ANS PHARMACOLOGY 1

INTRODUCTION TO ANS PHARMACOLOGY Review: Divisions of the ANS Difference between the 2 divisions Steps in neurotransmission

II. SYMPATHETIC Vs. PAR ASYMPATHETI C SYSTEMS A. Sympathetic and Parasympathetic Responses

I. DIVISIONS OF THE AUTONOMIC NERVOUS SYSTEM

Sympathetic and parasympathetic responses are usually the opposite of each other except in the sexual function, where both sympathetic and parasympathetic responses are complementary with each other. (Parasympathetic erection [point]; Sympathetic ejaculation [shoot])

B.

Neurotransmitters released by Preganglionic and Postganglionic fibers

Location of ganglia: Sympathetic paravertebral area Parasympathetic near or at the area of organs/effectors Length of preganglionic fiber and postganglinic fiber: Sympathetic - preganglionic fiber is short and post ganglionic fiber is long. Parasympathetic preganglionic fiber is long and post ganglionic fiber is short.

What is common between the sympathetic and parasympathetic division is that their preganglionic fibers are both cholinergic (which means the neurotransmitter released is acetylcholine), but they differ in their postganglionic fibers. Nature of preganglionic fibers: Sympathetic Cholinergic preganglionic fibers Parasympathetic Cholinergic preganglionic fibers Nature of postganglionic fibers: Sympathetic Adrenergic, Cholinergic, Dopaminergic postganglionic fibers o Adrenergic (neurotransmitter released is norepinephrine) In heart and blood vessels Neurotransmitter commonly released by postganglionic sympathetic fibers o Cholinergic (neurotransmitter released is acetylcholine) Sweat glands and some blood vessels Neurotransmitter less commonly released by postganglionic sympathetic fibers o Dopaminergic (neurotransmitter released is dopamine) Renal vessles Parasympathetic cholinergic postganglionic fibers

Dual innervations at most sites:

In the adrenals, most preganglionic fibers are parasympathetic, so most preganglionic fibers are cholinergic in nature. But in the adrenal medulla (which are embryologically analogous to postganglionic sympathetic neurons), there is a modified ganglia with nicotinic receptors (a cholinergic receptor). As a cholinergic receptor, this portion of the adrenal gland releases epinephrine rather than acetylcholine (which are secreted in other portions of the adrenal medulla). In the adrenals, postganglionic neurons release EPINEPHRINE more than norepinephrine, which affects the heart and the blood vessels)

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C.

Cell to cell interaction of neurons through Synapse

Neurons do not act in isolation. They are connected via cell cell interactions called SYNAPSES Flow/ direction of impulse: Presynaptic neuron

Presynaptic neuron axon

Synapse Figure above is a diagram of a chemical synapse. Notice the space between the 2 neurons are tight, to allow an efficient movement of ions. Loewis experiment (1921, Otto Loewi) Impulse is propagated by neurotransmitters. First evidence of neurotransmission is based on Loewis experiment. Hypothesis: Stimulation of the vagus nerve releases a chemical Isolated frog heart together with the vagus nerve and placed in a physiologic solution. When vagus nerve was stimulated, there was a response from the heart (slowing of the heart beat, decreased in the contraction). Neurotransmitter involved is acetylcholine. In 1926 the chemical was discovered and named as Acetylcholine Replicated the experiment with 2 hearts o Infused the 2nd heart with the solution from the 1st frog heart where the vagus was stimulated. True enough, the effects that was shown in the 1st heart were also duplicated in the 2nd frog heart

Postsynaptic neuron dendrite

2 types of Synapse (1) Chemical Impulse propagated by the use of neurotransmitter; there is a gap between the end of presynaptic neuron and beginning of post synaptic neuron (space where neurotransmitters are released before they can interact with the receptors in the post synaptic neurons) (2) Electrical Impulses propagated via the movement of ions; the junctions between the neurotransmitter is tight. There are channels in between the junctions where ions flow in and out to form an action potential.

III.

