Learning objectives

After this class you should be able to:

Explain the pathophysiological effects of autacoids and autacoid antagonists on the

human body.

Describe the pharmacology of anti-histamines.

Outline briefly serotonin agonists & antagonists.

Describe the physiological functions of prostaglandins and explain the therapeutic uses of
prostaglandin analogs.
What is autacoid?
What is autacoid?

Substances produced by variety of cells that act locally (local hormones)

Autos = self, akos = healing/remedy

Histamine Prostaglandi Bradykinin

Serotonin ns Angiotensin
Leukotrienes kallidin
Platelet
activating
Amin factor
Lipid Pepti
e de
I. Histamine (source, storage sites and receptors)
Source of histamine Receptors

Plant H1 (smooth muscle, endothelium and brain)

Animal tissue H2 (gastric mucosa, cardiac, mast cells, brain)

H3 (brain)
Component in venoms and stinging secretions
H4 (eosionophil, neutrophil, CD4 T cells)
Neoplasms (e.g. systemic mastocytosis)

Storage
As granules (vesicles) in mast cells and basophils
Non mast cell source:
brain (As neurotransmitter)
ECL cell (enterochromaffin like cells in GIT)
Physiological actions of histamine
Physiological actions of histamine

Tissue oedema (vasodilation transudation of fluid into tissue)

(Responsible for urtacaria)

Triple response (red spot (flush), edema, and flare response)

Allergic
reactions (eg.
urtacaria)
bronchoconstriction mediated by H1receptors.

H1 activation release of NO vasodilation decrease in blood

pressure (in anaphylactic shock)

Anaphylactic
shock
 Physiological actions of histamine

causes contraction of intestinal smooth muscle

H2
powerful stimulant of gastric acid secretion

Gastric acid secretion

H2
Increase in heart rate (directly by H2 or by reflex tachycardia due to
hypotension)

Metabolic effects (increase wakefulness, decrease appetite, body

temperature control)

local stimulation of peripheral pain nerve endings via H 3and

H1receptors, histamine may play a role in nociception in the central
nervous system. (Pain & itching)
Neurotransmitt
er
Histamine receptor antagonists (classification)
First generation antihistamines
1. Diphenhydramine (Benadryl,
Diphenhydramine (Benadryl, etc) etc)
Ethanolamines
2. Dimenhydrinate (Dramamine)
Dimenhydrinate (Dramamine)
3. Hydroxyzine
Hydroxyzine
4. Cyclizine
Cyclizine Piperazine derivatives
5. Meclizine
Meclizine
6. Brompheniramine
Brompheniramine Alkylamines
7. Chlorpheniramine
Chlorpheniramine
8. Promethazine
Promethazine Phenothiazine derivative
Cyproheptadine
9. Cyproheptadine Miscellaneous

Second generation antihistamines

Fexofenadine
Loratadine
Desloratadine
Cetirizine
Histamine receptor antagonists (Mechanism of action)
Mechanism of action

block the actions of histamine by

reversible competitive binding to
the H1 receptors.

first-generation H1-receptor
antagonists have many actions in
addition to blockade of histamine.
Endothelial cells
Includes blockade of muscarinic Blood vessel

receptor, alpha adrenoreceptor,

serotonin, and local anesthetic
receptor sites.
Histamine receptor antagonists (pharmacological actions)
Histamine (Therapeutic uses)

Histamine aerosol has been used as a provocative test of bronchial

hyper-reactivity.

Positive control for allergy skin test.

First and second generation antihistamines
Second generation antihistamines;

Do not cross BBB less sedation (lesser CNS adverse effects)

No anticholinergic effects (higher H1 selectivity)

Additional mechanisms of anti-allergic action (inhibit release of histamine from

mast cells)

No psychomotor impairment
Drug interactions of H1 antagonists
Terfenadine & Astemizole (metabolised by CYP3A4)
When co-administered with CYP3A4 inhibitors (erythromycin,
ketoconazole) fatal ventricular tachycardia
Withdrawn due to arrhythmogenic potential

1st generation agents (with significant sedation) + other CNS depressants

additive effects and is contraindicated while driving or operating machinery.

