Adrenergic Antagonists

What is the meaning of Adrenergic antagonists? Drugs which decrease the actions of adrenergic system in the body are adrenergic antagonists. This could be done by decreasing the synthesis of NA; or by blocking the release of NA from nerve endings; or blocking the adrenergic receptors using antagonists; or by decreasing the overall sympathetic outflow throughout. However, commonly used in therapy are the last two groups of which the last group discussed under adrenergic agonists ( Methyldopa & Clonidine) Although these two drugs are adrenergic receptor agonists, actually they are sympatholytic or anti adrenergic drugs. So we are discussing the adrenergic receptor antagonists in this chapter.

Adrenergic Receptor Antagonists (Blockers)

Classify adrenergic receptor antagonists -Receptor antagonists 1,2-antagonists ( Nonselective antagonists) 1- antagonists -Receptor antagonists 1,2 antagonists 1 antagonists 1 1 antagonists

What is the advantage of selective 1- antagonists over Nonselective antagonists (Phenoxybenzamine)? Nonselective -antagonists by blocking the 2 presynaptic receptors, bring about reflex tachycardia. Whereas reflex tachycardia is minimal with selective 1- antagonists. Phenoybenzamine is an irreversible antagonist rarely used in therapy
Pre synaptic adrenergic receptor

Phenoxyb enzamine Prazosin

X
X

 Name 1- antagonists & therapeutic uses There are subtypes of 1 receptors. 1B subtype are present in vascular smooth muscle. 1A subtype are present in bladder neck and prostate smooth muscle. Prazosin, Terazosin and Doxazosin block both subtypes of receptors so are useful in treating both hypertension as well as benign prostatic hypertrophy (BPH). But when these drugs are used to treat only BPH, then they produce hypotension which is an adverse effect. So selective 1A antagonists used will only relieve urinary obstructive symptoms of BPH without producing hypotension

Hypertension

1B

Prazosin Terazosin Doxazosin

Benign prostatic hyperplasia

1A

Tamsulosin
Blood vessels Bladder neck, Prostate

How these drugs bring down BP? By antagonizing the actions of NE at 1 receptor (reversible) in vascular smooth muscle block endogenous NE mediated vasoconstriction hence, vasodilatation. Second-line drug for treatment of hypertension What is the basis of using these drugs in BPH? Prostate enlargement obstructs the urinary outflow from bladder, so retention of urine and prone for infection. NE acts at 1A receptor on bladder neck smooth muscle to contract the sphincter. Blocking this receptor will prevent action of NE so Relaxation of sphincter and relieving obstruction to urine flow.

Enumerate the adverse effects of Prazo/Tera/ Doxa zosins Reflex tachycardia; Postural hypotension; Sexual dysfunction; Nasal congestion

 Why reflex tachycardia (RT)? Any drug if decreases BP below normal can give rise to reflex sympathetic stimulation (baro receptor dis inhibition of sympathetic outflow). However, it is less severe compared to nonselective 1,2 blockers. If the dose is adjusted properly to maintain normal BP then least fear of RT

Why postural hypotension (PH)? Any drug brings about veno dilatation will give rise to PH. ie: excess fall in BP while assuming upright position due to gravitational venous pooling. NA veno constriction (1) and blockade by these drugs bring about venodilatation and PH. Not seen with Tamsulosin

Why sexual dysfunction 1 mediated NE action is necessary for ejaculation. Blockade dysfunction

Blood vessels supplying nasal mucosa has 1 receptors NE action is vasoconstriction. Vasodilatation results in increased capillary permeability mucosal edema ( diagram below)

 Classify -Receptor antagonists ( blockers) 1,2 antagonists 1 antagonists Propranolol Atenolol Timolol Metoprolol Pindolol Esmolol Bisoprolol

