ANTI HISTAMINICS

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Histamine (H) - ‘Tissue amine’.

Pharmacological profile- Dale.

Its present in mast cells, Skin, GIT mucosa, lungs, liver &

Placenta.

Non-mast cells histamines present in brain, epidermis,

gastric mucosa & growing regions.

Its also present in blood, secretions, venoms & pathological

fluids.

Turn over of mast & non-mast cells.

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Synthesis, Storage & Metabolism-

Synthesized from Histidine-Oxidation & Methylation.

Histamine

Histamine actions resembles the manifestation of certain

allergic reactions.

So its a mediator of hypersensitivity & tissue injury

reactions.

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T-Pr-K

PIP2

IP3

Ca2+

Mechanism of histamine release

from Mast cell due to Ag- Ab

reaction.

Ag

Ab

Exocytosis

Mast cell

Storage vesicles

Granules contains histamine

Fc εRI

Ca2+/Na+

Histamine

CAMP- Ca2+ Histamine release

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+

L-Histidine

Histamine

Histaminase / oxidation

Imidazole acetic acid

Imidazole acetic acid

ribose

Ribose

Storage vesicle

Release Na+ ECF

Heparin

Protein

C=O

O Na

+ Histamine

Methylation/ Transferase

N-methyl histamine

N-methyl imidazole

Acetic acid

Histidine decarboxylase

MAO-BHeparin--

Protein

Histamine+

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L-amino acid

decarboxylase

Immune reaction,

Mechanical,

chemical physical

+

Histaminergic receptors

H1 & H2 receptors- Asch & Schild.

H1 blockers- Antihistamines

H2 blockers- Burimamide -Sir James Black.

H3 receptors- Auto receptors -controls H-release.

H4- Eosinophils, Neutrophils, CD4T cells, Chemotaxis of

WBC- blockers are used in Chr. allergy inflammatory

conditions

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H1 H2

Agonists 2-methyl histamine,

2-pyridylethylamine

4-methyl histamine

Dimaprit

Impromidine

Antagonist Mepyramine

Chlorpheniramine

Cimetidine

Ranitidine

Receptor type Gq -coupled receptor G s-coupled receptor

Effector pathway PIP2 hydrolysis—IP3/DAG

Intracellular Ca 2+ release

Ptn. Kinase C- activation.

Adenylyl cyclase

activation-

CAMP- phosphorylation of

specific proteins.

Distribution -Smooth muscles

-Blood vessels

-Afferent nerve endings-stimulation

-Ganglionic cell +.

Adrenal medulla- release of C.A’s

Brain- neurotransmitter.

-Gastric glands

-Blood vessels

-Heart

-Uterus (rats)

-Brain- neurotransmitter.

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Pharmacological actions

1) CVS & Blood vessels- vasodilation, B.P, tachycardia &

headache, flushing, heat.

Triple response- Flush, Wheal & Flare.

2) Smooth muscle-

Contraction- Br.spasm, GIT motility.

No action human uterus.

3) Glands- secretions of exocrine glands.

Bronchi, pancreas, salivary, gastric & lacrimal glands.

4) CNS- B.P, Behavioural change, N,V, hypothermia & ADH release.

5) Nerve endings- Pain & itching.

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Pathophysiological role-

1) Gastric acid secretions-

2) Allergic phenomena- Early type-1 hypersensitivity.

3) As transmitter-

4) Inflammation-

5) Tissue growth & repair -

6) Headache-

Contra indications- Asthma & P.U.

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3)As a transmitter- pathophysiology

Histamine-H1R

Peripheral

+ Sensory nerve

endings

Pain & Itching

Brain

Hypothalamus

Mid brain

Wakefulness

-Appetite centre

Wt.gain Regulates

Temp, CVS

&

Thirst

Release

Anterior

Pituitary hormones

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Histamine Uses

- Histamine is of no therapeutic value.

