B.

PHARMACY
5th Semester
Pharmacology-II
BP503T
Unit 3
Mr. Smrutiranjan Dash
Assistant Professor
Faculty of Pharmacy
Kalinga University
Naya Raipur (C.G.), India
BP503T- Pharmacology II 1
Pharmacology-II (BP503T)

Course Objectives-
Upon completion of this course the student should be able to-
1. Understand the mechanism of drug action and its relevance in the
treatment of different diseases.
2. Demonstrate isolation of different organs/tissues from the laboratory
animals by simulated experiments.
3. Demonstrate the various receptor actions using isolated tissue
preparation
4. Appreciate correlation of pharmacology with related medical sciences

Course Outcome-
After completion of this unit students will be able to understand different
drugs (classification, mechanism of action, therapeutic effects, clinical
uses, side effects and contraindications) used in the treatment of various
BP503T- Pharmacology II 2
inflammatory disorders. Also they will learn about various inflammatory
CONTENTS
B.Pharmacy
5th Semester
BP503T
Pharmacology II
S.No. Autocoids and related drugs
1 Introduction to autacoids and classification of autocoids
2 Histamine, 5-HT and their antagonists
3 Prostaglandins, Thromboxanes and Leukotrienes
4 Angiotensin, Bradykinin and Substance P.
5 Non-steroidal anti-inflammatory agents
6 Anti-gout drugs
7 Anti rheumatic drugs

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REFERENCE BOOKS
1. Goodman and Gilman’s, The Pharmacological Basis of Therapeutics
2. Marry Anne K. K., Lloyd Yee Y., Brian K. A., Robbin L.C., Joseph G. B., Wayne
A.K., Bradley R.W., Applied Therapeutics, The Clinical use of Drugs, The Point
Lippincott Williams & Wilkins.
3. Mycek M.J, Gelnet S.B and Perper M.M. Lippincott’s Illustrated Reviews-
Pharmacology.
4. K.D.Tripathi. Essentials of Medical Pharmacology, , JAYPEE Brothers Medical
Publishers (P) Ltd, New Delhi.
5. Sharma H. L., Sharma K. K., Principles of Pharmacology, Paras medical
publisher

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 LECTURE PLAN
Lecture No. Topics to be covered Slide No.
L27 Introduction to autacoids and classification 7-13
L28 Introduction to autacoids and classification 14-25
L29 Histamine and its functions 26-39
L30 5-HT and their antagonists. 40-66
L31 5-HT and their antagonists. 67-78
L32 Prostaglandins and its functions 79-88
L33 Thromboxanes and Leukotrienes and its functions 89-108
L34 Angiotensin system in RAS 109-119
L35 Bradykinin and Substance P. 120-136
L36 Non-steroidal anti-inflammatory agents 137-149
L37 Non-steroidal anti-inflammatory agents 150-159
L38 Non-steroidal anti-inflammatory agents 160-164
L39 Anti-gout drugs 165-170
L40 Antirheumatic drugs 171-173
Quiz Quiz 174-180
Answers Answers 174-180
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 UNIT 3

Module 1
Introduction to autacoids and
classification

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 AUTOCOID
• Auto- self , akos –healing substance or remedy
• Acts locally ( with in inflammatory cells) at the site of synthesis and
release
• Also known as local hormones
• Differ from the hormones in two way?
• Acts as mediator in physiological and pathological processes, reaction
to injury and immunological insult)
• Serve as transmitter or modulator in nervous system

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 Classification of autacoids

 Amine autocoids: Histamine, 5-Hydroxytryptamine

 Lipid derived autocoids: prostaglandins, leukotrienes, platelet activation factor

 Peptide autocoids: plasma kinins (bradykinins, kallidin), Angiotensin

In addition Cytokines ( interleukins, TNFalpha, GM-CSF etc)

Several peptides Gastrin, somatostatin, vasoactive intestinal peptide

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 Histamine
• Histos: Tissue
NH2
•Present mostly in mast cells:
5 4  skin, lungs, GIT Mucosa
H
1
N N
3
•Non mast cell histamine:
2 Brain, Gastric Mucosa
Histamine

Histamine is a biogenic amine present in many animal and plant tissues .

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 Histamine
• Meaning tissue amine, present in animal tissues and in certain plants eg:
stinging nettle
• Implicated as mediator in hypersentivity and tissue injury reactions
• Present almost and stored in mast cell
• Tissues rich in histamine are skin gastric mucosa and intestinal mucosa,
lungs,
liver and placenta.
• Non mast cell histamine occurs in brain , epidermis, gastric mucosa and growing
regions
• Also presents in body secretions, venoms and pathological fluids

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Synthesis, storage & metabolism of
histamine

• Synthesized by decarboxylation of
amino acid histidine

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Pharmacological actions
Stimulating H1, H2, H3 Receptors
• Blood vessels:
– Dilates arterioles, capillaries, venules,
Red spot
• IV injection- decreased BP (dilatation)
• Intradermal- Triple response
Wheal
(exudation of
fluids)
Flare(Reflex
arteriolar dilatation)

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• CVS: rate as well as force of contraction is increased (H2)
• Visceral smooth muscles:
Bronchoconstriction, abdominal cramps, colic by intestinal contractions,
uterus is contracted in animals
Smooth muscle is H1 response, sometimes H2 mediated relaxation is
also seen
• Secretions:
– Increased gastric secretion (H2) primarly of gastric but also pepsin
mediated by increase cAMP generation
– Increased nasal secretions (H1)

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• Sensory Nerve Endings: i.v/ Intracutaneosly occurs itching

Higher concentrations injected more deeply causes pain

• Autonomic ganglia and adrenal medulla: stimulated and release
Adr- causes secondary rise in BP
• CNS: Doesnot cross/ penetrate BBB- no central effects are seen on
i.v

– Wakefulness, rise in BP, cardiac stimulation, behavioral arousal,

hypothermia, vomiting and ADH release on intra
Cerebroventricular Injection (H1/H2)
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 Pathophysiological Roles
• Gastric secretion(H2)
• Allergic phenomena (H1)
• As transmitter : regulate body temperature, CVS, thirst etc (H1)
• Inflammation (p-selection adhesion of leukocytes)
• Tissue growth and repair
• Head ache

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Therapeutic Uses
• Betahistine
• H1 Selective histamine analogue
– To control vertigo in Meniere`s disease 8 mg tab ½
tablet (probably by vasodilatation in inner ear)
Histamine releasers
• stings and venom
•Ag-Ab reaction
•Drugs
 d-tubocurarine
Morphine
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 Histamine releasers
• Variety of mechanical , chemical and immunological stimuli are capable
of releasing histamine from mast cell
• Tissue damage: trauma, stings and venoms, proteolytic enzymes,
phospholipase A
• Polymers like dextrans, polyvinyl pyrrolidone
• Basic drugs: tubocurarine, morphine, atropine, pentamidine,
plymyxin B, vancomycin

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 Adverse effects of histamine release

• Itching, Urticaria
• Flushing
• Hypotension
• Tachycardia
• Bronchospasm
• Angioedema
• Wakefullness
• Increased acidity (Gastric acid secretion)

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Mechanism of Action of Histamine
Histamine

H1 Receptors H2 Receptors H3 Receptors

(presynaptic auto
receptors)

↑ Ca2+ ↑ cAMP ↓ cAMP

Smooth muscle contraction ↑ Gastric acid secretion ↓ histamine release

Increased capillary Blood vessels: ↓secretion
permeability vasodilation
Vasodilation Increased capillary Vasodilatio
Sensory nerve endings pain permeability n
& itching
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Classification of H1 Antagonists

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Mechanism of action

Competitive antagonism

Histamine General formula of H1 Blocker

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BP503T- Pharmacology II 22
 Pharmacological actions
• CNS depression: (More with first generation)
– Sedation and drowsiness
– Some have antiemetic and antiparkinsonian effects
• Antiallergic action
• Anticholinergic actions (More with first generation)
– Dryness of mouth , Blurring of vision
– Constipation
– Urinary retention

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Pharmacological Actions

• Local anesthetic
• BP: smooth muscle relaxation/ alpha
adrenergic blocade
• Antimotion sickness effect: Dimenhydrinate,
Promethazine
• Antiemetic: Promethazine
• Antiparkinsonism: Diphenhydramine,
orphenadrine, promethazine(IV)
• Antivertigo: cinnarizine
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Preparations & dosage (Daily)
Drug Dose
1. Diphenhydramine 25-50 mg oral
2. Dimenhydrinate 25-50 mg oral
3. Promethazine 25-50 mg oral/injection
4. Chlorpheniramine 2-4 mg oral
5. Pheniramine 25- 50 mg oral/im
6. Cinnarizine 25-150 mg oral
7. Cyprohepatidine 4 mg oral

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 Therapeutic uses
1. Allergic rhinitis & common cold
2. Allergic dermatitis, itching, urticaria
3. Wasp stings/ bite: pain and itching decreases
4. Mild blood transfusion reactions
5. Allergic conjunctivitis
6. Motion sickness: dimenhydrinate, promethazine
7. Morning sickness: promethazine

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8. Vertigo: cinnarizine
9. Chronic urticaria
10.Appetite stimulant: cyprohepatidine
11.Drug induced parkinsonism: Diphenhydramine,

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 Adverse effects
• Sedation
• Anticholinergic effects
• Dermatitis on local use
• Cyclizine, meclizine : teratogenicity

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 Second generation H1 Blockers
(Non Sedative:Less anticholinergic property)
• Fexofenadine
• Astemizole Uses:
• Allergic rhinitis
• Loratidine • Allergic Dermatitis
• Cetrizine • Allergic conjunctivitis
• Levocetrizine • Urticaria
• Common cold
• Azelastine
• Terfenadine

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 Advantages of second generation
antihistaminics
• They have no anticholinergic side effects
• Do not cross blood brain barrier (BBB), hence
cause minimal or no drowsiness and
sedation
• Do not impair Psychomotor performance