STEPS IN NEUROTRANSMISSION:

(1) Axonal conduction Propagation of impulse along the axons (2) Junctional transmission When action potential cause the neurotransmitter vesicles to move towards the terminal end of presynaptic neurons and the release of neurotransmitter. Interaction with receptors Production of response (3) Destruction or dissipation of neurotransmitter

Figure above is a diagram of a chemical synapse. The synaptic cleft is where the the presynaptic neuron release there neurotransmitters to be taken up by the receptors on the postsynaptic membrane.

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2 TYPES OF RECEPTORS: Receptors are found in both presynaptic and postsynaptic neurons. 1. Presynaptic receptors Heteroreceptors respond to neurotransmitter from OTHER systems or by other neurons. They can be inhibitory or excitatory. Example: Acetylcholine acting on M2 and M4 receptors (type of muscarinic cholinergic receptors) STIMULATE the release of norepinephrine from sympathetic neurons. Norepinephrine acting on 2 receptors (type of adrenergic receptor) STIMULATE the release of acetylcholine from parasympathetic neurons. Serotonin heteroreceptors can inhibit norepinephrine release M1 and M2 may also be presynaptically located may enhance and inhibit ach release

Production of post junctional potential: Increase permeability of Na+ and Ca2+ leads to depolarization (EPSP) Increase conduction of Cl- and K+ leads to hyperpolarization (IPSP)

ACETYLCHOLINE

Autoreceptors respond by releasing neurotransmitter from their own system or by the same neuron. located on or close to axon terminals of a neuron through which the neurons own neurotransmitter can modify neurotransmitter synthesis and release Example: Acetylcholine released from parasympathetic neurons interacting with M2 or M4 receptors to INHIBIT Acetylcholine release. Norepinephrine released from sympathetic neurons interact with -2 receptors can INHIBIT norepinephrine release. Dopaminergic neuron has D2 presynaptic dopaminergic receptors, which when activated can cause the release of dopamine.

o = Choline + Acetyl CoA o Acetyl CoA derived from Krebs Cycle. o Formed via the help of choline acetyltransferase Once synthesized, Ach is stored in vesicles in the presynaptic neurons. In the presence of impulse and action potential, the vesicles are mobilized towards the terminal ends of presynaptic neurons. In the presence of Calcium, Ach is released by exocytosis. Once it is released in the synaptic cleft, it binds to the cholinergic receptors of the postsynaptic neurons and when bound to the receptors, is acted upon by acetylcholine esterase and it hydrolyzes it into choline and acetyl acetate. Choline released is subsequently recycled back to the presynaptic nerve.

The activation of these both presynaptic receptors will cause the inhibition OR release of neurotransmitter (ONLY RESPONSE HA!)

ACETYLCHOLINESTERASE

2.

Postsynaptic receptors Located in the outer membrane of postsynaptic neurons Interaction of the neurotransmitter with the postsynaptic receptors will cause movement of ions across the membrane (causes localized increase or ionic permeability or conductance of the membrane)which is responsible for the response. Examples: 1 receptors in postsynaptic neurons M1 and M2 may also be postsynaptically located which can produce a visible response due to the movement of ions.

2 types of acetylcholinesterase: 1. SPECIFIC o True acetylcholinesterase o Found in neurons, synaptic clefts, neuromuscular junctions, RBC (serves as a basis for detection of organophosphate poisoning) 2. NONSPECIFIC o Pseudo-butyryl cholinesterase o Found in glial cells, plasma, liver, and other organs

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4 COMPOUNDS THAT INTERFERE WITH CHOLINERGIC TRANSMISSION:
(1) Inhibits Ach transport to the neuron terminal Hemicholinium* Vesamicol (2) Inhibits Ach release Botulinum toxin prevents wrinkles by relaxing smooth muscles (3) Stimulate Ach release Acetylcholine Latrotoxin Black widow spider poisoning from the spider is also manifested as cholinergic toxicity (4) Agonist/Antagonist at the receptor site Agonist/ antagonist acting on the cholinergic receptor sites. It indirectly interferes with the cholinergic transmission by increasing by inhibiting acetylcholinesterase and therefore inhibiting the destruction of acetylcholine.

