Rabin's Lecture 1

• Receptor-operated channel (ROC)
• Depolarize by increase Na and K conductance
• ANS ganglia
• Adrenal medulla

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

• G protein coupled receptor (GPCR)
• Hyperpolarize by opening GIRK
• Decrease Adenylyl cyclase
• M2 heart (SA, atrium, AV node)

• 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 potential

Very sparse PNS innervation of ventricular myocardium and low sensitivity to mAchR agonists

• insignificant contribution to overall vascular resistance
• few vascular beds innervated by PNS
• Erectile tissue is exception.

Stimulation M3Ach receptors on endothelial cells causes increase in NO secretion to diffuse and relax vascular smooth muscle

• Increased lypolysis
• Increased glycogenolysis and gluconeogenesys

decreased insulin secretion

• increase HR
• increase AV conduction
• increase stroke volume
• increase CO

bronchodilation, increase O2

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

increased renin release

• eye - mydriasis - pupil dilation
• skin - sweating (Ach)
• GI - increased sphincter tone, decreased peristalsis
• Bladder - increased sphincter tone, relax smooth muscle
• Lymphoid organs, immune cells - modulate immune response

• SA node - increased HR
• atrial muscle - increased contraction force
• AV node - increased conduction
• ventricular muscle - significantly increased contraction force, increased SV, increased CO

• Vasculature dilation or constriction
• Kidney - increased renin release

• SA node - decrease heart rate significantly
• atrial muscle - decreased force of contraction
• AV node - decreased conduction
• ventricular muscle - none

• Vasculature - minimal influence - dilate erectile tissue
• kidney - none

• NE - primary NT from MOST postganglionic sympathetic nerves
• Epi - primary neurohumor release by adrenal medulla
• Dopamine - NT in CNS but also in various vascular beds (e.g.) renal, mesenteric

Heart is mostly Beta 1 and some Beta 2 receptors

• Epi > NE
• increased phospholipase C
• Increased Ca
• Increased PKC
• Postsynaptic only

• Epi >/= NE
• decreased adenylyl cyclase
• increased K conductance
• postsynaptic in CNS

Epi >/= NE

• Found post-synaptically
• Regulated by neuronal NE
• Gs
• increase adenylyl cyclase

Heart, Kidney

Epi >> NE

• Typically non-innervated
• Regulated by circulating Epinephrine
• Gs
• Increases adenylyl cyclase

Lung, skeletal muscle, vasculature

Iso > NE > Epi

• Gs and Gi/o
• Adenylyl cyclase
• Increased MAPK
• Increased NO & cGMP

Fat, heart, GI

• Beta-1
• Increased HR
• Increased SV
• Increased AV conduction
• Increased CO

• dilation - Beta-2
• constriction - Alpha-1

• Beta-2
• bronchodilation

• Beta-1
• Increased renin release

• Alpha-1 : Increased sphincter tone
• Alpha / Beta : decreased peristalsis

• Alpha / Beta : relax xmooth muscle
• Alpha-1: increased sphincter tone

• Alpha-1: contraction
• Beta-2: relaxation

• Alpha-1
• Mydriasis

• Alpha / Beta
• Increased lipolysis
• Increased glyconeogenesis
• Increased glycogenolysis

• mAch
• Sweat

• Beta-2
• modulate immunity

• +'ve chronotropic
• +'ve inotropic
• increased CO
• decreased efficiency

• +'ve chronotropic:
• Increased HR
• SA node: SNS increases rate of phase 4 depolarization

• +'ve inotropic:
• Increased SV
• Increased force of ventricular contraction
• Increased dP/dt
• Increased rate of relaxation
• Shorten duration of contraction

Increased CO

Decreased efficiency: Increased work / Increased oxygen consumption

• Heart sensitized to carecholamine-induced arrhythmias by:
• - General anesthetic
• - Myocardial infarction

Normally, 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.

• High BP: decreased sympathetic activity, increased parasympathetic activity
• Low BP: increased sympathetic activity, decreased parasympathetic activity

CO and TPR

• Beta-2 - vasodilation
• Alpha - vasoconstriction

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

Affinity Alpha1~Alpha-2 > Beta-1 >> Beta-2

• Alpha-AR mediated vasoconstriction leads to:
• Increase in TPR and therefore to Increased B.P.
• Causes Vagal mediated reflex to DECREASE HR
• Increased stroke volume via ventricular B-1 AR
• Slight increase in CO at best

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

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

• HR would be lower than in a normal person
• BP would be lower than normal
• SV - would be lower than in a normal person?!

• Affinity: D-receptor >> Beta-1 AR >> Alpha-1 AR
• Vasodilation via D-1 receptor in:
• Renal
• Mesenteric
• Intracerebral
• Coronary beds

At higher doses +'ve inotropic effect with increased CO via Beta-1 AR with less effects on HR

• "Beta-1 agonist"
• Affinity: B-1 > B-2 > a
• increased CO due to increased myocardial contractility
• Modest increase in HR
• Not much change in TPR

Used short-term after surgery to increase CO

• 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]

Uses Uptake I to facilitate release of catecholamines (NE periphery; NE and DA centrally) fron CYTOSOLIC pool

• NOT exocytotic release of storage granules
• Inhibits re-uptake of extracellular catecholamines
• Alpha-AR mediated vasoconstriction -> increase in BP and vagal-mediated reflex bradycardia

• Analeptic
• decreased appetite
• Contracture of urinary sphincter
• D-isomer more potent in CNS
• L-isomer more potent in CV

