes continuous lysis of RBCs - the erythrocytic trophozoite form of plasmodium falciparum also synthesizes and secretes proteins that insert in the host RBC cell membrane - these proteins act as receptors that adhere to uninfected RBCs and vascular endothelial cells, thus causing aggregation of RBCs (rosettes) on the luminal surface of the vascular endothelial cells and following obstruction of the microcirculation - causes lysis of RBCs every 2 days (tertian malaria) - may produce hypnozoites - , thus may cause relapses of malaria years after treatment - same as plasmodium vivax (see above) - causes lysis of RBCs every 3 days (quartan malaria)

PLASMODIUM VIVAX

PLASMODIUM OVALE PLASMODIUM MALARIAE

Relevant Drugs
3 categories 1) ANTI-ERYTHROCYTIC FORM DRUGS - anti-erythrocytic form drugs are drugs that specifically attack the erythocytic forms of the plasmodium protozoa (see above) - all species of plasmodium protozoa go through the erythrocytic cycle, thus anti-erythrocytic form drugs are effective against all speices of plasmodium protozoa - however, plasmodium vivax and plasmodium ovale also produce hypnozoites - (see above), thus may cause relapse of malaria years after treatment with antierythrocytic form drugs - 5 groups A) 4-AMINOQUINOLINES - 4-aminoquinolines inhibit haem polymerase, thus causing buildup of toxic heme in the plasmodium protozoa - , thus 4-aminoquinolines are plasmodicidal

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plasmodium protozoa may develop resistance to 4-aminoquinolines by increased excretion of 4-aminoquinolines due to increased expression of P-glycoprotein transporter (human multidrug resistance transporter) 2 types DRUG NAME CHLOROQUINE DESCRIPTION General information - also a disease-modifying anti-rheumatic drug (see 53) - administered orally, subcutaneously, intramuscularly and/or IV Medical uses - treatment of malaria due to plasmodium falciparum and/or plasmodium malariae infection - treatment of malaria due to plasmodium vivax and/or plasmodium ovale infection (then administered in conjunction with an 8-aminoquinoline, see below) - treatment of invasive amoebiasis (then administerered in conjunction with diloxanide, see below) Side effects - headache - vertigo - nausea and/or vomiting - visual disturbances (due to accumulation in the retina) - hypotension, cardiac dysrhythmias and/or sudden cardiac death (if high doses, due to negative tropic effect on the heart) AMODIAQUINE General information - same as chloroquine (see above)

B) QUINOLINE-METHANOLS - quinoline-methanols have the same mechanism of action and plasmodial mechanism of resistance as with 4-aminoquinolines (see above) - 2 types DRUG NAME QUININE - 127 DESCRIPTION General information

- administered orally and/or IV Medical uses - treatment of malaria due to plasmodium falciparum and/or plasmodium malariae infection (if resistant to 4aminoquinolines, see above) - treatment of malaria due to plasmodium vivax and/or plasmodium ovale infection (if resistant to 4-aminoquinolines (see above), then administered in conjunction with an 8-aminoquinoline (see below)) Side effects - hypersensitivity reactions leading to fever and/or skin rashes - nausea and/or vomiting - hypoglycemia (due to increased insulin release) - thrombocytopenia (due to bone marrow depression) - delirium and/or coma (if high doses) - hypotension and/or cardiac dysrhythmias (if high doses, due to negative tropic effect on the heart) - cinchonism (headache, vertigo, nausea and visual disturbances) - blackwater fever (hemolytic anemia, acute renal failure and/or death) MEFLOQUINE General information - administered orally Medical uses - treatment of malaria due to plasmodium falciparum infection (if resistant to 4aminoquinolines (see above), then administered in conjunction with pyrimethamine (see 61)) - treatment of malaria due to plasmodium vivax infection (if resistant to 4aminoquinolines (see above), then administered in conjunction with an 8aminoquinoline (see below)) Side effects - nausea, vomiting and/or diarrhea - 128 -

- insomnia, confusion and/or dysphoria - teratogenicity

C) PHENANTHRENE-METHANOLS - phenanthrene-methanols have the same mechanism of action as with 4aminoquinolines (see above) - plasmodium protozoa may develop resistance to phenanthrenemethanols by an unknown mechanism - 1 type DRUG NAME HALOFANTRINE DESCRIPTION General information - administered orally Medical uses - treatment of malaria due to plasmodium falciparum infection (if resistant to both 4aminoquinolines and quinoline-methanols, see above) - treatment of malaria due to plasmodium vivax infection (if resistant to both 4aminoquinolines and quinoline-methanols (see above), then administered in conjunction with an 8-aminoquinoline (see below)) Side effects - gastic pain - nausea, vomiting and/or diarrhea - convulsions - hemolytic anemia - cardiac dysrhythmias - sudden cardiac death (if cardiac dysrhythmias are already present)

D) COMBINATIONS OF SULFONAMIDES AND DIHYDROFOLATE REDUCTASE INHIBITORS - combinations of sulfonamides and dihydrofolate reductase inhibitors inhibit folate synthesis by simultaneous displacement of PABA from dihydropteroate synthetase and inhibition of dihydrofolate reductase, thus inhibiting DNA synthesis in the plasmodium protozoa - , thus combinations of sulfonamides and dihydrofolate reductase inhibitors are plasmodicidal - they also prevent the formation of male/female gametocytes, thus preventing further spread of the plasmodium protozoa - 129 -

see 62

E) TETRACYCLINES - tetracyclines inhibit protein synthesis by blocking the attachment of the presently coded aminoacyl-tRNA to the A site of the ribosome-mRNA complex - , thus tetracyclines are plasmodistatic - see 64 2) ANTI-HYPNOZOITE FORM DRUGS - anti-hypnozoite form drugs are drugs that specifically attack the hypnozoite form of the plasmodium protozoa (see above) - only plasmodium vivax and plasmodium ovale produce hypnozoites, thus anti-hypnozoite form drugs are only effective against these plasmodial species - 1 group A) 8-AMINOQUINOLINES - 8-aminoquinolines are plasmodicidal, but act by an unknown mechanism - they also prevent formation of male/female gametocytes, thus preventing further spread of the plasmodium protozoa - 1 type DRUG NAME PRIMAQUINE DESCRIPTION General information - administered orally Medical uses - treatment of malaria due to plasmodium vivax and/or plasmodium ovale infection (then administered in conjunction with an anti-erythrocytic form drug (see above) - treatment of american trypanosomiasis (see below) Side effects - nausea, vomiting and/or diarrhea - methemoglobinemia - hemolytic anemia (if glucose-6phosphate dehydrogenase deficiency)

DRUGS USED AGAINST TRICHOMONIASIS

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Overview
trichomoniasis is a genital disease caused by the trichomonas vaginalis protozoa the symptoms of trichomoniasis depend on the gender of the infected individual GENDER MALES DESCRIPTION - asymptomatic - caused by trichomonas vaginalis infection of the urethra - dysuria and purulent vaginal discharge - caused by entamoeba histolytica infection of the vagina

