Section

3
Autacoids and Related Drugs
Chapter 11
Histamine and Antihistaminics
HISTAMINE
histos
mast cells
Synthesis, storage and destruction 

Fig. 11.1: Synthesis and degradation of histamine MAO—Monoamine oxidase

Histamine receptors Four 

Table 11.1: Distinctive features of three types of histaminergic receptors

H1 H2 H3
1. Selective agonists 2-Methyl histamine (8:1) Dimaprit (1:2000) (R) -Methyl histamine
(relative selectivity H1: H2) 2-Pyridylethylamine (30:1) Impromidine (1:10,000) (H1: H3 1:3000)
2-Thiazolyl ethylamine (90:1) Imetit
2. Selective antagonists Mepyramine (6000:1) Cimetidine (1: 500) Thioperamide (H1: H3 1: 23000)
(relative selectivity H1: H2) Chlorpheniramine (15000:1) Ranitidine (l : >500) Impromidine (also H2 agonist)
Tiprolisant, Clobenpropit
3. Receptor type Gq-protein coupled Gs-protein coupled Gi/Go-protein coupled
4. Effector pathway PIP2 hydrolysis IP3/DAG : Adenylyl cyclase activation — a. Restricting Ca2+ influx
Release of Ca2+ from intracellular stores; cAMP —phosphorylation of b. K+ channel activation
Protein kinase-C activation specific proteins c. cAMP 
NO releasecGMP
 5. Distribution in body: a. Smooth muscle (intestine, airway, a. Gastric glands—acid secretion a. Brain (presynaptic)—inhibition
actions mediated uterus)—contraction b. Blood vessels (smooth muscle)— of histamine release—sedation
b. Blood vessels dilatation b. Lung, spleen, skin, gastric
• Endothelium: Release of NO and, c. Heart mucosa —decrease histamine
PGI2—vasodilatation. Atria: +ive chronotropy release
widening of gap junctions— Ventricles: +ive inotropy c. Ileum—inhibition of ACh release
increased capillary permeability d. Uterus (rat)—relaxation from myenteric plexus neurones
• Smooth muscle of larger vessels— e. Brain (postsynaptic)—impulse d. Certain blood vessels—inhibit
vasoconstriction. NA release—vasodilatation
c. Afferent nerve endings—stimulation.
d. Ganglionic cell—stimulation.
e. Adrenal medulla—release of CAs.
f. Brain (postsynaptic)—impulse.

PIP2—Phosphatidyl inositol bisphosphate; IP3—Inositol trisphosphate; DAG—

Diacylglycerols; NO—Nitric oxide; PGI2—Prostacyclin;

CAs—Catecholamines; cAMP —Cyclic 3’, 5’ adenosine monophosphate; ACh—Acetylcholine

 176 aUtacOids and ReLated dRUGs

Fig. 11.2: Mechanism of antigen-antibody reaction induced release of histamine from mast cell
In sensitized atopic individual, specific reaginic (IgE) antibody is produced and gets bound to Fc epsilon receptor I (FcRI) on the surface
of mast cells. On challenge, the antigen bridges IgE molecules resulting in transmembrane activation of a tyrosine-protein kinase
(t-Pr-K) which phos- phorylates and activates phospholipaseC. Phosphatidyl inositol bisphosphate (PIP2) is hydrolysed and
inositol trisphosphate (IP3) is generated which triggers intracellular release of Ca2+. The Ca2+ ions induce fusion of granule
membrane with plasma membrane of the mast cell result- ing in exocytotic release of granule contents. In the granule, positively
charged histamine (Hist+) is held complexed with negatively charged protein (Prot–) and heparin (Hep–) mol- ecules. Cationic
exchange with extracellular Na+ (and Ca2+) sets histamine free to act on the target cells.

triple response
SECTION 3

2. Heart in situ

PHARMACOLOGICAL ACTIONS
1. Blood vessels

3. Visceral smooth muscle

Histamine and antiHistaminics

177

4. Glands see

5. Sensory nerve endings

6. Autonomic ganglia and adrenal medulla
7. CNS

2. Allergic phenomena
3. As transmitter

PATHOPHYSIOLOGICAL ROLES
1. Gastric secretion see

4. Inflammation

P-selectin

178 aUtacOids and ReLated dRUGs

5. Tissue growth and repair

6. Headache

USES

Betahistine

HISTAMINE RELEASERS

1.
2.
3.
4.
5. ‘histamine liberators’.

