NSAIDs, Opiod Analgesics, Anti-gout Drugs (Dr.

Guevara)
August 3, 2011
Scope:

Mechanism of pain
Drugs for pain
Gout

somatic

PAIN

Direct response to an untoward event

Subjective experience
Component of virtually all clinical pathologies
Both a sensation and an emotion
Associated with tissue damage
Motivates one to withdraw from damage
o Thus pain is a protective mechanism
Protect a damaged body part

From Goodman and Gillman:

Nociceptors, peripheral terminals of primary afferent fibers

that sense pain, can be activated by various stimuli such as
heat, acids, or pressure.

Inflammatory mediators released from non-neuronal cells

during tissue injury increase the sensitivity of nociceptors and
potentiate pain perception. Cytokines appear to liberate PGs
(prostaglandins) and some other mediators.

PGE2 and PGI2 reduce the threshold to stimulation of

nociceptors, causing peripheral sensitization.

Both COX-1 and COX-2 are expressed in the spinal cord under
basal conditions and release PGs in response to peripheral
pain stimuli.

Reversal of peripheral sensitization is thought to represent the

mechanistic basis for the peripheral component of the
analgesic activity of NSAIDs.

nociceptive

acute

Pain

visceral

neuropathic

chronic

Figure 1. Classifications or Descriptions of Pain

From Figure 1:
Pain can be an acute pain, from an injury, inflammation or
infection; and chronic pain if theres damage to the nerve itself.
Examples of diseases that causes neuropathic pain are: (1)
neuropathy of uncontrolled diabetes; and, (2) herpetic
neuralgia (when theres damage to trigeminal nerve).
Nociceptive pain, secondary to stimulation of nociceptors, can
either be somatic or visceral. Somatic pain is further classified
into superficial somatic pain and musculo-skeletal/deep
somatic pain. Examples of visceral pain: abdominal, gastric, or
colic pain.

Approach to Pain

Goal in management is to restore health and prevent

suffering
Increase in sympathomimetic activity
o Leads to an increase in heart rate, blood
pressure, etc.
Associated with a stress response
Accompanied by fear, anxiety and depression
Significantly interfere with ones quality of life
Goal of treatment is to restore health and prevent
suffering; and limiting adverse reactions

Figure 2. Image of a nociceptor afferent. As it goes to the spinal

cord and spinothalamic tract, there are parasympathetic and
sympathetic nerves inside, and also the pain receptors. The two
culprits in the sensation of pain are usually: A- and C fibers.

Trans by: Alimot, Alzona, Amante, Amit

Edited by: Sheda

Page 1 of 18

by release of PGs and thromboxane A2 (TXA2), COX inhibitors

appear to block only their pyrogenic effects.

INFLAMMATION

Cell Membrane Phospholipids

Most common condition that causes pain.

What happens after tissue injury?

The first mediators of inflammation are histamine and

IL-1. With the destruction of the cell membrane
(phospholipids), prostaglandins are produced. The
enzyme phospholipase A2 acts on phospholipids to
produce arachidonic acid (see Figure 4).

The action of the different drug groups for pain is

usually for inflammation. The NSAIDs usually inhibit

PLA2
Arachidonic Acid
COX-1

Prostanoids

TXA2

PGE2

PGI2

Bronchi
Kidney
Platelets
VSMC

Endothelium
CNS
Kidney Kidney
Mucosa Mucosa
VSMC

5-LOX

COX-2
Prostanoids

PGE2
VEGF Bone
Chondrocytes
CNS
Kidney
Nociceptors
Synovium

Leukotrienes
PGI2

CNS
Endothelium
Kidney
Nociceptors
Platelets
Uterus
VSMC

LTA4
LTC4
LTD4
LTE4

LTB4

Bronchi
MO
Neutrophils
Synovium
Bronchi
Synovium

Figure 4. Formation of arachidonic acid and its metabolites from

phospholipids of damaged cell membrane upon the action of specific
enzymes at each level. Shows the sites of action of each product of AA
metabolism

Drugs that can be used for pain

1.
2.
3.

NSAIDs
Opioids for moderate to severe pain
Others for chronic pain you usually give: antidepressants, sympatolytic agents

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

the prostaglandin synthesis.

Action is on the cyclooxygenase or prostaglandin synthase

enzyme. They inhibit COX-1 and COX-2 as compared to
steroids (corticosteroids) that inhibit PLA2.

Most NSAIDs are competitive, reversible, active site inhibitors of

the COX enzymes (Goodman&Gilman)

Figure 3. Arachidonic Acid metabolism and the functions of its

Metabolites as well as the actions of NSAIDs and other drugs.
From Goodman and Gillman:

Inflammatory process is the response to an injurious stimuli

evoked by a wide variety of noxious agents.

Prostanoid biosynthesis is significantly increased in inflamed

tissue. Inhibitors of the COXs, which depress prostanoid
formation, are effective and widely used anti-inflammatory
agents, highlighting the general role of prostanoids as proinflammatory mediators.

There is rapid induction of COX-2 in inflamed tissue and

infiltrating cells; thus, COX-2 is the major source of proinflammatory prostanoids, though COX-1 also contributes.

Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are the

primary prostanoids that mediate inflammation. They
increase local blood flow, vascular permeability, and
leukocyte infiltration through the activation of the respective
receptors.

Several cytokines play essential roles in inflammation,

especially tumor necrosis factor and IL-1. Together with other
cytokines and growth factors, they induce gene expression
and protein synthesis including expression of COX-2.

Other cytokines and growth factors (e.g. IL-2, IL-6, IL-8, GMCSF) contribute to manifestations of the inflammatory
response. Although some cytokine actions are accompanied

Trans by: Alimot, Alzona, Amante, Amit

Mechanism of Action

Inhibition of biosynthesis of prostaglandins (mediated by

cyclooxegenase, COX)
Anti-inflammatory
o Inhibition of PGE2 and PGI2 (thru inhibition of
COX-2 action on the receptors of PGE2 and PGI2)
o There is (1) inhibition of immune response, (2)
suppression of lymphocyte function, and (3)
inhibition of production of IL-1
Analgesic
o Inhibition of PGE2 and PGI2
o Increase threshold to stimulation
o Decrease central and peripheral sensitization
Anti-pyretic
o Inhibition of PGE2
o Decrease in hypothalamic set point control.

Edited by: Sheda

Page 2 of 18

If you will give non-selective COX inhibitors, both COX-1

and COX-2 will be inhibited.
BUT, most of the effects like pain relief, anti-inflammatory
effect and analgesic effect will be because of the inhibition
of COX-2 and a little of COX-1 only.
Most of the adverse reactions (especially GIT side effects) are
due to inhibition of COX-1.
o COX-1 usually participates in the normal
housekeeping function of the body
o Response to tissue injury/inflammtion is usually
COX-2.

From Goodman&Gilman:
Cyclooxygenase inhibition

Principal therapeutic effects of NSAIDs derive from their

ability to inhibit PG production

First enzyme in the PG synthetic pathway is COX or PG G/H

synthase which converts arachidonic acid to PGG2 and PGH2
leading to production of prostanoids, TXA2, and other PGs.

COX-1 is the dominant source of prostanoids for

housekeeping functions such as gastric epithelial
cytoprotection and hemostasis
o
Inhibition COX-1 at GIT site accounts largely for the
gastric adverse events that complicate therapy
with NSAIDs

COX-2, since it is induced by cytokines, shear stress, and

tumor promoters, is the more important source of prostanoids
inflammation and cancer
o
COX-2 inhibitors have the same efficacy as other
NSAIDs but with better GI tolerability

whether they had short plasma half-lives (<6

hours), half lives equal to 10 hours or half lives
longer than 10 hours (>10 hours).