FEMALES

the trichomonas vaginalis protozoa is transmitted by sexual intercourse

Relevant Drugs
2 types DRUG NAME METRONIDAZOLE DESCRIPTION General information - metabolized in the protozoa to form reactive oxygen species and following DNA damage - administered orally, rectally and/or IV - may cross the blood-brain barrier Medical uses - treatment of trichomoniasis due to trichomonas vaginalis infection - treatment of giardiasis due to giardia lambia infection (see below) - treatment of invasive amoebiasis due to entamoeba histolytica infection (then administered in conjunction with diloxanide, see below) - treatment of cutaneous leischmaniasis due to leischmania infection (see below) Side effects - headache - vertigo - central neuropathies - nausea, vomiting and/or diarrhea - alcohol sensitivity (due to inhibition of acetaldehyde dehydrogenase) - 131 -

TINIDAZOLE

General information - same as metronidazole (see above) Medical uses - treatment of trichomoniasis due to trichomonas vaginalis infection - treatment of giardiasis due to giardia lambia infection (see below) - treatment of invasive amoebiasis due to entamoeba histolytica infection (then administered in conjunction with diloxanide, see below) Side effects - same as metronidazole (see above)

DRUGS USED AGAINST GIARDIASIS


Overview
giardiasis is a disease of the intestine caused by the giardia lambia protozoa the giardia lambia protozoa adheres to the instestinal mucosa, thus causing malabsorption and following steatorrhea the giardia lambia protozoa is transmitted by the fecal-oral route

Relevant Drugs
2 types DRUG NAME METRONIDAZOLE DESCRIPTION General information - a drug used against trichomoniasis (see above) General information - a drug used against trichomoniasis (see above)

TINIDAZOLE

DRUGS USED AGAINST AMOEBIASIS


Overview
amoebiasis is a disease of variable clinical picture caused by the entamoeba histolytica protozoa there are 2 types of amoebiasis depending on the level of invasion of the entamoeba histolytica protozoa - 132 -

TYPE NON-INVASIVE AMOEBIASIS

DESCRIPTION - asymptomatic - caused by entamoeba histolytica infection of the intestinal lumen - abdominal pain and purulent hemorrhagic diarrhea - caused by entamoeba histolytica invasion of the intestinal mucosa - may complicate by hematogenous spread to the liver and following hepatic abscesses

INVASIVE AMOEBIASIS

the entamoeba histolytica protozoa is transmitted by the fecal-oral route

Relevant Drugs
2 categories 1) DRUGS USED AGAINST NON-INVASIVE AMOEBIASIS - 1 type DRUG NAME DILOXANIDE DESCRIPTION General information - administered orally Medical uses - treatment of non-invasive amoebiasis due to entamoeba histolytica infection - treatment of invasive amoebiasis due to entamoeba histolytica infection (then administered in conjunction with one or more of the drugs used against invasive amoebiasis, see below) Side effects - none ((!), does not enter the systemic circulation)

2) DRUGS USED AGAINST INVASIVE AMOEBIASIS - 3 types

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DRUG NAME METRONIDAZOLE

DESCRIPTION General information - a drug used against trichomoniasis (see above) General information - a drug used against trichomoniasis (see above) General information - a 4-aminoquinoline antimalarial drug (see above)

TINIDAZOLE

CHLOROQUINE

DRUGS USED AGAINST LEISCHMANIASIS


Overview
leischmaniasis is a disease of variable clinical picture caused by the leischmania protozoa there are 4 types of leischmaniasis depending on the state of the immune defense system of the infected individual TYPE SIMPLE LEISCHMANIASIS DESCRIPTION - a single skin ulceration at the initial site of infection - due to intact immune defense system and following local cell-mediated elimination of the leischmania protozoa - multiple generalized non-ulcerating skin nodules - due to mild immunodeficiency and following hematogenous spread of the leischmania protozoa across the skin - multiple mucous membrane ulcerations of the nasal- and oral cavities - due to moderate immunodeficiency and following hematogenous spread of the leischmania protozoa across the mucous membranes - severe hepatosplenomegaly - due to severe immunodeficiency and following hematogenous spread of the leischmania protozoa to the liver and

CUTANEOUS LEISCHMANIASIS

MUCOCUTANEOUS LEISHMANIASIS

VISCERAL LEISHMANIASIS

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spleen

the leischmania protozoa are transmitted to humans by the sandfly

Relevant Drugs
3 categories 1) DRUGS USED AGAINST CUTANEOUS LEISCHMANIASIS - 1 type DRUG NAME METRONIDAZOLE DESCRIPTION General information - a drug used against trichomoniasis (see above)

2) DRUGS USED AGAINST MUCOCUTANEOUS LEISCHMANIASIS - 1 type DRUG NAME AMPHOTERICIN B DESCRIPTION General information - a macrolide antifungal drug (see 68)

3) DRUGS USED AGAINST VISCERAL LEISCHMANIASIS - 1 type DRUG NAME SODIUM STIBOGLUCONATE DESCRIPTION General information - inhibits multiple vital protozoal metabolic pathways including glycolysis and beta-oxidation - administered intramuscularly and/or IV Side effects - nausea and vomiting - bradycardia - hypotension

DRUGS USED AGAINST TRYPANOSOMIASIS


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Overview
trypanosomiasis is a disease of variable clinical picture caused by the trypanosoma protozoa there are 2 types of trypanosomiasis depending on the species of trypanosoma protozoa TYPE AFRICAN TRYPANOSOMIASIS DESCRIPTION - sleeping sickness - fever, headache, vertigo and generalized lymphadenomegaly, hypersomnia, speech impairment and mental impairment, and finally coma and death - caused by trypanosoma brucei infection of the skin and following hematogenous spread to the CNS - transmitted to humans by the tsetse fly - changas disease - a single skin nodule (changoma) at the site of initial infection followed by fever, generalized lymphadenomegaly and meningoencephalitis - caused by trypanosoma cruzi infection of the skin and following hematogenous spread to the CNS - may complicate by hematogenous spread to the heart and colon leading to tachycardia, cardiac dysrhythmias and dilation of the esophagus and -colon (megaesophagus and megacolon, respectively) - transmitted to humans by the reduviid bug (kissing bug)

AMERICAN TRYPANOSOMIASIS

Relevant Drugs
2 categories 1) DRUGS USED AGAINST AFRICAN TRYPANOSOMIASIS - 3 types DRUG NAME SURAMIN DESCRIPTION General information - administered IV - may not cross the blood barrier, thus is only effective against trypanosoma brucei before it has entered the CNS Medical uses - 136 -