H1 ANTAGONISTS
(Conventional antihistaminics)

PHARMACOLOGICAL ACTIONS

1. Antagonism of histamine see

2. Antiallergic action

Histamine and antiHistaminics

179

Table 11.2: Clinical classification, doses and preparations of H1 antihistaminics

Drug Dose and route Preparations
I. HIGHLY SEDATIVE
Diphenhydramine 25–50 mg oral BENADRYL 25, 50 mg cap., 12.5 mg/5 ml syr.
Dimenhydrinate 25–50 mg oral DRAMAMINE 16 mg/5 ml syr, 50 mg tab, GRAVOL 50 mg tab
Promethazine 25–50 mg oral, PHENERGAN 10, 25 mg tab., 5 mg/ml elixir,
25 mg/ml inj
i.m. (1 mg/kg)
Hydroxyzine 25–50 mg oral, ATARAX 10, 25 mg tab., 10 mg/5 ml syr, 6 mg/ml
i.m. drops, 25 mg/ml inj.
II. MODERATELY SEDATIVE
Pheniramine 20–50 mg oral, AVIL 25 mg, 50 mg tab, 15 mg/5 ml syr,
i.m. 22.5 mg/ml inj.
Cyproheptadine 4 mg oral PRACTIN, CIPLACTIN 4 mg tab., 2 mg/5 ml syrup
Meclozine (Meclizine) 25–50 mg oral In DILIGAN 12.5 mg + niacin 50 mg tab
In PREGNIDOXIN 25 mg + Caffeine 20 mg tab
Cinnarizine 25–50 mg oral STUGERON, VERTIGON 25 and 75 mg tab.
III. MILD SEDATIVE
Chlorpheniramine 2–4 mg (0.1 mg/kg) PIRITON, CADISTIN 4 mg tab
oral, i.m.
Dexchlorpheniramine 2 mg oral POLARAMINE 2 mg tab, 0.5 mg/ 5 ml syr
Triprolidine 2.5–5 mg oral ACTIDIL 2.5 mg tab.
Clemastine 1–2 mg oral TAVEGYL 1 mg tab., 0.5 mg/5 ml syr
IV. SECOND GENERATION ANTIHISTAMINICS
Fexofenadine 120–180 mg oral ALLEGRA, ALTIVA, FEXO 120, 180 mg tab
Loratadine 10 mg oral LORFAST, LORIDIN, LORMEG, 10 mg tab,
1 mg/ml susp.
Desloratadine 5 mg oral DESLOR, LORDAY, NEOLORIDIN 5 mg tab
Cetirizine 10 mg oral ALERID, CETZINE, ZIRTIN, SIZON 10 mg tab, 5 mg/5 ml syr.
Levocetirizine 5–10 mg oral LEVOSIZ, LEVORID, TECZINE 5, 10 mg tab
LEVOCET 5 mg tab, 2.5 mg/5 ml syr.
Azelastine 4 mg oral AZEP NASAL SPRAY 0.14 mg
0.28 mg intranasal per puff nasal spray
Mizolastine 10 mg oral ELINA 10 mg tab
Ebastine 10 mg oral EBAST 10 mg tab
Rupatadine 10 mg oral RUPAHIST 10 mg tab

180 aUtacOids and ReLated dRUGs

3. CNS

see motion sicknessparkin- sonism

appetite stimulating

antitussives see
4. Anticholinergic action
 High Low Minimal/
Absent
Promethazine Chlorpheniramine Fexofenadine
Diphenhydramine Triprolidine Astemizole
Dimenhydrinate Cyproheptadine Loratadine
Pheniramine Cinnarizine Cetirizine
Mizolastine

5. Local anaesthetic

6. BP 

PHARMACOKINETICS

SIDE EFFECTS AND TOXICITY

Histamine and antiHistaminics

181

SECOND GENERATION ANTIHISTAMINICS

•
•
•

(i)
(ii)
(iii)

Fexofenadine (Tor- sades de pointes)

Dose:
Loratadine

182 aUtacOids and ReLated dRUGs

Desloratadine

Cetirizine

Levocetirizine
Azelastine

Mizolastine
Ebastine
Rupatadine

USES

1. Allergic disorders

Histamine and antiHistaminics

183

2. Other conditions involving histamine see

3. Pruritides
4. Common cold
5. Motion sickness

6. Vertigo

1. Labyrinthine suppressants
Antihistaminics

–Anticholinergics
–Antiemetic phenothiazines
2. Vasodilators
3. Diuretics

4. Anxiolytics, antidepressants
5. Corticosteroids
cinnarizine dimenhydrinate see
Cinnarizine:

184 aUtacOids and ReLated dRUGs



Prochlorperazine:
see
7. Preanaesthetic medication

8. Cough see
9. Parkinsonism
10. Acute muscle dystonia

11. As sedative, hypnotic, anxiolytic

H2 antagonist Burimamide Metiamide Cimetidine Ranitidine, famoti- dine, roxatidine,

H antagonist

 PROBLEM DIRECTED STuDy

11.1 a taxi driver aged 30 years presented with sudden onset running and itchy nose, bouts of
sneezing, partial nasal blockage, redness and watering from the eyes, but no fever,
bodyache or malaise. He gave history of similar episodes occurring off and on during the spring
season. A diagnosis of seasonal allergic rhinitis was made and the doctor prescribed an
oral antiallergic medication to be taken once a day till symptoms subside.
(a) Which antiallergic medicine would be suitable for this patient? Which antiallergic
drugs should be avoided?
(b) Will the above medication prevent/reduce recurrent episodes of rhinitis that this
patient gets during spring. If not, can some medications be added to prevent/subdue the
episodes during the vulnerable season.
(see Appendix-1 for solution).

