Alpha 2 Agonist Drugs Short Notes

 Write a short note on clonidine/α₂-agonists.
Clonidine:

• Clonidine apraclonidine and brimonidine are selective a₂-agonists. Clonidine is used in hypertension.
• Apraclonidine and brimonidine reduce intraocular pressure and are used topically in the treatment of glaucoma and other situations like post-trabeculoplasty and post iridotomy to lower the IOP.
• Guanfacine and guanabenz are central a₂-agonists like clonidine and effectively lower blood pressure.

Read And Learn More: Pharmacology Question And Answers

Selective β₂-Agonists

Orciprenaline, salbutamol, terbutaline, salmeterol, perbuterol, bitolterol, fenoterol, carmoterol and formoterol. They are smooth muscle relaxants → produce bronchodilation, vasodilatation, and uterine relaxation without significant cardiac stimulation.

Selective b₂-agonists are used in:

1. Bronchial asthma—they can be given by inhalation.
2. As uterine relaxants to delay premature labor.

Side effects include muscle tremors, palpitation, and arrhythmias.

β₃ Agonist:

• Mirabegron is a selective β₃ agonist used to treat overactive bladder symptoms with repeated urgency, increased frequency of micturition, and incontinence.
• Since b3-agonists promote lipolysis, they may also have a role in the treatment of obesity.

Anorectic Agents (Anorexiants):

Though amphetamine and amphetamine-like drugs fenfluramine, dexfenfluramine, mazindol, phenylpropanolamine, and phenmetrazine suppress appetite, they are not recommended for the treatment of obesity due to the risk of abuse and depression, and most of them are withdrawn.

α – Adrenergic Blocking Agents

α-receptor antagonists block the adrenergic responses mediated through α-adrenergic receptors.

Some of them have selectivity for a₁ or α₂ receptors:

Actions: The important effects of α receptor stimulation are α₁-mediated vasoconstriction and α₂ (presynaptic) receptor-mediated inhibition of NA release.

The results of the α₂-blockade are:

• α₁-blockade inhibits vasoconstriction leading to vasodilation and thereby ↓ BP. This fall in BP is opposed by the baroreceptor reflexes which tend to ↑ heart rate and cardiac output.
• α₂ – blockade increases the release of NA which stimulates only b-receptors (because a are already blocked). b₁ stimulation results in tachycardia and increased cardiac output.
• Thus, nonselective α-blockade → hypotension with tachycardia. Selective a₁-blockade results in → hypotension without much tachycardia.
• Selective α₂– blockade → ↑ NA release resulting in hypertension. a-blockade in the bladder and prostate leads to decreased resistance to the flow of urine.

Adverse effects of α-blockers:

Postural hypotension, palpitation, nasal stuffiness, miosis, impaired ejaculation, and impotence.

Classification of α-blockers:

a-blockers:

1. Nonselective
   • Irreversible: Phenoxybenzamine
   • Reversible: Phentolamine, ergot alkaloids, tolazoline
2. Selective
   • a₁-blockers: Prazosin, terazosin, trimazosin, doxazosin, tamsulosin, alfuzosin, indoramin
   • a₂-blocker: Yohimbine, idazoxan

Nonselective Alpha Blockers

Phenoxybenzamine:

• Phenoxybenzamine binds covalently to receptors causing irreversible blockade.
• Given IV, blood pressure gradually falls over 1–2 hours and is associated with tachycardia and ↑ CO.
• The action lasts for 3–4 days. It also blocks histamine, 5-HT, and cholinergic receptors.
• Phenoxybenzamine can be given orally but absorption is incomplete; should not be given by IM and SC route as injections are painful.

Phenoxybenzamine Adverse effects:

Postural hypotension, palpitation, nasal stuffiness, inhibition of ejaculation and depression, hence started with a low dose and gradually increased.

Phenoxybenzamine Use:

Treatment of pheochromocytoma.

Selective  a₁– Blockers:

• Prazosin highly selective a₁ -blocker with 1,000 times greater affinity for a1-receptors. In addition, it may decrease central sympathetic outflow.
• Prazosin also inhibits phosphodiesterase, the enzyme that degrades cAMP resulting in ↑ cAMP which also contributes to vasodilation

a₁– Blockers: Other Actions

• Prazosin and its congeners—↓ LDL triglycerides and ↑ HDL cholesterol.
• They relax the urinary bladder neck and prostatic capsule → useful in prostatic hypertrophy.
• Prazosin is orally effective, is extensively bound to plasma proteins, and is metabolized in the liver. Its duration of action is 8–10 hours.

Dose: 1–4 mg BD-TDS.

a₁– Blockers Adverse effects:

• First dose phenomenon 1 hour after the initial dose, marked postural hypotension occurs which may lead to fainting
• Other side effects include headache and dizziness.