PHARMACOKINETICS

First generation NSAIDs are non-selective and usually act

on COX-1 and COX-2.
All NSAIDs are antipyretic, analgesic, and anti-inflammatory; the
exception is acetaminophen, which is antipyretic and analgesic but
is largely devoid of anti-inflammatory activity.
Used as anti-inflammatory agents in the treatment of
musculoskeletal disorders, such as rheumatoid arthritis and
osteoarthritis

Other Therapeutic Uses:

Closure of patent ductus arteriosus (PDA)

o PGs (prostaglandins) have been implicated in the
maintenance of the patency of ductus arteriosus

Indomethacin and ibuprofen can close PDA (in

neonates)

Aspirin at low dose (not yet the anti-inflammatory dose),

prevent platelet activity and prevent aterogenesis,
thrombosis and M.I.
Other NSAIDs such as celecoxib and rofecoxib might be
able to prevent colon cancer.
Also clinically used for systemic mastocytosis,
chemoprevention and niacin tolerability (G&G).

cancer

CLASSIFICATION OF NSAIDs

NSAIDs were traditionally grouped based on their chemical

structures.
o E.g. Aspirin was part of salicylic acids.
Indomethacin and diclofenac were grouped under
acetic acids
Newer classifications are based on:
o (1) Whether the drug is more of a COX-1 or more
of COX-2 (COX isoform selectivity)

Trans by: Alimot, Alzona, Amante, Amit

Most NSAIDs are rapidly absorbed in the GIT

Peak plasma concentration is usually 2-3 hours
Antacids delay (but rarely reduce) absorption. Proton-pump
inhibitors (PPIs) do not delay absorption
o Most doctors would give antacids or PPIs together
with NSAIDs to avoid the gastrointestinal adverse
effects of NSAIDs
95-99% of NSAIDs are transported protein bound
(albumin)
o Plasma protein binding is often concentration depedent
(i.e. naproxen, ibuprofen) and saturable at high
concentrations

Therapeutic Uses/Benefits

COX-2 selective NSAIDs: Celecoxib,

Valdecoxib, Rofecoxib, Etoricoxib, and
Lumiracoxib.
COX-1 selective NSAIDs: Aspirin,
Ibuprofen, Indomethacin, Piroxicam,
Sulindac
(2) Duration of action (Plasma half life)
From G&G: NSAIDs were classified based on

NSAIDs can displace other drugs since they are proteinbound (and if these drugs compete for same binding sites); can
lead to toxicity.
All NSAIDs undergo varying degree of enterohepatic
circulation. Degree of lower GIT irritation correlates with
the amount of enterohepatic circulation (Katzung)
NSAIDs like Indomethacin and Diclofenac are very potent;
and the concentration inside the synovial fluid is equal to
the plasma concentration.
o Thats why such drugs are helpful in arthritic
diseases
Lipophilic high in fat and can cross blood brain barrier
o E.g. Celecoxib
Acidic drugs accumulate more in inflammation

ADVERSE EFFECTS/COMPLICATIONS OF NSAIDs

Most common complications:

NSAIDs that are COX-1 inhibitors can cause gastritis

(e.g. peptic ulcer usually happen for the more potent
drugs)

COX-2 inhibitors have cardiovascular effects (high risk

for myocardial infarction).
Other complications:

Abdominal pain

Nausea and vomiting

Anorexia

Gastric ulcer

GI hemorrhage

Anemia
o Due to gastric hemorrhage

Diarrhea

Perforation/obstruction

Inhibit platelet function (e.g. Aspirin)

Propensity to bruising
Due to inhibition of platelet
function

Increased risk of hemorrhage

Edited by: Sheda

Page 3 of 18

Aspirin intake of patients scheduled for

operation is stopped for 5-7 days.

Renal complications
o Analgesic nephropathy
Condition of slowly progressive renal
failure,
decreased
concentrating
capacity of renal tubule, and sterile
pyuria (G&G)

Except for acetaminophen, most of

the NSAIDs are usually given to
children
Ibuprofen is given to children with
uncontrolled
fever
as
an
alternative to paracetamol
o Decrease reabsorption of chloride and antidiuretic hormone function
o Salt and water retention
o Edema, renal dysfunction (in renal, cardiac
and liver patients)
o Hypertension
o Failure of diuretics.
Inhibit urate excretion
o Some NSAIDs are contraindicated for
patients with gout
Headache
Dizziness
Vertigo
Hyperventilation
Prolongation of gestation/inhibition of labor by NSAIDs
o Before parturition, there is induction of myometrial
COX-2 expression PGE2 and PGF2 levels in
myometrium for labor

To induce labor, oxytocin or drugs like

Misoprostol is given since misoprostol is a
potent prostaglandin analog
o NSAIDs inhibit PGs and actions of laborinducing drugs.
Hypersensitivity reactions
o Rhinitis, angioedema, urticaria, asthma,
shock

NSAID INTERACTIONS

NSAIDs decrease effect of ACE inhibitors

o If ACE inhibitors are given together with NSAIDs,
dosage of ACE inhibitors should be increased or
add another anti-hypertensive drug
o Thats why one of the complications of prolonged
NSAID use is usually hypertension
NSAIDs (especially non-selective COX inhibitors) increase
risk of bleeding when given with Warfarin
Steroids and SSRIs (Selective Serotonin Reuptake
Inhibitors) which are anti-depressants would increase
gastric side-effects if given with NSAIDs
If NSAIDs are given with Lithium excretion of lithium
more prone to lithium toxicity

ASPIRIN (ACETYL SALICYLIC ACID)

Trans by: Alimot, Alzona, Amante, Amit

First NSAID discovered

Irreversible, non-selective COX inhibitor
Standard for comparison for all new NSAIDs being
discovered

Derivative of salicylic acid

Pharmacokinetics (from Katzung)

**As additional info**

Simple organic acid with pKa =3.5

Salicylates are rapidly absorbed from stomach and upper

small intestine

Peak plasma salicylate level reached in 1-2 hours

Aspirin is rapidly hydrolyzed by esterases (serum half-life 15

minutes) to acetic acid and salicylate. Salicylate is non-linearly
bound to albumin.

Mechanisms of Action
From Katzung:

Aspirin irreversibly inhibits platelet COX

Anti-platelet effect lasts 8-10 days (which is equal to lifespan

of platelet)

In other tissues, synthesis of new COX replaces inactivated

enzyme so that ordinary aspirin doses have duration of
action: 6-12 hours.
From G&G:

The cardioprotective function of aspirin may be due to

permanent and complete suppression of platelet TXA2
formation

Dosage

Anti-platelet 40-80 mg/day

Pain/fever 325-650 mg/day
Rheumatic fever 1g every 6 hours
Aspirin is also uricosuric (increase excretion of uric acid)
o Low dose: 1-2 g/day decrease excretion
o Medium dose: 2-3g/day no effect
o High dose: >5g/day increase excretion (desired
effect)

Clinical Uses
From Katzung:

Aspirin decreases the incidence of

o
Transient ischemic attacks
o
Unstable angina
o
Coronary artery thrombosis w/ M.I.
o
Thrombosis after coronary artery bypass grafting

Long-term use at low dosage associated w/ lower incidence of

colon cancer

Adverse Effects

Avoid use in acute onset fever

o E.g. in Dengue, aspirin is not given
Risk of bleeding in dengue
Risk of Reyes syndrome
o Due to viral infection, the reaction of Aspirin would
result to encephalopathy, liver damage, etc. if
given to patients less than 20 years old
o Common in children <20 years old
Increase respiration, decrease iodine uptake and
clearance, decrease hearing
o Patients with hypothyroidism are not given Aspirin
Edited by: Sheda

Page 4 of 18

Trigger hypersensitivity reactions

Adverse Effects
NOTE: Almost all NSAIDs can trigger hypersensitivity reactions.
The worst hypersensitivity reaction is SJS (Steven-Johnsons
Syndrome)

NON-SELECTIVE COX INHIBITORS

INDOMETHACIN

GI upset occurs in 20-30% of patients

30% discontinue use of drug
Other major adverse effects are on central nervous system
(Katzung)

KETOROLAC

Acetic acid derivative

Mechanism of Action

Relatively selective for COX1

10-40x potent
o

More potent non-selective inhibitor of COXs than Aspirin

(G&G)

From G&G:

Inhibits motility of PMN leukocytes, depresses biosynthesis of

mucopolysaccharides; may have direct, COX-independent
vasoconstrictor effect

Prominent anti-inflammatory and analgesic-antipyretic

properties similar to salicylates

Pharmacokinetics (Absorption, Distribution, Elimination)

