Sympathomimetics Ed Bilsky, Ph.D. Department of Pharmacology University of New England Phone , x

Fight or Flight????

Drugs that Increase Adrenergic Activity Direct acting sympathomimetics –alpha-1 agonists (phenylephrine) –alpha-2 agonists (clonidine) –beta-1 agonists (dobutamine) –beta-2 agonists (albuterol) Indirect acting sympathomimetics –promote release (amphetamine) –block reuptake (cocaine)

Synthesis of Catecholamine Neurotransmitters

Sympathomimetics Structure: The structure of many sympathomimetics is based on the phenylethylamine structure and the catechol nucleus Modifications of the structure have significant effects on pharmacodynamics –changes in affinity and selectivity for adrenergic receptors –changes in efficacy (agonist versus antagonist) Changes in the chemical structure also alter the pharmacokinetic profile of the compound

Pharmacodynamics : Adrenergic receptors belong to the super family of G- protein coupled receptors –G s - stimulates adenylyl cyclase --> increases cAMP –G i - inhibits adenylyl cyclase --> decreases cAMP –G q - activates phospholipase C --> increases IP 3 and DAG Each type of receptor has a specific coupling mechanism –Alpha-1 receptors: G q --> increased calcium –Alpha-2 receptors: G i --> activate K + and blocks Ca 2+ channels –beta receptors: G s --> various effect (e.g., increased cardiac contractility, smooth muscle relaxation, increased glycogen phosphorylase activity) Sympathomimetics

Pharmacodynamics : Adrenergic receptors are under dynamic regulation that is affected by neurotransmitter activity, exogenous drugs, disease states and age –important clinical consequences are now being realized Desensitization of receptors can occur through a variety of mechanisms –transcription/translation of receptors –phosphorylation of receptors –internalization of receptors and decoupling with G-proteins –constitutive activity Sympathomimetics

Organ System Effects Cardiovascular system : Adrenergic receptors have major effects on arterial resistance (blood pressure/flow) and venous capacitance –alpha-1: vasoconstriction (skin and splanchnic vessels) –beta-2: vasodilation (skeletal muscle) –dopamine: vasodilation (renal, splanchnic, coronary and cerebral vessels) Direct effects on the heart are primarily mediated by beta-1 receptors –positive chronotropic, dromotropic and inotropic effects –leads to an increase in cardiac output

Organ System Effects Cardiovascular system (continued) : Reflexes can alter the blood pressure response seen with drugs in healthy individuals –alpha agonist effects would be opposed by barroreceptor reflexes that slow the heart –in hypotensive states, these drugs can bring blood pressure back to normal –beta agonist effects on the heart would be countered by decreased resistance in some vascular beds Drugs that increase both alpha and beta activity (amphetamines) can produce dramatic increases in blood pressure

Organ System Effects GI tract : Alpha and beta receptors produce relaxation of GI smooth muscle --> decreases motility GU tract : Beta agonists relax uterine smooth muscle Alpha receptors regulate sphincter tone of the bladder which promotes continence Exocrine glands : Increased sweat production in apocrine glands that respond to stress

Organ System Effects Eye : Activation of alpha receptors produces mydriasis Alpha agonists increase aqueous humor outflow while beta antagonists decrease aqueous humor production Respiratory tract : Beta-2 receptors mediate relaxation of bronchial smooth muscle (treatment of asthma) alpha-1 agonists produce vasoconstriction in vessels of the upper respiratory tract mucosa

Organ System Effects Metabolic effects : Activation of the sympathetic nervous system increases lipolysis and glycogenolysis CNS effects : Moderate doses of sympathomimetics can increase alertness, reduce fatigue and produce euphoria Higher doses can cause irritability, nervousness and psychotic reactions

Therapeutic Applications Increased blood flow/pressure: Hypotension can occur in response to a number of different conditions –decreased blood volume, cardiac insufficiency, neurological disease/trauma, infection, adverse drug reactions, etc. Sympathomimetics may be used in certain hypotensive emergencies (e.g., shock) to maintain adequate coronary and cerebral blood flow –volume replacement and treatment of the underlying cause are the mainstays of therapy –use in treating anaphylactic shock (s.c. epinephrine) Oral ephedrine is used for the treatment of chronic orthostatic hypotension

Therapeutic Applications Decreased blood flow/pressure: Reduction of regional blood flow can be accomplished with sympathomimetics –hemostasis during surgery –reduction of local anesthetic diffusion –prolongation of local anesthetic duration of action –reduction of mucous membrane congestion The unique properties of cocaine (local anesthetic and sympathomimetic) make it a valuable drug in certain types of surgery –facial, oral or nasopharyngeal

Therapeutic Applications Cardiac applications: Alpha agonists used to be used for paroxysmal atrial tachycardia –safer alternatives such as verapamil, adenosine and electrical cardioversion are now preferred Cardiac arrest can be treated with epinephrine, though electronic pacemakers are safer and more effective in heart block Beta-1 agonists are still used to increase cardiac output in congestive heart failure –problems with desensitization and toxicity with chronic therapy