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 Serotonin

RVS Chaitanya Koppala

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 SEROTONIN
• Named after the vasoconstrictor substances which appeared in serum
when blood clotted
• Smooth muscle contracting substance present in enterchromaffin cell of
GIT
• About 95% of 5-HT receptors concentrated in Intestine remaining in
platelets and brain
• Wasp and scorpion sting also contains serotonin
• Widely distributed in invertebrates and plants (banana , pear, pineapple,
tomato, stinging)

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 SYNTHESIS, STORAGE AND
DESTRUCTION
• 5-HT is ß-aminoethyl-5-hydroxyindole.
• It is synthesized from the amino acid tryptophan and
degraded primarily by MAO and to a small extent by a
dehydrogenase

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SEROTONERGIC (5-HT) RECEPTORS

• Gaddum and Picarelli (1957) classified 5-HT receptors into musculotropic (D type)
and neurotropic (M type).
• Four families of 5-HT receptors (5-HT1, 5HT2, 5-HT3, 5-HT4-7) comprising of 14
receptor subtypes have so far been recognized.
• All 5-HT receptors (except 5-HT3) are G protein coupled receptors

• which function through decreasing (5-HT1) or increasing (5-HT4, 5-HT6, 5-

HT7)
cAMP production or by generating IP3/ DAG (5-HT2) as second messengers.
• The 5-HT3 expresses large number of 5-HT2C
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II 34
Receptor 5-HT1 5-HT2 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7

Subtypes A/B/D/E/F 2A/B/C 3A/B 5A/B

Signalin cAMP↓ IP3-DAG Ion channel cAMP↑ cAMP↓ cAMP↑ cAMP↑

g
pathway

Location Brain stem, vascular Somatic mucosa, mucosa, mucosa, mucosa,

raphe nucleaus, visceral smooth autonomic, plexuses and plexuses and plexuses and plexuses and
nerve ending muscle, myenteric smooth smooth smooth smooth
platelets and plexus, Area muscle of the muscle of the muscle of the muscle of the
cerebral postrema Gut, brain, Gut, brain, Gut, brain, Gut, brain,
Neurones. nucleus hippocampus, hippocampus, hippocampus, hippocampus,
tractus colliculi colliculi colliculi colliculi
solitarious

Agonist Buspirone, Alpha- Alpha- Cisapride, ----- Clozapine Clozapine

methyl 5-HT methyl 5-HT renzaprid
sumatripti e
n
Antagonist Pindolol Ketenserin Odansetron ---- ----- ----

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Receptor 5-HT1 5-HT2 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7
Actions Antimigraine platelets, Antiemetic, gut Intestinal Cloned Cloned Cloned
aggregation, wall and brain secretions and receptors of receptors receptors of
bronchial peristalsis 5HT4 of 5HT4 5HT4
contriction

Roles Constricts cranial vascular and depolarizes Mediate unknown Unknown unknown
blood vessels and visceral smooth neurones by intestinal
inhibits release of muscle gating cation secretion,
inflammatory contraction, channels; elicits augmentation
neuropeptides in platelet reflex effects of peristalsis
them; sumatriptan aggregation, of 5-HT—
(antimigraine) acts neuronal emesis, gut
through these activation peristalsis,
receptors in brain bradycardia,
transient
hypotension,
apnoea, pain,
itch

Drugs Sumatriptan Ketanserin Odansetron Renzapride Unknown Unknown Unknown

acting (antimigraine)

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Pharmacological action of serotonin
1. CVS Arteries are constricted (by direct action on vascular smooth muscle) as well
as dilated (through EDRF release) by 5-HT, depending on the vascular bed and the
basal tone
BP: a triphasic response is classically seen on i.v. injection of 5-HT in animals.

2.Vascular smooth muscle: potent stimulator of g.i.t., both by direct action as well as
through enteric plexuses. Peristalsis is increased and diarrhoea can occur

3.Glands 5-HT inhibits gastric secretion: (both acid and pepsin), but increases mucus,
It thus has ulcer protective property. Effect on other glandular secretions is not
significant.
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4. Nerve endings and adrenal medulla Afferent nerve endings are activated causing
tingling and pricking sensation, as well as pain.

5.Respiration A brief stimulation of respiration (mostly reflex from bronchial

afferents) and hyperventilation are the usual response

6.Platelets By acting on 5-HT2A receptors 5-HT causes changes in shape of platelets,

but is a weak aggregator.

7. CNS Injected i.v. 5-HT does not produce central effects

Direct injection in the brain Produces sleepiness, changes in body temperature and
a variety of behavioural effects
BP503T- Pharmacology II 38
 Pathophysiological roles
• Neurotransmitter (sleep, temperature regulation, thought,
cognitive function, behaviour and mood, appetite, vomiting and
pain perception)
• Precursor of melatonin(regulate the biological clock and
maintain circadian rhythm)
• Neuroendocrine function (anterior pituitary hormones are
probably regulated by serotonergic mechanism)
• Nausea and vomiting (evoked by cytotoxic drugs or
radiotherapy is mediated by release of 5-HT)
BP503T- Pharmacology II 39
 Pathophysiological roles
 Migraine:5-HT is said to initiate the vasoconstrictor phase of migraine
 Haemostasis (5-HT accelerates platelet aggregation and clot formation
 Angina (5-HT released from platelets has been implicated in causing
coronary spasm and variant angina)
 Hypertension (Increased responsiveness to 5-HT as well as its reduced
uptake and clearance by platelets has been demonstrated in
hypertensive Patients)
 Intestinal motility (5-HT containing neurones may regulate peristalsis
and local reflexes in the gut)
 Carcinoid syndrome (Bowel hypermotility and bronchoconstriction in
carcinoid is due to 5-HT) BP503T- Pharmacology II 40
Drugs affecting serotonin system
•Drugs Action/activity
5-HT precursor Increase level of serotonin (tryptophan)
Synthesis inhibitor P-chloropheniramine –reduce 5-HT level
Uptake inhibitor TCA- antidepressant/antianxiety
Storage inhibitor Reserpine – anorectic property
Degradation inhibitor NON-MAO/ SELECTIVE MAO antidepressant

Neural degeneration 5-6-dihydoxy tryptamine

5-HT receptor agonist Azapirones, sumatriptin, cisapride
5-HT receptor antagonist Cyproheptadine, methysergide, ketanserin
BP503T- Pharmacology II 41
 Serotonin
antagonist
S.NO Drug Activity Adverse effect
1 Methysergide (5-HT2 and 5HT1) Migraine prophylazxis, Abdominal, intestinal,
endocarial fibrosis
2 Ketanserin (5HT2) Antihypertensive, Vasospastic
vasoconstriction,
bronchoconstriction
3 Clozapine (5HT blocker) Efficient cases in
schizophrenia
4 Risperidone (5-HT2A-D2) Ameloriative negative Extrapyramidal symptoms
symptoms
5 Odansetron (5-HT3) Nausea and vomiting Anticancer and
radiotherapy
6 Ergotamine (5-HT1 /2) (agonist) Vascular, visceral Damage to capillary
constractions, potent emetic endothelium

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PROSTAGLANIDS AND THROMBOXANES

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INTRODUCTION:
• Group of hormone-like lipid compounds
• Derived enzymatically from fatty acids
• Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring.
• They are produced in many places throughout the body and their target cells are present in the
immediate vicinity of the site of their secretion.
• The prostaglandins, together with the thromboxane and prostacyclin, form the prostanoid class of
fatty acid derivatives, a subclass of eicosanoids.
• They are autocrine and paracrine lipid mediators that act upon platelets, endothelium, uterine and
mast cells. They are synthesized in the cell from the essential fatty acids (EFAs).

BP503T- Pharmacology II 44
• Arachidonic acid is the precursor for the biosynthesis of all PGs. And the
enzyme involved is COX ( cyclooxygenase ).

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BP503T- Pharmacology II 46
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PROSTANOID RECEPTORS

• PGs act on prostanoid receptors to show their action.

• All are GPCRs.
• There are five classes of prostanoid receptors. They are –
• DP (for PGD 2) – subtypes DP1 and DP2
• EP (for PGE 2) – subtypes EP1 and EP4
• FP (for PGF 2 alpha)
• IP (for PGI 2)
• TP (for TXA2)

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BP503T- Pharmacology II 49
 PHARMACOLOGICAL ACTIONS
• On CVS:
mediator action role
PGD2 VD
PGE2 VD Maintain patency of ducutus
arteriosis before surgery.

PGI 2 VD Dec peripheral, pulmonary and

coronary resistance Regulate local
vascular tone.

PGF2 α VC pulmonary V&A VD Stimulate heart by prominent

reflex action due to fall in
BP. The CO incereases.

TXA 2 VC
BP503T- Pharmacology II 50
• On GIT:
• PGI 2 and PGE 2 – dec acid secretion and inc mucus secretion. And also increase
peristalsis.
• PGE 1 – reduce NSAIDS induced ulcers.
• Airways:
• PGF2α, PGD2 and TXA2 – are potent bronchoconstrictors.
• PGE2 is a powerful bronchodilator.
• PGI2 produces mild dilatation.
• Platelets:
• TXA2, produced locally by platelets, is a potent inducer of aggregation.
• PGG2 and PGH2 are also proaggregatory.
• PGI2- potent inhibitor of platelet aggregation.
• PGD2 has antiaggregatory action. Less potent

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• Eyes:
• PGF2α induces ocular inflammation and lowers i.o.t by enhancing uveoscleral outflow.
• Used in glaucoma.
• Kidneys:
• PGE2 and PGI2 increase water, Na+ and K+ excretion and have a diuretic effect.
• PGE2 has furosemide-like inhibitory effect on Cl¯ reabsorption as well.
• They cause renal vasodilatation and inhibit tubular reabsorption. PGE2 antagonizes
ADH action, and this adds to the diuretic effect.
• TXA2 causes renal vasoconstriction.
• PGI2, PGE2 and PGD2 evoke release of renin.
• CNS:
• injected intracerebroventricularly
• PGE2 produces a variety—sedation, rigidity, behavioral changes and marked rise in body temperature.
• PGI2 also induces fever, but TXA2 is not pyrogenic.
• PNS:
• both inhibition as well as augmentation of NA release from adrenergic nerve endings
has been observed.
• PGs may modulate sympathetic neurotransmission in the periphery.
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• Reproductive system:
• Female reproductive system:
• Uterus:
• PGE 2 &PGF2α –
• contract pregnant unterus.
• Induce labor at term
• Cervical priming.
• Control PPH.
• Male reproductive system:
• PGs facilitate motility of sperms and fertilization by coordinating the movement of the uterus.
• Endocrine system :
• PGE2 facilitates release of anterior pituitary hormones—growth hormone,
prolactin, ACTH, FSH and LH as well as that of insulin and adrenal steroids.
• It has a TSH like effect on thyroid.