From G&G:

Has excellent bioavailabilty

Peak concentrations occur 1-2hrs. after dosing

Concentration in synovial fluid is equal to that in plasma

within 5 hrs. of administration

Plasma half-life is variable

Therapeutic Uses

From Didactic Guide: Treatment

(juxtaglomerular cell hyperplasia)

Should be given 25mg twice or 3x a day

of

Bartters

syndrome

Adverse Effects
Frontal headache
GI upset
Neutropenia
Thrombocytopenia
Appear in 20-30% of patients, among which 20% would
discontinue drug (mostly due to GI symptoms)

KETOPROFEN

Propionic acid derivative

Most common brand name: Orudis

Also a potent NSAID
Inhibits both COX (nonselectively) and lipooxygenase (Katzung)

Aside from inhibiting COX, may stabilize lysosomal

membrane and antagonize bradykinin
o Increase the resolution of inflammation and pain
Recommended anti-inflammatory dosage: 50-70mg tid (katzung)

Trans by: Alimot, Alzona, Amante, Amit

Has highest potency but theres little anti-inflammatory

effect
Analgesic
o Accdg. to G&G, it is a potent analgesic but only a
moderately effective anti-inflammatory drug

Therapeutic Uses
From G&G and PPT:

Usually given in the first 5 days of pain and inflammation

only; rapid onset; short duration

Commonly given parenterally (e.g. IV route, IM route)

o 30-60mg intramuscular; 15-30mg intravenous; and 1020mg oral

Oral and IV preparations

o Usually impart strong analgesic rather than antiinflammatory effect

Widely used in post-operative patients but it should not be used

for routine obstetric analgesia

Topical form (i.e. eyedrops)

o Only form with potent anti-inflammatory effect
o FDA approved
o For treatment of seasonal allergic conjunctivitis
o Also for patients who have undergone cataract
surgery, glaucoma surgery

Good for arthritic diseases

o Synovial fluid concentration equals plasma
concentration
Used for closure of PDA (Patent Ductus Arteriosus)

Acetic acid derivative

From Didactic Guide: used successfully to replace morphne in mild
to moderate postoperative pain control

Adverse Effects
From Katzung:

Toxicities are similar to those of other NSAIDs though renal

toxicity may be more common with chronic use
From G&G:

Side effects at usual oral doses include: somnolence, dizziness,

headache, etc.

Possibility of serious adverse GI, renal, bleeding, and

hypersensitivity reactions

MEFENAMIC ACID

Fenamate (fenamic acid)

Most common in Philippines

Usually given dose: 250-500mg 4x a day for pain on a full
stomach

Therapeutic Uses
From G&G:

Mostly been used in short-term treatment of:

o Pain in soft tissue injuries

Edited by: Sheda

Page 5 of 18

o
o
o

Dysmenorrhea
Rheumatoid arthritis
Osteoarthritis

Therapeutic Uses

Not recommended for children and pregnant women even

though there are preparations available for them.

Adverse Effects

GI upset occurs in 25% in patients (at therapeutic doses)

Hemolytic anemia
o Potentially serious but rare side effect (G&G)

associated with decreased urine output and cause

less fluid retention (Katzung)

Diarrhea which may be severe and associated with steatorrhea

and bowel inflammation is relatively common (G&G)

NAPROXEN

Proprionic acid derivative

Most common use (aside for joint pains) is for migraines

Indicated for juvenile and rheumatoid arthritis, osteoarthritis,
ankylosing spondylitis, pain, primary dysmenorrhea, tendonitis,
bursitis, and acute gout (G&G).

Additional from G&G:

Doses of 800mg 4x daily can be used to treat rheumatoid

arthritis and osteoarthritis

Usual dose for mild to moderate pain (e.g. primary

dysmenorrhea): 400mg every 4-6hrs as needed

For pain or fever, IV ibuprofen administered at a dose of 100800mg over 30mins. every 4-6hrs.

Adverse Effects

Pharmacokinetics

Absorbed fully when orally administered

Food delays the rate but not extent of absorption (G&G)

Metabolites excreted almost entirely in urine

Almost completely bound to plasma proteins after normal
therapeutic doses (G&G)

Peak anti-inflammatory effect: 2-4 weeks

275 mg qid or 550mg bid
Better tolerated

Can be used in pregnancy (except during the 3rd trimester)

o Can delay parturition in 3rd trimester

Can be used with caution by breastfeeding women (G&G)

Prolonged half-life may afford cardioprotection (~10%

decreased risk for MI)

PIROXICAM

Typical GI symptoms occur at same frequency with other NSAIDs

but with less severity
CNS side effects (G&G)

Few cases of jaundice, thrombocytopenia

agranulocytosis were reported (with prolonged use)

and

Propionic acid derivative

Most common in USA: Advil

Inhibits neutrophil activation, proteoglycanase and

collagenase enzymes (independently of its ability to inhibit

Therapeutic Uses
From G&G and lecture:

Approved in U.S. for treatment of rheumatoid arthritis and

osteoarthritis

Not used for analgesia since the effect is usually delayed

(slow onset of action and delayed attainment of steady state)

o
o

Absorbed rapidly, bound avidly to protein; undergoes hepatic

metabolism
Renal excretion of metabolites
Half-life: ~2 hours (G&G)
Slow equilibration with synovial space anti-arthritic effects
may persist even after plasma levels decline

Even though Piroxicam is non-selective, it is more of a

COX-1 inhibitor
Usually given 20mg/day
o Theres good compliance since it is given only once
a day

COX)

Enolic acid derivative

Mechanism of Action

Pharmacokinetics

has been used in patients with history of GI intolerance to other

NSAIDs)
5-10% GI upset (in G&G, its 5-15%)
Relative risk of M.I. is unaltered or slightly increased by ibuprofen
but still less than risk from COX-2 selective inhibitors
Other less frequent adverse effects: thrombocytopenia, rashes,
headache, blurred vision, fluid retention, edema (G&G)

Variable half-life (G&G)

IBUPROFEN

Usually better tolerated (than aspirin and indomethacin and

Adverse Effects

Can achieve analgesia with 200-400 mg every 4-6 hours

For anti-inflammatory effects: 400-800 mg 3-4x/day
o At this dosage, adverse GI effects are experienced
Children: 5/10mg per kg q6hrs (every 6 hours); or, 2040mg/kg/day
Used for Patent Ductus Arteriosus (injectable formulation)
o This is similar to indomethacin but here it is

If you want pain relief, dont use Piroxicam

But if the anti-inflammatory effect is wanted, this
can be given (anti-inflammatory effect felt after
24-48 hours)
o Usually given for post-operative pain
Used in gout

Adverse Effects
Trans by: Alimot, Alzona, Amante, Amit

Edited by: Sheda

Page 6 of 18

GI upset (20%); 5% discontinue

May be associated with more GI and serious skin reactions than
other non-selective NSAIDs (G&G)

COX-2 SELECTIVE INHIBITORS

Also known as Coxibs

Risk of atherosclerosis, thrombosis, MI
Less GI irritation
Developed in an attempt to inhibit PG synthesis by the COX-2
isozyme induced at sites of inflammation without affecting the
action of the active housekeeping COX-1 isozyme found in the
GIT, kidneys, and platelets.
Coxibs selectively bind to and block the active site of COX-2
enzyme much more effectively than COX-1 inhibitors.
With analgesic, anti-pyretic, and anti-inflammatory effect
COX-2 inhibitors do not offer cardioprotective effects (compared to
nonselective NSAIDs)
o Reason: Inhibit COX-2 mediated prostacylcin synthesis in
vascular endothelium
Since COX-2 is active within the kidney, recommended doses of
COX-2 inhibitors cause renal toxicities similar to traditional
NSAIDs

MELOXICAM

Common brand name: Mobic

More COX-2 (10x) at lower doses
o Preferentially inhibits COX-2 over COX-1 particularly at its
o

lowest therapeuticdose of 7.5mg/d.

Not as selective as Celecoxib; not considered highly
selective (Katzung).

