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ADRENERGIC AGONISTS AND ANTAGONISTS

ADRENERGIC AGONISTS
Sympathomimetics Drugs that mimic actions of epinephrine and norepinephrine Pharmacology of sympathomimetics= physiologic role of catecholamines

SYMPATHETIC NERVOUS SYSTEM


Ultimate effects are mediated by release of NOREPINEPHRINE from nerve terminals and EPINEPHRINE from the adrenal medulla

SYNTHESIS

STORAGE REUPTAKE RELEASE

Tyrosine

DOPA

Dopamine SYMPATHETIC NERVE Norepinephrine ADRENAL GLAND Epinephrine

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

Postsynaptic effector cells especially LIPOCYTES

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)

Inhibition of adenyl cyclase, decreased cAMP

Dopamine (D) receptors


   

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

ISO (80nM)>E (800 nM)NE (1000 nM)


BETA-1 RECEPTOR

ISO (80nM)>E (800 nM)>>NE(10000 nM)


BETA-2 RECEPTOR

Signal Transduction by E2 - and F - Adrenergic Receptors

E (5 uM)NE (6 uM)>>ISO(1000 nM)


ALPHA RECEPTOR

EFFECTS OF ADRENERGIC RECEPTOR ACTIVATION

The response of any cell or organ to a sympathomimetic depends on the density and proportion of adrenergic receptors

Distribution of adrenoreceptor subtype




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

Distribution of adrenoreceptor subtype




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

Distribution of adrenoreceptor subtype




BETABETA-1 TISSUE Heart ACTIONS Increases force and rate contraction

Distribution of adrenoreceptor subtype




BETABETA-2 TISSUE Respiratory, uterine, and vascular smooth muscle Skeletal muscle Human liver ACTIONS Promotes smooth muscle relaxation Promotes potassium uptake Activates glycogenolysis

Distribution of adrenoreceptor subtype




BETABETA-3 TISSUE Fat cells D-RECEPTORS D1 Smooth Muscle D2 Nerve endings ACTIONS Activates lipolysis

Dilates renal blood vessels Modulates transmitter release

ADRENERGIC DRUGS

CLASSIFICATION OF ADRENERGIC DRUGS


ADRENERGIC AGONIST

DIRECT-ACTING

INDIRECT-ACTING

MIXED-ACTING

SELECTIVE 1 Phenylephrine 2 Clonidine 1 Dobutamine 2 Terbutaline

NON-SELECTIVE 1 2 Oxymetazoline 1 2 Isoproterenol 1 2 1 2 Epinephrine 1 2 1 Norepinephrine

Ephedrine 1 2 1 2 and releasing agent Dopamine D1 D2 releasing agent and

CLASSIFICATION OF ADRENERGIC DRUGS


ADRENERGIC AGONIST

DIRECT-ACTING

INDIRECT-ACTING

MIXED-ACTING

RELEASING AGENTS

Uptake inhibitor Cocaine

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

alpha1=alpha2;beta1>>beta2 alpha1=alpha2;beta1=beta2 beta1>beta2>>>>alpha Beta1=beta2>>>>alpha beta2>>beta1>>>>alpha D1=D2>>beta>>alpha D1>>D2

ORGAN SYSTEM EFFECTS OF SYMPATHOMIMETICS

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)


NE, high dose epinephrine

CARDIOVASCULAR SYSTEM
AlphaAlpha-2 receptor agonists


Reduce blood pressure by


 activation

of postsynaptic alpha-2 receptors dampening alphaactivity of vasomotor neurons in the medulla oblongata  Activation of presynaptic alpha-2 receptors decreasing alpharelease of norE


Hypertension (clonidine, methyldopa)

RESPIRATORY TRACT
BetaBeta-2 agonists


Bronchial smooth muscle relaxation/bronchodilation relaxation/bronchodilation

Bronchial asthma (terbutaline, albuterol) terbutaline, albuterol) AlphaAlpha-1 agonist




Vasoconstriction of blood vessels of the upper respiratory tract mucosa

Nasal decongestion (phenylephrine) phenylephrine)

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

AlphaAlpha-2 selective agonists


 

Treatment of diarrhea in diabetics with autonomic neuropathy (Clonidine)

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

AlphaAlpha-2 receptor agonists


 

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 receptor agonists




Alpha agonists and beta receptor antagonists decrease intraocular pressure by increasing outflow and decreasing production of aqueous humor, respectively

CENTRAL NERVOUS SYSTEM




DopamineDopamine-mediated processess (or other effects)


Catecholamines at high infusion rate: Ranges from nervousness to a feeling of impending disaster  Non-catecholamines: mild alerting-improved Nonalertingattention to boring tasks; elevation of mood, insomnia, euphoria, anorexia; full blown psychotic behavior


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)


Toxicity of sympathomimetic drugs




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

the actions of endogenous neurotransmitters or other sympathomimetics

ALPHA BLOCKERS

ADRENERGIC ANTAGONIST AlphaAlpha-2 Agonists




 

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

1 Prazosin Terazosin Doxazosin

2 Yohimbine

Phentolamine

Alpha receptor antagonists




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)

PostPost-synaptic Alpha receptor blockadeblockade- PHARMACOLOGIC EFFECTS




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


Relative selectivity of alphaalphaantagonists


Prazosin, terazosin, doxazosin Phenoxybenzamine Phentolamine Rauwolscine, yohimbine, tolazoline alpha1>>>>alpha2 alpha1>alpha2 alpha1=alpha2 alpha2>> alpha1

Alpha- AntagonistAlpha-1 Antagonist- Prazosin


 

 

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

Peripheral vasospasm (Raynauds syndrome), urinary obstruction

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

Effects not related to beta-blockade beta

Partial Agonists
Acebutulol, Carteolol, Labetalol, Pindolol  With some intrinsic sympathomimetic activity desirable to prevent untoward effects (precipitation of asthma, excessive bradycardia)


Local anesthetic action- blockade of Na actionchannels (Acebutulol, metoprolol, propranolol, labetalol)




Unlikely important after systemic administration (too low levels)

Sotalol (Class III Antiarrhythmic drug)- K drug)blockade

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

Beta Blockers- Clinical Effects and BlockersUses




Cardiovascular system


HypertensionHypertension- not fully understood mechanism


Heart, blood vessels  Suppression of renin-angiotensin system renin CNS or elsewhere


Angina/Ischemic heart disease  Supraventricular tachycarrhythmia  Heart Failure




Suppression of the renin-angiotensin system renin Blocks deleterious effect of sympathetic activation


Beta Blockers- Clinical Effects and BlockersUses




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


Reduction of intraocular pressure (decrease production of aqueous humor)

Beta Blockers- Clinical Effects and BlockersUses




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)


Beta Blockers- Clinical Effects and BlockersUses




CNS


Migraine  Stage fright- blocks somatic responses fright(palpitations, trembling)

Gastrointestinal


Portal hypertension

BETABETA-BLOCKERS


Propranolol - Prototypic Beta blocker


Standard against newer beta-antagonists developed betafor systemic use have been compared  Low and dose-dependent bioavailability dose High lipid solubility, readily cross the blood-brain bloodbarrier


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