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 THERAPEUTIC USES
• Gynecological and obstetrical:
• Abortion: • PGE 2 used
• Softenstimulate
• 2 alpha
PGE 2 and PGF cervix foruterine
induction of labor. and cause ripening of cervix.
contractions
• ofPPH:
• Facilitation labor:
• PGF 2 alpha used alternative to ergometrine.
• GIT:

• PGE 1 & 2 – prevent peptic ulcer on high dose of NSAIDs.

• CVS:Patent ductus arteriosus
• Glaucoma
• PGF 2 alpha reduce i.o.t
• Periphereal vacular diseases
• Pulmonary hypertension
• Erectile dysfunction

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ADVERSE EFFECTS
• Depending upon dose, type of PG and route.
• Diarrhoea, nausea, vomiting, fever, hypotension and pain are common
• unduly forceful uterine contractions, vaginal bleeding, flushing, shivering, fever, malaise, fall in BP,
tachycardia, chest pain.

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LEUKOTRIENES

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INTRODUCTION
• Leukotrienes are so named because they were first obtained from leukocytes
(leuko) and conjugated double bonds
• The straight chain lipoxygenase products of arachidonic acid are produced by a more
limited number of tissues (LTB4 mainly by neutrophils; LTC4 and LTD4—the cysteinyl
LTs—mainly by macrophages), but probably they are pathophysiologically as important
as PGs.

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BP503T- Pharmacology II 58
ACTIONS
• On CVS and blood.
• LTC4 and LTD4 injected i.v.evoke a brief rise in BP followed by a more prolonged fall. It is probably a result of
coronary constriction induced decrease in cardiac output and reduction in circulating volume due to
increased capillary permeability.
• markedly increase capillary permea bility .
• LTB4 is highly chemotactic for neutrophils and monocytes.
• LTC4 and D4 cause exudation of plasma
• Smooth muscles:
• LTC4 and D4 contract most smooth muscles.
• They are potent bronchoconstrictors and induce spastic contraction of g.i.t. at
low concentrations.
• They also increase mucus secretion in the airways
• Afferent nerves
• Like PGE2 and I2, the LTB4 also sensitizes afferents carrying pain impulses—
• contributes to pain and tenderness of inflammation.
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LEUKOTRIENE RECEPTORS
• Separate receptors for LTB4 (BLT) and for the cysteinyl LTs (LTC4, LTD4) have been defined.
• Two subtypes,
• Cys LT1 and cysLT2 of the cysteinyl LT receptor have been cloned.
• All LT receptors function through the IP3/DAG transducer mechanism.

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LEUKOTRIENES IN ASTHMA
• Leukotrienes assist in the pathophysiology of asthma, causing or potentiating the
following symptoms:
• airflow obstruction
• increased secretion of mucus
• mucosal accumulation
• bronchoconstriction
• infiltration of inflammatory cells in the airway wall

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LEUKOTRIENE RECEPTOR ANTAGONIST

• Mechanism of Action:
• Attenuates bronchoconstriction and inflammation
• Leukotriene Receptor Antagonists
• Zafirlukast (Accolate)
• Montelukast (Singulair)
• Leukotriene Synthesis Inhibitor
• Zileuton (Zyflo)

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USED IN PROPHYLAXIS

• Chronic asthma
• Allergic Rhinitis
• Chronic Urticaria
• COPD
• Atopic Dermatitis
• Migraine Prophylaxis
• Sino nasal polyposis

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ANGIOTENSIN

• Angiotensin-II (A-II) is an octapeptide generated in the plasma from a

precursor plasma α2 globulin, and is involved in electrolyte, blood volume
and pressure homeostasis.
• RAAS

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BP503T- Pharmacology II 65
ANGIOTENSIN RECEPTORS
• Specific angiotensin receptors are present on the surface of target cells.
• Two subtypes (AT1 and AT2) have been differentiated pharmacologically.
• Both are GPCRs.
• AT1:
• Location:
• Found in the heart, blood vessels, kidney, adrenal cortex, lung and brain and mediates the
vasoconstrictor effects.
• mechanism:
• The activated receptor in turn couples to Gq/11 and Gi/o and thus
activates phospholipase C and increases the cytosolic Ca2+ concentrations, which in turn triggers
cellular responses such as stimulation of protein kinase C.
• Effects:
• vasoconstriction, aldosterone synthesis and secretion,
vasopressin secretion, cardiac hypertrophy, augmentation of peripheral noradrenergic activity,
vascular smooth muscle cells proliferation, decreased renal blood flow, renal renin inhibition, renal
tubular sodium reuptake, modulation of central sympathetic nervous system activity, cardiac
contractility, central osmo control and extracellular matrix formation.

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ACTIONS
• CVS:
• vasoconstriction—produced directly as well as
• Increasing central sympathetic outflow.
• Vasoconstriction involves arterioles and venules and occurs in all vascular beds.
• BP rises acutely
• Increases force of myocardial contraction by promoting Ca2+ influx.
• Promotes the growth of vascular and cardiac muscle cells and may play a role in
the development of cardiac hypeertrophy.
• Adrenal cortex:
• enhance synthesis and release of aldosterone which acts on distal tubule to promote Na+
reabsorption and K+/H+ excretion.

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• Kidney:
• A-II promotes Na+/H+ exchange in proximal tubule → increased Na+, Cl– and HCO3¯ reabsorption.
• Further, it reduces renal blood flow and produces intrarenal haemodynamic effects which normally
result in Na+ and water retention
• CNS
• Angiotensin-II can gain access to certain periventricular areas of the brain to induce drinking
behaviour and ADH release.
• PERIPHERAL SYMPATHETIC STRUCTURES
• Releases adrenaline from adrenal medulla, stimulates autonomic ganglia, and increases output of
NA from adrenergic nerve endings.

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RENIN ANGIOTENSIN ALDOSTERONE SYSTEM
INHIBITORS
• SYMPATHETIC BLOCKERS (beta blockers):
• Propranolol, Metoprolol, Esmolol
• RENIN INHIBITORY PEPTIDES:
• Aliskerin
• ANGIOTENSIN CONVERTING ENZYME INHIBITOR:
• Captopril, Enalapril, Ramipril
• ANGIOTENSIN RECEPTOR ANTAGONIST:
• Candesartan, Valsartan, Telmisartan, Olmesartan
• ALDOSTRERONE ANTAGONIST:
• Spironolactone, Prorenone

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BRADYKININ

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INTRODUCTION
• It is a plasma kinin.
• Plasma kinins are polypeptides split off from a plasma globulin Kininogen by the action of specific
enzymes Kallikreins
• Bradykinin is plasma kinin produced by the liver and present in plasma.
• It is nonapeptide.

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GENERATION AND DEGRADATION OF
PLASMA KININS

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ACTIONS
• CVS:
• more potent vasodilators than ACh and histamine.
• The dilatation is mediated through endothelial NO and PGI2 generation, and involves mainly the
arterioles.
• Larger arteries, most veins and vessels with damaged endothelium are constricted through
direct action on the smooth muscle.
• In addition, they can release histamine and other mediators from mast cells.
• Kinins have no direct action on heart; reflex stimulation occurs due to fall in BP.
• Smooth muscle:
• Kinin induced contraction of intestine is slow (bradys—slow, kinein—to move).
• marked bronchoconstriction in asthmatic patients.

BP503T- Pharmacology II 73
• Neurones:
• stimulate nerve endings that transmit pain and produce a burning sensation.
• Kinins release CAs from adrenal medulla.
• Injected directly in brain they produce a variety of effects including enhanced sympathetic
discharge.
• They increase permeability of the blood brain barrier.
• Kidney:
• Kinins increase renal blood flow as well as facilitate salt and water excretion by action on tubules.
• The diuretic effect of furosemide is reduced by kinin B2 receptor antagonists, indicating
participation of locally generated kinins in this response.

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KININ RECEPTORS
• two types of kinin receptors
• Bradykinin has higher affinity for B2 than for B1 receptors
• B1
• located on the smooth muscle of large arteries and veins—mediates contraction
of these vessels.
• Inflammation induces synthesis of B1 receptors, so that they might play a major role at inflamed sites.
• B2
• present on:
• Visceral smooth muscle—contraction of intestine, uterus, airway.
• Vascular endothelium—NO release, vasodilatation, increased permeability.
• Sensory nerves—acute pain.

BP503T- Pharmacology II 75
PATHOPHYSIOLOGICAL ROLES
• Mediation of inflammation
• Kinins produce all the signs of inflammation—redness, exudation, pain and leukocyte mobilization.
• Mediation of pain
• By directly stimulating nerve endings and by increasing PG production kinins
appear to serve as mediators of pain.
• Production of kinins is integrated with clotting, fibrinolysin and complement systems.

BP503T- Pharmacology II 76
• Kinins cause closure of ductus arteriosus, dilatation of foetal pulmonary artery and constriction of
umbilical vessels.
• Role in angioedema.
• also appear to be involved in shock, rhinitis, asthma, ACE inhibitor induced cough, carcinoid,
postgastrectomy dumping syndrome, fluid secretion in diarrhoea, acute pancreatitis and certain
immunological reactions.