Usual dose: 7.5-15mg/day

Better tolerated

From G&G:

Analgesic, anti-pyretic, anti-inflammatory activities

Potentcy is substantially greater than that of indomethacin,

naproxen or several other traditional NSAIDs

Selectivity of diclofenac for COX-2 resembles that of celecoxib

Appears to reduce intracellular concentrations of free AA

(arachidonic acid) in leukocytes, perhaps by altering its
release or uptake

Pharmacokinetics
From G&G:

Has rapid absorption and extensive protein binding

Half life: 1-2hrs.

o
Short half-life makes it necessary for higher doses
to afford inhibition throughout dosing interval

Substantial first-pass effect

Accumulates in synovial fluid after oral administration, which

may explain why its duration of therapeutic effect is
considerably longer than its plasma half-life

Therapeutic Uses (from G&G)

Popular in Europe and other countries for treatment of most

rheumatic diseases
Approved in the USA for treatment of osteoarthritis (Katzung)

For long-term symptomatic treatment of:

o
Rheumatoid arthritis
o
Osteoarthritis
o
Ankylosing spondylitis
o
Pain
o
Primary dysmenorrhea
o
Acute migraine

Adverse Effects (from G&G)

Less gastric injury compared to piroxicam (20mg/day) at dose

7.5mg/d. This advantage is lost with a dosage of 15mg/day
(G&G)
Associated with fewer GIT symptoms and complications than
piroxicam,diclofenacand naproxen (Katzung)

Incidence of serious GI adverse effects did not diffr between

diclofenac and celecoxib and etoricoxib.
Same cardiovascular risks as other tNSAIDs

Hypersensitivity reactions for topical application

DICLOFENAC
Note: In Katzung, this drug was classified as a non-selective COX
inhibitor. Dr. Guevarra placed this together with the other COX-2
selective inhibitors. In Goodman&Gilman, it was described as selective
for COX-2.

Brand name: Voltaren

Phenylacetic acid derivative
Among the most commonly used NSAIDs (G&G)

More potent
Usual dose: 50mg tid
Rapid onset/short duration
20% AEs (Adverse Effects)
o 2% discontinue
15% develop elevated liver enzymes
Can be used in pregnancy

Additional Information:

Mechanism of Action
Trans by: Alimot, Alzona, Amante, Amit

CELECOXIB

Brand name: Celebrex

Selective cox2 inhibitor
o
10x more selective for COX-2 than for COX-1
Half-life: 11hrs
Recommended anti-inflammatory dosage: 100-200mg bid
Associated with fewers endoscopic ulcers than other NSAIDS
Does not affect platelet aggregation at usual doses
Interacts occasionally with warfarin (also metabolized via CYP2C9)
Indications:
o
Rheumatoid arthritis
o
Osteoarthritis
o
Acute pain
o
Dysmenorrhea (primary)
o
Ankylosing spondylitis (G&G)

Additional Information:

Pharmacokinetics
From G&G:

Edited by: Sheda

Page 7 of 18

Bioavailability not known

Peak plasma levels occur at 2-4hours after dose is taken
Bound extensively to plasma proteins
Half life: 11hours; drug is commonly given OD or BID per day
during chronic treatment

From G&G:

Confers risk of MI and stroke (related to dose and underlying

risk of CVD before drug administration)
Hypertension and edema (inhibition of PG synthesis in kidney)
o Same with non-selective COX inhibitors

Analgesic/anti-pyretic
o Raises the threshold for painful stimuli, thus exerting
o

Adverse Effects

analgesic effect against pain due to a variety of etiologies

Effective alternative to aspirin as an analgesic-antipyretic
agent (G&G)

Safe even in pregnant women and children

Well tolerated
o Lower incidence of GI side effects (G&G)
Can cause hepatic damage in overdosage (use activated
charcoal as antidote)
Metabolite of highly toxic phenacetin(pro-drug)
Management of intoxication:
o Considered a medical emergency
Severe damage > 300ug/ml/4hrs
Minimal damage<120ug/ml/4hrs

ETORICOXIB

Brand name: Arcoxia

Bypyrimidine derivative
2nd generation coxib with the highest selectivity ratio for
inhibition of COX-2
o According to G&G, etoricoxib has a selectivity second only
to that of lumiracoxib
Extensively metabolized by hepatic P450 enzymes
Elimination half-life: 22hrs
Therapeutic dose: 60-90mg OD

Additional Information:

Mechanism of Action

Incompletely absorbed (80%)

Has long half-life: 20-26hrs
Small studies have shown that those with moderate hepatic
impairment are prone to drug accumulation; dosing interval
should be adjusted

Approved in some countries as a once-daily medicine for

symptomatic relief in treatment of osteoarthritis, rheumatoid
arthritis, and acute gouty arthritis
For short term treatment of musculoskeletal pain, post-operative
pain, primary dysmenorrhea

Etoricoxib shows decreased GI injury

Increase risk of heart attack (MI) and stroke (together with other
coxibs)
o
Restricted use in patients with uncontrolled hypertension

ACETAMINOPHEN

Very weak COX inhibitor

Dosage :
o Children: 10-15mg/kg q4hrs
o Adults: 250-500mg q4hgrs
Total daily dose: 4000mg(2000mg for alcoholics)
FDA 2009 Recommendation:
o Daily dose: 2600mg
o Maximum single dose: 650mg
o Children: 160-480mg: 5 doses

Trans by: Alimot, Alzona, Amante, Amit

Has excellent bioavailability

Peak plasma concentrations occur within 30-60mins
Plasma half-life: 2hrs after dosing
Relatively uniformly distributed throughout most body fluids
A small proportion of acetaminophen undergoes CYP mediated Nhydroxylation to form NAPQI a highly reactive intermediated
o
Metabolite normally reacts with sulfhydryl groups in
glutathione (GSH) rendered harmless
o
However, after ingestion of large doses of
acetaminophen, metabolite is formed in sufficient

Adverse Effects

Has only weak anti-inflammatory effects

It has been thought to have a generally poor ability to inhibit COX
in the presence of high concentrations of peroxides (found at sites
of inflammation)

Pharmacokinetics

Therapeutic Uses

N-acetylcysteine detoxifies NAPQI

o Loading dose: 140mg/kg; 70mg/kg q4hrs for
17doses
>7.5g can result to toxicity
Results to hepatic necrosis (10-15g) and can be observed
2-4hrs after ingestion: renal tubular necrosis,
hypoglycemic coma
Due to metabolite NAPQI
Depletes glutathione stores
Activated charcoal in first 4hrs

Additional Information from G&G:

Pharmacokinetics

amounts to deplete hepatic GSH

overdose

toxic effects of

Therapeutic Uses

First line analgesic in osteoarthritis

Particularly valuable for patients in whom aspirin is
contraindicated
BUT not a suitable replacement for aspirin or other NSAIDs in
chronic inflammatory conditions such as rheumatoid arthritis

SOME DISCONTINUED DRUGS

A.

NIMESULIDE

Edited by: Sheda

Page 8 of 18

B.

Discontinued drug
o Its use is limited due to risk of hepatotoxicity

Other adverse effects:

o GI haemorrhage/perforation; bullous/erosive
stomatitis, purpura, thrombocytopenia, toxic
epidermal necrolysis, SJS and renal failure

VALDECOXIB

COX-2 selective inhibitor

Confer an increased risk of MI (heart attack) and stroke

Withdrawn from the market in view of its adverse event

OPIOIDS

association (from postmarketing studies) with increased

risk of myocardial infarction which may be present long
after drug has been discontinued (G&G)
Increased risk for stroke

profile (G&G)

ENDOGENOUS OPIOIDS

ROFECOXIB

COX-2 selective inhibitor

Withdrawal of drug from market was because of an

C.

