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ADRENERGIC AGONISTS
Sympathomimetics Drugs that mimic actions of epinephrine and norepinephrine Pharmacology of sympathomimetics= physiologic role of catecholamines
SYNTHESIS
Tyrosine
DOPA
ADRENERGIC RECEPTORS
BETABETA-ADRENOCEPTORS
BetaBeta-1 Postsynaptic effector cells; Stimulation of adenyl especially HEART, LIPOCYTES, cyclase, increased brain; presynaptic adrenergic and cAMP cholinergic nerve terminals Postsynaptic effector cells, especially SMOOTH MUSCLE and cardiac muscle Stimulation of adenyl cyclase, increased cAMP; activates cardiac Gi under some conditions Stimulation of adenyl cyclase, increased cAMP
BetaBeta-2
BetaBeta-3
ALPHAALPHA-ADRENOCEPTORS
AlphaAlpha-1 Postsynaptic effector cells; especially SMOOTH MUSCLE Formation of IP3 and DAG, increased intracellular calcium
AlphaAlpha-2
Presynaptic adrenergic nerve terminals, platelets, lipocytes, lipocytes, smooth muscle, lower brainstem region (medulla oblongata)
Brain Splanchnic and renal vasculature D1, D5 (D1-like)- Inc cAMP (D1-like)D2- (D2-like)D2-4 (D2-like)- Dec cAMP
Classification of Adrenoceptors
based on the interaction of a series of drugs (agonists and antagonists) with these receptors CONCEPT: Equilibrium dissociation constant [D] + [R] [D-R] [DKD= [D]FREE [R] FREE/ [D-R] [Dconcentration of free drug at which 50% of the available receptors are bound EC50 (?) fingerprint to identify receptors
The response of any cell or organ to a sympathomimetic depends on the density and proportion of adrenergic receptors
ALPHAALPHA-1 TISSUE Most vascular smooth muscle (innervated) Pupillary dilator muscle Pilomotor smooth muscle Prostate Heart ACTIONS Contraction Contraction (dilates pupil) Erects hair Contraction Increases force of contraction
ALPHAALPHA-2 TISSUE Postsynaptic CNS adrenoreceptors Platelets Adrenergic and cholinergic nerve terminals Some vascular smooth muscle Fat cells
ACTIONS Probably multiple Aggregation Inhibition of transmitter release Contraction Inhibition of lipolysis
BETABETA-2 TISSUE Respiratory, uterine, and vascular smooth muscle Skeletal muscle Human liver ACTIONS Promotes smooth muscle relaxation Promotes potassium uptake Activates glycogenolysis
BETABETA-3 TISSUE Fat cells D-RECEPTORS D1 Smooth Muscle D2 Nerve endings ACTIONS Activates lipolysis
ADRENERGIC DRUGS
DIRECT-ACTING
INDIRECT-ACTING
MIXED-ACTING
DIRECT-ACTING
INDIRECT-ACTING
MIXED-ACTING
RELEASING AGENTS
MAO/COMT inhibitors
Amphetamine Tyramine
RELATIVE SELECTIVITY OF ADRENOCEPTOR AGONISTS ALPHA AGONISTS alpha1>alpha2>>>>>beta Phenylephrine, Phenylephrine, methoxamine Clonidine, Clonidine, methylnorepinephrine alpha2>alpha1>>>>>beta
MIXED ALPHA and BETA AGONISTS
Norepinephrine Epinephrine BETA AGONISTS Dobutamine Isoproterenol Terbutaline, albuterol DOPAMINE AGONISTS Dopamine Fenoldopam
The rationale of use of sympathomimetic drugs in therapeutics rest on a knowledge of the physiological effects of catecholamine on tissue
CARDIOVASCULAR SYSTEM
BetaBeta-1 receptor agonist
Positive chronotropic effect (increased pacemaker activity) Positive inotropic effect (intrinsic contractility is increased Relaxation is accelerated Increased conduction velocity through the AV node and decreased refractory period
CARDIOVASCULAR SYSTEM
BetaBeta-2 receptor agonists
Promote vascular smooth muscle relaxation May invoke reflex response in heart rate
CARDIOVASCULAR SYSTEM
AlphaAlpha-1 receptor agonists
Constrict smooth muscles of resistance vessels (e.g., skin, splanchnic beds), increasing peripheral resistance and venous return In normotensive patients, increased blood pressure may invoke a reflex baroreceptor vagal discharge (slowing of heart rate, with or without change in cardiac output)
CARDIOVASCULAR SYSTEM
AlphaAlpha-2 receptor agonists