1) Testing gastric acid secretion-

- To test acid secreting ability of stomach.

2) Diagnosis of pheochromocytoma –

-Histamine releases CA & BP raises.

3) Pulmonary function-

- To test for bronchial hyper activity.

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Histamine substitutes-

Betahistine - H1 agonist – Meniere’s disease.

Betazole - H2 agonist- used in gastric acid function test.

Drugs that liberate H Drugs that inhibit H

Morphine, d-Tc, Trimethapan,

Polymyxin -B,

Sch, PVP, Dextran, bile salts.

Radio contrast media

Heat, cold, sunlight & x-rays.

Proteolytic enzymes- venoms,

trypsin & chymotrypsin.

Ag-Ab reactions

Adrenaline, Ephedrine,

Isoproterenol

Mast cell membrane

stabilizers- Cromogylate,

Pizotifen & Ketotifen.

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Pharmacological action of antihistamines

1) Antagonism of histamine-

Blocks histamine induced-

-Broncho constriction & smooth muscle constriction.

- Triple response

- Fall in B.P

- Animal death (pre-treatment with H1 blockers).

- Adrenaline release

- vasoconstriction of large B.V.

- No action on gastric acid secretion.

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2) Anti allergic action-

Type -1 manifestations - suppressed.

Fall in B.P- partially prevented.

Asthma is unaffected

3) CNS-

Cross BBB-sedation due high affinity to central H1R.

Stimulant effects- some individuals.

Excitement & convulsions – toxic dose.

Anti motion sickness

Morning sickness.

Anti cholinergic S/E- tremors, rigidity & sialorrhoea.

Antitussive action.

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Parkinsonism

4) Anticholinergic action-

5) Local anaesthetic action- membrane stabilizing activity.

6) Fall in B.P- on I.V inj.

High Low Minimal/ Absent

Promethazine Chlorpheniramine Fexofenadine

Diphenhydramine Hydroxyzine Astemizole

Dimenhydrinate Tripolidine Loratadine

Pheniramine Cyclizine Cetirizine

Cyproheptadine Mizolastin

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1st generation 2nd generation

Short- intermediate acting Long acting

Cross BBB- More sedative. X BBB- No CNS effects & No sedative

Anti-muscarinic S/E . No anti-muscarinic S/E.

Antihistamine action Anti allergic action- acting on LT’s / PAF.

X both central & peripheral H.R X only peripheral H.R

Impairs psychomotor performances. No

Antipruritic, Antiemetic & Antitussive

Anticholinergic & Antiparkinonian

Only antihistaminic & anti-allergic.

Urticaria, Dermographisim, atopic eczema,

Food & dug allergy.

Synergistic actions i.e., D.I No

Allergic rhinitis, conjunctivitis, hay fever,

pollinosis, sneezing, watery eyes.

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1st Generation Antihistamines

DRUGS Adult dose

(oral)

Duration of

action (Hr )

Uses

Highly sedative

Dimenhydrinate

Diphenhydramine

Doxylamine

Hydroxyzine

Promethazine

-25-50mg

-20-50mg

-1.5-25mg

-25-50g

-10-25mg

4-6 hrs

-Anti-motion sickness

- do-

- used as sleep aid

- anti emetic

- anti emetic

Moderately sedative

Pheniramine

Cyproheptadine

Meclizine

Buclizine

Cinnarizine

-20-50mg

-4mg

-25-50mg

-25-50mg

-20-50m

4-6hrs-Anti serotonin effects

-Anti motion sickness

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DRUGS Adult dose

(oral)

Duration of

action (Hr )

Uses

Mild sedative

-Cyclizine

-Chlorpheniramine

-Dimethindine

-Tripolidine

-50 mg

-2-4 mg

-1 mg

-2.5-5 mg

- 4-6hrs

2nd Generation antihistamines

-Fexofenadine

-Loratadine

-Des loratadine

-Astemizole

-Cetirizine

-Levo cetirizine

-Azelastine

-Ebastine

-120-180 mg

-10 mg

-5 mg

-10 mg

-10 mg

-5mg

-4mg

-10mg

12-24hrs- Anti inflammatory

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S/E & Toxicity

1st Generation- S/E are frequent & mild.