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BRADYKININ ANTAGONISTS

• Deltibant :
• It is a novel Bradykinin Antagonist used in treatment of Severe Systemic
Inflammatory Response Syndrome and Sepsis.
• Icatibant :
• It is a synthetic decapeptide functioning as a potent,competative antagonist of the bradykinin 2
receptor
• used inmanagement of Heriditary angioedema

BP503T- Pharmacology II 78
 UNIT 3

Module 2
Non-steroidal anti-inflammatory agents

BP503T- Pharmacology II 79
NSAIDs have following group of drugs
Analgesic
Antipyretic
Antiinflammatory

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80
Classification
A. Nonselective COX inhibitors (traditional NSAIDs)
1. Salicylates: Aspirin
2. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen,
Flurbiprofen.
3. Anthranilic acid derivative: Mephenamic acid
4. Aryl-acetic acid derivatives: Diclofenac, Aceclofenac.
5. Oxicam derivatives: Piroxicam, Tenoxicam.
6. Pyrrolo-pyrrole derivative: Ketorolac
7. Indole derivative: Indomethacin.
8. Pyrazolone derivative: phenylbutazone,
Oxyphenbutazone
BP503T- Pharmacology II 81
81
B.Preferential COX-2 inhibitors Nimesulide, Meloxicam,
Nabumeton.
C.Selective COX-2 inhibitors Celecoxib, Etoricoxib,
Parecoxib.
D. Analgesic-antipyratics with poor antiinflammatory
action
1. para aminophenol derivatives: Paracetamol
2. Pyrazolone derivative: Metamizol,
Propiphenazone.
3. Benzoxazocine derivative: Nefopam
BP503T- Pharmacology II 82
82
Mechanism of action of NSAIDs
1. Antiinflammatory effect
 due to the inhibition of the enzymes that produce prostaglandin H
synthase (cyclooxygenase, or COX), which converts arachidonic acid to
prostaglandins, and to TXA2 and prostacyclin.

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83
Aspirin irreversibly inactivates COX-1 and COX-2 by
acetylation of a specific serine residue.
This distinguishes it from other NSAIDs, which reversibly inhibit COX-1 and
COX-2.

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84
2. Analgesic effect
A. The analgesic effect of NSAIDs is thought to be
related to:
 the peripheral inhibition of prostaglandin production
 may also be due to the inhibition of pain stimuli at
a subcortical site.
B. NSAIDs prevent the potentiating action of prostaglandins on endogenous
mediators of peripheral nerve stimulation (e.g., bradykinin).

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85
3. Antipyretic effect
 The antipyretic effect of NSAIDs is believed to be related to:
 inhibition of production of prostaglandins induced by interleukin-1 (IL-1)
and interleukin-6 (IL-6) in the hypothalamus
 the “resetting” of the thermoregulatory system,
leading to vasodilatation and increased heat loss.

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86
NSAIDs and Prostaglandin (PG)
synthesis inhibition
NSAIDs blocked PG generation.
Prostaglandins, prostacyclin (PGI2), and thromboxane A2(TXA2) are produced
from arachidonic acid by the enzyme cyclooxygenase.
Cyclooxygenase (COX) exists in COX-1 and COX-2 isoforms.
COX -3 has recently been identified

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87
Cyclooxygenase (COX) is found bound to the endoplasmatic
reticulum. It exists in 3 isoforms:
• COX-1 (constitutive) acts in physiological conditions.
• COX-2 (inducible) is induced in inflammatory cells by pathological
stimulus.
• COX-3 (in brain).

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88
Nonselective COX inhibitor
Salicylates Aspirin:
Aspirin is Acetylsalicylic acid converts to salicylic acid in
body, responsible for action.

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89
PHARMACOLOGICAL ACTIONS
•Analgesic, antipyretic, antiinflammatory actions:
 Aspirin is a weaker analgesic than morphine type drugs.
 Aspirin 600 mg < Codeine 60 mg < 6 mg Morphine
 it effectively relieves inflammation, tissue injury, connective tissue and
integumental pain, but is relatively ineffective in severe visceral and ischaemic
pain.
 The analgesic action is mainly due to obtunding of peripheral pain receptors
• and prevention of PG-mediated sensitization of nerve endings.
 No sedation, subjective effects, tolerance or physical dependence is
produced.
 Aspirin resets the hypothalamic thermostat and rapidly reduces fever by
• promoting heat loss, but does not decrease heat production.
 Antiinflammatory action is exerted at high doses (3-6 g/ day or 100 mg/kg/ day)

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90
2. Metabolic effects:
significant only at antiinflammatory doses
Cellular metabolism is increased, especially in skeletal muscles, due to
uncoupling of oxidative phosphorylation increased heat production.
There is increased utilization of glucose blood sugar may decrease
(especially in diabetics) and liver glycogen is depleted.
Chronic use of large doses cause negative N2 balance by increased conversion of
protein to carbohydrate. Plasma free fatty acid and cholesterol levels are reduced.

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91
3. Respiration:
Effects are dose dependent.
At antiinflammatory doses, respiration is stimulated by peripheral (increased
C02 production) and central (increased sensitivity of respiratory centre to C02)
actions.
Hyperventilation is prominent in salicylate poisoning. Further rise in salicylate
level causes respiratory depression; death is due to respiratory failure.

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92
4. Acid-base and electrolyte balance:
Antiinflammatory doses produce significant changes in the acid-
base and electrolyte composition of body fluids.
Initially, respiratory stimulation predominates and tends to wash out
C02 despite increased production ….respiratory alkalosis, which is
compensated by increased renal excretion of HCO3;̄ (with
accompanying Na+, K+ and water).
Still higher doses cause respiratory depression with C02
retention, while excess C02 production continues…. respiratory
acidosis .

BP503T- Pharmacology II 93
93
5. CVS:
Aspirin has no direct effect in therapeutic doses.
Larger doses increase cardiac output to meet increased peripheral O2
demand and causes direct vasodilatation.
Toxic doses depress , vasomotor centre: BP may fall. Because of increased cardiac
work as well as Na+ and water retention,
CHF may be precipitated in patients with low cardiac reserve.

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94
6. GIT:
Aspirin and released salicylic acid irritate gastric mucosa,
cause epigastric distress, nausea and vomiting.
It also stimulates CTZ.
7. Urate excretion:
Aspirin in high dose reduces renal tubular excretion of
urate

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95
8. Blood:
Aspirin, even in small doses, irreversibly inhibits TXA2 synthesis by platelets.
Thus, it interferes with platelet aggregation and bleeding time is prolonged to
nearly twice the normal value.
long-term intake of large dose decreases synthesis of clotting factors in liver and
predisposes to bleeding; can be prevented by prophylactic vit K therapy.

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96
Pharmacokinetics
Aspirin is absorbed from the stomach and small intestines.
Its poor water solubility is the limiting factor in absorption: microfining the
drug particles and inclusion of an alkali (solubility is more at higher pH)
enhances absorption.
Aspirin is rapidly deacetylated in the gut wall, liver, plasma and other tissues to
release salicylic acid which is the major circulating and active form.
It slowly enters brain but freely crosses placenta.
The metabolites are excreted by glomerular filtration as well as tubular secretion.

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97
Uses of Aspirin
As analgesic (300 to 600 mg during 6 to 8 h) for headache, backache, pulled
muscle, toothache, neuralgias.
As antipyretic in fever of any origin in the same doses as for analglesia. However,
paracetamol and metamizole are safer, and generally preferred.
Acute rheumatic fever. Aspirin is the first drug of choice. Other drugs substitute
Aspirin only when it fails or in severe cases. Antirheumatic doses are 75 to 100
mg/kg/24 h (resp. 4–6 g daily) in the first weeks.
Rheumatoid arthritis. Aspirin a dose of 3 to 5 g/24 h after meal is effective in most
cases. Since large doses of Aspirin are poorly tolerated for a long time, the new
NSAIDs (diclofenac, ibuprofen, etc.) in depot form are preferred.

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98
Aspirin therapy in children with rheumatoid arthritis has been found to raise serum
concentration transaminases, indicating liver damage. Most cases are asymptomatic
but it is potentially dangerous.
An association between salicylate therapy and “Reye’s syndrome”, a rare form of
hepatic encephalopathy seen in children, having viral infection (varicella,
influenza), has been noted.
Aspirin should not be given to children under 15years unless specifically indicated,
e.g. for juvenile arthritis (paracetamol is preferred).
Postmyocardial infarction and poststroke patients: By inhibiting platelet
aggregation in low doses (100 mg daily) Aspirin decreases the incidence of
reinfarction.

BP503T- Pharmacology II 99
BP503T- Pharmacology II 100
Adverse effects
1. Gastrointestinal effects
 most common adverse effects of high-dose aspirin use (70% of patients):
 nausea
 vomiting
 diarrhea or constipation
 dyspepsia (impaired digestion)
 epigastric pain
 bleeding, and ulceration (primarily gastric).

BP503T- Pharmacology II 101

These gastrointestinal effects are thought to be due to:

1. direct chemical effect on gastric cells or

2. decrease in the production and cytoprotective activity of prostaglandins,

which leads to gastric tissue susceptibility to damage by hydrochloric acid.

BP503T- Pharmacology II 102

The gastrointestinal effects may contraindicate aspirin use
in patients with an active ulcer.

Aspirin may be taken with prostaglandins to reduce gastric damage.

Decrease gastric irritation by:

 Substitution of enteric-coated or timed-release preparations, or
 the use of nonacetylated salicylates, may decrease gastric
irritation.

BP503T- Pharmacology II 103

2. Hypersensitivity (intolerance)
 Hypersensitivity is relatively uncommon with the use of aspirin (0.3% of patients);
hypersensitivity results in:
 rash
 bronchospasm
 rhinitis
 Edema, or
 an anaphylactic reaction with shock, which may be life threatening.

 The incidence of intolerance is highest in patients with asthma,

nasal polyps, recurrent rhinitis, or urticaria.
 Aspirin should be avoided in such patients.