Chapter 12
5-Hydroxytryptamine, its Antagonists and
Drug Therapy of Migraine
5-HYDROXYTRYPTAMINE
(5-HT, Serotonin)
Serotonin Enteramine 5-hydroxytryptamine

SYNTHESIS, STORAGE AND DESTRUCTION


serotonin transporter (SERT),
Fig. 12.1: Synthesis and degradation of 5-hydroxy- tryptamine (5-HT)

vesicular monoamine transporter (VMAT-2)

SEROTONERGIC (5-HT) RECEpTORS

DM

186 AUTACOIDS AND RELATED DRUGS

5-HT2 Receptors 


Ketanserin

5-HT3 Receptor
5-HT1

Receptors

buspirone

5-HT4–7 Receptors
Cisapride renzapride

sumatriptan

clozapine

5-HT, iTs AnTAgonisTs And drug THerApy of MigrAine

187

Salient features of important 5-HT receptor subtypes

5-HT1 : Autoreceptors; inhibit serotonergic neural activity in brain.

5-HT1A—present in raphe nuclei and hippocampus; buspirone (antianxiety) may act through these
receptors.
5-HT1D/1B—Constricts cranial blood vessels and inhibits release of inflammatory neuropeptides in
them; sumatriptan (antimigraine) acts through these receptors.
5-HT2A : previously D type receptor; most important postjunctional receptor mediating direct actions of 5-
HT like vascular and visceral smooth muscle contraction, platelet aggregation, neuronal activation
in brain; ketanserin blocks these receptors.
 5-HT3 : previously M type receptor; depolarizes neurones by gating cation channels; elicits reflex effects
of 5-HT—emesis, gut peristalsis, bradycardia, transient hypotension, apnoea, pain, itch;
ondansetron (antiemetic) acts by blocking these receptors.
5-HT4 : Mediate intestinal secretion, augmentation of peristalsis. Renzapride (prokinetic) is a selective
5-HT4 agonist.

ACTIONS

1. CVS
Bp:

•
•

HT receptor function in the gut

5-HT2A : intestinal smooth muscle—contraction.

5-HT3 : fast depolarization of enteric plexus
neurones; release of 5-HT from entero-
chromaffin cells.
5-HT4 : lower esophageal sphincter—contraction;
enteric plexus—ACh release—enhanced
peristalsis; intestinal mucosa—secretion.
5-HTIp : slow depolarization of enteric plexus
neurones.

2. Visceral smooth muscles See

3. Glands
4. Nerve endings and adrenal medulla

188 AUTACOIDS AND RELATED DRUGS

5. Respiration
6. Platelets

7. CNS

pATHOpHYSIOLOGICAL ROLES
1. Neurotransmitter

2. Precursor of melatonin

3. Neuroendocrine function
4. Nausea and vomiting
5. Migraine
6. Haemostasis
7. Raynaud’s phenomenon
8. Variant angina
9. Hypertension
10. Intestinal motility
5-HT, iTs AnTAgonisTs And drug THerApy of MigrAine

189

11. Carcinoid syndrome

Use

DRUGS AFFECTING 5-HT SYSTEM

1. 5-HT precursor
2. Synthesis inhibitor
3. Uptake inhibitor
4. Storage inhibitor
5. Degradation inhibitor
6. Neuronal degeneration
7. 5-HT receptor agonists
(i) D-Lysergic acid diethyl amide (LSD)

(ii) Azapirones
(iii) Sumatriptan
(iv) Cisapride
8. 5-HT receptor antagonists

5-HT ANTAGONISTS


1. Cyproheptadine see

190 AUTACOIDS AND RELATED DRUGS

Side effects
2. Methysergide 
3. Ketanserin

Ritanserin

4. Clozapine see
5. Risperidone
olanzapine quetiapine
6. Ondansetron

ERGOT ALKALOIDS
Claviceps purpurea
Natural ergot alkaloids lysergic acid
(a) Amine alkaloid
(b) Amino acid alkaloids


Semisynthetic derivatives
(a)
(b) see
(c)


5-HT, iTs AnTAgonisTs And drug THerApy of MigrAine

191

Actions
Ergotamine 

Dihydroergotamine (DHE) 
Dihydroergotoxine (Codergocrine) see
Bromocriptine


Ergometrine (Ergonovine) see
Pharmacokinetics
Adverse effects
Preparations and dose
Ergotamine:
Dihydroergotamine:
Dihydroergotoxine (codergocrine)