Tolerance is developed on repeated use.

Sedation, alertness & concentration, headache, motor-

incoordination, fatigue & sleep.

Impaired psychomotor performances.

Should not drive & operate machines.

Anticholinergic effects

Teratogenicity- in animals.

Over dose- excitation, muscular incordination, respiratory &

cardiovascular failure.

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P.K-

Metabolised by liver microsomal enzymes

Terfenadine & Astemizole (CYP3A4) X Ketoconazole.

Hydroxyzine Cetirizine L isomer.

Terfenadine Fexofenadine

Loratadine Desloratedine

Long term use- effectiveness is reduced.

Excretion is slow in hepatic impairment.

Children eliminates faster than adults.

Less toxic

More potent

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Fexofenadine- Terfenadine

- Torsades de pointes- X delayed rectifier K+ channels.

- Less propensity to block K+ - No prolonged QTc interval.

- No D.I with CYP3A4 inhibitors.

Loratadine-

- Fast & long acting-

- Desloratadine is a active metabolite.

-Used in urticaria & atopic dermatitis.

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Cetirizine Hydroxyzine.

- Cross BBB- subjective somnolence at high dose.

- X release of H & cytotoxic mediators-2nd phase of allergy.

- Attains high & long lasting con. in skin.

- O.D dosing.

- Superior in urticaria, atopic dermatitis, respiratory allergies

- Adjuvant to seasonal asthma.

- Levo cetirizine- ½ dose is effective with less S/E.

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Azelastine -Topically effective,

- X H & inflammatory mediators release (LT & PAF).

- Bronchodilator property.

- Down regulates ICAM-1 expression in nasal mucosa.

- Nasal spray in seasonal & perennial allergic rhinitis.

Ebastine- carbastine.

- Used nasal & skin allergies.

- May prolong QT interval.

Rupatadine - Antihistaminic & PAF antagonist.

- used in allergic rhinitis.

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Therapeutic uses

1) Allergic disorders- itching, urticaria, hay fever,

conjunctivitis, angioedema of lips & eyelids.

- Adr - life saving in laryngeal angioedema & A. shock.

- Seasonal asthma-cetirizine.

-Drug induced hypersensitivity.

- Skin rashes.

-Ineffective in asthma, humoral & cell mediated allergies.

-Suppress urticaria and swelling in serum sickness but mot

other components.

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2) Antipruitic action- older antihistamines.

3) Common cold- symptomatic relief (older).

4) Motion sickness-prophylactic value & 1hr before journey.

Promethazine, Dimenhydrinate, Cyclizine.

Promethazine-Morning sickness, DIV, POV, RIV.

5) Vertigo- H1,M1 & 5HT blocker, sedative, vasodilator &

Ca2+ influx- Cinnarizine.

6) Preanaesthetic medication- Promethazine.

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7) Cough- symptomatic relief.

8) Parkinsonism-Promethazine.

9) Acute muscle dystonia - anti-dopaminergic & anti-psychotics.

10) As sedative, hypnotic & anxiolytic - Promethazine & Hydroxyzine.

-should not used below 2yrs child.

11) Appetite stimulant- Cyproheptadine.

12) Dermographisim, sting & ivy poisoning.

13) Prophylactic value in blood & saline infusion induced

rigour.

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Histamine release inhibitors

Disodium Cromogylate

Nedocromil

Iodoxasmide

Permirolast

Ketotifen

They act by preventing mast cell degranulation due to

immunological reaction.

Prevent the release of H & other inflammatory mediators.

Used in Br.asthma & allergic rhinitis.

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Thank u

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