MUSCARINIC RECEPTORS:
90% of cholinergic receptors in PNS and brain are muscarinic SLOW!! But can either excitatory or inhibitory G-protein coupled 5 Subtypes of Muscarinic receptors (M1 to M5); M1: (ganglionic) brain (cortex, hippocampus), salivary glands, sympathetic ganglia M2: (effector cell) heart, hindbrain, smooth muscle M3: blood vessels, smooth muscle, salivary glands, brain M4: brain (forebrain, stratum) M5: brain (substantia nigra), eye M4 and M5 not well characterized but seen in the brain M1 and M3 glands and smooth muscles (blood vessels, intestines, respiratory tract) M2 main muscarinic receptor

NICOTINIC RECEPTORS:
10% of cholinergic receptors in PNS and brain FAST!!! Excitatory only Ligand gated ion channels (linked to the sodium channel) 3 Subtypes of Nicotinic Receptors: (1) Nn - Autonomic ganglia/ adrenal medulla; (2) Nn - CNS (3) Nm - Motor endplate membrane, Activation increase permeability to Na+ Interaction of acetylcholine with the nicotinic receptor will open the sodium channel and allow the influx of sodium which leads to DEPOLARIZATION.

IV. CHOLINERGIC AGONISTS (CHOLINOMIMETIC or PARASYMPATHOMIMETIC DRUGS):

Drugs that are used may either be: 1. Direct acting 2. Indirectly acting

(1) DIRECTLY ACTING

Hemicholinium inhibits the transport of choline back into the neuron by inhibiting a transporter. Vesamicol inhibits the ___ of Ach into the vesicle by also acting on a transporter. Butolinum toxin inhibits the release of Ach.

CLASSIFICATION OF CHOLINERGIC RECEPTORS

Both receptors are activated by acetylcholine neurotransmitter:

(1) Muscarinic Smooth muscles Cardiac muscles Exocrine/endocrine glands CNS (2) Nicotinic Autonomous Nervous System Ganglia Neuromuscular Junction Central Nervous System

- Include drugs that are natural and synthetic choline esters and natural-occurring alkaloids - Choline Esters: Presence of methyl group less activity at nicotinic receptors Methacholine Bethanechol Carbamic acid esters are resistant to hydrolysis by Acetylcholinesterase Bethanechol Carbachol Pharmacokinetics o poorly absorbed from GIT o Quarternary compounds = not lipid soluble POORLY DISTRIBUTED TO THE CNS o hydrophilic Natural and Synthetic Choline Esters Acetylcholine (Natural) Methacoline (Semi synthetic) Carbachol (Synthetic) Bethanechol (Synthetic) Natural-occurring Alkaloids Muscarine Pilocarpine Arecoline Nicotine

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muscle and increase secretion of respiratory glands. NATURAL AND SYNTHETIC CHOLINE ESTERS: A. ACETYLCHOLINE 1st synthesized by Baeyer in 1867 Very short duration of action because it is rapidly hydrolyzed by Acetylcholinesterase and Plasma Butyrylcholinesterase soon as it released in the synaptic cleft; very brief duration of action hence no systemic therapeutic applications Quaternary ammonium compound (not lipid soluble) and therefore it does not penetrate the CNS Orally inactive Interacts with M1 M5 receptors C. CARBACHOL (Carbamyl choline) Synthetic Carbamyl derivatives carbamyl is important because it makes the compound resistant to acetylcholine esterase BETHANICOL (Carbamyl methyl choline) Synthetic