- treatment of african trypanosomiasis due to trypanosoma brucei infection Side effects - hypersensitivity reactions leading to fever and/or skin rashes - nausea and vomiting - optic nerve atrophy - seizures - nephrotoxicity - hemolytic anemia - bone marrow depression leading to leukopenia PENTAMIDINE General information - administered intramuscularly and/or IV - may not cross the blood barrier, thus is only effective against trypanosoma brucei before it has entered the CNS Medical uses - treatment of african trypanosomiasis due to trypanosoma brucei infection - treatment of toxoplasmosis due to toxoplasma gondii infection (see below) Side effects - nausea and vomiting - tachycardia - hypotension - dyspnea - hepatotoxicity - nephrotoxicity - bone marrow depression leading to pancytopenia MELARSOPROL General information - administered IV - may cross the blood-brain barrier, thus is also effective against trypanosoma brucei after it has entered the CNS Medical uses - treatment of african trypanosomiasis due to trypanosoma brucei infection

- 137 -

Side effects - cardiac dysrhythmias - hypotension - nephrotoxicity

2) DRUGS USED AGAINST AMERICAN TRYPANOSOMIASIS - 3 types DRUG NAME NIFURTIMOX DESCRIPTION General information - administered orally - is only effective against trypanosoma cruzi before it has entered the heart and/or GI tract Side effects - hypersensitivity reactions leading to fever and/or skin rashes BENZNIDAZOLE General information - same as nifurtimox (see above) Side effects - paresthesia - seizures PRIMAQUINE General information - an 8-aminoquinoline antimalarial drug (see above) - may also be moderately effective against trypanosoma cruzi after it has entered the heart and/or GI tract

DRUGS USED AGAINST TOXOPLASMOSIS


Overview
toxoplasmosis is a disease of variable clinical picture caused by the toxoplasma gondii protozoa there are 2 types of toxoplasmosis depending on the state of the immune defense system of the infected individual IMMUNOLOGICAL STATE IMMUNOCOMPETENT - 138 DESCRIPTION - asymptomatic

- caused by toxoplasma gondii infection of the intestine and following invasion of the intestinal mucosa IMMUNOCOMPROMIZED - fever, lymphadenomegaly and hepatosplenomegaly - caused by reactivation of latent toxoplasma gondii protozoa and following hematogenous spread to the liver and spleen - may complicate by hematogenous spread to the CNS and eye leading to meningoencephalitis and chorioretinitis

the toxoplasma gondii protozoa is transmitted by the fecal-oral route

Relevant Drugs
3 types DRUG NAME PYRIMETHAMINESULFADIAZINE DESCRIPTION General information - a combination of dihydrofolate reductase inhibitors and sulfonamides (see 62) General information - a combination of dihydrofolate reductase inhibitors and sulfonamides (see 62) General information - a drug used against african trypanosomiasis (see above)

TRIMETHOPRIMSULFAMETHOXAZOLE

PENTAMIDINE

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72. ANTIHELMINTHIC DRUGS


Overview
helminths are eukaryotic hermaphroditic parasitic worms that replicate sexually, either by heterologous fertilization (sequential hermaphrodites) or by autologous fertilization (synchronous hermaphrodites) they may exist in 3 common forms FORM EGG DESCRIPTION - the inactive, fetal form of the helminth - only occurs in some species of helminths (other species of helminths give birth to live larvae, see below) - the immature, non-reproductive form of the helminth - the mature, reproductive form of the helminth

LARVA ADULT

DRUGS USED AGAINST NEMATODES


Overview
roundworms species include SPECIES ASCARIS LUMBRICOIDES ANCYCLOSTOMA DUODENALE NECATOR AMERICANUS ENTEROBIUS VERMICULARIS STRONGYLOIDES STERCORALIS TRICHURIS TRICHIURA TRICHINELLA SPIRALIS WUCHERERIA BANCROFTI BRUGIA MALAYI DESCRIPTION

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ONCHOCERCA VOLVULUS

Relevant Drugs
7 types DRUG NAME PYRANTEL DESCRIPTION General information - an irreversible nicotinic receptor agonist (depolarizing neuromuscular blocking agent, see 16) - irreversibly binds to nicotinic receptors at the neuromuscular junction, thus causing spastic paralysis of the helminths - administered orally Medical uses - first-line treatment of ascaris lubricoides, ancyclostoma duodenale, necator americanus and/or enterobius vermicularis infection Side effects - vertigo - nausea, vomiting and/or diarrhea LEVAMISOLE General information - same as pyrantel (see above) - may cross the blood-brain barrier Medical uses - second-line treatment of ascaris lumbricoides, ancyclostoma duodenale, necator americanus and/or strongyloides stercoralis infection Side effects - vertigo - nausea, vomiting and/or diarrhea - mazzotti reaction (hypersensitivity reaction leading to fever, headache , skin rashes, myalgias and/or arthralgias caused by dying helminths) MEBENDAZOLE General information - a microtubule inhibitor - binds to depolymerized tubulin, thus inhibiting the polymerization of tubulin into microtubules and following inhibition of microtubule-dependent glucose - 141 -

uptake by the helminths - administered orally Medical uses - first-line treatment of tricuris trichiura and/or trichinella spiralis infection - second-line treatment of ascaris lubricoides, ancyclostoma duodenale, necator americanus, enterobius vermicularis and/or strongyloides stercoralis infection - first-line treatment of echinococcus granulosus and/or ecchinococcus multilocularis infection (cestodes, see below) Side effects - nausea, vomiting and/or diarrhea - epigastric pain THIABENDAZOLE General information - same as mebendazole Medical uses - first-line treatment of strongyloides stercoralis infection - also used in the treatment of scabies due to sarcoptes scabiei infection Side effects - vertigo - nausea, vomiting and/or diarrhea - epigastric pain - mazzotti reaction (see above) DIETHYLCARBAMAZINE General information - inhibits the metabolism of arachidonic acid within the helminths, thus rendering the helminths susceptible to the hosts immune defense system - administered orally Medical uses - first-line treatment of wuchereria bancrofti, brugia malayi and/or onchocera volvulus infection Side effects - headache - 142 -

- nausea, vomiting and/or diarrhea - mazzotti reaction (see above) IVERMECTIN General information - a GABA agonist - binds to presynaptic GABA receptors of the cholinergic neurons responsible for neuromuscular transmission, thus leading to hyperpolarization of the cholinergic neurons and following flaccid paralysis of the helminths - administered orally Medical uses - first-line treatment of onchocera volvulus infection Side effects - mazzotti reaction (see above) PIPERAZINE General information - same as ivermectin (see above) Medical uses - second-line treatment of enterobius vermicularis infection Side effects - vertigo - paresthesia - motor disturbances - bronchospasms - nausea, vomiting and/or diarrhea

DRUGS USED AGAINST TREMATODES


Overview
flukes species include SPECIES SCHISTOSOMA HEMATOBIUM SCHISTOSOMA JAPONICUM DESCRIPTION