Phenoxybenzamine and Prazosin:

Tamsulosin:

• Tamsulosin has higher activity on a_1A and a_1D receptors than a_1B subtype. a_1A is abundant in the bladder and prostate, while a_1B is in the blood vessels.
• Therefore, tamsulosin relieves the symptoms of BPH without a significant fall in BP (which is mediated by a1B receptors
• Hence, it is preferred in BPH. Tamsulosin can cause abnormal ejaculation.

Dose: 0.4 mg OD.

α₂ Blocker

 α₂-blockers Yohimbine:

• Yohimbine is a relatively selective a₂-blocker that increases BP and heart rate due to ↑ NA release.
• It causes congestion of the genitals because of which it was earlier used to treat psychogenic impotence but now sildenafil is preferred.
• It is also claimed to be an aphrodisiac though the effect could only be psychological and not used clinically for the purpose.

Uses of α₂-blockers:

1. Hypertension:

• Selective a₁-blockers like prazosin are used in the treatment of hypertension.
• Phenoxybenzamine or phentolamine can be used in hypertensive crises.

2. Pheochromocytoma:

• Pheochromocytoma is an adrenal medullary tumor that secretes large amounts of catecholamines resulting in hypertension. The tumor has to be removed surgically.
• Phenoxybenzamine and phentolamine are used for preoperative and intraoperative, management; inoperable cases need long-term treatment with phenoxybenzamine.

3. Peripheral vascular diseases like Raynaud’s phenomenon:  a₁ blockers may provide symptomatic relief.

4. Congestive cardiac failure: Because of its vasodilator action, prazosin is useful in CCF.

5. Benign prostatic hypertrophy (BPH):

Though BPH is common in men, it is fortunately not a precancerous condition. Enlargement of the prostate gland results in lower urinary tract symptoms. a1 blockers are useful in these patients—tamsulosin is preferred because of its selective activity on aA receptors.

6. Erectile dysfunction in men: A combination of phentolamine with papaverine injected directly into the corpora cavernosa is used as an alternative to sildenafil in erectile dysfunction.

β – Adrenergic Blocking Agents

b-blockers are drugs that block the actions of catecholamines mediated through the b-receptors.

β – Adrenergic Blocking Agents Classification:

β – Adrenergic Blocking Agents Pharmacological Actions:

• CVS: b-blockers decrease heart rate, force of contraction, and cardiac output.
  • Blood pressure falls. The effect is more pronounced in the presence of increased sympathetic tone than in a normal situation.
  • AV conduction is delayed due to the blockade of b-receptors in the AV node.
  • Myocardial oxygen requirement is reduced due to reduced cardiac work.

• Respiratory tract: Blockade of b₂ -receptors in the bronchial smooth muscle causes an increase in airway resistance and may precipitate acute attack in asthmatics.
• Eye: Reduce intraocular pressure by decreased secretion of aqueous humor.
• Metabolic: Block lipolysis and glycogenolysis (b₂ mediated) induced by sympathetic stimulation.→ may interfere with recovery from hypoglycemia in diabetics—triglycerides may increase and HDL levels may decrease.
• Other effects: Higher doses → block sodium channels → local anesthetic effect. This is not used therapeutically because of the higher dose needed.

β – Adrenergic Blocking Agents Pharmacokinetics:

Some b-blockers like propranolol undergo extensive first-pass metabolism which reduces the bioavailability to ~25%. Most of the b-blockers have short t½ and are metabolized in the liver. Dose: 40–160 mg/day in divided doses.

β – Adrenergic Blocking Agents  Adverse Reactions:

1. Bradycardia is common. Patients with AV conduction defects may develop arrhythmias and heart block.

2. CCF: In patients with impaired myocardial function, sympathetic activity supports the heart. b-blockade eliminates this compensatory effect and may precipitate CCF and acute pulmonary edema.

3. Cold extremities is seen particularly in patients with peripheral vascular disease.

4. Acute asthmatic attack in asthmatics → contraindicated in them. They can worsen COPD.

5. CNS: Insomnia, depression and rarely hallucinations can follow the use of B-blockers.

6. Fatigue due to decreased blood flow to the muscles during exercise and reduced cardiac output.

7. Metabolic effects

• Weakness, impaired carbohydrate tolerance in diabetics.
• ↑ Plasma triglycerides and LDL cholesterol.
• ↓ HDL cholesterol.

8. Sudden withdrawal → rebound HT, angina ← due to upregulation of b-receptors

9. b-blockers can also cause dizziness.

10. Topical: Timolol eye drops can sometimes cause burning and dryness of the eyes.

Some Important Drug Interactions