D. -

Ach interaction with M1 & M3 receptors

Ach interaction with M2 & M4 receptors

Activation of Gq protein Activation of Phospholipase-C

Activation of Gi & Gq protein

NATURAL OCCURRING ALKALOIDS A. MUSCARINE Alkaloid derived from Amanita muscaria - a poisonous mushroom; Toxic compontent of mushroom came from alkaloid muscarine Produce mycetism contains the alkaloid muscarine and amatoxins From which was derived the name muscarinic receptor B. PILOCARPINE Chief alkaloid found in Pilocarpus jaborandi an American shrub Tertiary amine and therefore lipid soluble Not hydrolyzed by Acetylcholinesterase Primarily used in Ophthalmology as a Miotic agent; basis of use is through the effect on the ciliary muscle not its miotic effect Potent stimulator of secretion of exocrine glands and therefore it is used in conditions wherein we have excessive dryness ARECOLINE NICOTINE Fatal dose of nicotine is approximately 40 mg (2 regular cigarettes), or 1 drop of the pure liquid Most of the nicotine in cigarettes is destroyed by burning or escapes via the "sidestream" smoke. Acute toxicity: In large doses CNS stimulation convulsions, coma; respiratory arrest In small doses = relaxant Neuromuscular blockade It can affect the nicotinic receptor in the neuromuscular junction skeletal muscle paralysis, respiratory failure Hypertension and cardiac arrhythmias Increases BP and cardiac arrhytmia If patient is hypertensive, patient can become resistant to antihyperstensive medications Chronic toxicity: Addiction Increase risk for coronary artery disease Increase incidence of recurrences of peptic ulcer Increase risk for malignancy (pulmonary malignancy)

Activation of cAMP

Hydrolysis of phosphoinositides

Inhibit adenylyl cyclase

IP3 and TAG are released

Ion channels are regulated

Mobilization of intracellular Calcium

Enhanced Potassium conductance

C. D.

Depolarization

Hyperpolarization

EPSP

IPSP

On the l eft: Ac etylcholin e interaction with M1 and M3 muscarin ic recep tors. Remember that M1 and M3 receptor s are linked to the Phospho inositol Pathway. On the right: Acetylcholine interaction with M2 and M4 mu scarinic receptors. Remember that M2 and M4 receptor s are linked to the c AMP Pa thway, lowers intracellular calcium, and enhances pota ssium conductance IPSP.

B.

METACHOLINE (Acetyl-b-methyl choline) Semisynthetic Has some degree of susceptibility to acetylcholine esterase but not as susceptible as acetylcholine Has methyl group at the second carbon of the Ach molecule Hydrolyzed by Acetylcholinesterase at a slower rate Predominant muscarinic, slight nicotinic Used as Bronchoprovocative Test to diagnose airway hyperreactivity. Airway hyperreactivity Important component in patients with asthma. If normal, no hyperreactive bronchial tree. If hyperreactive, when given metacholine bronchial asthma [ONLY USE OF METACHOLINE] Primarily used as diagnostic tool in asthma since it can produce contraction of bronchial smooth

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is determined by end-diastolic volume and myocardial contractility.) Stroke volume is not affected because atrial muscles are the ones contracted since stroke volume is determined by ventricular contraction not atrial contraction. Stroke volume is not significantly affected Dilatation of blood vessels Not a direct effect of the smooth muscles, but the endothelial cells. M3 in the endothelial cells which is linked to the Gq pathway, which causes the activation of Nitric Oxide Synthase (aka EDRF Endothelium Derived Relaxing Factor) activates guanylyl cyclase. It is cGMP that causes the relaxation, not Nitric Oxide synthase. Nitric Oxide synthase only activates guanylyl cyclase that increases cGMP. cGMP is the one that cause the relaxation Dilatation of the blood vessels Inhibition of the release of norepinephrine, heteroreceptors in the cholinergic nerves in the blood vessels inhibits norepinephrine, Vasodilatation Therefore decreased total peripheral resistance

(2) INDIRECTLY ACTING

A. ACETYLCHOLINESTERASE INHIBITORS They do not directly activate the receptors, but prevent the hydrolysis of the neurotransmitters so that more is available for neurotransmission. o

V. PHARMACOLOGIC ACTIONS DUE TO MUSCARINIC RECEPTORS: Recall:

Ach interaction with M1 & M3 receptors Ach interaction with M2 & M4 receptors

Activation of Gq protein Activation of Phospholipase-C

Activation of Gi & Gq protein

Activation of cAMP

Hydrolysis of phosphoinositides

Inhibit adenylyl cyclase

IP3 and TAG are released

Ion channels are regulated

Mobilization of intracellular Calcium

Enhanced Potassium conductance

Depolarization

Hyperpolarization

EPSP

IPSP

1.