- 143 -

SCHISTOSOMA MANSONI

Relevant Drugs
2 types DRUG NAME PRAZIQUANTEL DESCRIPTION General information - increases the permeability of the muscle cells to calcium, thus leading to depolarization of the muscle cells and following spastic paralysis of the helminths - administered orally Medical uses - first-line treatment of schistosoma hematobium, schistosoma japonicum and/or schistosoma mansoni infection - first-line treatment of hymenolepis nana infection (cestodes, see below) - second-line treatment of taenia solium, taenia sagginata and/or diphyllobothrium latum infection (cestodes, see below) Side effects - vertigo - nausea, vomiting and/or diarrhea - mazzotti reaction (see above) OXAMNIQUINE General information - interposes between adjacent base pairs in the DNA, thus causing an inability of DNA polymerase to move along the DNA during replication of helminthic cells - administered orally Medical uses - second-line treatment of schistosoma hematobium, schistosoma japonicum and/or schistosoma mansoni infection Side effects - headache - vertigo - dysphoria - convulsions - nausea, vomiting and/or diarrhea - mazzotti reaction (see above) - 144 -

DRUGS USED AGAINST CESTODES


Overview
tapeworms species include SPECIES ECHINOCOCCUS GRANULOSUS ECHINOCOCCUS MULTILOCULARIS TAENIA SOLIUM TAENIA SAGGINATA DIPHYLLOBOTHRIUM LATUM HYMENOLEPIS NANA DESCRIPTION

Relevant Drugs
3 types DRUG NAME MEBENDAZOLE DESCRIPTION General information - a drug used against nematodes (see above) General information - a drug used against trematodes (see above) General information - uncouples oxidative phosphorylation in the helminths - administered orally Medical uses - first-line treatment of taenia solium, taenia sagginata and/or diphyllobothrium latum infection - second-line treatment of hymenolepis nana infection Side effects - 145 -

PRAZIQUANTEL

NICLOSAMIDE

- nausea and/or vomiting

- 146 -

73. DRUGS USED IN THE CHEMOTHERAPY OF NEOPLASTIC DISEASES: ALKYLATING AGENTS, ANTIMETABOLITES 74. DRUGS USED IN THE CHEMOTHERAPY OF NEOPLASTIC DISEASES: ALKALOIDS, ANTIBIOTICS, HORMONAL AGENTS
Overview
a neoplasm (tumor) is a mass of cells that originate from a single endogenous cell that is dividing independently from the physiological regulatory mechanisms that preserve cellular growth and division the independence from these physiological regulatory mechanisms is caused by mutations in genes belonging to 2 broad genetic groups GENETIC GROUP PROTOONCOGENES DESCRIPTION - genes that facilitate cellular growth and division - induce neoplastic transformation upon gain-offunction mutations - genes that moderate cellular growth and division - induce neoplastic transformation upon loss-offunction mutations

TUMOR SUPPRESSOR GENES

mutations in multiple genes in both genetic groups are needed for the cell to undergo neoplastic transformation there are 2 types of neoplastic diseases TYPE BENIGN NEOPLASMS DESCRIPTION - consist of well differentiated cells that are sharply demarcated from the surrounding tissues by a fibrous capsule - consist of poorly differentiated cells that invade surrounding tissues

MALIGNANT NEOPLASMS

benign neoplasms usually remain localized, thus are treated by surgical excision (or simply left untouched (!)) on the other hand, malignant neoplasms may invade distant tissues by hematogenous spread (metastasis), thus are treated by a combination of surgical excision, irradiation and drugs (chemotherapeutic agents, see below)

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ALKYLATING AGENTS
Overview
alkylating agents are electron-poor (electrophilic) molecules that spontaneously form covalent bonds with electron-rich (nucleophilic) molecules upon encounter the alkylating agents used in treatment of neoplastic diseases have 2 electrophilic domains (bifunctional alkylating agents), thus have the ability to form covalent bonds with 2 nucleophilic molecules simultaneously upon encounter with DNA, the bifunctional alkylating agents form covalent bonds between the nucleophilic domains of guanine nucleotides, thus forming intrachain- and interchain cross-linkages of the DNA this causes inhibition of replication as well as inhibition of transcription of the affected cells the nucleophilic domains of the guanine nucleotides are only exposed when the complement DNA strands are unwound during replication, thus alkylating agents are relatively specific for the highly mitotic cells of neoplasms though this renders most of the physiological tissues of the body refractory to the alkylating agents, it also renders the less active cells of the neoplasms less susceptible , thus reoccurrence of the neoplasms are frequent upon increased mitotic activity of these unaffected neoplastic cells also, due to the alkylating agents primarily affecting highly mitotic cells, the physiologic tissues of the body with a high cell turnover are heavily affected, including TISSUE HAIR GI TRACT SIDE EFFECT - alopecia (hair loss) - mucosal ulcerations epigastric pain (due to mucosal ulceration) - nausea and vomiting (due to mucosal ulceration) - sterility (primarily in males) - growth inhibition (in children and teenagers) - pancytopenia (anemia, leucopenia and thrombocytopenia) - secondary microbial infections (due to leucopenia) - impaired wound healing (due to leucopenia) - hemorrhagic diathesis (due to thrombocytopenia)

GONADS MUSCLE AND BONE BONE MARROW

finally, due to the alkylating agents acting on DNA, the alkylating agents may also cause additional mutations in apparently healthy cells, and following secondary neoplasms (paradoxically (!))

Relevant Drugs
5 categories

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1) NITROGEN MUSTARDS - related to sulfur mustard (mustard gas, a chemical warfare agent) - 2 types DRUG NAME CYCLOPHOSPHAMIDE DESCRIPTION General information - pro-drug - activated in the liver by the cytochrome P450 system - administered orally, intramuscularly and/or IV - may not cross the blood-brain barrier Side effects - general side effects of alkylating agents (see above) - hemorrhagic cystitis IFOSFAMIDE General information - same as cyclophosphamide (see above)

2) NITROSUREAS - 2 types DRUG NAME CARMUSTINE DESCRIPTION General information - may cross the blood-brain barrier (, thus is primarily used against neoplasms of the CNS) Side effects - general side effects of alkylating agents (see above) LOMUSTINE General information - same as carmustine (see above)

3) TRIAZENES - 1 type DRUG NAME DACARBAZINE DESCRIPTION General information - pro-drug

- 149 -

- activated in the liver by the cytochrome p450 system - administered orally and/or IV Side effects - general side effects of alkylating agents (see above)

4) ALKYL SULFONATES - 1 type DRUG NAME BUSULFAN DESCRIPTION General information - selectively affects the bone marrow (, thus is primarily used against neoplasms of the bone marrow) Side effects - general side effects of alkylating agents (see above)

5) PLATINUM-CONTAINING COMPOUNDS - 2 types DRUG NAME CISPLATIN DESCRIPTION General information - administered IV Side effects - general side effects of alkylating agents (see above) - tinnitus and/or hearing loss (due to cochlear nerve damage) - peripheral neuropathies (due to peripheral nerve damage) - nephrotoxicity - hypersensitivity reactions leading to fever and/or skin rashes CARBOPLATIN General information - same as cisplatin (see above)

