Rabin's Lecture 1

Cholinergic receptors: Nicotinic nAchR

Receptor-operated channel (ROC)Depolarize by increase Na and K conductanceANS gangliaAdrenal medulla

Cholinergic receptors: Muscarinic mAchRM1, M3, M5

G protein-coupled receptor (GPCR)Phospholipase C [increased PKC and increased IP3 and Ca]M3 smooth muscle and glands

Cholinergic receptorsMuscarinic mAchR, M2, M4

G protein coupled receptor (GPCR)Hyperpolarize by opening GIRKDecrease Adenylyl cyclaseM2 heart (SA, atrium, AV node)

Parasympathetic cardiac response

PNS via vagus - SA and AV node- Hyperpolarization decreases HR and decreases AV conduction- Dominant cardiac influence of vagus is at SA node Decrease force of atrial contraction - reduced refractory period and shortens action potentialVery sparse PNS innervation of ventricular myocardium and low sensitivity to mAchR agonists

PNS Vascular response

insignificant contribution to overall vascular resistancefew vascular beds innervated by PNSErectile tissue is exception. Stimulation M3Ach receptors on endothelial cells causes increase in NO secretion to diffuse and relax vascular smooth muscle

Response to stress: SNS Blood FAsBlood glucose

Increased lypolysisIncreased glycogenolysis and gluconeogenesys

Response to stress SNSPancreas

decreased insulin secretion

SNSheart

increase HRincrease AV conductionincrease stroke volumeincrease CO

SNSlung

bronchodilation, increase O2

SNS Vasculature

Vasodilitation (skeletal)Vasoconstriction (e.g. GI)

SNSKidney

increased renin release

SNSeyeskinGIBladderLymphoid organs/immune cells

eye - mydriasis - pupil dilationskin - sweating (Ach)GI - increased sphincter tone, decreased peristalsisBladder - increased sphincter tone, relax smooth muscleLymphoid organs, immune cells - modulate immune response

Heart SNS responseSA nodeatrial muscleAV nodeventricular muscle

SA node - increased HRatrial muscle - increased contraction forceAV node - increased conductionventricular muscle - significantly increased contraction force, increased SV, increased CO

Vasculature and kidney SNS response

Vasculature dilation or constrictionKidney - increased renin release

Heart PNS responseSA nodeatrial muscleAV nodeventricular muscle

SA node - decrease heart rate significantlyatrial muscle - decreased force of contractionAV node - decreased conductionventricular muscle - none

Vasculature and kidney PNS response

Vasculature - minimal influence - dilate erectile tissuekidney - none

SNS Mediators - endogenous Catecholamines

NE - primary NT from MOST postganglionic sympathetic nervesEpi - primary neurohumor release by adrenal medullaDopamine - NT in CNS but also in various vascular beds (e.g.) renal, mesenteric

Heart receptors

Heart is mostly Beta 1 and some Beta 2 receptors

Alpha 1:1A, 1B, 1D

Epi > NEincreased phospholipase CIncreased CaIncreased PKCPostsynaptic only

Alpha 2:2A, 2B, 2C

Epi >/= NEdecreased adenylyl cyclaseincreased K conductancepostsynaptic in CNS

Beta 1:

Epi >/= NEFound post-synapticallyRegulated by neuronal NEGsincrease adenylyl cyclaseHeart, Kidney

Beta 2:

Epi >> NETypically non-innervatedRegulated by circulating EpinephrineGsIncreases adenylyl cyclaseLung, skeletal muscle, vasculature

Beta 3:

Iso > NE > EpiGs and Gi/oAdenylyl cyclaseIncreased MAPKIncreased NO & cGMPFat, heart, GI