192 AUTACOIDS AND RELATED DRUGS

DRUG THERAPY OF MIGRAINE

migraine with aura migraine without aura

Vascular theory Neurogenic theory

Mild migraine
(i) Simple analgesics

(ii) Nonsteroidal antiinflammatory drugs (NSAIDs) and their combinations

Drug therapy of migraine

 Severity Drug therapy
Mild : Simple analgesics/NSAIDs or their
combinations (± antiemetic)
Moderate : NSAIDs combinations/a triptan/
ergot alkaloids (+ antiemetic)
Severe : a Triptan/ergot alkaloids
(+ antiemetic)
+ prophylaxis
• Propranolol/other blockers
• Amitriptyline/other tricyclic
antidepressants
• Flunarizine/other Ca2+ channel
blockers
• Valproate/topiramate

(iii) Antiemetics
Moderate migraine

5-HT, iTs AnTAgonisTs And drug THerApy of MigrAine

193

Severe migraine

SpECIFIC ANTIMIGRAINE DRUGS

Ergotamine

Dihydroergotamine (DHE)
Current status Caffeine

Selective 5-HT1D/1B agonists (Triptans)

Sumatriptan


194 AUTACOIDS AND RELATED DRUGS

Contraindications:

Dose:
Pharmacokinetics:
Side effects

Rizatriptan:
Dose:
Naratriptan, Zolmitriptan, Almotriptan, Frovatriptan
Eletriptan

pROpHYLAxIS OF MIGRAINE

5-HT, iTs AnTAgonisTs And drug THerApy of MigrAine

195

Comparative features of triptans

Suma. Frova. Riza. Nara. Zolmi.

1. Oral bioavailability (%) 15 25 45 70 40
2. Tmax* (hr) 1.5–2 2–4 1–1.5 2–3 1.5–2
3. plasma t½ (hr) ~2 26 2–3 6 2–3
4. Oral dose
Initial (mg) 50–100 2.5 5–10 2.5 2.5
Max. in 24 hr (mg) 200 5–7.5 20 5 10

* Tmax: Time to peak plasma concentration after oral dosing.

(i) -Adrenergic blockers 

(ii) Tricyclic antidepressants amitriptyline

(iii) Calcium channel blockers
Flunarizine

Dose:
(iv) Anticonvulsants Valproic acid gabapentin topiramate 
(v) CGRP antagonist Erenumab see
(vi) 5-HT antagonists


196 AUTACOIDS AND RELATED DRUGS

  PROBlEM DIRECTED STUDY

12.1 A 36 years lady presents with the complaint of episodes of unilateral pulsatile headache
for the past 2 years or so. during the initial episodes, the headache was mild, was relieved
by paracetamol/ibuprofen tablets, and did not interfere with her daily activities. However, the
severity and frequency of pain episodes has progressively increased, so that now epi- sodes
recur nearly every 1-2 weeks, especially at the beginning of her periods. Headache is preceded
by lethargy, anorexia, nausea and is accompanied by blurred vision, flashes of light seen
on closing the eyes, unsteadiness and frequent vomiting. The pain lasts for 12–18 hours and
she is incapacitated for nearly 24 hours. The headache is not relieved now by over-the-counter
analgesics or combination analgesics.
(a) What medication can be prescribed to treat the headache episodes. What instructions
should be given regarding timing, dose, etc. of this medication?
(b) What specific medical history needs to be elicited, physical examination/investigation
performed before prescribing the above medication?

(c) Apart from treatment of pain episodes, can this patient be put on some regular medica-
tion to prevent/minimise the episodes?

Chapter 13
Prostaglandins, Leukotrienes (Eicosanoids)
and Platelet Activating Factor
Prostaglandins and leukotrienes (eicosanoids)

CHEMISTRY, BIOSYNTHESIS AND DEGRADATION

prostanoic acid,

leuko

3 triene

eicosanoids. 5,8,11,14 eicosa tetraenoic acid (arachidonic acid).

4


198 AUTACOIDS AND RELATED DRUGS

Fig. 13.1: Biosynthesis of prostaglandins (PGs) and leukotrienes (LTs). Less active metabolites are shown in italics
TX—Thromboxane; PGI—Prostacyclin; HPETE—Hydroperoxy eicosatetraenoic acid (Hydroperoxy arachidonic
acid); HETE—Hydroxyeicosatetraenoic acid (Hydroxy arachidonic acid); SRS-A—Slow reacting substance of
anaphylaxis
Cyclooxygenase (COX) pathway lipoxygenase Ether Fosfat

PROSTAGLANDINS, LEUkOTRIENES AND PLATELET ACTIvATING FACTOR

199

Lipoxygenase pathway ‘slow reacting substance of anaphylaxis’ (SRS-A)

hep- oxilins, trioxilins 19- 20-HETEs epoxyeicosatrienoic acids. iso- prostanes anandamide
inhibition of synthesis

Zileuton
annexins
degradation

ACTIONS AND PATHOPHYSIOLOGICAL ROLES

Prostaglandins, thromboxanes and prostacyclin

1. CVs 

200 AUTACOIDS AND RELATED DRUGS

•
•

3. uterus


 

Role
•
•
•
2. Platelets

Role

in vivo.

