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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