BP503T- Pharmacology II 104

Cross-hypersensitivity may exist:
to other NSAIDs
to the yellow dye tartrazine, which is used in many pharmaceutical
preparations.

Hypersensitivity is not associated with:

sodium salicylate or
magnesium salicylate.

BP503T- Pharmacology II 105

The use of aspirin and other salicylates to control fever during viral infections
(influenza and chickenpox) in children and adolescents is associated with an
increased incidence of Reye's syndrome, an illness characterized by vomiting,
hepatic disturbances, and encephalopathy that has a 35% mortality rate.

Acetaminophen is recommended as a substitute for children with fever of

unknown etiology.

BP503T- Pharmacology II 106

Miscellaneous adverse effects and
contraindications
May decrease the glomerular filtration rate, particularly in patients with renal
insufficiency.
Occasionally produce mild hepatitis
Prolong bleeding time.
Aspirin irreversibly inhibits platelet COX-1 and COX-2 and, thereby, TXA2
production, suppressing platelet adhesion and aggregation.

The use of salicylates is contraindicated in patients with bleeding disorders

Salicylates are not recommended during pregnancy; they may induce:

postpartum hemorrhage
premature closure of the fetal ductus arteriosus.

BP503T- Pharmacology II 107

 Drug interactions
Drugs Result

Diuretics Decrease diuresis

Beta-blockers Decrease antihypertensive effect
ACE inhibitors Decrease antihypertensive effect

Anticoagulants Increase of GI bleeding

Sulfonylurea Increase hypoglycemic risk

Cyclosporine Increase nephrotoxicity
GCS Increase of GI bleeding
Alcohol Increase of GI bleeding
BP503T- Pharmacology II 108
PROPIONIC ACID DERIVATIVES
Ibuprofen was the first member
The analgesic, antipyretic and antiinflammatory efficacy is rated somewhat
lower than high dose of aspirin.
 All inhibit PG synthesis, naproxen being the most potent; but their in vitro
potency tor this action does not closely parallel in vitro antiinflammatory potency.
 Inhibition of platelet aggregation is short-lasting with ibuprofen, but
longer lasting with naproxen.

BP503T- Pharmacology II 109

Ibuprofen:
In doses of 2.4 g daily it is equivalent to 4 g of Aspirin in anti- inflammatory effect.
Oral ibuprofen is often prescribed in lower doses (< 2.4 g/d), at which it has
analgesic but not antiinflammatory efficacy. It is available in low dose forms under
several trade names (e. g. Nurofen® – film-tabl. 400 mg).
A topical cream preparation is absorbed into fascia and muscle. A liquid gel
preparation of ibuprofen provides prompt relief in postsurgical dental pain.
In comparison with indometacin, ibuprofen decreases urine
output less and also causes less fluid retention.
It is effective in closing ductus arteriosus in preterm infants, with much the same
efficacy as indometacin.

BP503T- Pharmacology II 110

Flurbiprofen:
Its (S)(-) enantiomer inhibits COX nonselectively, but it has been shown in rat
tissue to also affect TNF-α and NO synthesis.
 Hepatic metabolism is extensive. It does demonstrate enterohepatic
circulation.
The efficacy of flurbiprofen at dosages of 200–400 mg/d is comparable to that of
Aspirin and other NSAIDs for patients with rheumatoid arthritis, gout, and
osteoarthritis.
Flurbiprofen i.v. is effective for perioperative analgesia in minor ear, neck, and nose
surgery and in lozenge form for sore throat.

BP503T- Pharmacology II 111

Adverse effect
Ibuprofen and all its congeners are better tolerated than aspirin.
Side effects are milder and their incidence is lower.
Gastric discomfort, nausea and vomiting, though less than aspirin or indomethacin,
are still the most common side effects.
Gastric erosion and occult blood loss are rare.
CNS side effects include headache, dizziness, blurring of vision, tinnitus and
depression.
Rashes, itching and other hypersensitivity phenomena are
infrequent.
They are not to be prescribed to pregnant woman and should be avoided in peptic
ulcer patient.
BP503T- Pharmacology II 112
Pharmacokinetic and interactions
Well absorbed orally.
Highly bounded to the plasma protein (90-99%).
Because they inhibit platelet function, use with anticoagulants should,
nevertheless, be avoided.
Similar to other NSAIDs, they are likely to decrease diuretic and
antihypertensive action of thiazides, furosemide and β blockers.
All propionic acid derivatives enter brain, synovial fluid and cross placenta.
They are largely metabolized in liver by hydroxylation and glucuronide
conjugation and excreted in urine as well as bile.

BP503T- Pharmacology II 113

Uses
Ibuprofen is used as a simple analgesic, and antipyretic in the same way as low
dose of aspirin. It is particularly effective in dysmenorrhoea. In which the action
is clearly due to PG synthesis inhibition.
It is available as an over-the-court drug.
Ibuprofen and its congeners are widely used in rheumatoid arthritis,
osteoarthritis and other musculoskeletal disorders.
They are indicated in soft tissue injuries, vasectomy, tooth extraction, postpartum
and postoperatively: suppress swelling and inflammation.

BP503T- Pharmacology II 114

Anthranilic acid derivative
Mephenamic acid:
An analgesic, antipyretic and weaker antiinflammatory drug, which inhibits
COX as well as antagonises certain actions of PGs.
Mephenamic acid exerts peripheral as well central analgesic action.

BP503T- Pharmacology II 115

 Adverse effects:
 Diarrhoea is the most important dose-related side effect. Epigastric distress is complained, but gut
bleeding is not significant.
 Skin rashes, dizziness and other CNS manifestations have occurred.
 Haemolytic anaemia is a rare but serious complication.
 Pharmacokinetics:
 Oral absorption is slow but almost complete. It is highly bound to plasma proteins-
displacement interactions can occur; partly metabolized and excreted in urine as well as bile.
Plasma t1/2 is 2-4 hours.
 Uses:
 Mephenamic acid is indicated primarily as analgesic in muscle, joint and soft tissue pain where
strong antiinflammatory action is not needed. It is quite effective in dysmenorrhoea. It may be
useful in some cases of rheumatoid and osteoarthritis but has no distinct advantage.

BP503T- Pharmacology II 116

Aryl-acetic acid derivatives
 Diclofenac:
 An analgesic-antipyretic antiinflammatory drug, similar in efficacy to naproxen. It inhibits PG
synthesis and is somewhatCOX-2 selective. The antiplatelet action is short lasting. Neutrophil
chemotaxis and superoxide production at the inflammatory site are reduced.
 Adverse effects of diclofenac are generally mild epigastric pain, nausea, headache, dizziness,
rashes. Gastric ulceration and bleeding are less common. Reversible elevation of serum
aminotransferases has been reported more commonly; kidney damage is rare.
 A preparation combining diclofenac and misoprostol (PGE1) decreases upper GI ulceration
but may result in diarrhoea.
 Diclofenac is among the most extensively used NSAID; employed in rheumatoid and osteoarthritis,
bursitis, ankylosing spondylitis, toothache, dysmenorrhoea, post-traumatic and postoperative
inflammatory conditions- affords quick relief of pain and wound edema.

BP503T- Pharmacology II 117

Aceclofenac:
 A somewhat COX-2 selective congener of diclofenac having similar
properties. Enhancement of glycosaminoglycan synthesis may confer
chondroprotective property.

BP503T- Pharmacology II 118

Oxicam derivatives
Piroxicam:
 It is a long-acting potent NSAID with antiinflammatory potency similar to
indomethacin and good analgesic- antipyretic action.
It is a reversible inhibitor of COX; lowers PG concentration in synovial fluid and
inhibits platelet aggregation-prolonging bleeding time.
In addition, it decreases the production of IgM rheumatoid factor and
leucocyte chemotaxis.

BP503T- Pharmacology II 119

Pharmacokinetics:
It is rapidly and completely absorbed
99% plasma protein bound;
Largely metabolized in liver by hydroxylation and glucuronide conjugation;
Excreted in urine and bile;
Plasma t1/2 is long nearly 2 days.
Adverse effects:
The g.i. side effects are more than ibuprofen, but it is better tolerated and less
ulcerogenic than indomethacin or phenylbutazone; causes less faecal blood loss
than aspirin. Rashes and pruritus are seen in < 1% patients. Edema and
reversible azotaemia have been observed.
Tenoxicam:
 A congener of piroxicam with similar properties and uses.

BP503T- Pharmacology II 120

Pyrrolo-pyrrole derivative
 Ketorolac:
 A novel NSAID with potent analgesic and modest antiinflammatory activity.
 In postoperative pain it has equalled the efficacy of morphine, but does not interact with
opioid receptors and is free of opioid side effects.
 it inhibits PG synthesis and relieves pain by a peripheral mechanism.
 rapidly absorbed after oral and i.m. administration.
 It is highly plasma protein bound and 60% excreted unchanged in
urine.
 Major metabolic pathway is glucuronidation.
 plasma t1/2 is 5-7 hours.

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Adverse effects:
 Nausea, abdominal pain, dyspepsia, ulceration, loose stools, drowsiness,
headache, dizziness, nervousness, pruritus, pain at injection site, rise in serum
transaminase and fluid retention have been noted.
Use:
 Ketorolac is frequently used in postoperative, dental and acute musculoskeletal
pain: 15-30 mg i.m. or i.v. every 4-6 hours (max. 90 mg/day).
It may also be used for renal colic, migraine and pain due to
bony metastasis.
Continuous use for more then 5 days is not recommended.

BP503T- Pharmacology II 122

Indole derivative
 Indomethacin:
 It is a potent antiinflammatory drug with prompt antipyretic action.
 Indomethacin relieves only inflammatory or tissue injury related
pain.
 It is a highly potent inhibitor of PG synthesis and suppresses neutrophil motility.
 In toxic doses it uncouples oxidative phosphorylation (like aspirin).
 Pharmacokinetics:
 Indomethacin is well absorbed orally
 It is 90% bound to plasma proteins, partly metabolized in liver to inactive products and
excreted by kidney.
 Plasma t1/2 is 2-5 hours.

