Adrenergic & Antiadrenergic Drugs By Dr. F. Tavakoli

Catecholamines

Adrenoceptors α-adrenoceptor β - adrenoceptor dopamine-receptor

Adrenoceptors

Mechanism of Action

Adrenergic Transmission

Adrenergic Agonists

Relative Receptor Affinities

Distribution of adrenoceptor subtypes

Organ System Effects Of Sympathomimetic Drugs A. Central Nervous System

Organ System Effects Of Sympathomimetic Drugs A. Central Nervous System Stimulant effects: mild alerting or reduction of fatigue anorexia, euphoria, and insomnia. Repeated dosing of amphetamines tolerance and dependence. Very high doses of amphetamines marked anxiety or aggressiveness, paranoia, and, less commonly, seizures. Overdoses of cocaine seizures

Organ System Effects Of Sympathomimetic Drugs A. Central Nervous System B. Eye Contraction and Mydriasis (smooth muscle of the pupillary dilator) Accommodation is not affected Outflow of aqueous humor reduction of intraocular pressure Alpha2-selective agonists reduce intraocular pressure (by reducing synthesis of aqueous humor)

Organ System Effects Of Sympathomimetic Drugs A. Central Nervous System B. Eye C. Bronchi Relaxation of the smooth muscle (β2 agonists) reversing bronchospasm

Organ System Effects Of Sympathomimetic Drugs A. Central Nervous System B. Eye C. Bronchi D. Gastrointestinal Tract Relaxation of the smooth muscle Decrease salt and water secretion into the intestine (Alpha2 agonists )

Organ System Effects Of Sympathomimetic Drugs A. Central Nervous System B. Eye C. Bronchi D. Gastrointestinal Tract E. Genitourinary Tract Contraction of the bladder sphincter Contraction of Prostatic smooth muscle (α1) Increase sphincter tone Relaxation of uterine in pregnant women near term, but significant tachycardia ( Beta2 agonists )

Organ System Effects Of Sympathomimetic Drugs A. Central Nervous System B. Eye C. Bronchi D. Gastrointestinal Tract E. Genitourinary Tract F. Vascular System 1. Alpha 1 agonists : contract vascular smooth muscle increase peripheral vascular resistance increase venous pressure compensatory reflex bradycardia 2. Alpha 2 agonists : vasoconstriction (iv or topically) accumulation in the CNS and reduce sympathetic outflow and blood pressure (PO) 3. Beta 2 agonists (eg. albuterol, metaproterenol, terbutaline) : significant reduction in arteriolar tone in the skeletal muscle vascular bed peripheral vascular resistance arterial blood pressure. 4.Dopamine: vasodilation in the splanchnic and renal vascular beds by activating D1 receptors. (very useful in the treatment of renal failure associated with shock.

Organ System Effects Of Sympathomimetic Drugs A. Central Nervous System B. Eye C. Bronchi D. Gastrointestinal Tract E. Genitourinary Tract F. Vascular System G. Heart: both β receptors mediate increased rate of cardiac pacemakers (normal and abnormal) increased atrioventricular node conduction velocity increased cardiac force

Organ System Effects Of Sympathomimetic Drugs A. Central Nervous System B. Eye C. Bronchi D. Gastrointestinal Tract E. Genitourinary Tract F. Vascular System G. Heart H. Net Cardiovascular Actions I. Metabolic and Hormonal Effects Beta1 agonists increase renin secretion Beta2 agonists increase insulin secretion Beta2 agonists increase glycogenolysis in the liver All β agonists stimulate lipolysis via the β3 receptor

Cardiovascular Responses to Sympathomimetic Amines

Therapeutic Uses Of Sympathomimetic Drugs Cardiovascular Applications A. Conditions in which an increase in blood flow is desired Norepinephrine, Dobutamine, dopamine B. Conditions in which a decrease in blood flow or increase in blood pressure is desired epinephrine,phenylephrine, norepinephrine, ephedrine, midodrine. C. Conditions in which acute cardiac stimulation is desired Epinephrine, Isoproterenol

