Selective ß1-adrenoceptor Antagonists-β-adrenoceptor antagonists with partial agonist activity

 

A: Selective ß1-adrenoceptor Antagonists

- These agents may be safer in patients who experience bronchoconstriction in response to propranolol.   

 - These agents may be preferable in patients with diabetes or peripheral vascular disease.

Betaxolol (Betoptic®)

- Betaxolol is a selective B1-blocker. - Used topically to treatment of chronic open-angle glaucoma. - Less likely to induce bronchoconstriction than non-selective antagonists.

Esmolol (Brevibloc®)

- Esmolol is an ultra-short-acting β1-selective adrenoceptor antagonist. - It has a very short half-life (about 10 minutes) due to metabolism of an ester linkage. - It is only available intravenously and is used to control blood pressure or heart rhythm     during surgery or diagnostic procedures

Bisoprolol (Concor®)

- Bisoprolol is a selective B1-blocker (cardioselective). - It is used in the management of hypertension and heart failure.

Nebivolol (Nebilet®)

- Nebivolol is the most highly selective β1-blocker with nitric oxide-potentiating vasodilatory effect. - Nebivolol approximately 3.5 times more β1-selective than Bisoprolol. - Nebivolol releases nitric oxide (endothelium-derived relaxing factor; EDRF) from endothelial cells   and causes vasodilation. - It is used as antihypertensive and anti-anginal agent. - C\A (Contraindicated) in severe renal and severe hepatic impairment.

Metoprolol (Lopressor®)

- Metoprolol is a selective B1-blocker. - It is one of the most prescribed drug in the United States. - It has moderately lipophilic properties penetrate BBB à cause sleep disturbances. - It is used in hypertension, angina, heart failure, acute myocardial infarction, arrhythmias,   migraine prophylaxis and anxiety symptoms.

Atenolol (Tenormin®)

- Atenolol is a selective B1-blocker. - It has hydrophilic properties less suitable in migraine prophylaxis compared to propranolol. - It is used in hypertension, angina, acute myocardial infarction and arrhythmias.

                       

Selective β2-adrenoceptor Antagonists 

Butaxamine or Butoxamine

- Butoxamine is a research drug selective for ß2-receptors, non-available for clinical uses.

 

 

β-adrenoceptor antagonists with partial agonist activity

These agents usually has intrinsic sympathomimetic activity (ISA): This term is used particularly with B-blockers that can show both agonist and antagonist  effect at B-receptors à cause activation of adrenergic receptors so as to produce effects similar to stimulation of the sympathetic nervous system.

Partial agonist activity of these agents may be less likely to cause bradycardia   and abnormalities in plasma lipids (not decrease plasma HDL levels) than are antagonists.

Acebutolol (Sectral®)
- Acebutolol is a cardioselective B-blocker with mild ISA. - It is used in hypertension and ventricular arrhythmias.
Pindolol (Visken)
- Pindolol is a non-selective B-blocker with ISA. - It is used in hypertension, may be used alone or with other antihypertensive      agents, particularly with thiazide-type diuretic. - It also functions as a 5-HT (serotonin) receptors, so may considered as augmentation therapy of depression or premature ejaculation.
Celiprolol (Selectol®)
- Celiprolol is a β1-selective blocker with modest capacity to activate B2 receptors. - It may have less bronchoconstriction effect in asthma and may even promote    bronchodilatation.
Oxprenolol (Trasicor®)	Penbutolol (Levatol®)
- Oxprenolol and Penbutolol  are a non-selective B-blocker with ISA, used in hypertension,   may be'used alone or with other antihypertensive agents.

 

                                   

 

 

  Mixed Adrenoceptor Antagonists

 

Labetalol (Trandate®)

- Labetalol is a reversible (competitive) adrenoceptor antagonist. - It is a non-selective B-adrenergic blocker and selective a1-adrenergic blocker. - Labetalol potency is somewhat lower than that of Propranolol. - Labetalol affinity for α-receptors is less than that of Phentolamine (but Labetalol is α1-   selective). - Hypotension induced by Labetalol is accompanied by less tachycardia than occurs with   Phentolamine and similar a-blockers. Therapeutic uses:   - Treatment of pregnancy-induced hypertension associated with pre-eclampsia.   - Treatment of chronic or acute hypertension of pheochromocytoma and hypertensive crisis. common side effects: dizziness, fatigue and nausea.