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ANTIMETABOLITES
Overview
antimetabolites are structural analogues of substrates needed for the synthesis of the complementary DNA strands during replication they competitively inhibit the enzymes that act on these substrates, thus inhibiting the synthesis of the complementary DNA strands and following inhibition of replication since replication only occurs preceeding mitosis, antimetabolites are relatively specific for the highly mitotic cells of neoplasms due to the same reason, they have the same effect on physiological tissues and less active cells of neoplasms as the alkylating agents (see above)

Relevant Drugs
3 categories 1) DIHYDROFOLATE REDUCTASE INHIBITORS - dihydrofolate reductase inhibitors used in the treatment of neoplastic diseases are structural analogues of folate (see 32) - like the dihydrofolate reductase inhibitors used in treatment of bacterial and protozoal infections (see 62), the dihydrofolate reductase inhibitors used in the treatment of neoplastic diseases competitively inhibit dihydrofolate reductase, thus leading to inhibition of conversion of dihydrofolate (FH2) to tetrahydrofolate (FH4) - FH4 is a cofactor of thymidylate synthetase in the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP, one of the two pyrimidine nucleotides needed for DNA synthesis) - , thus dihydrofolate reductase inhibitors indirectly inhibit the synthesis of the complementary DNA strands during replication - 1 type DRUG NAME METHOTREXATE DESCRIPTION General information - administered orally, intramuscularly, IV and/or intrathecally - may not cross the blood-brain barrier Side effects - general side effects of alkylating agents (see above) - drug-induced pneumonitis - nephrotoxicity

2) THYMIDYLATE SYNTHETASE INHIBITORS - thymidylate synthetase inhibitors are structural analogues of deoxyuridine monophosphate (dUMP") - 151 -

they competitively inhibit thymidylate synthetase, thus inhibiting the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate (dTMP) , thus thymidylate synthetase inhibitors indirectly inhibit the synthesis of the complementary DNA strands during replication 1 type DRUG NAME FLUOROURACIL DESCRIPTION General information - pro-drug - converted to fluorodeoxyuridine monophosphate (F-dUMP) inside the cells - administered IV Side effects - general side effects of alkylating agents (see above) - motor disturbances (due to cerebellar damage)

3) DNA POLYMERASE INHIBITORS - DNA polymerase inhibitors are structural analogues of the normal purine- and pyrimidine nucleotides used by DNA polymerase during synthesis of the complementary DNA strands - they competitively inhibit DNA polymerase, thus directly inhibiting the synthesis of the complementary DNA strands during replication - 2 groups A) PURINE ANALOGUES - 2 types DRUG NAME FLUDARABINE DESCRIPTION General information - adenosine analogue Side effects - general side effects of alkylating agents (see above) CLADRIBINE General information - same as fludarabine ( see above)

B) PYRIMIDINE ANALOGUES - 2 types - 152 -

DRUG NAME CYTARABINE

DESCRIPTION General information - cytosine analogue Side effects - general side effects of alkylating agents (see above)

GEMCITABINE

General information - same as cytarabine (see above)

ALKALOIDS
Overview
alkaloids are naturally occurring, cyclic, nitrogen-containing compounds isolated from plants alkaloids used in treatment of neoplastic diseases act on cellular events preceding mitosis, thus are relatively specific for the highly mitotic cells of neoplasms due to the same reason, they have the same effect on physiological tissues and less active cells of neoplasms as the alkylating agents (see above)

Relevant Drugs
2 categories 1) DNA TOPOISOMERASE INHIBITORS - like the DNA topoisomerase inhibitors used in treatment of bacterial and protozoal infections (see 62), the DNA topoisomerase inhibitors used in treatment of neoplastic diseases bind to DNA topoisomerase and prevent it from religating the DNA strands after cutting them - , thus DNA topoisomerase inhibitors used in treatment of neoplastic diseases cause fragmentation of the DNA and following inhibition of mitosis - 2 groups A) CAMPOTHECINS - campothecins are DNA topoisomerase I inhibitors (see 62) - they are naturally found in the campotheca tree (happy tree) - 2 types DRUG NAME IRINOTECAN DESCRIPTION Side effects - general side effects of alkylating agents (see above) General information - same as irinotecan (see above)

TOPOTECAN

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B) PODOPHYLLINS - podophyllins are DNA topoisomerase II inhibitors (see 62) - they are naturally found in the podophyllium flower (mayapple flower) - 2 types DRUG NAME ETOPOSIDE DESCRIPTION Side effects - general side effects of alkylating agents (see above) Side effects - same as etoposide (see above)

TENIPOSIDE

2) MICROTUBULE INHIBITORS - microtubule inhibitors inhibit the function of microtubules, thus inhibiting mitosis - however, due to inhibition of microtubules, the microtubule inhibitors also inhibit the microtubule-mediated functions of leukocytes and neurons - 2 groups A) VINCA ALKALOIDS - vinca alkaloids bind to depolymerized tubulin, thus inhibiting polymerization of tubulin into microtubules - this leads to inhibition of formation of the mitotic spindle during cell division and following inhibition of mitosis - they are normally found in the vinca flower (periwinkle flower) - 2 types DRUG NAME VINCRISTINE DESCRIPTION Side effects - general side effects of alkylating agents (see above) - paresthesia (due to inhibition of axonal transport in neurons) - asthenia (due to inhibition of axonal transport in neurons) Side effects - same as vincristine (see above)

VINBLASTINE

B) TAXANES - 154 -

taxanes bind to polymerized tubulin (microtubules) thus inhibiting their ability to remodel this leads to inhibition of separation of the sister chromatides during cell division and following inhibition of mitosis they are normally found in the taxus tree (pacific yew tree) 2 types DRUG NAME PACLITAXEL DESCRIPTION General information - administered IV Side effects - general side effects of alkylating agents (see above) - paresthesia (due to inhibition of axonal transport in neurons) - asthenia (due to inhibition of axonal transport in neurons) - leg edema (due to fluid retention) - hypersensitivity reactions leading to fever and/or skin rashes DOCELATEL General information - administered orally Side effects - same as paclitaxel (see above)

ANTIBIOTICS
Overview
antibiotics used in the treatment of neoplastic diseases act on cellular events preceeding mitosis, thus are relatively specific for the highly mitotic cells of neoplasms due to the same reason, they have the same effect on physiological tissues and less active cells of neoplasms as the alkylating agents (see above)

Relevant Drugs
2 categories 1) ANTHRACYCLINES - anthracyclines are DNA topoisomerase II inhibitors (see 62 and above) - , thus they cause fragmentation of DNA and following inhibition of mitosis - 3 types DRUG NAME - 155 DESCRIPTION

DOXYRUBICIN

General information - administered IV Side effects - general side effects of alkylating agents (see above) - cardiac dysrhythmias - heart failure

IDARUBICIN

General information - same as doxyrubicin (see above) General information - same as doxyrubicin (see above)

