Histamine

A depressor amine (as it causes lowering of the blood pressure). It is derived from histidine (as shown below) and is also present in ergot and animal tissues.
Synthesis:

Storage:

It is stored in most tissues in
(1) mast cells and in blood, in
(2) basophil. Histamine is stored in their secretary granules.
It is also present in
(3) cells of the epidermis,
(4) cells in the gastric mucosa,
(5) neurons in the central nervous system and
(6) cells in regenerating or rapidly growing tissues.

Release of Histamine:
Histamine is released by the process of exocytosis. This is stimulated
1. Either by the interaction of complement components C3a and C5a with specific receptors on the cell surface or
2. Interaction of antigen with cell fixed IgE antibodies.

This secretion of histamine is initiated by Ca2+.

Some drugs like morphine and tubocurarine, release histamine by some non-receptor action.

Metabolism:

Metabolized by
1. Histaminase
2. Methylating enzyme “Imidazole N. Methyltransferase” which converts this into methylhistamine.

Histamine receptors:
Following are the histamine receptors and the table shown below is giving an overview histamine receptors:

Clinical Uses of Histamine agonists:
1. As a provocative test of bronchial asthma hyperactivity.
2. As a diagnostic agent in testing for gastric acid secreting ability.

Histamine antagonists:

Mechanism of action of Histamine antagonists:
They block the action of histamine receptors at all level.

Generations of H1 receptor blocking agents:
There are two generations of H1 receptor blocking agents:

1st generation:

Key Members

• Diphenhydramine
• Chlorpheniramine
• Doxylamine
• Hydroxyzine

Characteristics
• High lipophilicity, easily enters CNS
• Highly sedative (Triprolidine, Promethazine, Hydroxyzine)
• Anti-muscarinic, anti-α-adrenergic, anti-5HT
• Some have anti-motion sickness effect (Dimenhydrinate)
• Some have local anaesthetic effect.
• May cause increase appetite and weight gain. (Cyproheptadine)

2nd generation:

Key Members
• Desloratadine (loratadine)
• Fexofenadine (terfenadine)
• Cetirizine
• Azelastine
• Astemazole

Characteristics
• No CNS entry (Low lipophilicity, most ionized; also protein binding)
• Non-sedating
• No significant autonomic receptor blocking effect
• Generally long-acting
• Some are cardiotoxic
• May cause anorexia. (Loratidine)

Pharmacokinetics:
1. Orally they are well absorbed with maximum serum levels occur after 1-2 hours.
2. Average plasma T1/2 is 4-6 hours.
3. H1 receptor blockers distribute to all the tissues.
4. Biotransformation is mainly in the liver.
5. Excreted in the urine.

Clinical uses of H1 receptor antagonists:
1. Allergic conditions.
2. Motion sickness and nausea.
3. Somnifacients. Diphenhydramine can be used for the treatment of insomnia.

Clinical uses of H2 receptor antagonists:
1. In the treatment of ulcers.
2. Treatment of Zollinger-Ellison syndrome (severe hypersecretion and ulceration).
3. Gastro-esophageal reflux disease (GERD).

Adverse effects:
Sedation, Headache, Flushing, tachycardia, Diarrhea, Cause itching and pain.

Classification of autacoid antagonists

1. Histamine antagonists
a. H1 receptor antagonists
Cyclizine, Meclizine, Diphenhydramine, Dimenhydrinate, Fexofenadine

b. H2 receptor antagonists
Cimetidine, Famotidine, Nizatidine, Ranitidine

c. H3 receptor antagonists
Impromidine

2. Serotonin Antagonists
Ondansteron, Ketanserin

3. Eicosanoids
a. Thromboxanes
b. Leukotrienes
c. Prostaglandins
Carboprost, Dinoprost, Dinoprostone, Misoprostol

4. Drugs used to treat migraine headache
β-blockers, Dihydroergotamine, Ergotamine, Methysergide, Sumatriptan

Autacoids

Autacoids are local biological factors which act like local hormones.

Speciality:

1. They have a short life time.
2. They act near their site of synthesis.

These things are differentiating them from other hormones and neurotransmitters.

Acetylcysteine

It is a mucolytic agent. It is also referred to as N-acetyl, l-cysteine. Here l-cysteine is used as a mucolytic agent that reduces the viscosity of mucus secretions and is a sulfhydryl donor.


