Aspirin and other salicylates

Mechanism of Action:

Aspirin reduces pain at subcortical sites also.

Action:

Analgesic:

There is sensitization of nerve endings to the action of bradykinin, histamine and other chemical mediators by PGE2, thereby, reduce pain.

It is used to relieve low to moderate pain coming from integumental structures rather than that coming from viscera.

Anti-pyretic:

Aspirin stops PGE2 production. Also there is heat dissipation (of febrile subjects) as a result of peripheral vasodilatation and sweating and in this way it acts as anti-pyretic.

Anti-Inflammatory:
Aspirin reduces inflammation in which PG acts as mediators.

Respiratory Actions:
It causes increased alveolar ventilation and increased respiration.

If the dose exceeds the therapeutic range it may cause some side effects.

Gastrointestinal effects:

Aspirin causes epigastric distress, ulceration or hemorrhage.

Effect on platelets:
It causes reduced platelet aggregation.

Actions on kidneys:
It may cause retention of water and sodium resulting in edema and hyperkalemia.

Pharmacokinetics:
Absorption:
Salicylates are well absorbed through the undamaged and normal skin. On the other hand, unionized form of salicylates are passively absorbed by the stomach and small intestine.

Distribution:
They can pass through the Blood brain barrier except diflunisal.

Metabolism:

Elimination:
Plasma half life of salicylates is 3.5 hours. Salicylate is converted by the liver to water soluble conjugates. It is at last cleared by the kidney.

Doses:
Low doses act as Analgesic

High doses act as Analgesic and anti-inflammatory

Therapeutic Uses:
1. It is used as Anti-pyretic and analgesic.
2. Salicylic acid is also used topically for the treatment of corns, calluses and epidermophytosis.
3. It is also used prophylactically for the heart.
4. It may also help in the reduction of colon cancer.

Adverse effects:
1. GI disturbance.
2. Prolonged bleeding time due to the inhibition of the platelet aggregation.
3. Reduced respiratory activity.
4. Hypersensitivity reactions.
5. Reye’s syndrome.
6. Salicylates in toxic quantities may cause hyperthermia due to uncoupling of oxidative phosphorylation.

Nonsteroidal anti-inflammatory drugs

Classification of Anti-Inflammatory Drugs

1. Non-steroidal anti-inflammatory drugs:

a. Salicylates:
Aspirin, Methyl salicylate

b. Propionic Acid Derivatives:
Ibuprofen, Naproxen, Fenoprofen, Ketoprofen, Flurbiprofen, Oxaprozin

c. Acetic Acid Derivatives:
Indomethacin, Sulindac, Etodolac

d. Oxicam Derivatives:
Piroxicam, Meloxicam

e. Fenamates:
Mefenamic Acid, Meclofenamate

f. Other Agents:
Diclofenac, Ketorolac, Tolmetin, Nabumetone, Diflunisal

2. COX-2 Selective NSAIDs:
Celecoxib, Lumiracoxib, Etoricoxib

3. Drugs for Arthritis:
a. Drugs for anti-cytokine therapy
Etanercept, Infliximab, Adalimumab, Anakinra

b. Methotrexate

c. Leflunomide

d. Chloroquine and hydroxychloroquine

e. d-Penicillamine

f. Gold salts

4. Drugs used to treat Gout:
Colchicine, Allopurinol, Uricosuric agents such as Probenecid and Sulfinpyrazone

Phentolamine

Mechanism of action:

It competitively blocks α adrenergic receptors. It causes inhibition to the response to serotonin.

It causes weak activation of the muscarinic receptors in GI tract and H1 and H2 histaminic receptors in the stomach.

Action:
It causes vasodilatation by

1. Blocking α adrenergic receptors

2. Nonadrenergic activity on vascular smooth muscles

This causes a decrease in peripheral vascular resistance and elevated venous capacitance.

It causes cardiac stimulation through blockade of α2 adrenergic receptors and reflex effect.

It also causes stimulation of salivary, lacrimal, pancreatic and respiratory tract secretions.

Pharmacokinetics:
It has a relatively short duration of action.

Therapeutic uses:
It is used effectively in the diagnosis of Pheochromocytoma and hypertensive crisis caused by Pheochromocytoma.

It is also used in Raynaud’s phenomenon and frost bite.

It is also used for erectile dysfunction.

It can be used to prevent dermal necrosis.

Adverse effects:
It may cause severe tachycardia, angina pectoris, arrhythmia and diarrhea.

Precautions:
It should be used with caution in patients with
1. Peptic ulcer
2. Coronary artery disease

Prazosin, Terazosin and Doxazosin

Mechanism of action:

It selectively blocks postsynaptic α1 adrenergic receptors.

Actions:
It causes the dilatation of the resistance vessels as well as capacitance vessels. This results in reduced blood pressure in upright position.

Its long term use may cause water and salt retention. This effect can be reduced by using diuretics.

Therapeutic uses:
1. It is used for mild to moderate chronic hypertension. It is even more useful on combination with diuretic or propranolol.
2. It is also used for acute congestive cardiac failure.
3. To relieve urinary obstruction (Terazosin).

Adverse effects:
It may cause dizziness, headache, lassitude, nasal congestion, postural hypotension, retention of salt and fluid.

Phenoxybenzamine

Mechanism of action:

It gets bind to α-adrenergic receptors causing the irreversible blockade of these receptors.

It blocks reuptake of norepinephrine by the presynaptic adrenergic nerve terminals.

In addition to α-adrenergic receptors blockade, it also causes blockade of histamine (H1), acetylcholine and serotonin receptors.

Actions:
It inhibits vasoconstriction caused by catecholamine resulting in decrease of total peripheral resistance and blood pressure.

It decreases blood pressure in upright position or as a result of reduced blood volume. In these situations sympathetic tone is elevated.

It causes an elevation of cardiac output as a result of reflex effects and by some blockade of presynaptic α2 receptors present in cardiac sympathetic nerves.

Pharmacokinetics:
It is well absorbed orally. It has plasma half life of about 12 hours.

Therapeutic uses:
They are used for regulating hypertension in Pheochromocytoma.

It is also used to relieve spasm of the vessels in Raynaud’s phenomenon.

It is used to alleviate urinary blockage in patients of spinal cord injury and prostatic hypertrophy (by partial reversal of contraction of the smooth muscles)

It is also used to regulate autonomic hyperreflexia caused by spinal cord transaction.

Adverse effects:
It may cause fatigue, sedation, miosis, nasal stuffiness, nausea and vomiting local tissue irritation by injection and hyperventilation.

Dosage:
It is given orally in the dose of 10-20 mg /day; The dose may be increased up to 200 mg, gradually.
It is also given by IV infusion in the dose of 1 mg/kg diluted in 5% dextrose or 0.9% saline.

Mecamylamine

Pharmacokinetics:

It is well absorbed orally. Its duration of action is about 5-12 hours. It is eliminated by renal tubular secretion.

Therapeutic uses:
It is used in hypertension.

Adverse effects:
Mecamylamine results in sedation, tremor and mental deviations.