Role
• 
•
4. Bronchial muscle 

Role 

table 13.1 : A summary of the actions of major prostaglandins, prostacyclin and thromboxane
Organ Prostaglandin E2 (PGE2) Prostaglandin F2(PGF2) Prostacyclin (PGI2) Thro
(TXA
1. Blood vessels Vasodilatation, BP Constricts larger veins and Vasodilatation (marked and Vas
some arteries, little effect on BP widespread), BP
2. Heart Weak inotropic, reflex cardiac Weak inotropic —
stimulation
3. Platelets Variable effect — Antiaggregatory Agg
rele
4. Uterus Contraction (in vivo), Contraction (in vivo and — Con
softening of cervix in vitro), softening of cervix
5. Bronchi Dilatation, Constriction Dilatation (mild), Con
Inhibit histamine release inhibit histamine release
6. Stomach acid secretion, — acid secretion (weak),
mucus production mucosal vasodilatation
7. Intestine Contracts longitudinal & relaxes Spasmogenic, fluid & Weak spasmogenic, inhibits Wea
circular muscles, peristalsis, electrolyte secretion (weak) toxin-induced fluid secretion
Cl¯ & water secretion
8. Kidney Natriuresis, Cl¯ reabsorption, — Natriuresis, vasodilatation, Vas
inhibit ADH action, vasodilatation, renin release
renin release
9. CNS Pyrogenic,
variety of effects on i.c.v. inj.
10. Afferent nerves Sensitize to noxious stimuli  — Same as PGE2
tenderness
11. Endocrine Release of ant. pituitary hormones, — —
system steroids, insulin; TSH-like action
12. Metabolism Antilipolytic, insulin like action, — —
mobilization of bone Ca2+
 202 AUTACOIDS AND RELATED DRUGS

6. kidney

5. git


Role
see
Role

Role
•
•
7. Cns

Role
•

PROSTAGLANDINS, LEUkOTRIENES AND PLATELET ACTIvATING FACTOR

203

•
8. sympathetic nerves
Role
9. Peripheral nerves
Role

Fig. 13.2: Sensitization of nociceptors (pain receptors) to

latanoprost
see
Role
11. endocrine system
12. Metabolism

leukotrienes

1. CVs and blood

mediators of pain by prostaglandins at the inflammatory

site. Subs. P—Substance P; CGRP—Calcitonin gene related peptide

10. eye: 

Role

204 AUTACOIDS AND RELATED DRUGS

2. smooth muscle

Role

3. afferent nerves

PROSTANOID RECEPTORS

contractile group 

Fig. 13.3: Prostanoid receptors, their primary signaling pathways and major responses elicited through them.
All prostanoid receptors are G-protein coupled receptors. On the basis of their functional characterization,
prostanoid receptors have been grouped into contractile, relaxant and inhibitory groups.
PLC—Phospholipase C; IP3—Inositol trisphosphate; DAG—Diacyl glycerol; AC—Adenylyl cyclase; cAMP—
Cyclic AMP; PKA—Protein kinase A.

PROSTAGLANDINS, LEUkOTRIENES AND PLATELET ACTIvATING FACTOR

205

relaxant group inhibi- tory

DP
EP enprostil
EP1
EP2 and EP4
EP3

FP fluprostenol
IP cicaprost
TP 

LEUKOTRIENE RECEPTORS

cyscyscyscyscysviz. Montelukast, Zafirlukast, see

USES

1. Abortion

206 AUTACOIDS AND RELATED DRUGS




2. Induction/augmentation of labour 
3. Cervical priming (ripening)

4. Postpartum haemorrhage (PPH) 

PGE2 (Dinoprostone)
Vaginal gel
Vaginal tab
Extraamniotic solution
Intravenous solution
Oral tablet
Cervical gel
Gemeprost
PGF(Dinoprost)
15-methyl PGF(Carboprost)


5. Glaucoma latanoprost, travoprostbimatoprost see

6. Peptic ulcer

PROSTAGLANDINS, LEUkOTRIENES AND PLATELET ACTIvATING FACTOR

207

see
7. To maintain patency of ductus arteriosus

8. To avoid platelet damage

9. Pulmonary hypertension pulmonary hypertension

10. Peripheral vascular diseases

11. Impotence

SIDE EFFECTS

Platelet aCtiVating FaCtor (PaF)

actions
Platelets
WBC
Blood vessels

Visceral smooth muscle

synthesis and degradation

Stomach
Mechanism of action

208 AUTACOIDS AND RELATED DRUGS

PaF antagonists

Pathophysiological roles
1. Inflammation:
2. Bronchial asthma:
3. Anaphylactic (and other) shock conditions:
4. Haemostasis and thrombosis:
5.