EPIRUBICIN

2) STREPTOMYCES-DERIVED ANTIBIOTICS - the streptomyces-derived antibiotics are an extremely diverse group of pharmacologically active compounds that have found their use in treatment of neoplastic diseases an well as in treatment of bacterial and fungal infections (aminoglycosides (see 66), chloramphenicol (see 64) and macrolides (see 64 and 68)) - the streptomyces-derived antibiotics used in treatment of neoplastic diseases have distinct mechanisms of action from the streptomyces-derived antibiotics used in treatment of bacterial and fungal infection - the streptomyces-derived antibiotics used in treatment of neoplastic diseases also have distinct mechanisms of action from each other - , thus these mechanisms will be discussed separately below - they are naturally found in the streptomyces bacterium - 3 types DRUG NAME MITOMYCIN DESCRIPTION General information - a bifunctional alkylating agent (see above) - causes intrachain- and interchain cross-linkages - , thus inhibits DNA replication and translation - administered orally Side effects - general side effects of alkylating agents (see above) - pulmonary fibrosis - nephrotoxicity BLEOMYCIN General information - forms a pseudo-enzyme by chelation of iron - 156 -

- the pseudoenzyme generates oxygen free radicals from intracellular oxygen - the oxygen free radicals cause double-stranded breaks of the DNA and following DNA fragmentation Side effects - general side effects of alkylating agents (see above) - pulmonary fibrosis - hypersensitivity reactions leading to fever and/or skin rashes (primarily on the palms) DACTINOMYCIN General information - interposes between adjacent guanosine-cytosine pairs in the DNA - the interposition causes an inability of RNA polymerase to move along the DNA during transcription - , thus transcription and following protein translation is inhibited Side effects - general side effects of alkylating agents (see above)

HORMONAL AGENTS
Overview
unlike the other chemotherapeutic drugs used in the treatment of neoplastic diseases (see above), the hormonal agents used in the treatment of neoplastic diseases do not act by cytotoxic mechanims they are hormone agonists and/or -antagonists acting on normal hormone receptors found in physiological tissues as well as in some neoplasms , thus they are only effective against neoplasms that have retained their ability to express these hormone receptors (hormone-sensitive neoplasms) due to the same reason, they do not have the same general side effects as the other chemotherapeutic agents used in the treatment of neoplastic diseases (see above), but exhibit the side effects commonly associated by the agonism and/or antagonism of the respective hormone receptors

Relevant Drugs
5 categories 1) GLUCOCORTICOIDS - 157 -

glucocorticoids act on glucocorticoid receptors found in vascular endothelial cells, mast cells, macrophages and T lymphocytes, thus decreasing the synthesis and secretion of GM-CSF (see 32) by these cells and following decreased proliferation of leucocytes in the bone marrow used in the treatment of bone marrow neoplasms see 55

2) PROGESTOGENS - progestogens act on progestogen receptors found in the uterus, thus downregulating the oestrogen receptors of the endometrium and following inhibition of the proliferation of the endometrial tissues - used in the treatment of endometrial neoplams - see 56 3) OESTROGEN RECEPTOR ANTAGONISTS - oestrogen receptor antagonists inhibit the action of oestrogens on oestrogen receptors found in the mamma, thus inhibiting the proliferation of the mammary tissues - used in the treatment of mammary neoplasms - see 56 4) OESTROGEN SYNTHESIS INHIBITORS - oestrogen synthesis inhibitors inhibit aromatase (see 55) found in the adrenal cortex, thus inhibiting the synthesis of oestrogens - this leads to decreased stimulation of oestrogen receptors found in the mamma, and following decreased prolifereation of the mammary tissues - used in the treatment of mammary neoplasms (primarily if postmenopausal) - see 56 5) ANDROGEN RECEPTOR ANTAGONISTS - androgen receptor antagonists inhibit the action of dihydrotestosterone (see 58) on androgen receptors found in the prostate, thus inhibiting the proliferation of the prostatic tissues - used in the treatment of prostatic neoplasms - see 58

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75. IMMUNOSUPPRESSANTS AND IMMUNOMODULATORS


Overview
a super-fun fill-it-in-yourself exam question :)

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76. DRUGS USED IN THE INTOXICATED PATIENT: DECONTAMINATION, FACILITATION OF TOXICANT ELIMINATION, ANTIDOTE ADMINISTRATION, SUPPORTIVE TREATMENT
Overview
another super-fun fill-it-in-yourself exam question :))

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77. DRUG INTOXICATIONS: MECHANISMS, SYMPTOMS, TREATMENT


Overview
the last and final super-fun fill-it-in yourself exam question :)))

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A1. DRUGS, 3RD SEMESTER


54. PITUITARY HORMONES 1) ANTERIOR LOBE HORMONES A) GROWTH HORMONE - Somatropin B) ADRENOCORTICOTROPHIC HORMONE - Tetracosactide C) PROLACTIN I) D2 RECEPTOR ANTAGONISTS D) THYROID-STIMULATING HORMONE E) FOLLICLE-STIMULATING HORMONE/LUTENIZING HORMONE I) ORAL CONTRACEPTIVES 2) POSTERIOR LOBE HORMONES A) ANTIDIURETIC HORMONE - Vasopressin - Terlipressin - Desmopressin B) OXYTOCIN I) OXYTOCIN RECEPTOR AGONISTS II) OXYTOCIN RECEPTOR ANTAGONISTS 55. CORTICOSTEROIDS 1) MINERALOCORTICOIDS A) ALDOSTERONE RECEPTOR AGONISTS - Aldosterone - Fludrocortisone B) ALDOSTERONE RECEPTOR ANTAGONISTS C) CORTICOSTEROID SYNTHESIS INHIBITORS - Trilostane - Methyrapone 2) GLUCOCORTICOIDS - 162 -

A) GLUCOCORTICOID RECEPTOR AGONISTS - Hydrocortisone - Cortisone - Prednisolone - Prednisone - Betamethasone - Dexamethasone 3) SEX HORMONES 56. OESTROGENS, ANTI-OESTROGENS, PROGESTOGENS, ANTI-PROGESTOGENS 1) OESTROGENS A) NATURAL OESTROGENS - Estradiol - Estriol B) SYNTHETIC OESTROGENS - Ethinylestradiol - Mestranol 2) ANTI-OESTROGENS A) OESTROGEN RECEPTOR ANTAGONISTS - Tamoxifen - Clomiphene B) OESTROGEN SYNTHESIS INHIBITORS - Anastrazole - Formestane 3) PROGESTOGENS A) PROGESTERONE AND PROGESTERONE DERIVATIVES - Hydroxyprogesterone - Medoxyprogesterone B) SYNTHETIC PROGESTOGENS - Norethisterone - Ethynodiol - Levonorgestrel - Desogestrel - Gestodene 4) ANTI-PROGESTOGENS - Mifepristone 57. ORAL CONTRACEPTIVES - 163 -