Heart:Primary ReceptorSNS Response

Beta-1Increased HRIncreased SVIncreased AV conductionIncreased CO

Vasculature:Primary ReceptorSNS Response

dilation - Beta-2constriction - Alpha-1

Lung:Primary ReceptorSNS Response

Beta-2bronchodilation

Kidney:Primary ReceptorSNS Response

Beta-1Increased renin release

GI:Primary ReceptorSNS Response

Alpha-1 : Increased sphincter toneAlpha / Beta : decreased peristalsis

Bladder:Primary ReceptorSNS Response

Alpha / Beta : relax xmooth muscleAlpha-1: increased sphincter tone

Uterus:Primary ReceptorSNS Response

Alpha-1: contractionBeta-2: relaxation

Eye:Primary ReceptorSNS Response

Alpha-1Mydriasis

Metabolic:Primary ReceptorSNS Response

Alpha / BetaIncreased lipolysisIncreased glyconeogenesisIncreased glycogenolysis

Skin:Primary ReceptorSNS Response

mAchSweat

Immune Cells:Primary ReceptorSNS Response

Beta-2modulate immunity

Isolated Denervated Heart

+'ve chronotropic +'ve inotropicincreased COdecreased efficiency

Isolated Denervated heart

+'ve chronotropic: Increased HRSA node: SNS increases rate of phase 4 depolarization+'ve inotropic: Increased SVIncreased force of ventricular contractionIncreased dP/dtIncreased rate of relaxationShorten duration of contractionIncreased CODecreased efficiency: Increased work / Increased oxygen consumption

Catecholamine Induced ArrhythmiasHigh concentration of catecholamines can result from:- Pheochromocytoma- Severe anxiety- Cocaine overdose

Heart sensitized to carecholamine-induced arrhythmias by:- General anesthetic- Myocardial infarctionNormally, 95 % of NE gets reabsorbed, but cocaine will make this transporter function in the opposite derection, causing very increased levels of NE in the synaptic clefts.

Baroreceptor reflex in response to High and Low BP

High BP: decreased sympathetic activity, increased parasympathetic activityLow BP: increased sympathetic activity, decreased parasympathetic activity

Blood pressure response to exogenous catecholamines depends upon the change in

CO and TPR

Vascular response:Beta-2 adrenergic receptorsAlpha adrenergic receptors

Beta-2 - vasodilationAlpha - vasoconstriction

The specific vascular response to a compound depends on:

Relative affinity of the compound for beta-1 vs. alpha adrenergic receptorsANDRelative density of beta-2 vs. alpha adrenergic receptors in tissue

CV response to Norepinephrine (NE)

Affinity Alpha1~Alpha-2 > Beta-1 >> Beta-2Alpha-AR mediated vasoconstriction leads to: Increase in TPR and therefore to Increased B.P.Causes Vagal mediated reflex to DECREASE HRIncreased stroke volume via ventricular B-1 ARSlight increase in CO at best

CV response to Epinephrine (Epi)

Affinity: B-1~B2 > a-1~a-2Effects: +'ve Inotropic +'ve chronotropic Increased CO Decreased TPR Minimal effect (slight increase) mean BP at therapeutic levels.

CV response to Isoproterenol

Affinity: B-1~B-2 >>> aEffects: +'ve inotropic +'ve chronotropic Increases CO Decreases TPR Decreases BP

In familial dysautonomia, how would the absense of the baroreceptor reflex affect the response to ISO?

HR would be lower than in a normal personBP would be lower than normalSV - would be lower than in a normal person?!