 ProBleM direCted study

 13.1 A full term primigravida presented with labour pains. On examination the BP was 110/70
mm Hg and she was not anaemic. The presentation was vertex, head was engaged, foetal
heart sound was normal, there was no cephalopelvic disproportion, no placenta previa,
membranes were intact and uterine contractions were adequate. The labour was allowed
to progress under observation. After 8 hours the cervix was still firm and not adequately
dilated.
(a) Can some medicaion be used to soften the cervix, help its ripening and facilitate delivery?
If so, which drug and route of administration should be used?
(b) Given the above findings, is there any contraindication to the use of such
medication? (see Appendix-1 for solution)

Chapter 14
Nonsteroidal Antiinflammatory Drugs and
Antipyretic-Analgesics
nonnar cotic, nonopioid aspirinlike

Salix albaSodium salicylate Phenacetin antipyrine Indomethacin

210 AUTACOIDS AND RELATED DRUGS

ibuprofen

NSaIds and prostaglandin (pg) synthesis inhibition

see

Beneficial actions due to pg synthesis inhibition

• Analgesia: prevention of pain nerve ending

sensitization
• Antipyresis
• Antiinflammatory
• Antithrombotic
• Closure of ductus arteriosus in newborn

Analgesia see 

Antipyresis 
Antiinflammatory
NSAIDs and antipyretic-analgesics

211

Shared toxicities due to pg synthesis inhibition

Table 14.1: Features of nonselective COX

inhibitors and selective COX-2 inhibitors
Action COX-1/ COX-2
COX-2 inhibitors
inhibitors
1. Analgesic + +
2. Antipyretic + +
3. Antiinflammatory + +
4. Antiplatelet  
aggregatory
5. Gastric mucosal  
damage
6. Renal salt/water  
retention
Gastric
7. Delay/prolongation of  
labour
8. Ductus arteriosus  
closure
9. Aspirin sensitive  
asthma precipitation

• mucosal damage

selectins integrins
Dysmenorrhoea 

Antiplatelet aggregatory Aspirin is highly active

Ductus arteriosus closure
Parturition

212 AUTACOIDS AND RELATED DRUGS

Gastric mucosal damage

Renal effects
•
•
•

Analgesic nephropathy
Anaphylactoid reactions

SALICYLATES

aspirin

Pharmacological Actions
1. Analgesic, antipyretic, antiinflammatory actions

NSAIDs and antipyretic-analgesics

213

2. GIT
see

3. Blood

4. Metabolic and other effects of high (antiinflammatory/toxic) doses

•
•

• compensated respiratory alkalosis. respiratory acidosis. metabolic acidosis,

•

214 AUTACOIDS AND RELATED DRUGS

• 

Pharmacokinetics

Adverse effects
(a) Side effects
(b) Hypersensitivity and idiosyncrasy

(c) Antiinflammatory doses

(d) Acute salicylate poisoning

Treatment

Precautions and contraindications

•
•

•
•

NSAIDs and antipyretic-analgesics

215

•
•

Interactions
1.
2.
3.

Uses
1. As analgesic

2. As antipyretic
3. Acute rheumatic fever

4. Rheumatoid arthritis
5. Osteoarthritis
6. Postmyocardial infarction and poststroke patients

7. Prevention of preeclampsia

216 AUTACOIDS AND RELATED DRUGS

adverse effects of NSaIds

Gastrointestinal
Nausea, anorexia, gastric irritation, erosions, peptic ulceration, gastric bleeding/perforation, esophagitis

Renal
Na+ and water retention, edema, chronic renal failure, nephropathy, papillary necrosis (rare)

CVS
Rise in BP, risk of myocardial infarction (especially with COX-2 inhibitors), CHF

Hepatic
Raised transaminases, hepatic failure (rare)
CNS
Headache, tinnitus, mental confusion, vertigo, seizure precipitation
Haematological
Bleeding, thrombocytopenia, haemolytic anaemia, neutropenia
Others
Asthma exacerbation, rhinitis, nasal polyposis, skin rashes, pruritus, angioedema

8.

–
–
–

PROPIONIC ACID DERIVATIVES

in vitro in vivo

Adverse effects

Pharmacokinetics and interactions

NSAIDs and antipyretic-analgesics

217

drug interactions with NSaIds

Pharmacodynamic Pharmacokinetic

Diuretics : diuresis
blocker : antihypertensive effect
ACE inhibitors : antihypertensive effect
Anticoagulants : risk of g.i. bleed
Sulfonylureas : risk of hypoglycaemia
Alcohol : risk of g.i. bleed
Cyclosporine : nephrotoxicity
Corticosteroids : risk of g.i. bleed Selective serotonin

reuptake inhibitors : risk of g.i. bleed

Coumarin anticoagulants Sulfonylureas

Phenytoin Valproate

Digoxin Lithium
Aminoglycosides Methotrexate
Metabolism inhibited; competition
for plasma protein binding

Renal excretion of interacting drug

Uses
1.
2.
3.
Ibuprofen

Naproxen

in vivo

Table 14.2: Dosage and preparations of propionic acid derivatives

Drug Plasma t½ Dosage Preparations
1. Ibuprofen 2–4 hr 400–600 mg BRUFEN, EMFLAM, IBUSYNTH 200, 400, 600 mg
(5–10 mg/kg) TDS tab, IBUGESIC also 100 mg/5 ml susp.
2. Naproxen 12–16 hr 250 mg NAPROSYN, NAXID, ARTAGEN, XENOBID
BD–TDS 250 mg tab., NAPROSYN also 500 mg tab.
3. Ketoprofen 2–3 hr 50–100 mg KETOFEN 50, 100 mg tab; OSTOFEN 50 mg cap.
BD–TDS RHOFENID 100 mg tab, 200 mg SR tab;
100 mg/2 ml amp.
4. Flurbiprofen 4–6 hr 50–100 mg ARFLUR 50, 100 mg tab, 200 mg SR tab,
BD–QID FLUROFEN 100 mg tab.

