AUTACOIDSAUTACOIDS(I)(I)

HISTAMINE HISTAMINE

AND AND

ANTI HISTAMINESANTI HISTAMINES

Aims and ObjectivesAims and Objectives

The term autacoid is used for a group of

hormone like substances, which

originate from tissues, and produce

effects at the site of release.

Important members of this group are: -

I. Histamine

II. 5 Hydroxytryptamine (5HT)

III. Eicosanoids

1. Prostaglandins

2. Leukotrienes

3. Thromboxanes

IV. Kinins

Autacoids play an important role in

the causation of inflammatory

reactions, and a variety of other

clinical disorders.

The agonists and antagonists belonging to this

group of substances are of considerable clinical

importance, and will, therefore, be discussed in

detail.

This lecture deals with Histamine and

Antihistamines.

HISTAMINE

Histamine is derived from amino acid

Histidine. It is found in lungs, skin and GIT.

Present in high concentrations in mast cells.

Also a component of venoms and secretions

from insect stings.

In the mast cells histamine is stored in

granules. The release of histamine from the

granules is responsible for inflammatory

and allergic reactions.

RECEPTORS LOCATION

H1

i. Smooth muscles

ii. Endothelium

iii. Brain

H2

i. Gastric mucosa

ii. Cardiac muscle

iii. Mast cells

iv. Brain

H3 (Presynaptic)i. Brain

ii. Myenteric Plexus

H1 and H2 Receptors

ANTIHISTAMINESANTIHISTAMINES (H(H11 BLOCKERS) BLOCKERS)

DRUGS ANTICHOLINERGIC

ACTIVITYCOMMENTS

ETHANOLAMINES

Carbinoxamine

Dimenhydrinate

(Dramamine)

Diphenhydramine

(Benadryl)

+++

+++

+++

Slight to moderate

sedation

Marked sedation; anti-

motion sickness activity

Marked sedation; anti-

motion sickness activity

FIRST GENERATION

DRUGS ANTICHOLINERGIC ACTIVITY

COMMENTS

ETHYLAMINE DIAMINE

Tripelennamine

+ Moderate sedation

PIPERAZINE DERIVATIVES

Cyclizine

(Marezine)

Meclizine

-

-

Slight sedation; anti-motion sickness activity

Slight sedation; anti-motion sickness activity

DRUGSANTICHOLINERGIC

ACTIVITYCOMMENTS

ALKYLAMINES

Brompheniramine

(Dimetane)

Chlorpheniramine

+

+

Slight sedation

Slight sedation;

DRUGS ANTICHOLINERGIC ACTIVITY

COMMENTS

PHENOTHIAZINE DERIVATIVE

Promethazine (Phenergan) +++

Marked sedation

antiemetic; block

MISCELLANEOUS

Cyproheptadine

(Periactin)+ Moderate sedation

Antiserotonin activity

DRUGS ANTICHOLINERGIC ACTIVITY

COMMENTS

PIPERIDINEFexofenadine -

MISCELLANEOUS

Loratadine

Cetrizine (Zyrtec)

-

-

Longer action

SECOND GENERATION

PHARMACOLOGICAL ACTIONS

1. Smooth Muscles

i. Intestine: - Antagonism of Histamine

(competitive antagonism)

ii. Bronchi: - Histamine is blocked

Guinea-pig can tolerate 100 times lethal

dose of Histamine in the presence of a

suitable dose of Antihistamine.

2. Blood Pressure

The initial rapid hypotensive effect is

antagonized by H1 blockers. The hypotensive

effect in the second phase is antagonized by

H2 blockers.

3. HCl secretion: No effect

4. CNS

The first generation induces sedation.

Central excitation is the striking effect of Poisoning.

5. Anticholinergic actions

Atropine like actions. The second generation has no such effects.

6. Local anesthetic action

Promethazine

Pyrilamine

However, large doses are required.

7. Blockade of 1 Adrenergic receptors

Promethazine Hypotension

8. Other Effects

i. Capillary Permeability and Edema

H1 antagonists strongly block the action

of Histamine, that results in increased

capillary permeability and formation of

edema and wheal.

ii. Flare and Itch:

The flare component of the triple response

and the itching caused by intradermal

injection of histamine are two different

manifestations of the action of histamine on

nerve endings. H1 antagonists suppress

both.

iii. Serotonin (5HT) Blocking Action

Strong blocking effects at serotonin

receptors have been demonstrated for H1

antagonist cyproheptadine. This drug is

promoted as an anti serotonin agent.

THERAPEUTIC USESTHERAPEUTIC USES

I. ALLERGIC DISORDERS

1. Pruritis (Itching)

2. Urticaria

3. Vasomotor Rhinitis

4. Allergic responses to insect bites, chemicals

5. Allergic responses to Drugs

6. Common cold

II. MOTION SICKNESS (Prophylaxis)

Promethazine strongest in the group,

because of anticholinergic effect (See

Scopolamine).

III. NAUSEA & VOMITING

Dimenhydrinate (Drammamine)

Cyclizine HCl (Marezine)

Vestibular Disturbance; Meniere’s Disease

IV. SEDATION (CNS DEPRESSION)

Diphenhydramine (Benadryl)

V. ANAPHYLACTIC SHOCK

1. Edema & Itch Blocked

2. Hypotension Controlled to a lesser extent

3. Bronchospasm No Effect

Note: - Other substances involved.

SIDE EFFECTSSIDE EFFECTS

1. ANTIMUSCARINIC EFFECTS

i) Dryness of mouth

ii) Retention of urine

iii) Dryness of respiratory passages.

These effects are not seen with Second

Generation.

2. CENTRAL ACTIONS (CNS)

i) Sedation (not 2nd generation). May be

useful effect in some cases.

ii) Other central actions.

Dizziness; Tinnitus; Lassitude*; Euphoria;

Tremors; Nervousness

_______________________________________

* Laziness, Sluggishness

3. DIGESTIVE TRACT

Loss of Appetite; Epigastric distress

4. POLYMORPHIC VENTRICULAR

TACHYCARDIA

Terfenadine Withdrawn

5. OTHER EFFECTS

Mutagenecity; Leukopenia;

Agranulocytosis

ACUTE POISONINGACUTE POISONING

• Effects strikingly resemble acute

Atropine poisoning.

• Central excitatory effect

• Dilated pupils

• Flushed face

• Dry mouth

• Sinus tachycardia

• Retention of urine

• Fever

• Finally coma with cardio-respiratory

collapse, and death with in 2-18 hours.

SIDE EFFECTS

SIDE EFFECTS

QUESTIONS

1. An antihistamine which has comparatively lower potential to induce drowsiness / sedation:

a) Loratidine

b) Cetrizine

c) Acrivastine

d) Dimenhydrinate

e) Diphenhydramine

2. A drug which belongs to second generation of antihistamines:

a) Chlorpheniramine

b) Cyclizine

c) Meclizine

d) Promethazine

e) Acrivastine

3. A second generation antihistamine which has been withdrawn from the market:

a) Loratidine

b) Cetrizine

c) Terfenadine

d) Promethazine

e) Meclizine

4. Many antihistamines (H1 Blockers) have additional non-histamine related effects: These are likely to include which one of the following?

a) Muscarinic increase in the bladder tone

b) General anesthetic effects if the drug is injected

c) Antimotion sickness effect

d) Increase in total peripheral resistance

e) Insomnia