Action:
This reduces the viscosity of the festering or non-festering pulmonary secretions and makes it easy for their removal by coughing, postural drainage, or mechanical means.

Its mucolytic effect is thought to be done by free sulfhydryl group which through two way traffic reduce disulfide linkages resulting in a mixed disulfide. This action is effective at pH 7-9.

Therapeutic uses:
1. It is used in the treatment of cough.
2. It is used as antidote for acetaminophen over dosage. Acetylcysteine may protect the liver by maintaining or restoring glutathione levels so that it can metabolize the intermediate metabolite, which is thought to be responsible for liver necrosis.
3. It can also be used in acute and chronic bronchitis.
4. It is used in the prevention of acute renal failure associated with radiographic contrast media. It is thought that this media may reduce anti-oxidant activity. As acetylceyteine is a thiol containing anti-oxidant, so it may increase this activity and helpful in this respect.

Administration and dosage:
Acetylcysteine may be given by nebulization, direct application or intratracheal instillation. The dosage varies according to the dosage form and disease.

Pharmacokinetics:
Orally, Acetylcysteine is absorbed from the GI tract.

Most of the administered drug participates in sulfhydryl disulfide reaction and the remainder is absorbed by the pulmonary epithelium.

It is deacetylated by the liver and subsequently metabolized.

Adverse Effects:
This drug may cause stomatitis, nausea, vomiting, drowsiness or fever. Sometimes GI symptoms may appear.

Guaifenesin

It is an expentorant. This is also called as Glyceryl guaiacolate. This is one of the medicine to be used Over the Counter. It is often used in combination with anti-histamines, decongestants and anti-tussives in combination products.


Action:
It is used for reducing the viscosity of the sputum by increasing respiratory tract fluid and thus helps in expectoration.

Therapeutic Uses:
This is used for symptomatic treatment of cough associated with common cold, influenza, pertussis, pharyngitis or bronchitis. (If there is persistant cough for more than one week than a physician should be consulted).

Administration and dosage:
It is taken orally and in some cases extended release tablets are also there. Its usual dosage in adults and children over 12 years is 200-400 mg every 4 hours.

Adverse Effects:
GI tract disturbance at ordinary dosage level is rare. Higher doses may cause emesis.

Dextromethorphan HCl

A synthetic morphine derived from levorphanol . Dextromethorphan HBr salt is also in use.


Action:
They have the same anti-tussive activity as other morphine derivatives. And it is almost similar in depressing the cough as codeine.

Therapeutic Uses:
It is used for cough in minor throat and bronchial irritation such as that in common cold. It is most effective in reducing chronic non-productive cough.

Administration and dosage:
It is administered orally and its lozenges are also used for adults. The usual dosage of Dextromethorphan HBr is 10-20 mg every 4 hours for adults and children above 6 years.

Pharmacokinetics:
1. It is absorbed rapidly from GI tract.
2. Its onset of action is 12-30 minutes.
3. Its duration of action is 2-6 hours.

Adverse Effects:
Very rare but nausea and GI tract disturbances may occur sometimes.

Benzonatate

It is a local anesthetic anti-tussive drug.


Mechanism of Action:
It acts as cough depressant in two ways:
1. It anesthetizes the stretch receptors of vagal afferent fibers in bronchi, alveoli and pleura that are involved in cough reflex.
2. It depresses the cough reflex at the level of medulla at the point where afferent impulse is transmitted to the motor nerves.

Therapeutic Uses:
1. Cough:
It is used for the symptomatic treatment of cough. It can be effective in reducing cough in conditions like pneumonia, common cold, bronchial asthma and tuberculosis.

2. As local anesthetic:
It is used in liquid filled capsules (Which are chewed), as local anesthetic of oropharyngeal cavity for attentive intubation.

Administration and dosage:
It is given orally. And its dose for adults and children older than 10 years of age is 100 to 200 mg 3 times daily.

Pharmacokinetics:
1. Its onset of action is 15-25 minutes.
2. Its duration of action is 2.5-8 hours.
3. Anesthesia of oropharyngeal cavity occurs within 1 minute.

Adevrse Effects:
Sedation, Headache, Nausea, Pruritis and skin eruptions, Hypersensitivity and nasal congestion.