CV response to Dopamine

Affinity: D-receptor >> Beta-1 AR >> Alpha-1 ARVasodilation via D-1 receptor in: Renal Mesenteric Intracerebral Coronary bedsAt higher doses +'ve inotropic effect with increased CO via Beta-1 AR with less effects on HR

Dobutamine

Beta-1 agonist"Affinity: B-1 > B-2 > aincreased CO due to increased myocardial contractilityModest increase in HRNot much change in TPRUsed short-term after surgery to increase CO

Other actions of catecholamines:GILungEyeBladderUterusImmune cellsMetabolic

Other actions of catecholamines:GI - decreased peristalsis (a/B) and increased sphincter tone (a-1)Lung bronchodilation (B-2)Eye - mydriasis (a-1)Bladder relaxation of detrusor (B-2) and contraction of sphincter (a-1)Uterus Decreased frequency, duration and intensity of contraction (B-2)Immune cells - modulate magnitude of response (B-2)Metabolic - Increase blood glucose increased glycogenolysis and glyconeogenesis, decreased insulin release]; increased blood fatty acids [increased lypolysis]

Sympathomimetic: Amphetamine

Uses Uptake I to facilitate release of catecholamines (NE periphery; NE and DA centrally) fron CYTOSOLIC poolNOT exocytotic release of storage granulesInhibits re-uptake of extracellular catecholaminesAlpha-AR mediated vasoconstriction -> increase in BP and vagal-mediated reflex bradycardiaAnalepticdecreased appetiteContracture of urinary sphincter D-isomer more potent in CNS L-isomer more potent in CV

Sympathomymetic: Ephedrine

Also uses Uptake I, but CAN also stimulate A and B-ARIncreased blood pressure: Alpha-AR mediated vasoconstrictionBUT increased heart rate (don't see the reflex bradycardia) - reflex sloweing is balanced by direct stimulation of myocardiumRelaxation of bronchial smooth muscleMydriasis w/o affecting accommodation - from local administration

Direct-Acting Sympathomymetics

Alpha agonists: Phenylephrine, MethoxamineIncrease TPR, increase HR, Reflex bradycardya"Selective" Beta-2 Agonists: Albuterol, terbutaline, metaproterenol

Adrenergic Amines: Uses

Decongestant (phenylephrine, ephedrine):alpha-AR mediated vasoconstriction to reduce blood flow to mucous membranesCombination with local anesthetic (Epi):increases frequency of successful nerve block(localizes anesthetic), prolongs duration and decreases systemic toxicityLocal tissue hemostats (Epi):alpha-AR mediated vasoconstriction; possible "rebound effect"Hypotension (IF inadequate perfusion):Ephedrine to offset hypotension with spinal anesthetic, increases HR a little bitShock: except for anaphylactic shock, or life threatening hypotension, sympathomimetics used when treatment of etiology unsatisfactoryshock usually activates sympathetics with increased vasoconstriction ( with spinal cord inury, might not get the sympathetic activation)Dopamine Mild-moderate HF: Dobutamine (Beta-1 > Beta-2 >> Alpha) for short-term therapy to increase CO after cardiac or major vascular surgeryCardiac Arrest: Epi if external cardiac compression and defibrillation failBronchial asthma: Beta-2 selective (Albuterol) agonists; epi, iso for bronchodilation)Severe allergic reaction: EpiDecreases edema, maintains BP, Relaxes bronchial smooth muscle, suppresses histamine and leukotriene release from mast cellsPreterm Labor: Uterus relaxationOpthamology:Mydriasis - topical PhenylephrineWide-Angle Glaucoma - stimulation of alpha-AR reduce production of aqueous humor

Drugs that alter Cenral Regulation of Sympathetic Activity

Clonidine, Methyl-dopa

Drugs that deplete NE from Nerve Terminal

Guanethedine, Reserpine

Alpha-AR antagonists:

PhenoxybenzaminePhentolaminePrazosin

Beta-AR antagonists

PindololCarvedilolLabetalolNebivololAtenololLabetalolExmololSotalol

Clonidine

In CNS: stimulates POSTSYNAPTIC alpha-2AR and imidazoline I-1 receptors- reduction in sympathetic outflow - reduces tonic sympathoexcitatory tone

Effects of Clonidine

Decreased TPR: from decreased sympathetic vascular tone and decreased Beta-1AR stimulation of renin releaseDecreased HRDecreased CODecreased BP: Supine - mainly decreased HR and decreased SV; Upright - decreased HR, decreased SV and decreased vascular resistanceSympathetic reflexes minimally affected