Autonomic blocking effects of older (1st generation) antihistamines +

other antimuscarinic or -blockers additive effect (Eg. Orthostatic
hypotension or urine retention/blurred vision)
 Serotonin syndrome

Serotonin syndrome occurs when overdose with a single drug, or concurrent use of several
drugs resulting excess serotonergic activity in the central nervous system.
Precipitating Clinical Therapy
drugs presentatio
n
SSRI (selective Hypertension Sedation
serotonin Tremor (benzodiazepin
reuptake inhibitor) Hyperthermi es)
Antidepressants a Paralysis
MAOI (mono Hyperactive Intubation
amine oxidase bowel sounds Ventilation
inhibitors) etc. Diarrhoea 5HT block with
Agitation drugs
Coma (cyproheptadin
e or
chlorpromazine
)
III. Ergot alkaloids
Produced from fungus; Claviceps purpurea.
Contains many active substances
affect on adrenoceptors, dopamine receptors, 5-HT receptors, and other receptor types.
IV. Eicosanoids
20 carbon unsaturated fatty acids

derived from arachidonic acid

(AA) from cell membranes

Synthesized by virtually all tissues

Products:

Prostaglandins, thromboxanes,
leukotrienes, lipoxins
Eicosanoids
Organ Pharmacological action Name of drug with use/adverse
effects
Smooth muscle Alprostadil: (PGE1) analogue, given
1. Vascular TXA2 & PGF2 (potent iv to maintain patency of ductus
vasoconstrictor) arteriosus,
2. Non vascular PGI2and PGE2 (Vasodilator)

GI smooth
muscle PGI2, PGF2, thromboxanes, Increased GI motility (Adverse
leukotrienes effect) of prostaglandins
(activate GI smooth muscle
Respiratory contraction) PGE2is a bronchodilator (not useful
smooth muscle clinically)
PGE2 (relaxation of resp smooth
Reproductive muscle)
PGD2, TXA2, and PGF2
(contraction)
Alprostadil: (PGE1) treatment of
PGF2 (uterine smooth muscle erectile dysfunction
Eicosanoids
Organ Pharmacological action Name of drug with
use/adverse effects
Platelet PGD2, PGI2inhibit aggregation Eoprostenol: (PGI2) vasodilator
TXA2 enhance platelet aggregation and antithrombotic action, used in
pulmonary hypertension
TXA2 synthesis inhibitors or COX
inhibitors are used to inhibit
platelet aggregation.
Kidney PGE2& PGI2maintain renal blood Long term use of PG synthesis
flow and glomerular filtration rate inhibitors (e.g NSAIDs (COX
through their local vasodilating inhibitors) renal damage)
effects.

Protection PGE2& PGI2 enhance mucus and Misoprostol: (PGE1) suppresses

of GI bicarb secretion, inhibit gastric gastric acid secretion, used with
mucosa acid secretion. NSAID
Eicosanoids
Organ Pharmacological action Name of drug with
use/adverse effects
CNS and PGE2increases body temperature
PNS (febrile response) PG synthesis inhibitors (COX
(pain, fever and inflammation) inhibitors/NSAIDs) used as
Inflammatio PGE2& PGI2- causes antipyretic, anti-inflammatory and
n and inflammation. analgesic.
immunity
Eye PGE, PGF, and PGD - lower Latanoprost PGF2 - use for
intraocular pressure glaucoma
Reproductiv PGF2 (uterine smooth muscle Dinoprostone gel: (PGE2), to
e contraction) induce labour and for abortion

Gemeprost: for induction of late

therapeutic abortion

Carboprost: for post partum

haemorrhage
Prostaglandin synthesis inhibitors