BP503T- Pharmacology II 123

Adverse effect:
A high incidence (up to 50%) of GI and CNS side effects is produced: GI
bleeding, diarrhoea, frontal headache, mental confusion, etc.
It is contraindicated in machinery operators,
drivers, psychiatric patients, epileptics, kidney
disease, pregnant women and in children.

BP503T- Pharmacology II 124

 PREFERENTIAL COX-2 INHIBITORS
Nimesulide:
weak inhibitor of PG synthesis and COX-2 selectivity.
Antiinflammatory action may be exerted by other mechanisms as well, e.g. reduced
generation of superoxide by neutrophils, inhibition of PAF synthesis and TNFa
release, free radical scavanging, inhibition of metalloproteinase activity in
cartilage.
The analgesic, antipyretic and antiinflammatory activity of
nimesulide has been rated comparable to other NSAIDs.
It has been used primarily for short-lasting painful inflammatory conditions like
sports injuries, sinusitis and other ear-nose-throat disorders, dental surgery, bursitis,
low backache, dysmenorrhoea, postoperative pain, osteoarthritis and for fever.

BP503T- Pharmacology II 125

47
Nimesulide is almost completely absorbed orally, 99% plasma protein bound,
extensively metabolized and excreted mainly in urine with a t1/2 of 2-5 hours.
Adverse effects of nimesulide are gastrointestinal (epigastralgia, heart burn,
nausea, loose motions), dermatological (rash, pruritus) and central
(somnolence, dizziness).

BP503T- Pharmacology II 126

12
6
SELECTIVE COX-2 INHIBITORS
They cause little gastric mucosal damage; occurrence of peptic ulcer and ulcer
bleeds is clearly lower than with traditional NSAIDs. They do not depress TXA2
Production by platelets (COX-I dependent); do not inhibit platelet aggregation or
prolong bleeding time but reduce PGI2 production by vascular endothelium.
It has been concluded that selective COX-2 inhibitors should be used only in
patients at high risk of peptic ulcer, perforation or bleeds. If selected, they should be
administered in the lowest dose for the shortest period of time. Moreover, they
should be avoided in patients with history of ischaemic heart disease/ hypertension/
cardiac failure/ cerebrovascular disease, who are predisposed to CV events.

BP503T- Pharmacology II 127

12
7
Celecoxib:
It exerts antiinflammatory, analgesic and antipyretic actions with low ulcerogenic
potential. Comparative trials in rheumatoid arthritis have found it to be as
effective as naproxen or diclofenac, without affecting COX- 1 activity in
gastroduodenal mucosa . Platelet aggregation in response to collagen exposure
remained intact in celecoxib recipients and serum TXB2 levels were not reduced.
Though tolerability of celecoxib is better than traditional NSAIDs, still abdominal
pain, dyspepsia and mild diarrhoea are the common side effects. Rashes, edema
and a small rise in BP have also been noted.
Celecoxib is slowly absorbed, 97% plasma protein bound and metabolized primarily
by CYP2C9 with a t1/2 of 10 hours. It is approved for use in osteo- and rheumatoid
arthritis in a dose of 100-200 mg BD.

BP503T- Pharmacology II 128

Etoricoxib:
This newer COX-2 inhibitor has the highest COX-2 selectivity. It is suitable for
once-a-day treatment of osteo /rheumatoid / acute gouty arthritis, dysmenorrhoea,
acute dental surgery pain and similar conditions, without affecting platelet function
or damaging gastric mucosa. The t1/2 is 24 hours. Side effects are dry mouth,
aphthous ulcers, taste disturbance and paresthesias.
Parecoxib:
 It is a prodrug of valdecoxib suitable for injection, and to be used in
postoperative or similar short-term pain, with efficacy similar to ketorolac.

BP503T- Pharmacology II 129

 UNIT 3

Module 3
Anti-gout drugs

BP503T- Pharmacology II 130

Definition: Gout is metabolic disease in which plasma urate concentration get
increased (hyperuricaemia),
( Normal urate level: 1-4 mg/dl).

Uric acid is product of purine metabolism at low pH

(acidic) has low water solubility. When urate level
increases in blood it gets precipitates and deposits in
joints, kidney and cutaneous tissue which is called as
tophy.

BP503T- Pharmacology II 131

 Overdrinking of alcoholic beverages, especially beer, or purine-rich
foods.

 Leukaemia's, lymphomas, polycythaemia condition treated with

chemotherapy radiation causes enhanced nucleic acid metabolism
and uric acid production.

 Drug like thiazides, furosemide, pyrazinamide, ethambutol,

levodopa, clofibrate reduce uric acid excretion by kidney and
produces gout.

BP503T- Pharmacology II 132

 Antigout drugs
These are the drugs which are used in treatment of gout condition which are acts by one
of the following mechanism: By
 Inhibiting Uric acid synthesis ( Allopurinol).
 Increasing Uric acid excretion (Probencid, Sufinpyazone).
 Inhibiting leukocyte migration toward joint (Colchicine).
 Providing general NSAID’s action (Glucocorticoids)

Classification
For acute gout: Acute gout is a painful condition that often affects only one joint. Drugs used
are Ex- NSAID’s, Colchicine, Glucocorticoids.

For chronic gout/ hyperuricaemia: Chronic gout is the repeated episodes of pain and
inflammation. More than one joint may be affected Ex- Probencid, Sufinpyazone, Allopurinol

BP503T- Pharmacology II 133

 1. NSAID’s drugs
 Various drugs used are indometahcin, naproxen, piroxicam, diclofenac or
etoricoxib given at high and repeated dose to terminate attack.

 Produces responses slow as compared to colchicine but well tolerated so more

preferred than colchicine.

 Naproxen, piroxicam inhibits chemotactic migration of leucocytes into the

inflamed joint.

 But not recommended for long term management due to risk of toxicity.

BP503T- Pharmacology II 134

 2. Colchicine
 Alkaloid from Colchicum autumnale / autumn crocus found as antigoute in 1763
and isolated as pure form in 1820.

 Not having anti-inflammatory or analgesic activity but used specifically in

treatment of gouty inflammation.

 First
dated information of colchicine was available in Ebers Papyrus/Papyrus
Ebers and it was written in about 1500 BC).

BP503T- Pharmacology II 135

 Precipitation of urate crystals in synovial fluid

Start inflammatory response

By producing Chemotactic factors Migration of

granulocytes in to joints

Which phagocytose (engulf) urate crystals

Release glycoprotein

Increases lactic acid production form inflamed Release lysosomal

cell enzyme

Decreases PH
Joint destruction
More urate crystals get precipitate and affect joint

Aggrevates/ Worsen inflammatory

BP503T- Pharmacology II condition 136
 Colchicine Precipitation of urate crystals
in synovial fluid

Bind to fibrillar protein Start inflammatory

tubulin response

Depolymerisation of
By producing
microtubules
Chemotactic factors

Prevent
Decreases cell
Migration of granulocytes
motility
in to joints

Symptomatic relief for gout

BP503T- Pharmacology II 137

Other actions of Colchicine:
Antimitotic: Binding to microtubules of mitotic spindle
metaphase arrest tried for cancer chemotherapy But
causes toxicity.
Gut action: gut motility through neural mechanism.

Pharmacokinetics:
• Absorption: Rapid orally.
• Distribution: Uniform.
• Metabolism: Liver
• Elemination: bile-undergoes enterohepatic circulation,
Urine & faeces.

BP503T- Pharmacology II 138

* Toxicity of Colchicine: High and dose related.

At therapeutic dose: Nausea, vomiting, watery or bloody diarrhoea

and abdominal cramps.
Accumulation of the drug in intestine and inhibition of mitosis .

In overdose: colchicine produces kidney damage, CNS depression,

intestinal bleeding; death is due to muscular
paralysis and respiratory failure.

Chronic therapy: Not recommended because it causes aplastic anaemia,

agranulocytosis, myopathy and loss of hair.

BP503T- Pharmacology II 139

Sr . Category of drug Example from class Interaction
No.
1. atorvastatin, fluvastatin,
Cholesterol drugs
lovastatin, gemfibrozil
2. Antiarrhythmic drug. Digoxin,
3. indinavir, atazanavir, nelfinavir, Serious muscle
HIV drugs, damage.
saquinavir, or ritonavir.
4. Antidepressressants nefazodone.
5.
Antibiotics, clarithromycin or telithromycin

6. Increases
Antifungal drugs ketoconazole or itraconazole. concentrationof
colchicine
7. stomach pain,
Calcium channel constipation, diarrhea,
blocker verapamil or diltiazem nausea, or vomiting.

BP503T- Pharmacology II 140

1. Treatment of acute gout: Best drug to control an acute attack of gout, 1 mg orally
followed by 0.25 mg 1-3 hourly till control of the attack.

2.Prophylaxis condition of gout: Colchicine 0.5-1 mg/day prevent

gout attack but now a days NSAID’s are preferred.

3. Other uses: Used in plant breeding by inducing polyploidy ( state of a cell or

organism having more than two paired) in plant cells for new or improved varieties,
strains and cultivars.

BP503T- Pharmacology II 141

 3. Corticosteroid
 Intraarticular injection of soluble steroids suppress symptoms of acute gout.

 Corticosteroids decrease the pain, swelling, redness and (inflammation) of

gout.

 But Corticosteroids are used only for patients suffering from renal failure or peptic
ulcer( Bcause NSAID’s are contraindicated).

 Risk of rebound of attack is observed on drug withdrawal.

 Example; Prednisolone 40-60 mg given once a day.

BP503T- Pharmacology II 142

 4. Probenecid
 Lipid soluble organic acid developed in 1951.
*Mechanism of action Probenecid:

Probenecid
Uric acid
Block

Active transport of
organic acid

By Blocking

OATP ( organic anion Inhibit

transporting Reabsorbed by active
polypeptide receptor) transport
Causes
excretion

BP503T- Pharmacology II 143

 Absorption: Rapid orally.
 Distribution: 90% bound to plasma protein
 Metabolism: Liver
 Elimination: Urine.