CENTRAL NERVOUS SYSTEM o All muscarinic receptor subtypes present o M1 and M2 for cognitive functioning particularly learning and memory o M1 blockage = inhibits learning and memory (alzheimers disease) o M2 blockage = facilitates cognitive function o M3, M4 and M5 have no role in cognition CARDIOVASCULAR SYSTEM o Hyperpolarization of SA node M2 increases potassium and therefore hyperpolarizes SA node (IPSP); reduces the heart rate o Hyperpolarization of atrial muscles Only the atrial muscles are affected because it is the only one thats sufficiently innervated by the parasympathetic nervous system o Decreased Blood Pressure Net effect on cardiac output = Decreased due to decreas ed heart rate (CO is determined by (1) Heart rate (2) Stroke volume, which

o o o

2.

(-) Chronotropic effect Contributes to the decrease in heart rate (-) Inotropic effect Contributes to the decrease in myocardial contractility (-) Dromotropic effect Contributes to the decreased rate of conduction in sinoatrial (SA) and atrioventricular (AV) nodes Less dense cholinergic innervation of ventricles so it has more effect on atrial muscles (contracted) Stroke volume is not significantly affected (Because nga it is determined by ventricular contraction!!!!) RECALL: Cardiac Output Heart rate

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Stroke volume not significantly affected o Myocardial contractility is not affected Total Peripheral Resistance Vasodilatation

VI. DIFFERENCES IN PHARMACOLOGIC ACTIONS OF DIRECT-ACTING CHOLINERGI C AGONISTS

3. o o OCULAR M3 receptors in the constrictor pupillae and ciliary muscles On the eye, ciliary muscles contain stimulatory M3 receptors (EPSP), which lead to contraction. Constrictor pupillae contains M3 also, which also causes contraction. When it is contracted, it narrows the lumen of the pupil (aka Miosis). Ciliary muscles are responsible for accommodation:
Looking at distant objects Looking at near objects

Almost similar effect in the GIT, GUT, EYE, and glands Pilocarpine has marked effect secretion on glands No effects for carbachol, bethanechol, and alkaloids on the Respiratory system Take note for +3 for metacholine which is used as diagnostic tool in asthma Nicotinic receptors are found in ganglia, neuromuscular jxn, o CNS : Low dose = stimulation; o High dose = depression

Ciliary muscles relax

Ciliary muscles contract

Angle in canal of schlemm is narrow/ closed

Angle of canal of schlemm is wide/open

Accumulation of aquaeous humor

No accumulation of aquaeous humor

Increased IOP

Decreased IOP

4. o o o 5. o o o o 6. o o 7. o o o o 8. o o GASTROINTESTINAL TRACT increase tone and amplitude of contraction increased motility increase secretory activity of glands in the stomach and intestines Excess cholinergic activity = increased bowel movement and secretion of intestinal contents diarrhea GENITOURINARY TRACT increase tone of detrusor muscle (contracted) trigonal sphincter is open urination increase voiding pressure increase ureteral peristalsis relaxation of trigone and sphincter RESPIRATORY SYSTEM increase secretion of tracheobronchial glands contraction of bronchial smooth muscles INCREASED SECRETION OF OTHER GLANDS salivary sweat lacrimal pancreatic SEXUAL FUNCTION stimulate penile and clitoral arousal erection

The -methyl group in the nicotinic receptors would make it less active so expect no nicotinic effects with metacholine and bethanicol. The carbamyl group makes it resistant to acetylcholinesterase hydrolysis Only ach, methacoline, carbachol have activities in nicotinic receptors. Ach and methacoline are susceptible to ach esterase.