Carvedilol (Dilatrend®)

- Carvedilol is a reversible adrenoceptor antagonist. - It is a non-selective β-adrenergie blocker and selective α1-adrenergic blocker. - More potently at β-receptors than α1-receptors. - Carvedilol has benefits (or protective efffects) in heart failure :       - Decrease lipid peroxidation and oxidative injury to endothelial cells       - Decrease vascular wall thickening.  It is used in the treatment of mild to severe congestive heart failure (CHF) and hypertension.

 

Choice of ß-adrenergic Antagonist Drug

- Congestive Heart Failure (CHF): Carvedilol > Metoprolol > Bisoprolol. - Open-angle glaucoma: Timolol, Betaxolol >Carteolol > Levobunolol> Metipranolol. - Pheochromocytoma hypertension and hypertensive crisis: Labetalol. - Pregnancy-induced hypertension with pre-eclampsia: Labetalol. - Migraine prophylaxis and anxiety symptoms: Propranolol > Metoprolol > Nadolol. - Prevent bleeding in people with portal hypertension (cirrhosis): Nadolol> Propranolol. - Most highly selective B1-blocker with nitric oxide-potentiating vasodilatory effect:    Nebivolol. - Augmentation therapy of depression or premature ejaculation: Pindolol. - Control blood pressure or heart rhythm during surgery: Esmolol. - Effective in asthma and may even promote bronchodilatation: Celiprolol. Note; African ancestry and elderly hypertensive patients: B-blockers are less effective.

 

 

 

 

 

Drug interactions with Most B-adrenoceptor antagonists
Pharmacokinetics Drug Interactions
Enzyme Inhibitors Drugs: Cimetidine, Erythromycin and Ketoconazole.	* Inhibit hepatic metabolism of β-blockers à↑ plasma    concentration of ß blockers à increase activity of ß blockers    and may lead to toxicity.
Enzyme Inducers Drugs: Rifampicin, Phenytoin, and Phenobarbital.	* Increase hepatic metabolism of B-blockersà decrease    plasma concentration of β blockersà decrease activity of β    blockers and may lead to loss of activity.
Pharmacodynamics Drug Interactions
Sympathomimetic drugs or drugs having a1-agonist effect.	*  increase Epinephrine release act only in a receptors due to β- receptors are blocked à enhance reflex VC effect.
Calcium channel blockers (CCB) e.g.: Verapamil	* Verapamil à (-ve) inotropic and (-ve) Chronotropic à  when    given with β-blockers additive effect     à Cause Cardiac depression (bradycardia and may lead to     heart block).
Non-steroidal anti-inflammatory drugs (NSAIDS) e.g.: Indomethacin	* NSAIDS inhibit formulation of prostaglandins à decrease renal VD à  decrease renal blood flow à increase sodium and water retentionà decrease antihypertensive effect of β-blockers.
Insulin	* Non-selective B-blockers potentiate the hypoglycemic   effect of Insulin.

 

Adrenergic Neuron Blockers

 Drugs that interfere with neurotransmitters release

Guanethidine (Ismelin®)

- Guanethidine is an antihypertensive drug that reduces the release of catecholamines, such   as norepinephrine. - It acts by blocking the release of stored norepinephrine (NE) (replacing NE in these vesicles)   gradual depletion of NE stores in the nerve endings gradual decrease in BP and HR. - It is used in the treatment of moderate and severe hypertension and renal hypertension. - Side effects: Bradycardia, orthostatic hypotension, failure of ejaculation and nasal   congestion.

Bretylium (Bretylol®)

- Bretylium is an antiarrhythmic drug that block the release of norepinephrine. - Uses: in emergency for acute ventricular tachycardia and acute ventricular fibrillation.

Reserpine (Hypoten®)

- Reserpine is one of the remaining agents in this category. - It is a plant alkaloid from dried root of Rauwolfia serpentina (Indian snakeroot). - It acts by irreversibly blocks vesicular monoamine transporter (VMAT) (block Mg²/adenosine   triphosphate-dependent transport) of monoamine neurotransmitters (norepinephrine,     dopamine, and serotonin) from storage vesicles in the adrenergic nerve terminals in all body   tissues. - It has a slow onset,but a long duration of action. - After discontinuation The effects persist for many days. - It is used in the treatment of mild hypertension but has largely been replaced with newer   agents. - Most common side effects: Diarrhea, hyperacidity and dry mouth. - Bradycardia and nasal congestion. - Anxiety and depression (Rare) due to depletion of NE and serotonin in the brain. - Parkinsonian syndrome (Rare) due to depletion of dopamine from basal ganglia.

 

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