*Drug interaction with other drug: Probenecid shows interaction with;

Sr . Category of drug Example from class Interaction

No.
1. penicillins, cephalosporins, Inhibits the
Antibiotics
sulfonamides, urinary excretion
2. NSAID’s Indomethacin, salicylates
3. Antibiotics
rifampicin. Biliary excretion

4.
Inhibits tubular
Antimicrobial nitrofurantoin
secretion of drug

BP503T- Pharmacology II 144

* Toxicity of Probenecid :
Dyspepsia (indigestion).
Rashes and other hypersensitivity .
Toxic doses cause convulsions and respiratory failure.
* Use of Probenecid:
Chronic gout and hyperuricaemia:
 second line or adjunct drug to allopurinol.
 0.25 g-0.5g BD gradually lower blood urate level along with arthritis, tophi and other
lesions but ineffective during renal insufficiency.
 Plenty of fluids should be given with probenecid to avoid urate crystallization in
urinary tract.

Prolong drug action:

 Probenecid is also used to prolong penicillin or ampicillin action by enhancing and sustaining
their blood levels, e.g. in gonorrhoea, Subacute bacterial endocarditis (SABE).

BP503T- Pharmacology II 145

 5 Sulfinpyrazone
 It is a pyrazolone derivative related to phenylbutazone having consistent uricosuric action.

 Not having anti-inflammatory or analgesic activity but used specifically in

treatment of gouty inflammation.

* Mechanism of action Sulfinpyrazone:

• It inhibits ttubular reabsorption of uric acid
• Also inhibits platelet aggregation.

* Pharmacokinetics:
• Absorption: Rapid orally.
• Distribution: 98% bound to plasma protein.
• Elemination: active secretion in proximal tubule Urine.

BP503T- Pharmacology II 146

Sr . Category of drug Example from class Interaction
No.
1. warfarin
oral anticoagulant increase the effects
2. tolbutamide
3. Anti asthmatic theophylline worsening asthma
4. Calcium channel high blood pressure or an irregular heartbeat.
verapamil
blocker

* Adverse effect of Sulfinpyrazone:

 Gastric irritation so contraindicated in patients with peptic ulcer.
 Rashes and other hypersensitivity reactions.
 At overdose convulsions, coma, anaemia, jaundice, and ulceration.

* Use of Sulfinpyrazone:
Used in treatment of chronic gout 100-200mg BD
BP503T- Pharmacology II 147
 6. Allopurinol
 This hypoxanthine analogue was synthesized a purine antimetabolite for cancer chemotherapy it
had no antineoplastic activity.
 It has substrate as well as inhibitor of xanthine oxidase, the enzyme
responsible for uric acid synthesis.

Allopurinol
Hypoxanthine

Xanthene oxidase
Xanthene oxidase

Alloxanthene Inhibit both steps

xanthine

Xanthene oxidase

Uric acid

BP503T- Pharmacology II 148

 * Pharmacokinetics:
• Absorption: Rapid orally.
• Distribution: Not bound to plasma protein.
• Metabolism: During chronic administration inhibit self metabolism.
• Elemination: 1/3 excreted as unchanged form in urine.

*Drug interaction with other drug: Allopurinol shows interaction with;

Sr . Category of Example from class Interaction

No. drug
1. Allopurinol prevent
Anticancer f 6-mercaptopurin & azathioprine
degradation of all drugs
2. Uricosurics Probenecid kidney or liver disease
3. Anti asthmatic theophylline skin rashes
4. mobilization of hepatic iron stores
Haematinics Iron therapy

BP503T- Pharmacology II 149

* Adverse effect of Allopurinol:
 Hypersensitivity- rashes fever, malaise and muscle pain.
 Stevens-Johnson syndrome(serious disorder of the skin and mucous membranes. painful
red or purplish rash)
 Gastric irritation, headache, nausea and dizziness infrequent
 Liver damage.

* Use of Allopurinol:
• Drug of choice in Chronic gout.
• To potentiate 6-mercaptopurine or azathiopurine- During cancer therapy and
immunosuppressant therapy.
• In treatment of Kala-azar- Inhibit leishmania by altering purine metabolism.

BP503T- Pharmacology II 150

 UNIT 3

Module 4
Antirheumatic drugs

BP503T- Pharmacology II 151

Background – Rheumatoid
arthritis
• Autoimmune disorder
• Joint inflammation
• Non-Suppurative Proliferative Synovitis
• Articular cartilage destruction

• Disabling Arthritis - pain, swelling, stiffness and loss of function in the

joints ..
• Systemic Manifestations
• Prevalence - 1 to 2% , increases with age – 5% women over age 55

BP503T- Pharmacology II 152

Rheumatoid arthritis -
Mechanism
• Immune complexes composed of IgM activates Complements
• Release of cytokines – mainly TNFα, IL-1 – chemotactic for neutrophils
• Inflammatory cells secrete lysosomal enzymes – Cartilage damage and
erosion of bones
• PGs produced – Vasodilatation and pain

BP503T- Pharmacology II 153

 Rheumatoid
arthritis – Patient
presentation
• Chronic progressive crippling (unable to move properly) with waxing and waning course (alternate increases and decreases)

Pain and swelling of joints, morning stiffness, immobility etc.

•
Symptoms can be divided into 3 types:
•
 General: fatigue, malaise, depression, occasional fever

 Articular: persistent symmetrical joint swelling for long

 Extra articular: Rheumatoid Nodules - extensor surfaces of the arms and elbows - rarely in visceral organs (lungs,
heart)

70% of patients disease begins with general symptoms like weakness, loss of appetite, vague muscle aches, tiredness
•
NSAIDS are the first line drugs
•

BP503T- Pharmacology II 154

Deformities in advance
cases
• Swan neck deformity: PIP
Hyperextension and DIP
flexion

• Boutonniere deformity: PIP

flexion and DIP Hyperextension

• Z like deformity: DIP

Hyperextension and fixed
flexion and subluxation of the
MCP

• Hammer toe (claw toe):

Curling and stiffening of
position of toes
BP503T- Pharmacology II 155
• Carpel tunnel syndrome
Extra-articular
Manifestations
• Skin – Rheumatoid nodules – vasculitis – splinter haemorrhages Eye
• - keratoconjunctivitis sicca
• Oral - Oral dryness and salivary gland swelling
• GIT - mesenteric vasculitis leading to intestinal infarction – bleeding and perforation
• Pulmonary - Pleural effusions
• Cardiac - thickening of the artery walls (atherosclerosis) and heart attacks Renal -
• mesengial glomerulonephritis
• Haematological: anaemia, neutropenia, thrombocytopenia, thrombocytosis, eosinophilia etc.
Neurological – Peripheral neuritis
•

BP503T- Pharmacology II 156

Antirheumatoid Drugs
• Drugs which (except corticosteroids) can suppress the rheumatoid
process and bring about a remission, but do not have nonspecific
antiinflammatory or analgesic action - Used in addition to NSAIDS
• Disease Modifying Antirheumatoid Drugs (DMARDs) or Slow acting
Antirheumatoid Drugs (SAARDs)
– Slow onset and relapses
•
Biologic Response Modifiers (BRMs)

BP503T- Pharmacology II 157

Role of NSAIDs
 First line of Drug

Symptomatic relief in pain, swelling, morning stiffness, immobility

Preserve function

But

Little effect on the progression of bone and cartilage destruction

BP503T- Pharmacology II 158

Available drugs for treatment
 DMARDs:
1. Immunosuppressants: Methotrexate, Azathioprine and Cyclosporine
2. Salfasalazine
3. Chloroquine/Hydroxychloroquine
4. Leflunomide
5. Gold sod. Thiomalate, Auranofin
6. D-Penicillamine
• BRM:
1. TNFα inhibitors: Etanercept, Infliximab and adalimumab
2. IL-1 antagonist: Anakinra
• Adjuvant: Corticosteroids, Prednisolone and others

BP503T- Pharmacology II 159

Treatment Goals
1. Relief of pain
2. Reduction of swelling & stiffness
3. Protection of articular structures – cartilage damage
4. Maintenance of function
5. Control of systemic involvement

BP503T- Pharmacology II 160

Methotrexate
(Mtx)

• One of the oldest and highly efficacious antineoplastic drug

• Primarily kills cells in S phase – inhibits DNA synthesis – also RNA and protein

• Repeated doses – Bone marrow toxicity - Megaloblastic anaemia, high doses -

pancytopenia, desquamation and bleeding in GIT
• Basically - Inhibitor of dihydrofolate reductase enzyme (50,000 times) –
immunosuppressant and potent antiinflammatory (blocks conversion of DHFA to THFA
– de novo purine synthesis and amino acid interconversion) – affects lymphocyte and
macrophage function

BP503T- Pharmacology II 161

Methtrexate
(Mtx)
• MOA
(antirheumatic):
• Inhibitory effects on proliferation and stimulates apoptosis in immune-inflammatory cells
• Inhibition of proinflammatory cytokine production, chemotaxis and CMI reactions

• Kinetics: Absorbed orally (variable) - 70%, affected by food. Binds to plasma

protein 50%, little metabolized and largely excreted unchanged in urine – renal
diseases, interaction with aspirin and probenecid (plasma protein bound)

• Dose: 7.5 to 15 mg weekly Vs 15-30 mg per day

• Takes 4- 6 weeks for onset of action – preferred for initial treatment – including juvenile RA

BP503T- Pharmacology II 162

Mtx –
contd.
A D R s : Nodulosis, Oral ulceration, GI disturbances, Hepatotoxicity, Megaloblastic anaemia
– Bone marrow depression …. Inj. Leucovorin 24 hrs after each dose
Cirrhosis on prolonged administration – also chest infection

 C I : pregnancy, lactation, liver disease, active infection, peptic ulcer etc.