218 AUTACOIDS AND RELATED DRUGS

Ketoprofen
Flurbiprofen

naproxen

FENAMATE (Anthranilic acid derivative)

Mephenamic acid
Adverse effects
Pharmacokinetics
Uses Dose:

Comorbid conditions aggravated by NSaIds

• Peptic ulcer
• Hypertension
• Congestive heart failure
• Renal insufficiency
• Hemostatic disorders
ENOLIC ACID DERIVATIVES (Oxicams)
piroxicam
Pharmacokinetics
Adverse effects
Uses
Dose:

NSAIDs and antipyretic-analgesics

219

Tenoxicam

ACETIC ACID DERIVATIVES

Ketorolac

Adverse effects

Use

Indomethacin
Pharmacokinetics
Adverse effects

Dose:

Uses

220 AUTACOIDS AND RELATED DRUGS

Nabumetone
PYRAZOLONES
Phenylbutazone oxyphenbutazone
propyphenazone

PREFERENTIAL COX-2 INHIBITORS

Nimesulide

fulminant hepatic failure

Dose:

diclofenac sodium

NSAIDs and antipyretic-analgesics

221

Adverse effects

Dose:

aceclofenac
Dose:

Meloxicam

Dose:

Etodolac
Dose:

SELECTIVE COX-2 INHIBITORS (Coxibs)

CelecoxibEtoricoxib Parecoxib Rofecoxib

222 AUTACOIDS AND RELATED DRUGS

Selective COX-2 inhibitors and cardiovascular risk

Other concerns with selective COX-2 inhibitors

 COX-2 inhibitors reduce endothelial PGI2 production

without affecting platelet TXA2 synthesis. This appears to exert prothrombotic influence and enhance CV risk.
• VIGOR (VIOXX gastrointestinal outcomes research) study in over 8000 patients found 4-fold higher incidence of myocardial
infarction (MI) in rofecoxib (VIOXX) recipients compared to those on naproxen.
• APPROVE (adenomatous polyp prevention on VIOXX) a placebo controlled trial among subjects with history of colorectal
adenomas was stopped prematurely at 3 years because it confirmed higher risk of heart attack and stroke: rofecoxib was
withdrawn globally in 2004.
• A metaanalysis of 18 trials with rofecoxib for musculoskeletal disorders has also inferred that it increases incidence of MI.

• Valdecoxib increased occurrence of MI in patients undergoing coronary bypass surgery. There were reports of severe skin
reactions as well. It was withdrawn in 2005.
• Though CLASS (celecoxib long-term safety study) did not find any increase in CV events, the APC (adenoma prevention
with celecoxib) trial has been terminated prematurely due to 2.5 fold higher risk of the same.
• There is no clear evidence as yet that etoricoxib also increases CV risk.
• A joint committee in USA (2005) concluded that enough evidence to withdraw all selective COX-2 inhibitors is lacking, but
that their labelling should include a warning of CV risk.

Valdecoxib Lumiracoxib
selective COX2
inhibitors should be used only in patients at high risk of peptic ulcer, perforation or bleeds.
see

• COX-1 generated PGs may also play a role in

inflammation: COX-2 inhibitors may not have as
broad range of efficacy as traditional NSAIDs.
• Ulcer injury and H. pylori induce COX-2 in gastric
mucosa, which may contribute to
gastroprotective PG synthesis; COX-2 inhibition
may delay ulcer healing. Moreover, part of
gastric mucosal COX-2 activity may be
constitutive.
• Juxtaglomerular COX-2 is constitutive; its
inhibition can cause salt and water retention.
Pedal edema, precipitation of CHF and rise in BP
can occur with all coxibs.

Celecoxib

Etoricoxib

NSAIDs and antipyretic-analgesics

223

Dose:
parecoxib Dose:

PARA-AMINO PHENOL DERIVATIVES

Phenacetin see
paracetamol (acetaminophen)

Actions
Pharmacokinetics
Adverse effects
Acute paracetamol poisoning

Mechanism of toxicity

224 AUTACOIDS AND RELATED DRUGS

Note:

Treatment
Specific antidote:

Uses heat stroke

Dose:

BENZOXAZOCINE DERIVATIVE
Nefopam

Dose:

Topical NSaIds

NSAIDs and antipyretic-analgesics

225

preparations
Choice of nonsteroidal antiinflammatory drug

1.
2.
3. viz.
4.