Sulfonamide compound available in Europe that

demonstrates COX-2 selectivity similar to celecoxib
Administered orally in doses 100mg BID daily as an antiinflammatory, analgesic, and anti-pyretic (G&G)

For moderate to severe pain

Any agent, regardless of structure, that has the functional
and pharmacological properties of an opiate (compounds
structurally related to products found in opium obtained
from the poppy, Papaver somniferum and P album)
o ex. natural plant alkaloids, such as morphine,
codeine, thebaine, and many semisynthetic
derivatives
Full agonists, partial agonists, and antagonists

Figure 5: Pain Pathway

Trans by: Alimot, Alzona, Amante, Amit

Naturally occurring ligands for opioid receptors (to control

the pain)
Function
as
neurotransmitters,
modulators
of
neurotransmission, or neurohormones
Acts on these classical opioid receptor types: , , and
o Produces very potent analgesia
Continuously secreted by the body
1. Endorphin
usually secreted at high levels
E.g. secreted during exercise
2. Enkephalin
3. Dynorphin

ACTIONS OF ENDOGENOUS AND EXOGENOUS OPIOIDS

From G&G:
1.

Supraspinal level

Opiate agonists will, in a manner consistent with their

respective activity at a MOR, block pain behavior after
delivery into a number of highly circumscribed brain
regions and that these analgesic effects are naloxone
reversible

Best characterized of these sites is the mesencephalic

periaqueductal gray (PAG) matter

Microinjections of morphine into this region will block

nociceptive responses

Figure 6: Mechanisms of opiate action in producing analgesia (Goodman

& Gilman).

Edited by: Sheda

Page 9 of 18

Top left (Figure): Schematic of organization of opiate action in the

periaqueductal gray. Top right: Opiate-sensitive pathways in PAG Mu
opiate actions block the release of GABA from tonically active systems
that otherwise regulate the projections to the medulla (1) leading to an
activation of PAG outflow resulting and activation of forebrain (2) and
spinal (3) monoamine receptors that regulate spinal cord projections (4)
which provide sensory input to higher centers and mood.
Bottom left: Schematic of primary afferent synapse with second order
dorsal horn spinal neuron, showing pre- and post-synaptic opiate
receptors coupled to Ca2+ and K+ channels, respectively. Opiate receptor
binding is highly expressed in the superficial spinal dorsal horn
(substantia gelatinosa). These receptors are located presynaptically on
the terminals of small primary afferents (C fibers) and postsynaptially on
second order neurons. Presynaptically, activation of MOR blocks the
opening of the voltage sensitve Ca2+ channel, which otherwise initiates
transmitter release. Postsynaptically, MOR activation enhances opening
of K+ channels, leading to hyperpolarization. Thus, an opiate agonist
acting at these sites jointly serves to attenuate the afferent-evoked
excitation of the second order neuron. (G&G)

2.

Drug Dependence
o Can produce withdrawal syndrome
Addiction
o With behavioural changes to achieve goal
(E.g. will kill someone just to get something
he wants)
Opioid stimulation is usually due to Kappa receptor
stimulation

* Tolerance and dependence is treated with an opioid agonist with long

onset/duration or an opioid antagonist

OPIOID REACTION TO RECEPTOR

Inhibition of inhibitory NT
G protein coupled reaction
Inhibits GABBA (an inhibitory NT)

Spinal cord level

Depress the discharge of spinal dorsal horn neurons evoked

by small (high-threshold) but not large (low-threshold)
afferent nerve fibers

Specific opiate binding and receptor protein are limited for

the most part to the substantia gelatinosa of the superficial
dorsal horn

The joint capacity of spinal opiates to reduce the release of

excitatory neurotransmitters from C fibers and to decrease
the excitability of dorsal horn neurons is believed to account
for the powerful and selective effect of opiates on spinal
nociceptive processing

Opioid Receptor Subtypes, Their Functions, and Their Endogenous

Peptide Affinities.
Receptor
Functions
Endogenous Opioid
Subtype
Peptide Affinity
Mu ()
Supraspinal and spinal
analgesia; sedation;
MOR
inhibition of respiration;
Endorphins> enkephalins
slowed gastrointestinal
> dynorphins
transit; modulation of
hormone and
neurotransmitter release
Delta () Supraspinal and spinal
Enkephalins > endorphins
analgesia; modulation of
& dynorphins
DOR
hormone and
neurotransmitter release
Kappa
Supraspinal and spinal
Dynorphins > >
()
analgesia;
endorphins&enkephalins
psychotomimetic effects;
KOR
slowed gastrointestinal
transit
Note:

Tolerance, Drug Dependence and Addiction

o Caused by continuous kappa receptor
stimulation
Tolerance
o Ineffectivity of agents
o There will be dependence afterwards

Trans by: Alimot, Alzona, Amante, Amit

Figure 7. Addiction is because of inhibition of GABA there will

be continuous stimulation there is +reaction to this causes
drug dependency

PHARMACOLOGIC EFFECTS OF OPIOIDS

Analgesia
o Suppresses the perception of pain and altering
emotional state inducing euphoria and sleep
Respiratory depression
o Decreases respiratory rate and insensitivity to an
increase in pCO2; there is shut down of the
respiratory center

Sedation
In males: decrease cortisol and testosterone
In females: decrease LH and FSH
Miosis disinhibition of Edinger-Wesphal nucleus; little or
no tolerance develops = valuable in diagnosing opiod
overdose
Seizures and convultions
Anti-tussive effect at does lower than those needed for
analgesa
Nausea and vomiting
May prolong labor
Has cardioprotective effects
Muscle rigidity in high doses
Edited by: Sheda

Page 10 of 18

o
o
o

Constipation some opioids are used for diarrhea;

tolerance does not develop to opiod-induced constipation

Degrees of Tolerance that May Develop to Some of the Effects of

the Opioids
High
Moderate
Minimal or none
Analgesia
Bradycardia
Miosis
Euphoria, dysphoria
Constipation
Mental Clouding
Convulsion
Sedation
Respiratory
depression
Antidiuresis
Nausea and vomiting
Cough suppression

Asthma
Immunocompromised state
Head trauma

Derivatives:
a. CODEINE
o Partial agonist
o Often used as anti-tussive
o
o
o
o

Metabolized to morphine (binds to receptors)

Effective orally
Used for its antitussive effect
Most common opioid drug combined with nonopioid drug

Some derivatives:
Hydromorphone 8x more potent
Oxycodone 10x (can be used in
children)

Oxymorphone

10x

(w/

little

antitusive effect)

b.

Adverse Effects of the Opioid Analgesics

Behavioral restlessness, tremulousness, hyperactivity (in
dysphoric reactions)
Respiratory depression
Nausea and vomiting
Increased intracranial pressure
Postural hypotension accentuated by hypovolemia
Constipation
Urinary retention
Itching around nose, urticaria (more frequent with parenteral and
spinal administration)
Drug Group
Sedativehypnotics
Antipsychotic
tranquilizers

Monoamine
oxidase
inhibitors

Opioid Drug Interactions.

Interaction with Opioids
Increased central nervous system depression,
particularly respiratory depression.
Increased sedation. Variable effects on
respiratory depression. Accentuation of
cardiovascular effects (antimuscarinic and blocking actions).
Relative contraindication to all opioid analgesics
because of the high incidence of hyperpyrexic
coma; hypertension has also been reported.

OPIOID DRUGS: STRONG AGONISTS

MORPHINE

MOR (Mu Opioid Receptor) agonist

the standard
Effects are on receptors
Used for moderate to severe pain
Used as pre-operative medication for sedation and its anxiolytic
property;
Right now it is used for post-op; and for MI (myocardial
infarction)
Oral route
o
Undergoes first pass effect;
o
Used for cancer patients
CI (Contraindications):

Trans by: Alimot, Alzona, Amante, Amit

HEROIN
o Potent, fast acting
o Highly addictive
o Prohibited in most countries
o Same efficacy as morphine
c. HYDROMORPHONE, OXYMORPHONE,
HYDROCODONE, OXYCODONE
o Used in very severe pain
o Very potent

METHADONE

Long acting MOR agonist

Suppresses withdrawal symptoms
Used as treatment for dependence/ addiction
Drug dependence can develop with prolonged use
Same potency as morphine
Used for moderate to severe pain;
Used for drug addiction (long duration of action); neuropathic
pain
Potent receptor agonist; blocks NMDA and monoamine uptake
transporters
Rifampicin and hydantoins increase its metabolism and tricyclic
anti-depressants and benodiazepines decreases its metabolism

From G&G:

Analgesic activity almost entirely the result of Lmethdadone which is more potent than the D-form

Absorbed well from GI tract; can be detected in plasma within

30mins. of oral ingestion

Peak concentration at 4hrs.