of postsynaptic alpha-2 receptors dampening alphaactivity of vasomotor neurons in the medulla oblongata Activation of presynaptic alpha-2 receptors decreasing alpharelease of norE
RESPIRATORY TRACT
BetaBeta-2 agonists
Gastrointestinal tract
Alpha and Beta receptor agonists
Relax gastrointestinal smooth muscle (Beta receptors located directly on smooth muscle) Reduce release of ACh by a prejunctional action Enhance salt and water reabsorption from intestine
Genitourinary tract
BetaBeta-2 receptor agonists
Relax uterine smooth muscle- Ritodrine, terbutaline muscleRelaxation of bladder wall Constriction of bladder base, urethral sphincter, prostate (urinary continence)- Ephedrine continence)-
AlphaAlpha-1 agonists
Metabolic effects
Beta receptor agonists
Increase liver and skeletal muscle glycogenolysis Increase lipolysis (Beta-3) in fat cells (BetaIncrease insulin (Beta-2) and renin (Beta-1) secretion (Beta(BetaPromotes uptake of potassium in cells Decrease insulin and renin secretion Inhibition of lipolysis
EYE
Beta receptor agonists
Relaxation of ciliary muscle with some decrease in accommodation Mydriasis (Contract the radial muscle of the iris and dilate the pupil)- phenylephrine pupil)-
Alpha agonists and beta receptor antagonists decrease intraocular pressure by increasing outflow and decreasing production of aqueous humor, respectively
PhenylephrinePhenylephrine- 1 agonist
Differs from epinephrine only in lacking a hydroxyl group at position 4 of benzene ring (implications? potency, bioavailability, CNS effect) Marked arterial vasoconstriction Nasal decongestant Mydriatic Found in various nasal and ophthalmic preparations
Dobutamine 1 agonist
More inotropic than chronotropic compared to isoproterenol Enhance automaticity of sinus node 2 receptor mediated vasodilation Congestive heart failure
Indirect Sympathomimetics
require presence of endogenous catecholamines to produce their effects Cocaine: blocks reuptake of NE into nerve endings Amphetamine: Promotes the release of NE from nerve endings; blocks the reuptake of norepinephrine Narcolepsy, hyperactivity in children (amphetamine analogs)
Primarily extensions of their pharmacologic effects in the cardiovascular and central nervous system
Pressor agents marked increase in BP, cardiac ischemia and failure Beta-agonists- sinus tachycardia, ventricular Beta-agonistsarryhthmias Amphetamines- restlessness, tremor, anxiety; Amphetaminesparanoid state Cocaine- convulsions, hemorrhage, arrhythmias, MI Cocaine
ADRENERGIC ANTAGONISTS
Adrenergic Antagonists
Sympatholytics block
ALPHA BLOCKERS
AlphaAlpha-2 receptors mainly found presynaptically (nerve terminals) Activation of these receptors inhibits release of Norepinephrine Decrease sympathetic outflow to heart and blood vessels Clonidine, Clonidine, guanabenz (active drugs) MethyldopaMethyldopa- prodrug converted to alphaalphamethylnorepinephrine
Clonidine 2 agonist
Intially tested as a topical nasal decongestant to act on post-synaptic 2 receptors post Anti-hypertensive effect demonstrated Anti Activates 2 receptors in the lower brainstem region Activates presynaptic 2 receptors
ADRENERGIC ANTAGONIST
ANTAGONIST
ANTAGONIST
SELECTIVE
NON-SELECTIVE Phenoxybenzamine
2 Yohimbine
Phentolamine
Reversible antagonists dissociate from antagonists receptors (e.g., prazosin, phentolamine, tolazoline); surmountable Irreversible antagonists e.g., antagonists phenoxybenzamine (recovery may take several daysdays- dependent on synthesis of new receptors)
CARDIOVASCULAR
Relaxes smooth muscle Decreases peripheral vascular resistance, venous return, systemic arterial blood pressure Side Effect: Orthostatic hypotension (BP falls >20 mmHg upon standing); reflex vasoconstriction is blocked
OTHER EFFECTS
Decreases resistance to urine flow (bladder base and prostate) Miosis, nasal stuffiness
