Anti-hypertensives Part III (Adrenergic Receptor Antagonists)

*This section will be expanded upon. 

Part 1: Alpha receptor antagonists

(a) Non-selective

Phenoxybenzamine

Phentolamine

(b) alpha 1 selective

Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin, Indoramin, Urapidil, Bunazosin

(c) a2 selective-Yohimbine

1.1 Alpha 1 Receptor antagonists

Mechanism of action: Blockade of alpha 1 adrenergic receptors inhibits vasoconstriction induced by endogenous catecholamines. This results in a decrease in BP due to decreased TPR. The magnitude depends on the activity of the sympathetic nervous system. Decreases in BP is smaller in supine position than in upright subjects. Decreases also enhanced by low blood volume.

  • For most a-receptor antagonists, fall in BP is opposed by baroreceptor reflexes that cause increases in heart rate and cardiac output, as well as fluid retention.
  • These compensatory reflexes are worsened if the antagonist also blocks alpha 2 receptors on periperal sympathetic neurons which leads to enhanced release of NAdr. Increased stimulation of B1 postsynaptic receptors in the heart and on JGA cells.
  • Since a1 receptors are blocked, the endogenous catecholamines will bind to other receptors (B2 receptors). This triggers vasodilation which means that Adr now becomes a vasodepressor (presor responses are inhibited).

Drug 1: Prazosin (Potent and selective a1 receptor antagonist)-Used frequently in hypertension  

-The affinity for a1 adrenergic receptors is 1000x that for a2 adrenergic receptors.

Mechanism of action:

1. Major effect is that due to the blockage of a1 receptors in arterioles and veins, leading to a fall in TPR and venous return to the heart.

2. Also acts in CNS to suppress sympathetic outflow. ***Prazosin appears to depress baroreceptor reflex in hypertensive patients.

3. *Prazosin and related drugs tend to have favourable effects on serum lipids in humans–>Decreases LDL and triglycerides while increasing concentrations of HDL 

-Decreases cardiac preload and thus have little tendency to increase cardiac output and heart rate (compared to vasodilators which have minimal dilatory effects on veins)

Pharmacokinetics of Prazosin:

-Well absorbed with bioavailability of 50-70% and peak plasma concentration is 1-3 hours after oral dose.

-Prazosin binds with greatest affinity a1-acid glycoprotein (only 5% of the drug is free). Diseases may change the free fraction.

-Extensively metabolised in the liver (plasma half life, 2-3 hours, may be prolonged to 6-8 hours in CHF)

-In treatment of hypertension, the duration of action is 7-10 hours.

Adverse effects:

*First dose effect (marked postural hypotension and syncope which may occur 30-90 mins after initial dose)

-Risk is minimised by limiting the initial dose (e.g. 1mg at bedtime, increasing dosage slowly and introducing additional anti-hypertensive drugs cautiously)

1.2 Alpha 2 Receptor agonists (+)

Mechanism of action: Activation of alpha 2 receptors in the pontomedullary region of the CNS inhibits sympathetic nervous system activity and leads to a decrease in BP

Drugs that are a2 receptor agonists: Clonidine and methyldopa (CAT A-AUS) [Methyldopa can be used during pregnancy!]

Note: Yohimbine is an a2 receptor antagonist (Just good to know)

1.3 Non-selective Alpha antagonists

-Phentolamine (‘Non’-Friend told amine). Competitive alpha receptor with similar affinities for a1 and a2 receptors.

Clinical indications: (a) Short term control of hypertension in patients with pheochromocytoma (adrenal tumour producing Adr and NAdr) (b) Useful for treatment of hypertensive cases that follow the abrupt withdrawl of clonidine (c) Sexual dysfunction-Can be administered bucally, orally or intracavernously (injection at the base of the penis) into penis 

1.4 Alpha 1 selective

Part 2: Beta Receptor antagonists [B-blockers can be distinguished by relative specificity of B1 over B2, intrinsic sympathomimetic activity, capacity to block B-receptors, differences in lipid solubility, capacity to induce vasodilation, pharmacokinetic properties] 

(a) Non-selective (first generation)

Propranolol, Pnebutolol, Pindolol, Nadolol, Timolol (3P NoT)

(b) B1 selective (Second Generation)

Atenolol, Acebutolol, Bisoprolol, Metroprolol, Esmolol (ABME) 

(c) Non-selective with additional cardiovascular actions (Third Generation)

Carteolol, Carvedilol, Bucindolol, Labetalol

(d) B1 selective additional cardiovascular actions (Third Generation)

Betaxolol, Celiprolol, Nebivolol

-Additional features of certain b-blockers: 

Carteolol (NO production, beta 2 receptor agonism), Labetalol (A1 receptor antagonist), Carvedilol (Ca2+ entry blockade and antioxidant activity), Betaxolol (Ca2+ channel blockade)

2.1 Mechanism of action: Antagonists inhibits interaction of NAdr, Adr and sympathomimetic drugs with B receptors. Effects of B-adrenergic antagonists may be predicted from the consequences of B-receptor stimulation (due to effects of elevated cAMP) 

*Note: Beta-blockers generally do not reduce blood pressure in patients with normal BP but lower BP in patients with hypertension.

***Reduction of B1-stimulated renin release from JGA cells is a contributing mechanism!!!

-Long term administration of B-blockers to anti-hypertensive patients decresae peripheral vascular resistance.

2.2 Comparison of various B-blockers

-Propranolol interacts with B1 and B2 with equal affinity. No ISA and doesn’t block a receptors.                                               *Hepatic metabolism CYP 1A2, 2C19, 2D6, 3A4. Individual variation in                                                                                                                                                                                                                           hepatic clearance of propranolol contributes to variability in plasma                                                                                                                                                                                                                           concentration (20x) after oral administration. Propranolol readily enters                                                                                                                                                                                                                     the CNS.

-Pindolol is a weak partial B-agonist (ISA). ISA drugs preferred when diminished cardiac activity or bradycardia.                    *Hepatic metabolism by 2D6.

-Metoprolol is a B1-selective antagonist.                                                                                                                                            *Extensive first pass metabolism. Wide variability in t1/2 based on genetic                                                                                                                                                                                                                  differences in 2D6 activity. t1/2 (normally 3-4 hrs) can double in CYP2D6                                                                                                                                                                                                                    poor metabolisers, who have 5x higher risk for adverse effects compared                                                                                                                                                                                                                  to normal metabolisers.

-Atenolol is a B1-selective antagonist.                                                                                                                                                 *Largely excreted by kidneys; dosage should be reduced when creatinine                                                                                                                                                                                                                   clearance is <35ml/min

2.3 Adverse effects and precautions

1. Exacebate heart failure 

2. Bradycardia (life-threatening bradycardia with partial or complete AV conductoin defects). Caution in patients taking other drugs (e.g. verapamil or various anti-arrhythmic agents which may impair sinus node function or AV conduction)

3. Raynaud’s syndrome-Cold extremities while taking B-blockers

4. Increased response after abrupt B-blocker withdrawal

5. Blunt recognition of hypoglycemia and delayed recovery from insulin-induced hypoglycemia

6. Depression, sleep disturbances, fatigue

7. Bronchoconstriction

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