Peak concentration occur in brain within 1-2hrs of SQ or IM

administration correlates with intensity and duration of
analgesia

Half-life is 15-40hrs.

Similar adverse effects to morphine

TRAMADOL

Synthetic codeine analog

o Weak MOR agonist
Used as analgesic for post-operative pain
o Part of its analgesic effect is produced by inhibition of

As effective as meperidine/morphine

uptake of noreepinephrine and serotonin (G&G)

Edited by: Sheda

Page 11 of 18

o
o

In the treatment of mild to moderate pain

For treatment of severe or chronic pain, it is less effective
(G&G)
As effective as meperidine in treatment of labor pain

May cause less neonatal respiratory depression

Can have tolerance, withdrawal and can reinitiate
dependence
Weak agonist actions at the -opioid receptor, releases serotonin,
and inhibits the reuptake of norepinephrine
Synthetic analog of codeine
Adverse Effects:
o
Nausea, vomiting, constipation, drowsiness (far less seen
than in other opioids)
Low dependence potential but can cause typical opiate-like
withdrawal symptoms

FENTANYL

MOR agonist
Important anesthetic agent
o Due to its relatively short time to peak analgesic effect,
rapid termination of effect, minimal direct depressant
effects on myocardium, and ability to significantly reduce
dosing requiremnt for volatile agents (G&G)

Given with neuromuscular blocker

Used in cardiovascular surgery (dec. coronary flow and BP)
Rapid onset, short duration, fast clearance
Extremely potent (80-100x)
o
Sufentanyl (500-1000x) use for long neurosurgical cases
o
Alfentanyl (20x)
Adjunct to anesthesia
Onset: 20mins
Can get trapped in fats
All adverse effects similar to morphine are produced with far
greater intensity but shorter duration (useful as an adjunct to
anesthesia)

MEPERIDINE

Potent MOR agonist

Strong analgesic action
Used for local anesthesia (epidural)
Can trigger an excitatory syndrome
One fifth as potent as morphine
Parenterally administered; poorly absorbed in GIT
Developed as a potential anti-cholinergic agent
Rapid onset; short duration of action (2hrs)
Less risk of addiction
Metabolite, normeperedine, is proconvulsant and hallucinogenic
Less antitussive and constipative effect (good for cancer and
pulmonary patients)
Indicated for severe pain in renal colic and biliary spasm due to its
antispasmodic effect

Additional from G&G:

Major use of meperidine is for analgesia; not used for

treatment of cough or diarrhea

Analgesic effects detectable 15 minutes after oral

administration

Peak concentration in 1-2hrs.

Clinical use:
o
Duration of effective analgesia: 1.5-3 hrs.

OPIOID DRUGS: MILD TO MODERATE AGONISTS

Trans by: Alimot, Alzona, Amante, Amit

CODEINE

less analgesic, sedative, respiratory depressant effects

than morphine and fewer GIT effects
mainly used as antitussive
w/ paracetamol = oral analgesic

DIPHENOXYLATE, LOPERAMIDE

Used as anti-diarrheal agents

Daily dose:
o Diphenoxylate 20mg
o Loperamide 4-8mg/day

Can cause greater drug dependency

From G&G:

Diphenoxylate
o
Piperidine derivative
o
At high doses can cause typical opioid activity and
after chronic administration can cause morphinelike physical dependency

Loperamide
o
Piperidine derivative
o
Slows GI motility as a result of interactions with
opioid receptors in the intestine
o
Most common side effect is abdominal cramps
o
Very low potential for abuse because of limited
access to brain (Katzung)

OPIOIDS DRUGS: MIXED AGONIST-ANTAGONIST

NALBUPHINE

Mixed agonist- antagonist

KOR agonistMOR antagonist opioid
Related structurally to naloxone/ oxymorphone
Very effective for post-operative pain
Less likely to produce dysphoric effects
Can produce dependence
More effective in women than in men (for agents that act
through KOR)
Similar in structure to naloxone and oxymorphone
Equipotent to morphine
Far greater antagonist activity
Produces less psychomimetic effects
For moderate to severe pain, postoperative and obstetric
analgesia
Low abuse potential; can precipitate withdrawal symptoms

Additional from G&G:

Usual adult dose: 10mg parenterally every 3-6 hours

OPIOID DRUGS: ANTAGONISTS

NALOXONE

Opioid receptor antagonist

Shorter duration of action (1-2 hours)
Can have overshoot phenomenon
Used in opioid overdosage
Pure opioid antagonist
For opioid overdose (fast onset, therefore can reverse S/Sx of
opiod overdose)
Can precipitate severe withdrawal signs

Edited by: Sheda

Page 12 of 18

Given alone to non-addicts, no observable pharmacological

effects
Other uses:
o
Alcohol overdose
o
Appetite suppressant
o
Dementia in schizophrenia
Adverse effects are minor

More common in under-excretors than over-producers (of

urates)

Additional: foods high in purine include soy,

intestines, peanuts, beans
Inflammatory response activated by urate crystals
o Monosodium
urate
crystals
activate
monocytes/macrophages via TLR pathway mounting
an immune response secretion of cytokines (e.g. IL-1
and TNF-) endothelial activation attraction of
neutrophils to site of inflammation secrete mediators
lowering of local pH further urate precipitation
(Katzung)

NALTREXONE

Opioid receptor antagonist

Higher oral efficacy/ longer duration of action (t1/2 = 10
hours)
o

Single oral dose of 100 mg blocks the effects of injected

heroin for up to 48 hrs (Katzung)

Aims of treatment:
1. Decrease the symptoms of an acute attack
2. Decrease risk of recurrent attacks
3. Lower serum urate levels

Step-wise management of gout (treatment options)

1. Relief of pain and inflammation: NSAIDs,
Colchicine, steroids
2. Prevent inflammatory response to crystals:
NSAIDs, Colchicine
3. Inhibit urate formation or augment excretion:
Allopurinol (decreases formation of uric acid),
Probenecid (augment excretion)

Used for drug dependence and addiction/alcoholism

3-5x as potent as naloxone
24-72 hrs duration of action
For opioid abstinence (good alternative to Methadone)
Undergoes first pass effect
Blocks subjective effects of opioid abuse and decreases cravings
Can cause liver damage
a

World Health Organization Analgesic Ladder

Step 1 Mild to Moderate Pain
Non-opioid adjuvant agent
Acetaminophen or an NSAID should be used, unless
contraindicated. Adjuvant agents are those that enhance
analgesic efficacy, treat concurrentsymptoms that
exacerbate pain, and/or provide independent analgesic
activity for specifictypes of pain.
Step 2 Mild to Moderate Pain or Pain Uncontrolled after Step 1
Short-acting opioid as required non-opioid around the clock
(ATC) adjuvant agent
Morphine, oxycodone, or hydromorphone should be added
to acetaminophen or an NSAID for maximum flexibility of
opioid dose
Step 3 Moderate to Severe Pain or Pain Uncontrolled after Step
2
Sustained release/long-acting opioid ATC or continuous
infusion + short-acting opioid as required non-opioid
adjuvant agent
Sustained release oxycodone, morphine, oxymorphone or
transdermal fentanyl is indicated.

Additional from 2013A trans:

Types of Gout:
1. Primary

2.