First selective alpha-1 antagonist alphaUsed in hypertension and benign prostatic hypertrophy Orally administered (50% bioavailability) SlowSlow-onset (2-4 h), long duration of action (10 (2h), extensively metabolized by the liver Analogs: terazosin, doxazosin, tamsulosin
AlphaAlpha-1 Antagonists
Pheochromocytoma
Phentolamine, phenoxybenzamine
BETA BLOCKERS
Beta Blockers
Competitive antagonists of beta adrenergic receptors Most are pure antagonists; a few are partial agonists Either selective for the Beta-1 receptor or nonBetanonselective Selectivity is relative; higher doses will also block betabeta-2 receptors
Relative selectivity of B-blockers BRECEPTOR AFFINITY Propranolol, carteolol, penbutolol, pindolol, timolol Metoprolol, acebutolol, atenolol, esmolol, alprenolol, betaxolol Labetalol, carvedilol
Beta1 = Beta2
Beta1>>>Beta2
Beta1=Beta2alpha1>alpha 2
Partial Agonists
Acebutulol, Carteolol, Labetalol, Pindolol With some intrinsic sympathomimetic activity desirable to prevent untoward effects (precipitation of asthma, excessive bradycardia)
Beta Blockers
Most are well absorbed after oral administration Peak concentration: 1-3 hours 1FirstFirst-pass effect: low bioavailability, great individual variability (except betaxolol, penbutolol, pindolol, sotalol)
Beta blockers
Two Categories (Pharmacokinetic properties): 1. Eliminated by hepatic metabolism and relatively short half-lives (Propranolol, halfMetoprolol); 2. Eliminated unchanged by the kidneys with longer half-lives (Atenolol, Nadolol) half*CYP2D6 genotype- differences in metoprolol genotypeplasma clearance
Beta Blockers
Most beta antagonists have half-lives in the halfrange of 3-10 hours; major exception is esmolol 3(beta(beta-1 selective), with a half-life of 10-15 half10minutes
Short half-life relates to the rapid metabolism of halfdrug by blood and hepatic esterases
Cardiovascular system
Suppression of the renin-angiotensin system renin Blocks deleterious effect of sympathetic activation
Respiratory system
Increase in airway resistance due to blockade of B2 receptors in bronchial smooth muscle Should generally be avoided in patients with asthma; BetaBeta-1 selective antagonist preferred
Eye
Endocrine effects
Partial inhibition of beta-2 receptor mediated betaglycogenolysis and glucose release Blockers mask tachycardia associated with hypoglycemia Inhibit lipolysis Chronic use: Inc VLDL, dec HDL Inhibition of peripheral conversion of thyroxine to triiodothyronine (hyperthyroidism)
CNS
Gastrointestinal
Portal hypertension
BETABETA-BLOCKERS
Metoprolol, atenolol
BetaBeta-1 selective Safer in patients with asthma/COPD, diabetes, peripheral vascular disease
BETABETA-BLOCKERS
Glaucoma
Timolol and related Beta antagonists (betaxolol, carteolol, levobunolol, metipranolol) Propranolol (in part to inhibition of peripheral conversion of thyroxine to triiodothyronine)
Hyperthyroidism
MigraineMigraine- propranolol (decrease intensity and frequency); preventive efficacy metoprolol, atenolol, timolol, nadolol
BETABETA-BLOCKERS
Portal hypertension
Decrease incidence of first episode of bleeding, decrease mortality associated with bleeding: propranolol, nadolol
Beta Blockers
CONTRAINDICATIONS TO BETABETABLOCKERS:
asthma, other bronchospastic condition severe bradycardia AV block, bradycardia-tachycardia syndrome bradycardia
ADVERSE EFFECTS:
Related to consequences of beta-blockade; beta sedation, fatigue, depression (highly lipophilic drugs), impaired exercise tolerance, insomnia, exacerbation of peripheral vascular disease, erectile dysfunction
Indirect Sympatholytics
Guanethidine can inhibit the Ca2+-dependent release of norepinephrine (3) Reserpine inhibits VMAT. NE subject to catabolism by MAO; higher doses- damage to storage vesicles= pharmacological sympathectomy