1) COMBINED PILL - Monophasic Combined Pill - Biphasic Combined Pill - Triphasic Combined Pill 2) PROGESTOGEN-ONLY PILL 3) POSTCOITAL CONTRACEPTION PILL 58. ANDROGENS, ANABOLIC STEROIDS, ANTI-ANDROGENS 1) ANDROGENS - Testosterone - Testosterone Ethanate - Testosterone Propionate - Testosterone Undecanoate - Methyl Testosterone 2) ANABOLIC STEROIDS - Nandrolone - Stanozolol 3) ANTI-ANDROGENS A) ANDROGEN RECEPTOR ANTAGONISTS - Flutamide B) DIHYDROTESTOSTERONE SYNTHESIS INHIBITORS - Finasteride 59. THYROID HORMONES, ANTITHYROID DRUGS 1) THYROID HORMONES A) NATURAL THYROID HORMONES - Thyroxine - Triiodothyronine B) SYNTHETIC THYROID HORMONES - Levothyroxine - Liothyronine 2) ANTITHYROID DRUGS A) IODIDE - Potassium Iodide B) RADIOACTIVE IODINE - Radioiodine

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C) THIOUREYLENES - Methimazole - Carbimazole - Thiouracil - Methylthiouracil D) NON-SELECTIVE BETA ANTAGONISTS E) GLUCOCORTICOIDS 60. INSULIN, GLUCAGON AND ORAL HYPOGLYCAEMIC AGENTS 1) ENDOCRINE PANCREATIC HORMONES A) INSULIN I) SHORT/RAPIDLY ACTING - Insulin - Insulin Lispro I) INTERMEDIATELY ACTING - Insulin Lente - Insulin NPH I) LONG/SLOWLY ACTING - Insulin Glargine - Insulin Detemir B) GLUCAGON - Glucagon 2) ORAL HYPOGLYCAEMIC DRUGS A) SULFONYLUREAS - Tolbutamide - Glibenclamide B) SULFONYLUREA-LIKE DRUGS - Repaglinde - Nateglinde C) GLITAZONES - Rosiglitazone - Pioglitazone D) BIGUANIDES - Metformin C) ALPHA-GLUCOSIDASE INHIBITORS - Acarbose

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61. PARATHYROID HORMONE, CALCITONIN AND VITAMIN D, DRUGS USED TO TREAT OSTEOPOROSIS 1) CALCIUM SALTS - Hydroxyapatite - Calcium Lactate - Calcium Gluconate 2) VITAMIN D - Ergocalciferol - Calcitriol 3) OESTROGEN RECEPTOR AGONISTS 4) OESTROGEN RECEPTOR ANTAGONISTS 5) CALCITONIN - Calcitonin - Salcatonin 62. SULFONAMIDES AND TRIMETHOPRIM. FLUOROQUINOLONES 1) FOLATE ANTAGONISTS A) SULFONAMIDES I) SHORT-ACTING - Sulfadiazine - Sulfadimidine II) INTERMEDIATELY-ACTING - Sulfadoxin - Sulfamethoxazole III) LONG-ACTING - Sulfamethoxydiazine - Sulfamethoxypyrazine B) DIHYDROFOLATE REDUCTASE INHIBITORS - Pyrimethamine - Trimethoprim C) COMBINATIONS - Pyrimethamine-Sulfadiazine - Trimethoprim-Sulfamethoxazole 2) DNA-TOPOISOMERASE II INHIBITORS A) FLUOROQUINOLONES - Ciprofloxacin - Norfloxacin - Ofloxacin - 166 -

63. BETA-LACTAM ANTIBIOTICS 1) PENICILLINS A) NARROW-SPECTRUM PENICILLINS - Penicillin G - Penicillin V B) BROAD-SPECTRUM PENICILLINS - Ampicillin - Amoxicillin C) EXTENDED-SPECTRUM PENICILLINS - Carbpenicillin - Piperacillin D) BETA-LACTAMASE RESISTANT PENICILLINS - Flucloxacillin - Methicillin 2) CEPHALOSPORINS A) FIRST-GENERATION - Cephalexin - Cephalothin B) SECOND-GENERATION - Cefaclor - Cefuroxime - Cefoxitin C) THIRD-GENERATION - Cefotaxime - Ceftazidime - Ceftriaxone D) FOURTH-GENERATION - Cefepim - Cefpirom 3) CARBAPENEMS - Imipenem 4) MONOBACTAMS - Aztreonam 5) BETA-LACTAMASE INHIBITORS - Tazobactam - Sulbactam

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64./65./66. TETRACYCLINES, CHLORAMPHENICOL, MACROLIDE ANTIBIOTICS. CLINDAMYCIN, POLYMIXINS, VANCOMYCIN. AMINOGLYCOSIDES 1) PEPTIDOGLYCAN ANTAGONISTS A) BETA-LACTAM ANTIBIOTICS B) GLYCOPEPTIDE ANTIBIOTICS - Vancomycin 2) INHIBITORS OF mRNA TRANSLATION A) AMINOGLYCOSIDES I) STREPTOMYCES-DERIVED - Streptomycin - Tobramycin II) MICROMONOSPORA-DERIVED - Gentamicin - Netilmicin B) TETRACYCLINES - Tetracycline - Oxytetracycline - Doxycycline - Minocycline C) CHLORAMPHENICOL - Chloramphenicol D) MACROLIDES - Erythromycin - Clarithromycin - Azithromycin E) LINCOSAMINDES - Clindamycin 3) DETERGENTS A) POLYMIXINS - Polymixin B - Polymixin D 67. ANTITUBERCULOTIC DRUGS. ANTI-LEPROSY DRUGS 1) ANTITUBERCULOTIC DRUGS A) FIRST-CHOICE - Isoniazid - Ethambutol - 168 -

- Pyrazinamide - Rifampicin A) SECOND-CHOICE - Capreomycin - Cycloserine - Ciprofloxacin - Streptomycin 2) ANTI-LEPROSY DRUGS A) FIRST-CHOICE - Dapsone - Clofazimine - Rifampicin A) SECOND-CHOICE - Ofloxacin - Azithromycin 68. ANTIFUNGAL DRUGS 1) NATURAL ANTIFUNGAL DRUGS A) MACROLIDES - Amphotericin B - Nystatin B) GRISEOFULVIN - Griseofulvin 2) SYNTHETIC ANTIFUNGAL DRUGS A) ECHINOCANDINS - Caspofungin - Micafungin B) AZOLES - Ketoconazole - Fluconazole - Itraconazole - Miconazole C) TERBINAFINE - Terbinafine D) FLUCYTOSINE - Flucytosine 69. ANTIVIRAL DRUGS