GOUT

Inflammatory arthritic disease

Causes:
o A painful distal monoarthritis (for weeks to
months; but can be polyarthritic)
o Joint destruction
o Subcutaneous deposits
o Renal calculi and damage

Metabolic disease characterized by recurrent episodes of acute

arthritis due to deposits of monosodium urate in joints and
cartilage (Katzung)

Hyperuricemia is a pre-requisite but does not always lead

to gout
o Hyperuricemia refers to high serum levels of uric acid a
poorly soluble substance that is the major end product of
purine metabolism (Katzung and 2013A trans)

Trans by: Alimot, Alzona, Amante, Amit

For an acute attack:

o
First line: NSAIDs
o
Coxibs (Arcoxia and Celebrex); Indomethacin; Ibuprofen
and Diclofenac
o
High dose for 3-4 days, then lower dose for 7-14 days
To prevent recurrent attack:
o
Colchicine
o
Hypouricemic therapy
o
Uricosuric agents

Overproduction of uric acid (10%)

Under-secretion of uric acid (90%)
Genetic aberration (Lesch-Nyhan syndrome)

Secondary

Accumulation of uric acid due to:

o
Drugs thiazide diuretics, aspirin, nicotinic
acid
o
Lymphoproliferative disease
o
Hemoglobinopathies
o
Chronic renal disease
o
Lead poisoning

COLCHICINE

Oldest available therapy for gout

o Secondary treatment (second-line) today because
of adverse reactions (e.g. increase chances of being
diabetic; GI effect like diarrhea)
Anti-mitotic effects on cells with rapid turnover (e.g.
neutrophils, GI epithelium)
MOA: binds to tubulin prevents polymerization into
microtubules inhibition of leukocyte migration and
phagocytosis anti-inflammatory effects (Katzung)

Edited by: Sheda

Page 13 of 18

Other effects:
o Inhibits release of histamine from mast cells
o Inhibits secretion of insulin
o Inhibits movement of melanin granules

in

melanophores (G&G)

Pharmacokinetics
From G&G:

Absorption of oral colchicines is rapid but variable

Peak plasma concentration: 0.5-2hrs after dosing

In plasma, 50% protein bound

Narrow therapeutic window

Only 10-20% excreted in urine
Plasma half-life: ~9 hrs
o But drug can be detected in urine for at least 9 days after
single IV dose

Therapeutic Uses

Treatment for 3 days (minimum) (7-14 days between

courses) to avoid cumulative toxicity
Should be given within 24 hours of acute attack
Colchicine dramatically relieves acute attacks of gout if given
within 24 hrs. (G&G).

For prevention of recurrent attacks:

o 0.6 mg 3-4 days/week if <1 attack/ year
o 0.6 mg daily if >1 attack/ year
o 0.6 2-3x/day if with severe attack
Used for prophylaxis of recurrent episodes of gouty arthritis,
effective in preventing attacks of acute Mediterranean fever, and
may have beneficial effect in sarcoid arthritis and in hepatic
cirrhosis. (Katzung)

Pharmacokinetics
From G&G:

Absorbed (around 80%) relatively rapidly after oral ingestion

Peak plasma concentrations reached within 60-90 minutes

Plasma half-life: 1-2 hours

o Allows for once-daily dosing = most commonly
used anti-hyperuricemic agent

Therapeutic Uses

Lowers body temperature; depresses respiration, GI

stimulation and sympathetic stimulation

From G&G:

Theres GIT susceptibility to colchicines toxicity: Nausea,

vomiting, diarrhea, abdominal pain

(Additional) Other adverse effects: myelosuppression,

leukopenia, granulocytopenia, thrombopenia, palastic
anemia, rhabdomyolysis
From Katzung:

Hepatic necrosis, acute renal failure, DIC, and seizures have

also been observed

The more severe adverse events have been associated with

intravenous administration of colchicines

An analog of hypoxanthine
Inhibits xanthine oxidase and prevents synthesis of urate
from hypoxanthine and xanthine

Mechanism of Action
From G&G:

Allopurinol competitively inhibits xanthine oxidase at low

concentrations and is a non-competitively inhibitor at high
concentrations

Allopurinol is also a substrate for xanthine oxidase

Trans by: Alimot, Alzona, Amante, Amit

Goal of therapy: reduce plasma uric acid

concentration to <6mg/dl
Dose: 100 mg/ day increments of 100 mg weekly

Adverse Effects

Well tolerated
Adverse reactions include:
o Hypersensitivity reactions
Most common adverse effect
May manifest ater months or years of therapy
(G&G)

SJS (Steven Johnson Syndrome)

Rarely occurs

PROBENECID

ALLOPURINOL

Reverses hyperuricemia
Other effects: inhibits release of histamine from mast
cells, secretion of insulin and movement of melanin

From G&G:

Oral thereapy: provides effective treatment for primary and

secondary gout, hyperuricemia 2 to malignancies, and
calcium oxalate calculi

IV therapy: indicated for hyperuricemia 2 to cancer

chemotherapy (if patient cant tolerate oral therapy)

Adverse Effects

Primary metabolite formed: oxypurinol

noncompetitive inhibitor of enzyme also
Formation and long persistence of oxypurinol in tissues is
responsible for much of the pharmacological activity of
allopurinol
During allopurinol treatment, concentration of plasma uric
acid is reduced and purine excretion increased w/o exposing
the urinary tract to an ecessive load of uric acid (since the
urinary purines formed during treatment are hypoxanthine,
xanthine and uric acid; and each has its independent
solubility)
o
In the absence of allopurinol, the dominant urinary
purine is uric acid
o

A uricosuric agent
o Uricosuric agents increase rate of excretion of uric acid
(G&G)

Highly lipid-soluble benzoic acid derivative (G&G)

Mechanism of Action

Inhibit transport of organic acids across eptihelial barrier

Inhibits reabsorption of uric acid
o Probenecid inhibits reabsorption of uric acid by organic
o

anion transporters, principally URAT-1

Uricosuric action is decreased by administration of
salicylates (G&G)

Other effects:
Edited by: Sheda

Page 14 of 18

o
o

Inhibits renal secretion of methotrexate, clofibrate

and metabolites of NSAIDs
Depresses biliary secretion of rifampin leading to

higher plasma concentrations (G&G)

Delay excretion of pencillin

Pharmacokinetics (from G&G)

Absorbed completely after oral administration (high lipid

solubility)
Peak concentrations in plasma reached in 2-4 hours
Plasma half-life is dose dependent
o Varies from <5 hours to >8 hours

Therapeutic Uses

Dose: 250 mg bid daily, may increase over 1-2 weeks to

500 - 1000 mg bid daily

Probenencid increases urinary urate levels

May precipitate an attack of gout early in the course of therapy
(among 20% of gouty patients) if used alone (G&G)

Adverse Effects

Well tolerated
Adverse reactions:
o Mild GI irritation
In approximately 2% of patients
Risk is increased at higher doses
o Hepatoxicity
o Hypersensitivity reactions are usually mild (2-4% patients)

----------------------------------FIN-------------------------------------References:
Dr. Guevarras lecture
Goodman &Gillman
Katzung
2013 trans

Trans by: Alimot, Alzona, Amante, Amit

Edited by: Sheda

Page 15 of 18

PAIN KILLERS, GOUT AND OPIOD ANALGESICS (from previous batchs trans. It might help )
Drug group

General description

I. NSAIDS

Used to dec incidence of

ischemic attacks,
angina, coronary artery
thrombosis

MOA
Inhibits:
- COX1 & COX2
- Eicosanoids
- Biological oxidants
- Cytokines
- Adhesion factors
- Digestive enzymes
Pain
- Mild analgesic
- Sensitize pain receptor
causing hyperalgesia
- Release of bradykinin
fever
Inhibit cytokine prod
(IL1, TNF)
Anti-inflammatory, antiplatelet aggregation
Inhibits PG synthesis:
irreversibly blocking COX
enz

A. Aspirin

B. propionic acid
derivative

Pharmacologic actions

Indications
Myositis, bursitis
tendonitis, arthritis
Viscera
headaches

Pharmacokinetics

ADR/CI
Hepatitis, inc ALT AST
SJS, TEN

Analgesia
- Centrally mediated
- Peripheral (anti-inflam):
block PG synthesis,
antagonism of
bradykinin
Antipyresis
Anti inflammatory
- DOC: rheumatic ds
- Inhibit PG syn
- Inhibit PMNs &
macrophages migration
Effects on uric acid levels
- Dec urate sec (1gm/day)
- Uricosuric (5gm/day)
Blood
- Inhibits thromboxane
synthesis (8-10 days)
Skin
- Irritation
- Slow & painless e.
destruction
- Keratolytic