 Uses:

 Autoimmune diseases:

 RA , Psoriasis, Pemphigus, Chronic active hepatitis, Myasthenia gravis

 Cancer:

Choriocarcinoma, Leukemia, NHL, Ca Breast, Bladder, Head & neck Cancer,

Osteogenic Sarcoma
BP503T- Pharmacology II 163
Azathioprine
 Purine antimetabolite – acts after getting converted to 6-mercaptopurine by enzyme
Thiopurine methyl transferase (TPMT)

 M O A : Suppressions of CMI – selectively affects differentiation and function of T-cells andnatural

killer cells – also suppresses inflammation

 Drawback: Smaller percentage of success rate of treatment – less commonly used

 U s e s : Along with Corticosteroids - Steroid sparing effect – however not to be combined wtihMtx

 A D R s : Bone marrow suppression, GI disturbances, infection risk, Lymphomas, fever, rash, and
hepatotoxicity

BP503T- Pharmacology II 164

Sulfasalazine
Compound of sulfapyridine and 5-amino salicylic acid (5-ASA) –
atiinflammatory – used in ulcerative colitis

 M O A : sulfapyridine splits offin colon by bacterial action and active

compound gets (5-ASA is active in ulcerative colitis) absorbed
systemically – generation of superoxide radicals and cytokine
liberation suppressed

 Uses: 2ndline of drug in RA

 A D R s : Neutropenia, Thrombocytopenia, Hepatitis

BP503T- Pharmacology II 165
 Chloroquine and hydroxychloroquine
• Antimalarial drugs – 50% of patients of RA remission
• Low toxicity but low efficacy – bony erosion not prevented
• Takes 3 - 6 months to for onset of action
• MOA:
• Suppression of T-lymphocyte responses to mitogens
• Decreased leukocyte chemotaxis
• Stabilization of lysosomal enzymes
• Trapping of free radicals (free radical scavenging)
• Accumulates in tissues (prolonged administration) – toxicity – retinal and corneal opacity
• ADRs: Rashes, graying of hair/loss, IBS, myopathy and neuropathy
• Uses: Mild no-responsive diseases – when 1 or few joints involved – combined with Mtx

BP503T- Pharmacology II 166

Leflunomide
 Immunomodulator – comparable efficacy with Mtx – onset 4 weeks - can
retard the disease progression

 M O A : Converted to active metabolite with long t1/2 (2 weeks) – inhibits

dihydrofolate reductase and pyrimidine synthesis
Antibody production by B-cells are depressed

Active metabolite- long half life – 2 weeks

 Given in loading dose 100 mg 3 days followed by 20 mg OD

 A D R s : Diarrhoea, nausea, rashes, loss of hair, thrombocytopenia,

leucopeniachest infection and hepatic damage
BP503T- Pharmacology II 167
The Gold Therapy
 Once very popular – before Mtx

 Used for arresting RA process and involvement of additional joints

 M O A : Reduces chemotaxis, phagocytosis, macrophage and lysosomal activity

and inhibits CMI

 Kinetics: Bound to plasma and tissue proteins and stays in body for years

 A D R s : hypotension, dermatitis, stomatitis, kidney and liver damage andbone

marrow depression - diarrhoea

 Auranofi n: 29% gold - 25% bioavailability

 D-Penicillamine: gold like action – Pharmacology

BP503T- not used nowII - toxicity 168
BRMs – General points
 TNFα has key role in RA – activates membrane bound receptors TNFR1 andTNFR2
on surface of T-cells and macrophages etc.

Exogenously administered inhibitors or antibodies can neutralize it and

interrupt reaction

Mainly suppress Macrophage and T-cells

Inflammatory changes and bone erosion – slowed down and also new
erosions slowed down

Effective as monotherapy, but given with Mtx – in low Mtx responsive andhighly
rapidly progressing cases

 Few side effects – but opportunistic infections

BP503T- Pharmacology II 169
Etanercept
• Recombinant fusion protein of TNF-receptor and Fc portion of human IgG –
administered SC
• Binds TNF-α molecules and also inhibits lymphotoxin- α 50
• mg weekly subcutaneously

BP503T- Pharmacology II 170

 Infliximab
• Infliximab is a chimeric (25% mouse, 75% human) IgG1 monoclonal antibody
• Binds with high affinity to soluble and membrane-bound TNF-α. 3–5
• mg/kg every 8 weeks intravenous infusion
• ADRs: Acute reactions – fever, chills, urticaria, bronchospasm,
anaphylaxis
• Susceptibility to respiratory infections
•
Combined with Mtx – improved result

BP503T- Pharmacology II 171

 Adalimumab
• Fully human IgG1 anti-TNF monoclonal antibody
• Complexes with soluble TNF-α
• Down-regulation of macrophage and T cell function 40
• mg every 2 weeks; subcutaneously
• Advantage of combining with MTx:
• Formation of human anti mAb is reduced
• Duration of action increases

BP503T- Pharmacology II 172

 Common toxicities of BRMs
• Bacterial infections and macrophage-dependent infection (TB and other
opportunistic infections)

• •Leukopenias and vasculitis

• •Demyelinating syndromes (multiple sclerosis)

•
Hepatitis, activation of hepatitis B
•
• •Infusion/ injection site reactions
Rarely lymphomas
BP503T- Pharmacology II 173
IL-1 antagonist
• A N A K I N RA
• Recombinant human IL-1 receptor
• antagonist Clinically less effective than TNF
• inhibitors Used in refractory RA

BP503T- Pharmacology II 174

Corticosteroids and RA
 Potent immunosuppressant and anti-inflammatory

 Any stage – 1st line as well as 2nd line

 Potent antiinflammatory action required – DMARD + NSAIDs + steroids

 Prompt symptomatic relief

 Low dose (5-10 mg prednisolone or equivalent)

 Symptomatic relief - do not arrest RA process – slows down joint destruction and bony erosion

 High dose steroids – severe systemic manifestations – organ threatening disease, vasculitis etc.

 Intra-articular steroids

 R EMEMBER!!! LONG TERM USE OF COR T ICOSTEROI DS CAR R I ES SERI OUS

DISADVANTAGES

BP503T- Pharmacology II 175

 MCQ’S

BP503T- Pharmacology II 176

1. Agents that often cause vasoconstriction include all of the following except
A)Angiotensin II (B) Methysergide (C) PGF2α (D) Prostacyclin
Ans: D
2. Which of the following is a reversible inhibitor of platelet cyclooxygenase?
A) Alprostadil (B) Aspirin (C) Ibuprofen (D) LTC4
Ans: C
3. Vasodilation by prostaglandins involves
(A) Arterioles
(B) Precapillary sphincters
(C) Postcapillary venules
(D) All of the above
Ans: D
4. Following is an example of paraaminophenol NSAID
(A) Diclofenac (B) Acetaminophen (C) Piroxicam (D) Celecoxib
Ans: B
5. Which one of the following drugs is notuseful in dysmenorrhea?
A) Aspirin (B) Colchicin (C)Ibuprofen (d) Rofecoxib
Ans: B
6. Following gold compound is generally administered orally
A) Aurothioglucose
(B) Auronafin
(C) Gold sodium thiomalate
(D) All of the above
Ans: B BP503T- Pharmacology II 177
7. Following is an example of preformed and not lipid derived mast cell mediator of inflammatory process
A) LTC4 (B) PGD2 (C) PAF (C) Histamine
Ans: D
8. The toxicity spectrum of aspirin does not include
A) Increased risk of encephalopathy in children with viral infections
(B) Increased risk of peptic ulcers
(C) Hyperprothrombinemia
(D) Metabolic acidosis
(e) Respiratory alkalosis
Ans: C
9. A drug that decreases blood pressure and has analgesic and spasmolytic effects when given intrathecally is
A )Atenolol (B) Clonidine (C) Morphine (D) Nitroprusside
Ans: B
10. Cyclooxygenase-1 and –2 are responsible for
(A) The synthesis of prostaglandins from arachidonate
(B) The synthesis of leukotrienes from arachidonate
(C) The conversion of ATP to cAMP
(D) The metabolic degradation of cAMP
Ans:A
11. Following agent is generally used in allergic rhinitis
(A) Beclomethasone (B) Fluticasone (C) Triamcinolone (D) All of the above
Ans: D

BP503T- Pharmacology II 178

12. Acetyl salicylic acid is soluble in
A) An aqueous base (B) Water (C) An aqueous acid (D) All of the above
Ans: A
13. Diamprit is an agonist of ______ receptors, except
A) H1 (B) H2 (C) H3 (D) All of the above
Ans: A
14. Low doses of heparin prolong
B) Bleeding time B) Activated partial thromboplastin time
C) Prothrombin time D) Both (b) and (c)
Ans: B
15. Which of the following medications would represent arthritis therapy that is least
likely to cause gastric ulceration?
A)Acetaminophen (B) Piroxicam (C) Meclofenamate (D) Rofecoxib
Ans: D
16. The termination of heparin activity by protamine sulfate is due to:
(A) Chelating action
(b) The inhibition of gastrointestinal absorption of heparin
(c) The displacement of heparin-plasma protein binding
(d) An acid-base interaction
Ans: D

BP503T- Pharmacology II 179

17. What is the most commom sign/symptom of hemorrhoids?
(A) Bleeding (B) Pain (C) Seepage (D) Pruritus
Ans: A
18. Which of the following agents is designated as a safe and effective analgesic, anesthetic and antipruritic by the Food and
Drug Administration?
(A) Witch hazel (B) Juniper tar (C) Hydrocortisone (D) Phenylephrine
Ans: B
19. Colchicine is used mainly to treat
(A) Gout (B) Arthiritis (C) Diabetes (D) Carcinomas
Ans: A
20. Which type of patient is most likely to hypersensitive to aspirin?
(A) Intrinsic asthamatic
(B) Extrinsic asthamatic
(C) Chronic bronchitic
(D) Patient with viral injection
Ans: A

BP503T- Pharmacology II 180

BP503T- Pharmacology II 181