Adverse effects of Clonidine

SecationXerostomiaSexual DysfunctionAbrupt withdrawal associated with rebound sympathetic tone:-Rebound HTN-Tachycardia-Sweating-Abdominal pain-Headache-Nervousness

Methyl Dopa

methyl dopa -> Alpha-methyl DA -> alpha-methyl NEAlpha-methyl NE is a potent and selective against at alpha-2ARIn CNS Alpha-methyl NE interacts with postsynaptic alpha-2 AR to: decrease sympathetic outflow from medullar centers (no affinity for beta-1, beta-1 nor alpha-1)

Effects of Methyl Dopa

Younger pts: Decreased BP, due to Decreased TPR; not much change in COOlder pts: Decreased BP, due to Decreased TPS AND Decreased CO due to Decreased HR and Decreased stroke volume secondary to relaxation of veins and reduction in preloadNOT 1st line anti-HTN, but may be preferred in pregnancy - because effective and safe to fetus and mother and maintains uretine perfusion, not teratogenic

Adverse side effects of Methyl Dopa

SedationSexual DysfunctionAbrupt withdrawal -> rebound HTNHepatitisAnemia

Guanethedine

Transported into neurons by Uptake I and disrupts storage granuleReduction in neuronal NE stores

Effects of Guanethedine

Decreases neuronal NE stores -> decreases NE amt releasec by action potentialDecreases BOTH alpha-AR and beta-AR mediated responses:Decreases BPDecreases CO and HRDecreases sympathetic reflexesDecreased response indirect acting sympathomimetics

Adverse effects of Guanethedine

Orthostatic hypotensionGI cramping, pain, diarrheaFluid retention: Decreased CO -> Decreased GFRChronic admin - supersensitivity to exogenous adrenergic aminesMuscle weaknessSexual dysfunction

Reserpine

blocks vesicular transporter for NE, DA, 5-HTReduction in neuronal monoamine storesRate of depletion proportional to neuronal activity

Effects of Reserpine

Decreased alpha-AR and beta-AR mediated responses: Decreased BP Decreased CO and HRDecreased response to indirect ating sympathomimetics

Adverse effects of reserpine

CNS effects: Depression, nightmaresGI cramping, pain, diarrheaChronic Admin: Supersensitivity to exogenous adrenergic aminesSexual dysfunction

Phenoxybenzamine

Alpha-AR antagonist: Irreversible, insurmountable, noncompetitiveBlockade is slow-developing, but long-lasting (3-4 days)Does NOT block Beta-ARNo intrinsic activityDegree of Antagonism is directly proportional to alpha-adrenergic tone - greater effect in "upright" patients-Decreases BP if supported by sympathetic activity of sympathomimetics

Phentolamine

Competetive, reversible antagonismm of Alpha-ARDoes NOT block Beta-ARNo intrinsic activityResponse proportional to level of alpha-AR toneMost effective antagonizing effects circulating carecholamines

CV effects when:NE administered in addition to phentolamine?

NE alone: Alpha-AR vasoconstriction - increase in TPR and increase in BP AND reflex bradycardiaNE+Phentolamine: Increased HR, Increased CO

Prazosin

Selective Alpha-1-AR antagonistNo effect on alpha-2 AR or Beta-ARDecreases TPR therefore Decreases BP without significant tachycardiaBlock alpha-1 AR in CNS involved with baroreceptor reflexpresynaptic alpha-1 AR autoreceptors not blockedFaborable changes in blood lipid chemistry: Decreased total cholesterol and TG and Increased HDL-cholesterol"First Dose Effect": postural hypotension and syncope with 1st dose or increase in dosing