Therapeutic Applications CNS effects: Sympathomimetics such as amphetamine have medical and non-medical uses: –increase level of alertness and reduction in boredom –elevation in mood –suppression of appetite –treatment of narcolepsy –treatment of ADHD There are problems with the abuse potential and toxicity of this class of agents

Therapeutic Applications Respiratory applications: Beta-2 agonists remain a mainstay for treating asthma –other beneficial effects besides bronchodilation Other applications: Phenylephrine used to produce mydriasis and as a decongestant for minor allergic hyperemia of the conjunctival membranes Glaucoma responds well to alpha agonists and beta antagonists Questionable efficacy of beta agonists for suppressing premature labor

Sympatholytics Ed Bilsky, Ph.D. Department of Pharmacology University of New England Phone , x

Drugs that Decrease Adrenergic Activity Direct acting sympatholytics –reversible alpha antagonists (phentolamine, prazosin) –irreversible alpha antagonist (phenoxybenzamine) –nonselective beta antagonist (propranolol) –selective beta-1 antagonist (metoprolol) Indirect acting sympatholytics –decrease storage (reserpine)

Pharmacokinetics : The oral bioavailability and biodistribution of these compounds can vary, though in general, these compounds are given p.o. The half-life of these agents varies considerably –esmolol-ultrashort acting beta blocker (t 1/2 =10 min) –propranolol-nonselective beta blocker (t 1/2 =3-6 hrs) –atenolol-nonselective beta blocker (t 1/2 =6-9 hrs) –nadolol- nonselective beta blocker (t 1/2 =14-24 hrs) Sympatholytics

Pharmacodynamics : Two major classes of agents for the alpha blockers –reversible (phentolamine) –irreversible (phenoxybenzamine) Beta blockers are typically reversible antagonists The selectivity and efficacy of these drugs varies considerably –phentolamine is considered a dirty drug due to affinity at alpha-1 and 2, histamine, muscarinic and serotonin receptors –carvedilol has affinity for both alpha and beta receptors –beta blocker selectivity (propranolol vs metoprolol) –pure antagonists versus partial agonists (metoprolol vs pindolol) Sympatholytics

Organ System Effects: Alpha Blockers Cardiovascular system : Major effects on arteriolar and venous tone –alpha antagonists produce vasodilation by relaxing smooth muscle –decreased vascular resistance and a fall in blood pressure The alpha blockers can produce postural hypotension and reflex tachycardia Other effects : Alpha blockers can produce miosis and nasal stuffiness

Therapeutic Applications: Alpha Blockers Pheochromocytoma: Typically caused by a tumor in the adrenal medulla that releases large amounts of epinephrine and norepinephrine –hypertension, tachycardia, arrhythmias Alpha-antagonists (phenoxybenzamine) can be used in the management of this disease –used in preoperative care and for patients that have inoperable tumors Hypertension: Prazosin is a tertiary drug for treatment of hypertension Hypertensive emergencies: Limited applications for management of hypertensive emergencies –other drugs are preferred in the management of this condition

Organ System Effects: Beta Blockers Cardiovascular system : Primary effect is on cardiac beta-1 receptors Beta antagonists produce negative chronotropic, inotropic and dromotropic effects –reduction in blood pressure Other effects include an inhibition of renin release which contributes to the antihypertensive actions Respiratory system : Nonselective blockade of beta-2 receptors may increase airway resistance, especially in asthmatics

Organ System Effects: Beta Blockers Other effects : Blockade of beta receptors in the CNS may produce changes in mood and wakefulness Several beta blockers reduce intraocular pressure by decreasing aqueous humor production Metabolic effects on lipid and carbohydrate metabolism may occur –complications in insulin-dependent diabetic patients –elevations of VLDL and decreases in HDL cholesterol Some beta blockers have local anesthetic actions –probably not of clinical significance

Therapeutic Applications: Beta Blockers Hypertension: Beta blockers are one of the primary drugs used in the management of hypertension –safe, well tolerated and effective in reducing morbidity and mortality Angina: Beta blockers can be used prophylactic for the treatment of angina –decreased cardiac oxygen demand Cardiac arrhythmias: Beta blockers are effective for treating some supraventricular and ventricular arrhythmias –particularly effective when the arrhythmia is caused by excessive sympathetic tone

Therapeutic Applications: Beta Blockers Congestive heart failure: There is some clinical evidence that beta-blockers can decrease morbidity in congestive heart failure –need to assess sympathetic compensation for cardiac output –possibly reduces aspects of cardiac remodeling and oxidative stress CNS diseases: Utility in treating some forms of migraine headache, tremor and anxiety Glaucoma: Beta blockers decrease production of aqueous humor and intraocular pressure –eye drops available

Side-Effects: Beta Blockers Beta blockers are typically well tolerated with serious side-effects being rare Some occurrence of drug allergies (rash, fever, etc.) CNS effects can include sedation, sleep disturbances and depression –advantage of more water soluble compounds? Beta blocker should not be withdrawn abruptly in patients being treated for hypertension Exacerbation of disease symptoms possible in asthmatics with all beta blockers Increased hypoglycemic episodes might be possible –avoid their use in insulin-dependent diabetics