Analgesic
Antipyretic
Anti-inflammatory
Uricosuric at high doses
Anti-platelet

Half life:
- analgesic: 3-6 hrs
- anti-inflam: 15-30 hrs

ADR:
Allergy
Salicylism toxicity
Gastric upset, ulcers
Reyes syndrome

Alter plateletfxn, prolong BT

GIT effects < aspirin
Often combined with
paracetamol

Trans by: Alimot, Alzona, Amante, Amit

Edited by: Sheda

CI:
Last trimester of
pregnancy
Bleeding d/o
gastric duodenal
ulcers
children w/ varicella
or influenza (reye)

liver: acetylation
water soluble conjugates:
glucoronides & salicyluric
acid
salicylate excretion: inc
alkalinization

Arthritis, myositis,
tendonitis; Can close
patent ductus arteriosus

1. Ibuprofen

absorption:
rapid, stomach &
intestine
food interference
effervescent drug
mixtures dec gastric
emptying time
methyl salicylate
(cutaneous app) absorbed
rapidly, drug traces are
detected in the urine w/in
15 mins

Side effects: epigastric

pain, nausea,
thrombocytopenia,
skin rash, headache
CI: px taking aspirin
Page 16 of 18

2. Naproxen

C. Diclofenac

D. Indomethacin

Most common in
Europe

Potent NSAID

All types of headaches

Pain relief

Longer halflife (2x/day)

Better COX2 inhibition

Arthritic conditions
Topical for ocular inflam

Reversible elevation in
serum aminotransferase

Gastric discomfort,
headache, sweating
Low incidence of GI
bleeding
Lumiracoxib
hepatotoxicity
CVS hazard

Long half life (1x/day)

Anorexia, nausea,
abdominal pain,
ulcers, acute
pancreatitis, diarrhea
Frontal headache,
dizziness, depression
Neutropenia,
thrombocytopenia,
impaired platelet fxn
hypersensitivity
Higher incidence of GI
bleeding

Gouty arthritis
Ankylosing spondylitis
Osteoarthritis
Closure of patent ductus
arteriosus
Treatment of Bartters
syndrome

COX1 = COX2 inhibiton (?)

Inhibit activation of
neutrophils
Dec ROS
COX1 = COX2 inhibiton (?)
COX2 >>>> COX1

E. Piroxicam

F. Meloxicam

G. Mefenamic acid

Most common in
Philippines

H. Tolmetin

Same potency w/
aspirin

I. Ketorolac

COX1 = COX2 inhibiton

Often used for acute gout

Osteoarthritis
Rheumatoid arthritis

COX1 = COX2

Short half life

Replace morphine in mild
to moderate
postoperative pain
control

Potent analgesic
Topical agts
st

J. Coxibs

II. Paracetamol

1 gen: celecoxib (celebrex), rofecoxib (vioxx),

valdecoxib (bextra)
Selectivity to COX2: lumiracoxib (prexige) = etorcoxib
(arcoxia) > valdecoxib = rofecoxib > celecoxib

Npara-aminopenol
group

Trans by: Alimot, Alzona, Amante, Amit

GI side effects

COX 2 inhibitors

Weak COX1 & COX2

inhibitor

Celecoxib: Osteoarthritis
Acute paine
Primary dysmennorhea

Mild to moderate pain

Edited by: Sheda

GI bleeding & diarrhea

Dyspepsia, upper GI
discomfort, diarrhea
Hemolytic anemia
common

Peptic ulceration
Renal compromise
Bleeding tendencies

Arcoxia long half life

Prodrug: phenacetin
(toxic)
Metabolite:
acetaminophen

CVS complications

Hepatoxocity
(>500mg)
Cyanosis (formation of
methemoglobin
Mild hemolytic
anemia
Renal tubular necrosis

Page 17 of 18

Drugs for Gout

Antimitotic effect: inhibit
microtubule formation
Inhibits chemotactic
property of leukocytes
Inhibits lipooxygenase
pathway (leukotriene syn)

I. Colchicine

Inhibit xanthine oxidase

prevents syn of urate from
hypoxanthine & xanthine
Low conc: competitive
High conc: noncompetitive

II. Allopurinol

Alleviating inflammation
of gouty arthritis
Prophylaxis of recurrent
episodes of gouty
arthritis

Lowers uric acid conc in

plasma
Prevents development or
progression of chronic gouty
arthritis
Disappearance of uric stone

Primary uricemia of the

gout

III. Probenecid
Inc rate of excretion of uric
acid

IV. Sulfinpyrzone
(Uricosuric)

Severe acute attacks of

gouty arthritis

Oral: rapidly absorbed

IV: rapid relief, fewer GI
effects

Active metabolite:
alloxanthine (oxypurinol)
long half life,
noncompetitive
Can inc half-life of
probenecid & enhance its
uricosuric effect
Dec plasma uric acid to
<6mg/dl

Reabsorbed completely
by the kidney and
metabolized slowly
Rapidly excreted by the
kidneys

Diarrhea
Bone marrow
suppression

Precipitation of acute
gouty attact
Maculopapular skin
rash
Interstitial nephritis
Nausea, vomiting,
diarrhea
Bone marrow
suppression
Hepatitis, vaculitis
DI:
Oral anticoagulant
Mercaptopurine,
azothioprine
probenecid
GIT irritation
Allergic dermatitis
Nephritic syndrome
Aplastic anemia

OPIOID ANALGESICS
I. Opioid agonist
CNS analgesia, sefation,
euphoria, respiratory
depression, nausea &
vomiting, antitussive, miosis,
reduce shivering

A. Morphine

the standard

GIT dec motility, inc

sphincter tone, constipation
Inc intrabiliary pressure
CVS orthostatic
hypotension, peripheral
vasodilatation, bradycardia
Genitourinary urinary
retention, may prolong
labor, oligo/amenorrhea,
delayed/absent ejaculation

Trans by: Alimot, Alzona, Amante, Amit

Edited by: Sheda

Moderate to severe pain

Pre-op: sedation and
anxiolytic
Post-op MI
Analgesia MI, postoperative pain,
obstetrical analgesia
Anesthesia
Acute pulmonary edema
Diarrhea
Cough

Oral: first pass effect

DI:
CNS depressants
Antidepressants MAO
inhibitors, tricyclic
antidepressants

Precaution:
respiration is
compromised, biliary
colic, acute
pancreatitis, head
injury, hepatic
insufficiency,
convulsant state,
hypotension
Toxicity
Tolerance
Physical dependence
CI: asthma,
ummunocompromised
stated, head trauma

Page 18 of 18

Potential anti-cholinergic
agent
Anti-muscarinic effects

B. Meperidine
(Pethidine)

C. Fentanyl/
suftenyl/
alfetanyl

D. Codeine

II. Mixed opioid

agonist &
antagonist

A. Nalbuphine

Extremely potent

80x analgesic potency &

respiratory depressant

Metabolized to
morphine

Antitussive effect

Potent analgesics
Withdrawal symptoms

Equipotent to morphine
Low abuse potential

Severe pain in renal colic

& biliary spasm
Choice in obstetric
analgesia

Long neurological cases

Adjunt to anesthesia
(droperidol)
Open heart surgery

Parenteral
Rapid onset, short
duration
Metabolite:
normeperedine
proconvulsant &
hallucinogenic
Trapped in fats

Bradycardia
Muscle rigidity

Oral
Derivatives:
hydromorphone 8x more
potent

Less sedation,
respiratory
depression, and GIT
effects
Hallucinogenic, low
degree of
dependence, produce
withdrawal signs &
stimulates
sympathetic discharge
Respiratory
depression
Antagonized by
naloxone
Sedation, sweating,
headache, dizziness
Tolerance & physical
dependence

Slow IV or continuous
infusion

Precipitate severe
withdrawal signs

Moderate to severe pain

Kappa receptor agonist

More potent mu receptor
antagonist

Greater antagonistic act

Less psychomimetic effects

Moderate to severe pain,

postoperative & obstetric
analgesia

III. Opioid Antagonist

A. Naloxone

No observable

B. Naltrexone

Blocks subjective effects of

opioid abuse & decreases
cravings

Trans by: Alimot, Alzona, Amante, Amit

Edited by: Sheda

Opioid overdose
Alcohol overdose,
appetite suppressant,
dementia &
schizophrenia
Opioid abstinece

Liver damage

Page 19 of 18