Alpha-AR Antagonists: USES

Acute HTNive crisis (e.g. phentolamine):OD aphetamine or alpha-AR agonistCombo with beta-AR blocker for abrupt clonidine withdrawalEssential HTN (e.g. prazosin):Adjunct rather than monotherapyReported increased risk cardiac failure with doxazosinRaynaud's Syndrome:Combined with Beta-AR blocker for pre- and operative management of pheochromocytoma ( so have increased circulating catecholamines - to protect give Alpha and Beta blocker, Beta blocker 1st)

Benign prostatic hyperplasia (BPH):

increased size of prostate with change in composition, functioning and sympatheti controlMay cause lower urinary tract symptomesTreat with Alpha-1 selective antagonists: Tamsulosin - Affinity Alpha1-A >~Alpha1-D > Alpha1-B / Alfuzosin - nonselective alpha-1 AR antagonist BUT "clinically uroselective"Mainly Alpha-1AR in prostate smooth muscle, proximal urethra and neck of bladder

Beta-AR antagonists

Competetive antagonistsEffects proportional to Beta-adrenergic toneIncreased tone during exercise and myocardial inadequacy

Beta-AR antagonists

Some have weak intrinsic activity (e.g. pindolol):Manifestation inversely related to beta-adrenergic toneLess decrease in HR, CO and exercise toleranceLess likely to increase serum TG and decrease HDL-colesterolMaybe preferred in diabetic and possibly in patients with bradycardiaNOT for angina, after MI, or in heart failureSome have membrane-stabilizing effect-as antiarrhythmics - block Ca current into cell - (e.g. propranolol, acebutolol)Fatigue and "Sexual dysfunction

Newer generation beta blockers, additional properties

Carvedilol, Labetalol: Vasodilation due to alpha-AR blockadeNebivolol: Vasodilation via generation of NODrug profules of beta blockers may differ due to differences in physiochemical and pharmacologic properties"Heterogeneous drug class

Effects of Beta-AR antagonists

Decrease: HR, SV, CO, AV conduction - Beta-1 blockadeBlock Beta-2 vasodilation supported by ISO and EPIBlock Beta-2 bronchodilation: increase resistance to airflow; precipitate asthmatic attack in individuals with asthma or with chronic obstructive bronchiole disordersInhibit increase in blood glucose & FFA by sympathomimetics: slow recovery from insulin-induced hypoglycemiaChronic administration of non-selective beta-blockers associated with increased serum TG, and decreased HDL-cholesterol: Beta-1 selective blockers improve lipid profile

Adverse effects/contraindications of Beta-AR blockers

Heart Block: decreased AV conduction may convert partial to complete blockSevere Bradycardia:Asthma and active obstructive airway disease: because they increase airflow resistanceRaynaud's syndrome: Exacerbate alpha-AR vasoconstrictionWithdrawal syndrome with abrupt discontinuation: Rebound HTNExacerbate anginal attacksSupersensitivity to exogenous Beta-AR agonists

Uses of Beta-AR blockers

ArrhythmiasAngina pectorisEssential HTNPost-MI HyperthyroidismMigraine prophylaxixBenign essential tremorPeri-operativeCongestive Heart FailureAdverse myocardial remodelingToxix effects of catecholamines on myocardium primarily via Beta-AR

Uses of Beta-AR blockersArrhythmias:

Decreases HR, and Decreases Ca2+ overload and inhibits delayed afterdepolarization:Increases AV conduction time and prolongs SV refracoriness:Controlling ventricular response to atrial tachy, fibrillation, or flutterTerminate reentrant arrhythmias involving AV node: because increases refractory period so arrhythmia comes around and hits tissue in refractory periodSotalol: Nonselective Beta blocker that also blocks K+ channels

Uses of Beta-AR blockersAngina pectoris:

Effective in stress-induced where have decreased O2 demand:Combo therapy to counter adverse effects of nitrates:--Beta blockers decrease reflex tachycardia and (+) inotropic effects of nitrates--Nitrates alleviate increased coronary vascular resistance with Beta blockers and attenuate the increase in left ventricular end diastolic volume associated with beta blockers by increasing venous compliance