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1) DRUGS USED AGAINST DNA VIRUSES A) INDIRECT VIRAL DNA POLYMERASE INHIBITORS - Aciclovir - Penciclovir - Ganciclovir B) DIRECT VIRAL DNA POLYMERASE INHIBITORS - Foscarnet 2) DRUGS USED AGAINST RETROVIRAL RNA VIRUSES A) INDIRECT VIRAL REVERSE TRANSCRIPTASE INHIBITORS - Didanosine - Abacavir - Lamivudine - Zidovudine B) DIRECT VIRAL REVERSE TRANSCRIPTASE INHIBITORS - Nevirapine - Efavirenz C) VIRAL PROTEASE INHIBITORS - Saquinavir - Ritonavir - Amprenavir - Indinavir 3) DRUGS USED AGAINST RNA VIRUSES A) VIRAL RNA-DEPENDENT RNA POLYMERASE INHIBITORS - Ribavirin B) INHIBITORS OF VIRAL UNCOATING AND ASSEMBLY - Amantidine C) INHIBITORS OF VIRAL EXIT - Zanamivir 4) IMMUNOMODULATORS A) INTERFERONS - Interferon-Alpha2 70. ANTISEPTICS AND DISINFECTANTS 1) HALOGENS A) IODINE - Iodine Solution - Iodine Tincture

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B) CHLORIDE AND CHLORIDE DERIVATIVES - Chloride Solution - Chlorhexidine Gluconate - Hexachlorophene - Chlorogenate 2) HEAVY METALS A) MERCURY DERIVATIVES - Merbromin - Thiomersal - Nitromersol B) SILVER DERIVATIVES - Silver Nitrate - Colloidal Silver C) ZINC DERIVATIVES - Zinc Oxide 3) ALCOHOLS - Ethanol - Isopropanol 4) DIOLS - Propylene Glycol 5) PHENOLS - Resorcinol - Thymol 6) ALDEHYDES - Formaldehyde - Glutaraldehyde 7) ACIDS - Acetate - Salicylate - Lactate - Benzoate 8) DYES - Carbofuchsin - Gentian Violet - Brilliant Green 9) OXIDIZING AGENTS - Hydrogen Peroxide - Potassium Permanganate 10) SURFACTANTS

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A) CATIONIC - Benzalkonium Chloride - Cetylpyridinium Chloride B) ANIONIC - Sodium Laureth Sulfate - Sodium Dodecyl Sulfate 71. ANTIPROTOZOAL DRUGS 1) ANTIMALARIAL DRUGS A) ANTI-ERYTHROCYTIC FORM DRUGS I) 4-AMINOQUINOLINES - Chloroquine - Amodiaquine II) QUINOLINE-METHANOLS - Quinine - Mefloquine III) PHENANTHRENE-METHANOLS - Halofantrine IV) COMBINATIONS OF SULFONAMIDES AND DIHYDROFOLATE REDUCTASE INHIBITORS V) TETRACYCLINES B) ANTI-HYPNOZOITE FORM DRUGS I) 8-AMINOQUINOLINES - Primaquine 2) DRUGS USED AGAINST TRICHOMONIASIS - Metronidazole - Tinidazole 3) DRUGS USED AGAINST GIARDIASIS - Metronidazole - Tinidazole 4) DRUGS USED AGAINST AMOEBIASIS A) DRUGS USED AGAINST NON-INVASIVE AMOEBIASIS - Diloxanide B) DRUGS USED AGAINST INVASIVE AMOEBIASIS - Metronidazole - Tinidazole - Chloroquine - 172 -

5) DRUGS USED AGAINST LEISCHMANIASIS A) DRUGS USED AGAINST CUTANEOUS LEISCHMANIASIS - Metronidazole B) DRUGS USED AGAINST MUCOCUTANEOUS LEISCHMANIASIS - Amphotericin B C) DRUGS USED AGAINST VISCERAL LEISCHMANIASIS - Sodium Stibogluconate 6) DRUGS USED AGAINST TRYPANOSOMIASIS A) DRUGS USED AGAINST AFRICAN TRYPANOSOMIASIS - Suramin - Pentamidine - Melarsoprol B) DRUGS USED AGAINST AMERICAN TRYPANOSOMIASIS - Nifurtimox - Benznidazole - Primaquine 7) DRUGS USED AGAINST TOXOPLASMOSIS - Pyrimethamine-Sulfadiazine - Trimethoprim-Sulfamethoxazole - Pentamidine 72. ANTIHELMINTHIC DRUGS 1) DRUGS USED AGAINST NEMATODES - Pyrantel - Levamisole - Mebendazole - Thiabendazole - Diethylcarbamazine - Ivermectin - Piperazine 2) DRUGS USED AGAINST TREMATODES - Praziquantel - Oxamniquine 3) DRUGS USED AGAINST CESTODES - Mebendazole - Praziquantel - Nicclosamide 73./74. DRUGS USED IN THE CHEMOTHERAPY OF NEOPLASTIC DISEASES: ALKYLATING AGENTS, ANTIMETABOLITES. DRUGS USED IN THE - 173 -

CHEMOTHERAPY OF NEOPLASTIC DISEASES: ALKALOIDS, ANTIBIOTICS, HORMONAL AGENTS 1) ALKYLATING AGENTS A) NITROGEN MUSTARDS - Cyclophosphamide - Ifosfamide B) NITROSUREAS - Carmustine - Lomustine C) TRIAZENES - Dacarbazene D) ALKYL SULFONATES - Busulfan E) PLATINUM-CONTAINING COMPOUNDS - Cisplatin - Carboplatin 2) ANTIMETABOLITES A) DIHYDROFOLATE REDUCTASE INHIBITORS - Methotrexate B) THYMIDYLATE SYNTHETASE INHIBITORS - Fluorouracil C) DNA POLYMERASE INHIBITORS I) PURINE ANALOGUES - Fludarabine - Cladribine II) PYRIMIDINE ANALOGUES - Cytarabine - Gemcitabine 3) ALKALOIDS A) DNA TOPOISOMERASE INHIBITORS I) CAMPOTHECINS - Irinotecan - Topotecan II) PODOPHYLLINS - Etoposide - Teniposide

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B) MICROTUBULE INHIBITORS I) VINCA ALKALOIDS - Vincristine - Vinblastine II) TAXANES - Paclitaxel - Docelatel 4) ANTIBIOTICS A) ANTHRACYCLINES - Doxyrubicin - Idarubicin - Epirubicin B) STREPTOMYCES-DERIVED ANTIBIOTICS - Mitomycin - Bleomycin - Dactinomycin 5) HORMONAL AGENTS A) GLUCOCORTICOIDS B) PROGESTOGENS C) OESTROGEN RECEPTOR ANTAGONISTS D) OESTROGEN SYNTHESIS INHIBITORS E) ANDROGEN RECEPTOR ANTAGONISTS 75. IMMUNOSUPPRESSANTS AND IMMUNOMODULATORS - 76. DRUGS USED IN THE INTOXICATED PATIENT: DECONTAMINATION, FACILITATION OF TOXICANT ELIMINATION, ANTIDOTE ADMINISTRATION, SUPPORTIVE TREATMENT - 77. DRUG INTOXICATIONS: MECHANISMS, SYMPTOMS, TREATMENT -

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