VII. PHARMACOLOGIC ACTIONS DUE TO ACTIVATION OF NICOTINIC RECEPTORS:

1. 2. 3. AUTONOMIC GANGLIA PSNS and SNS adrenal medulla Epinephrine NEUROMUSCULAR GANGLIA depolarization contraction CENTRAL NERVOUS SYSTEM low dose stimulation high dose depression

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VIII. INDIRECTLY ACTING CHOLINERGI C AGONISTS
(1) ACETYLCHOLINESTERASE INHIBITORS
Structure of an acetylcholinesterase enzyme: o 2 sites where an acetyl choline can bind: 1. Anionic site Hydrogen or ionic bond Ach Reversible binding Where edrophonium binds 2. Esteratic site Covalent bond to Ach Irreversible Where carbamyl and organophosphate inhibitors bind -

Once acetylcholine binds to acetylcholinesterase, it yields 2 metabolites: 1. Acetate 2. Choline Results in the accumulation of the neurotransmitter acetylcholinesterase at the cholinergic nerve terminal More enhanced neurotransmission Produce effects due to increased activation of cholinergic receptors throughout the CNS and peripheral nervous system. 2 types of acetylcholinesterase inhibitors: 1. Reversible acetylcholinesterase inhibitors 2. Irreversible acetylcholinesterase inhibitors o

Reversible Acetylcholinesterase Inhibitors NONCOVALENT INHIBITORS Edrophonium Tacrine/ Donepezil CARBAMATE INHIBITORS Carbamylated anticholinesterase Physostigmine Neostigmine Pyridostigmine Ambenonium Demecarium

Irreversible Acetylcholinesterase Inhibitors DILSOFLUOROPHOSPHATE (DFP) INSECTICIDES Malathion Parathion NERVE GASES Sarin Soman Tabun ECHOTHIOPHATE IODIDE

Various states of an Acetylcholinesterase enzyme: 1. Free Acetylcholinesterase 2. Acetylated Acetylcholinesterase With acetyl grp 3. Carbamylated Acetylcholinesterase Bound to a carbamyl compound react covalently with serine hydrolyzed by acetylcholinesterase much more slowly than Ach Act as alternate substrate for Ach Binding is not permanent; it can unbind itself so it is not permanent and can actually be reversed some other time Binding to the active center serine generates a carbamylated enzyme which is more stable (half-life for hydrolysis of the dimethylcarbamoyl enzyme is 15-30 minutes) But in actual use, the duration of inhibition by the carbamoylating agents is 3-4 hours 4. Phosphorylated Acetylcholinesterase Bound to a phosphate containing compound

REVERSIBLE ACETYLCHOLINESTERASE
NONCOVALENT INHIBITORS 1. EDROPHONIUM Binds to the ionic site and therefore is reversible. The inhibition of acetylcholinesterase of short duration.

Synthetic quaternary ammonium compound Moderate affinity to AchE Activity is limited to the peripheral nervous system synapses Small volume of distribution, rapid renal elimination Very short duration of action (10-20 min.)

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Used for diagnosis of Myasthenia gravis o (Tensilon Test tradename of edrophonium) due to the short onset and duration of action. o Ptt with myasthenia gravis will have a dramatic result of weakness 6. 7. DEMECARIUM CARBAMATE INSECTICIDES Have similar cholinesterase inhibiting activity as organophosphorus compounds and nerve agents. carrbamate-cholinesterase bond does not age and spontaneously hydrolyzes with a half-life of 1-2 hours which inactivates the compound clinical recovery occur in several hours, and only rarely in >24 hours. They do not age because it does not undergo loss of an alkyl group. Binding or inhibition of enzyme is reversed, not as stable as organophosphate. PROPOXUR CARBARYL ALDICARB

2.

TACRINE Synthetic Tertiary compound; of long duration of action Higher affinity to AchE Readily cross the blood brain barrier to inhibit AChE in the CNS Useful in patients with Alzheimers disease because one of the idipathogenesis to result alzheimers result from cholinergic activity of the brain DONEPEZIL Tx for alzheimers

3.