Cardiovascular Applications Pulmonary Applications: albuterol, metaproterenol, terbutaline, salmeterol,formoterol,indacaterol Anaphylaxis: Epinephrine Ophthalmic Applications: phenylephrine, tetrahydrozoline, apraclonidine, brimonidine(Newer α2 agonists) Genitourinary Applications: ritodrine, terbutaline, ephedrine Central Nervous System Applications: phenylisopropylamines such as amphetamine, Methylphenidate

Adrenergic Antagonists

ALPHA-BLOCKERS A. Classification Irreversible, long-acting: Phenoxybenzamine Reversible, shorter-acting: Phentolamine Alpha1-selective: Prazosin Alpha2-selective: Yohimbine, rauwolscine

ALPHA-BLOCKERS A. Classification B. Pharmacokinetics Oral and Parenteral (phentolamine is rarely given orally) Phenoxybenzamine : a short elimination half-life but a long duration of action Phentolamine: duration of action of 2–4 h (orally ) and 20–40 min (parenterally) Prazosin and the other α1-selective blockers act for 8–24 h.

ALPHA-BLOCKERS A. Classification B. Pharmacokinetics C. Mechanism of Action Phenoxybenzamine : irreversible blockade The other agents : competitive antagonists

ALPHA-BLOCKERS A. Classification B. Pharmacokinetics C. Mechanism of Action D. Pharmacologic Effects

ALPHA-BLOCKERS D. Pharmacologic Effects 1. Nonselective blockers: Phenoxybenzamine, phentolamine reduction in vascular tone reduction of both arterial and venous pressures no significant direct cardiac effects baroreceptor reflex-mediated tachycardia 2. Selective α blockers: Prazosin, doxazosin, terazosin, tamsulosin, silodosin reducing blood pressure : α1 ˃˃˃ α2 much less reflex tachycardia useful effects on smooth muscle in the prostate

ALPHA-BLOCKERS A. Classification B. Pharmacokinetics C. Mechanism of Action D. Pharmacologic Effects E. Clinical Uses

ALPHA-BLOCKERS E. Clinical Uses 1. Nonselective α blockers Presurgical management of pheochromocytoma Carcinoid tumor Mastocytosis Overdose with drugs of abuse Raynaud’s phenomenon Erectile dysfunction 2. Selective α blockers Hypertension Urinary hesitancy Urinary retention

ALPHA-BLOCKERS A. Classification B. Pharmacokinetics C. Mechanism of Action D. Pharmacologic Effects E. Clinical Uses F. Toxicity Orthostatic hypotension Marked reflex tachycardia Some non-alpha- mediated vasodilating effects (Phentolamine) Angina Nausea and Vomiting

BETA-BLOCKERS

A. Classification, Subgroups, and Mechanisms 1. Receptor selectivity 2. Partial agonist activity 3. Local anesthetic activity 4. Pharmacokinetics

Properties of several a-adrenoceptor-blocking drugs. Beta1-receptor selectivity and Partial agonist activitymay be an advantage when treating patients with asthma. Labetalol and carvedilol have combined α- and β-blocking actions. Nebivolol has vasodilating action in addition to β1-selective antagonism. Local anesthetic activity (“membrane-stabilizing activity”) is a disadvantage when β blockers are used topically in the eye.

BETA-BLOCKERS A. Classification, Subgroups, and Mechanisms B. Effects and Clinical Uses Open-angle glaucoma Hypertension Angina Arrhythmias Chronic (not acute) heart failure : labetalol, carvedilol, metoprolol Ischemic Heart Disease Hyperthyroidism Pheochromocytoma Neurologic Diseases

BETA-BLOCKERS A. Classification, Subgroups, and Mechanisms B. Effects and Clinical Uses C. Toxicity Cardiovascular : bradycardia, atrioventricular blockade, heart failure Severe asthma attacks Insulin secretion reduction ( masking of premonitory symptoms of hypoglycemia from insulin overdosage, impaired mobilization of glucose from the liver and sequestration of K+ in skeletal muscle) CNS : sedation, fatigue, sleep alterations Sexual dysfunction

Drugs used in glaucoma