Uses of Beta-AR blockersEssential HTN:

Beta-1 AR selective, nonselective Beta blockers, and newer generation Beta-blockers:--slow developing antihypertensive action (weeks) for traditional Beta-blockers (i.e. Beta-1 selective and non-selective)--Delay not observed with vasodilaroty Beta blockers (labetalol, carvedilol, nebivolol)Some recent question regarding exact role in HTN therapy:--meta-analysis suggest compared with other antihypertensives, Beta-blockers may increase risk adverse CV outcomes, especially in elderly

Uses of Beta-AR blockersPost-MI:

Decreases mortality: with administration of drugs during early MI and continued long-termMechanism: Decreased O2 demand and therefore decreases ischemiaRedistribution of myocardial blood flowAnti-arrhythmic action

Uses of Beta-AR blockersHyperthyroidism:

Management of peripheral symptoms: tachycardia, tremor

Uses of Beta-AR BlockersMigraine prophylaxis:Benign Essential tremor:Perioperative:

Uses of Beta-AR BlockersMigraine prophylaxis: decreases frequemcy which may lead to suppressionBenign Essential tremor:Perioperative: Adverse cardiac outcome in 1-5% patients undergoing noncardiac surgery;Initiation peri-ip Beta-Blockers found to decrease incidence of non-fatal MI but increased incidence of non-fatal stroke + significant hypotension and bradycardiaPeri-operative Beta-blockers for patient already on Beta-blocker therapy

Uses of Beta-AR blockerCongestive Heart Failure:

Activation of sympathetic and renin-angiotensin aldosterone systems are compensatory for acure myocardial inadequacy:Direct action on hear to increase COVasoconstriction to maintain BP and allow organ perfusionVenous constriction to increase venous return and increased cardiac fillingVolume expansion due to H2O and Na+ retention

Uses of Beta-AR blockerCongestive Heart Failure:

BUT chronic activation Contributes to downward spiral of:-excessive vasoconstriction-volume expansion-progressive left ventricular dysfunctionChronic excessive sympathetic activation causes vasoconstriction of coronary arteries with thichen ventricular wall -> myocardial ischemiaLong-term exposure to excessive EPI and NE leads to pathological remodeling:

Uses of Beta-AR blockers: CHF and prolonged exposure to excessive catecholamines:

Adverse myocardial remodeling:Increased apoptosis: increased Ca++ leads to Ca++ overload which uncouples mitochondrial oxidative phosphorylation with decreased ATPHypertrophy of myocytes and fibroblast growth --- increase the risk of ischemiaFetal gene expression:Remodeling also leads to electrophysiological heterogeneity which can promote re-entry arrhythmiasDesensitization of Beta-1 and Beta-1 BUT not Beta-3

Uses of Beta-AR blockers: CHF

Toxic effects of catecholamines on myocardium promarily via Beta-AR but also involve alpha-ARCarvedilol: (Beta-1, Beta-2, Alpha-1 antagonist + antioxidant)Alter natural history and slow progression:Prevent and reverse catecholamine-mediated myocardial dysfunction and remodeling:Slow developing efficacy (months):Decreases sudden cardiac death:Allow Beta-AR to resensitize:

Proprandolol

nonselective Beta-1 and Beta-2 blocker

Metoprolol

selective" beta-1 blocker

Atenolol

selective Beta-1 blocker; limited CNS penetration - ADVANTAGE

Carvedilol

Beta-1, Beta-2, Alpha-1 blocker and antioxidant

Labetalol:

Beta-1, Beta-2, Alpha-1 blocker --> so without delay

Esmolol:

very short-acting Beta-1 blocker (T1/2 ~9mins)

Sotalol:

Nonselective Beta-1 and Beta2 blocker + blocks K+ channel

Nebivolol:

Beta-1 selective blocker + NO generator