(2) ORGANOPHOSPHATE INHIBITORS OF ACETYLCHOLINESTERASE

ORGANOPHOSPHATES: o covalent binding o cause inhibition of physiologic function of enzyme o Phosphorylated enzyme complex undergo aging, which makes inhibition permanently irreversible. Loss of alkyl group produce aging of enzyme. o Pharmacological properties: highly lipid soluble except Echothiophate effectively absorbed from all routes so it is advised that in organophosphate poisoning, remove the clothing of patient endogenous Ach stimulates all cholinergic receptors (peripheral and CNS) They phosphorylate the esteratic site and produce irreversible inhibition of the enzyme. o serve as true hemisubstrates o the resultant conjugate with the active center serine phosphorylated or phosphonylated is extremely stable o The covalent bonding produced by organophosphate is exteremely stable. o For the return of usual AChE, you would need new enzymes because binding will permanently destroy the enzyme. o Phosphorylation of the enzyme causes aging. Aging of enzyme inhibition becomes permanently irreversible due to the loss of one alkyl group. Mostly pesticides and nerve gases used in wars. 1. DILSOFLUOROPHOSPHATE (DFP) produce virtually irreversible inactivation of AchE high lipid solubility low molecular weight volatile inhalation, transdermal and GIT absorption CNS penetration low volatility and stability in aqueous solutions widely used as insecticides employed for home (in lower concentration), garden and o

CARBAMYL INHIBITORS OF ACETYLCHOLINESTERASE 1. CARBAMATE ESTERS Covalently bound to esteratic site but binding can be reversible It does not alter enzyme function, unlike the organophosphates. 2. PHYSOSTIGMINE an alkaloid obtained from Physostigma venenosum tertiary amine activates both muscarinic and nicotinic receptor because of Ach which activates both muscarinic and nicotinic receptors can easily enter the CNS 2-4 hours duration of action Maintenance treatment for myasthenia due to long duration of action. NEOSTIGMINE Synthetic quaternary ammonium compound more polar do not pass thru the BBB directly stimulates Nicotinic Receptor at the motor end plate 2-4 hrs duration of action Dual action. Reversibly inhibits acetylcholinesterase Activates nicotinic receptors at the motor end plate Important for patients with myasthenia PYRIDOSTIGMINE synthetic quaternary ammonium compound used for long term treatment of Myasthenia gravis longer duration of action (4-6 hrs) AMBEMONIUM

3.

4.

5.

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agricultural use (in higher concentration) also use in suicide attempts or deliberate poisoning also used topically in the treatment of Pediculosis (lice infestations ) Converted to active metabolites by CYP450 system in the liver (drug metabolic enzyme) i. ii. 5. Bethanechol Neostigmine

2. 3.

4.

INSECTICIDES a. MALATHION b. PARATHION NERVE GASES most potent synthetic toxins known used in warfare and terrorism attacks a. SARIN b. TABUN c. SOMAN ECHOTHIOPHATE IODIDE

Myasthenia gravis (characterized by destruction of nicotinic receptors by Ig from the thymus gland ) a. Autoimmune neuromuscular disease b. characterized by severe weakness and fatigability of skeletal muscles c. loss of nicotinic receptors due to autoimmune mechanisms d. use of acetylcholinesterase inhibitors to Ach to stimulate limited receptors e. For Diagnosis: Edrophonium f. For Treatment: i. Neostigmine ii. Pyridostigmine g. Myasthenic crisis = extreme muscle weakness; low amt of Ach h. Cholinergic crisis = extreme muscle weakness; excess amt of Ach i. If you give neostigmine: i. Myasthenic Crisis = improvement ii. Cholinergic Crisis = aggravate the weakness Alzheimers disease a. a neurodegenerative disease b. believed to be associated with decrease functioning of the cholinergic system in the brain c. activation of postsynaptic M1 receptors in the CNS without concomitantly activating presynaptic M2 receptors that inhibit release of endogenous Ach d. Cholinergic Deficits in AD i. loss of the enzyme choline acetyltransferase ii. reduced synthesis of the transmitter acetylcholine iii. limbic and neocortical cholinergic deficits iv. Acetylcholine receptors largely intact e. Drugs given: i. Tacrine ii. Donezepil Antidote for Toxicity to: a. Anticholinergic drugs b. Tricyclic antidepressants (poisoning is similar to anticholinergic toxicity) c. Nondepolarizing (Competitive) neuromuscular blockers d. Drugs given: i. Physostigmine ii. Neostigmine Other Use / Misuse of Organophosphates a. Pesticides i. Propoxur ii. Malathion iii. Parathion b. Chemical warfare i. Sarin ii. Soman iii. Tabun c. Suicide

ACE TYLCHOLINESTERASE REGENERATOR

6.