226 AUTACOIDS AND RELATED DRUGS

5.
6.
7.

8.
9.
10.
11.
12.

analgesic combinations

 pROBlEM dIRECTEd STudy

14.1 A 65-year-old lady presented with pain in both knees, more on the left side. The pain is
worsened by walking or standing for some time. X-ray of knee shows narrowing of joint
space, mild effusion and osteophytic projections. a diagnosis of osteoarthritis of knee is
made. she gave history of suffering a heart attack one year back which was treated by
angioplasty and a stent was placed. she regularly takes aspirin 75 mg daily for prophylaxis
of further myocardial infarction.
(a) Which analgesic/nsaid will be suitable for relieving her knee pain?
(b) Which analgesic/nsaids should not be prescribed for her?
(c) Whether any locally applied medication can be helpful in relieving her knee pain?
(see appendix-1 for solution)

Chapter 15
Antirheumatoid and Antigout Drugs
AntirheumAtoid drugs

disease modifying antirheumatic drugs slow acting antirheumatic drugs

 Rheumatoid arthritis 

228 AUTACOIDS AND RELATED DRUGS

•
•

nonbiological drugs
1. immunosuppressants (see Ch. 65)
Methotrexate (Mtx)

Azathioprine
Dose:

2. other immunomodulators
Sulfasalazine (see Ch. 49)

ANTIRhEUmATOID AND ANTIGOUT DRUGS

229

Dose:
Hydroxychloroquine/Chloroquine (see Ch. 61)

Hydroxychloroquine

Chloroquine

Leflunomide
dihydro-orotate dehydrogenase

Tofacitinib
Dose:

Biological agents


tnFinhibitors


230 AUTACOIDS AND RELATED DRUGS


Etanercept: 

Dose:

Infliximab: 
Adalimumab:
Certolizumab Golimumab 

other biological agents

Anakinra:
Dose:

Rilonacept Canakinumab

Abatacept 

Rituximab (see Ch. 64) 

Corticosteroids (see Ch. 20)

•
•

drugs used in gout

gout

ANTIRhEUmATOID AND ANTIGOUT DRUGS

231

Secondary hyperuricaemia
(a)
(b)

ACUTE GOUTy ArThriTis

1. nsAids
naproxen, piroxicam, diclofenac, indomethacin etoricoxib

2. Colchicine
Colchicum autumnale

• 
•

232 AUTACOIDS AND RELATED DRUGS

(a)

(b)

Toxicity
Use

3. Corticosteroids
Intraarticular

Systemic

ChrONiC GOUT/hypErUriCAEmiA

A. uricosuric drugs Probenecid

•
•

ANTIRhEUmATOID AND ANTIGOUT DRUGS

233

Interactions
1.
2.
3.
4.
Pharmacokinetics
Adverse effects
Uses

2.
3.

Sulfinpyrazone

Lesinurad

B. Uric acid synthesis inhibitors

Allopurinol
xanthine oxidase
alloxanthine (oxypurine) in vivo
de novo
Pharmacokinetics

234 AUTACOIDS AND RELATED DRUGS

Fig. 15.1: Uric acid synthesis and the action of allopurinol

Interactions
1.
2.
3.

4.
Adverse effects

Precautions and contraindications

Uses chronic goutover producers under excretors viz.

• Secondary hyperuricaemia
ANTIRhEUmATOID AND ANTIGOUT DRUGS
235
• potentiate 6-mercaptopurine or azathioprine
Dose:

Caution

Febuxostat

Dose:
Pegloticase

 ProBlem direCted study

15.1 A 44-year-old lady presents with complaints of pain, swelling and stiffness of the in-
terphalangeal and metacarpophalangeal joints of both hands for the last 8 months. Initially the
symptoms were mild, but are increasing progressively despite treatment by her neigh-
bourhood doctor. Her prescription reveals that she is taking Diclofenac sod. 75 mg SR tab
twice daily and Pantoprazole 40 mg tab once daily in the morning. Though, initially she was
getting good relief, but now the relief is incomplete, and she is disabled for 2–3 hours in the
morning. Physical examination confirmed the swelling, tenderness and stiffness of hand and
finger joints. Investigations were ordered. The significant findings of the test reports are: mild
normocytic anaemia (Hb–10.2 g/dl), ESR-54 mm at 1 hour, TLC-6,800/mm3, rheumatoid factor
and Anti-CCP antibodies positive, C-reactive protein 2.2 mg/L (raised). X-ray of hand revealed
mild soft tissue swelling around the affected joints, but no joint and bone abnor- mality. She
was diagnosed as a case of active rheumatoid arthritis.
(a) Should the diclofenac dose be increased, or should it be substituted by another NSAID?
Will these measures treat her adequately?
(b) Should any drug, other than an NSAID, be prescribed for this patient? If so, which
one, and why?
(c) What needs to be done before prescribing this drug? When and what benefits are expected
to be obtained from this drug?
oprazole has been prescribed to this patient? Should it be continued or stopped?