1 , antagonists Labetalol Carvedilol

What are the advantages of cardio- selective 1 antagonists over (non-selective) 1,2 antagonists ? Following AE due to 2 blockade are not seen with cardio- selective 1 antagonists Worsening of bronchial asthma Worsening of Peripheral vascular disease Exercise intolerance Plasma Triglyceride; LDL cholesterol Precipitation of hypoglycemia with anti diabetic drugs

Explain the basis for each of above AE associated with by 2 blockers Worsening of bronchial asthma 2 receptor mediated action of endogenous adrenaline is broncho dilatation. Blockade 2 receptor in bronchial smooth muscle can give rise to broncho constriction. In bronchial asthma patients 2 blockers can worsen the condition. Worsening of Peripheral vascular disease 1 receptor mediate vasoconstriction; 2 receptor mediate vasodilatation. 2 receptor blockade by Propranolol results in unopposed 1 receptor mediated vasoconstriction by endogenous NA & Ad Exercise intolerance Glycogenolysis & vasodilatation skeletal muscle are 2 receptor mediated actions of circulating Adrenaline. Blockade by Propranolol decrease energy production and blood flow to skeletal muscle giving rise to fatigue. Precipitation of hypoglycemia with anti diabetic drugs Anti diabetic drug induced hypoglycemia is corrected by 2 receptor mediated ( by circulating adrenaline) glycogenolysis in liver and skeletal muscle. Blockade of this prevents glucose production in response to hypoglycemia so worsening of hypoglycemia. Plasma Triglyceride; LDL cholesterol ?

Why blockers should not be stopped abruptly? Long term usage of blockers result in upregulation of receptors. When blockers stopped abruptly the receptors remain unoccupied for the endogenous agonists (NA & Ad) to act on them resulting in BP, HR that can again result in oxygen demand by myocardium (Ischemia of myocardium). Hence if at all blockers need to be stopped it has to be done gradually over weeks period.

Explain the therapeutic uses of blockers (B)? Hypertension: B CO BP; B rennin secretion angiotensin II( a vasoconstrictor) BP B sympathetic outflow from medulla ( how ?) BP Ischemic heart disease ( Angina/ Myocardial infarction): HR is one of the determinants of myocardial Oxygen demand. An imbalance between myocardial Oxygen demand & supply ischemia. B HR thereby myocardial Oxygen demand Cardiac arrhythmia: (Excess, regular/irregular HR). commonly due to excess of sympathetic activity (1). 1B arrhythmia Thyrotoxicosis: Excess of thyroid hormone secretion sympathetic activityHR & BP, skeletal muscle tremors 2). 1,2 BlockersHR & BP & skeletal muscle tremors Anxiety: Manifestations are due to sympathetic activity. (HR & BP & skeletal muscle tremors) same reason as above Essential tremors: skeletal muscle tremors (1,2 blockers) Hypertensive emergency: Use only Labetalol (which is + blocker) and not other pure blockers All blockers CO initial reflex (1receptor mediated) vasoconstriction (refer baro receptor reflex) when give by IV route. This can cause sudden BP when used IV for hypertensive emergency. Labetalol is a blocker that also blocks receptors so do not produce initial vasoconstriction so no fear initial worsening of BP. Congestive heart failure: Discussed later on under CVS module. Only 3 Blockers used (Carvedilol; Metoprolol; Bisoprolol) Chronic wide angle glaucoma Timolol eye drops ( will be discussed in detail by Ophthalmologist later years) Prophylaxis of migraine headache Propranolol (reason?)

Note : Essential tremors; Migraine; Anxiety; Thyrotoxicosis; Glaucoma ( non selective 1,2 blockers preferred)

How propranolol helps in reducing essential (Skeletal muscle)tremors? The direct effect of circulating adrenaline on skeletal muscle fibres is exerted through 2 receptors and differs according to the type of fibre. The active state is abbreviated and less tension is developed in the slow contracting red fibres incomplete fusion of individual responses. This along with enhanced firing of muscle spindles is responsible for the tremors produced by Adrenaline inessential tremors or by 2 agonists. 2 blockade by Propranolol reduces tremors .