Treat carbamate poisoning by pralidoxime (an AchE regenerator) Pralidoxime before can only be used by organophosphate poisoning pero now, kahit carbamate poisoning. MOST ARE TERTIARY! SO THEY PASS THROUGH THE SKIN, LUNGS, GIT, and REACH THE CNS. THEY ARE LIPID SOLUBLES.

IX. THERAPEUTIC USES OF CHOLINERGIC AGONISTS

1. Glaucoma Acute: Pilocarpine Chronic: Isofluorophate Echothiophate

In glaucoma, it contracts the ciliary muscles and therefore opens the action relieves IOP Faciilate drainage of aqueous humor or stop its synthesis Increasing IOP compromised blood supply to the retina and optic nerve blindness 2. Xerostomia usually 2 to head and neck radiation therapy or Sjgrens syndrome Pilocapine (ORAL) Gastrointestinal tract a. Postoperative abdominal distension b. Gastric atony or gastroparesis c. adynamic ileus due to toxic states d. congenital megacolon it contracts intestinal smooth muscles so it gives tone to induce motility e. Drugs given: i. Bethanechol ii. Neostigmine Genitourinary tract a. postoperative or postpartum urinary retention b. chronic hypotonic, myogenic, or neurogenic bladder c. partial sensory or motor paralysis of the bladder after spinal injury d. Drugs given:

7.

3.

8.

4.

Clinical Signs of Intoxication

(Organophosphate Poisoning) 1. Due muscarinic excess miosis, conjunctival congestion, blurring of vision

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dyspnea due to bronchoconstriction and increase bronchial secretion abdominal cramps, nausea, vomiting diarrhea increase sweating salivation involuntary defecation and urination penile erection 2. Due to Nicotinic excess involuntary twitching generalized spasms severe muscle weakness and paralysis (extreme) respiratory failure 3. Due to CNS involvement confusion ataxia slurred speech generalized convulsions respiratory depression coma 4. Death arrhythmias respiratory depression Hyperthyroidism Asthma Coronary insufficiency Acid Peptic Disease Organic obstruction in bladder in or GIT

Diagnosis of OP poisoning
History of exposure Characteristic signs and symptoms Determination of Cholinesterase activity in RBC and plasma Remove all sources of contamination Reduce absorption from the GIT with activated charcoal Support respiration Administer Atropine intravenously Atropine = anticholinergic Atropine is given until full atropinization Full atropinization occurs when: Pupil is already dilated (since anticholinergics produce miosis) Increased heart rate (cholinergic poisoning decreases heart rate) Administer enzyme reactivator if aging has not occurred

Treatment of OP poisoning

ENZYME REACTIVATORS Pralidoxime 2-PAM (2-pyridine aldoxime methyl chloride) belongs to a class of chemicals, called oximes that reverse the binding of cholinesterase inhibitors with acetylcholinesterase currently the only FDA approved oxime in the United States Obidoxime is the agent commonly used in Europe and other parts of the world attaches to the site where the cholinesterase inhibitor has attached to and blocked cholinesterase. then attaches to the cholinesterase inhibitor and removes it from cholinesterase, allowing the enzyme to work normally again. this is sometimes referred to as regeneration of cholinesterase. reverses the phosphorylation of cholinesterase improves neural synaptic transmission corrects muscle weakness and paralysis reserved for those who are symptomatic should be used early because the organophosphate-enzyme complex becomes irreversible after 24 to 36 hours. Beyond 36 hours= aging occurs Obidoxime

Contraindications to the Use of Cholinergic Agonists