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

• Alpha agonists: Phenylephrine, Methoxamine
• Increase TPR, increase HR, Reflex bradycardya

"Selective" Beta-2 Agonists: Albuterol, terbutaline, metaproterenol

• Decongestant (phenylephrine, ephedrine):
• alpha-AR mediated vasoconstriction to reduce blood flow to mucous membranes

• Combination with local anesthetic (Epi):
• increases frequency of successful nerve block(localizes anesthetic), prolongs duration and decreases systemic toxicity

• Local 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 bit

• Shock: except for anaphylactic shock, or life threatening hypotension, sympathomimetics used when treatment of etiology unsatisfactory
• shock 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 surgery

Cardiac Arrest: Epi if external cardiac compression and defibrillation fail

Bronchial asthma: Beta-2 selective (Albuterol) agonists; epi, iso for bronchodilation)

• Severe allergic reaction: Epi
• Decreases edema, maintains BP, Relaxes bronchial smooth muscle, suppresses histamine and leukotriene release from mast cells

Preterm Labor: Uterus relaxation

• Opthamology:
• Mydriasis - topical Phenylephrine
• Wide-Angle Glaucoma - stimulation of alpha-AR reduce production of aqueous humor

Clonidine, Methyl-dopa

Guanethedine, Reserpine

• Phenoxybenzamine
• Phentolamine
• Prazosin

• Pindolol
• Carvedilol
• Labetalol
• Nebivolol
• Atenolol
• Labetalol
• Exmolol
• Sotalol

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

• Decreased TPR: from decreased sympathetic vascular tone and decreased Beta-1AR stimulation of renin release
• Decreased HR
• Decreased CO
• Decreased BP: Supine - mainly decreased HR and decreased SV; Upright - decreased HR, decreased SV and decreased vascular resistance

Sympathetic reflexes minimally affected

• Secation
• Xerostomia
• Sexual Dysfunction
• Abrupt withdrawal associated with rebound sympathetic tone:
• -Rebound HTN
• -Tachycardia
• -Sweating
• -Abdominal pain
• -Headache
• -Nervousness

• methyl dopa -> Alpha-methyl DA -> alpha-methyl NE
• Alpha-methyl NE is a potent and selective against at alpha-2AR
• In 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)

• Younger pts: Decreased BP, due to Decreased TPR; not much change in CO
• Older 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 preload

NOT 1st line anti-HTN, but may be preferred in pregnancy - because effective and safe to fetus and mother and maintains uretine perfusion, not teratogenic

• Sedation
• Sexual Dysfunction
• Abrupt withdrawal -> rebound HTN
• Hepatitis
• Anemia

• Transported into neurons by Uptake I and disrupts storage granule
• Reduction in neuronal NE stores

• Decreases neuronal NE stores -> decreases NE amt releasec by action potential
• Decreases BOTH alpha-AR and beta-AR mediated responses:
• Decreases BP
• Decreases CO and HR
• Decreases sympathetic reflexes
• Decreased response indirect acting sympathomimetics

• Orthostatic hypotension
• GI cramping, pain, diarrhea
• Fluid retention: Decreased CO -> Decreased GFR
• Chronic admin - supersensitivity to exogenous adrenergic amines
• Muscle weakness
• Sexual dysfunction

• blocks vesicular transporter for NE, DA, 5-HT
• Reduction in neuronal monoamine stores
• Rate of depletion proportional to neuronal activity

• Decreased alpha-AR and beta-AR mediated responses:
• Decreased BP
• Decreased CO and HR

Decreased response to indirect ating sympathomimetics

• CNS effects: Depression, nightmares
• GI cramping, pain, diarrhea
• Chronic Admin: Supersensitivity to exogenous adrenergic amines
• Sexual dysfunction

• Alpha-AR antagonist: Irreversible, insurmountable, noncompetitive
• Blockade is slow-developing, but long-lasting (3-4 days)
• Does NOT block Beta-AR
• No intrinsic activity
• Degree of Antagonism is directly proportional to alpha-adrenergic tone - greater effect in "upright" patients
• -Decreases BP if supported by sympathetic activity of sympathomimetics

• Competetive, reversible antagonismm of Alpha-AR
• Does NOT block Beta-AR
• No intrinsic activity
• Response proportional to level of alpha-AR tone
• Most effective antagonizing effects circulating carecholamines

NE alone: Alpha-AR vasoconstriction - increase in TPR and increase in BP AND reflex bradycardia

NE+Phentolamine: Increased HR, Increased CO

• Selective Alpha-1-AR antagonist
• No effect on alpha-2 AR or Beta-AR

• Decreases TPR therefore Decreases BP without significant tachycardia
• Block alpha-1 AR in CNS involved with baroreceptor reflex
• presynaptic alpha-1 AR autoreceptors not blocked
• Faborable 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

• Acute HTNive crisis (e.g. phentolamine):
• OD aphetamine or alpha-AR agonist
• Combo with beta-AR blocker for abrupt clonidine withdrawal

• Essential HTN (e.g. prazosin):
• Adjunct rather than monotherapy
• Reported increased risk cardiac failure with doxazosin

Raynaud'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)

• increased size of prostate with change in composition, functioning and sympatheti control
• May cause lower urinary tract symptomes
• Treat 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

• Competetive antagonists
• Effects proportional to Beta-adrenergic tone
• Increased tone during exercise and myocardial inadequacy

• Some have weak intrinsic activity (e.g. pindolol):
• Manifestation inversely related to beta-adrenergic tone
• Less decrease in HR, CO and exercise tolerance
• Less likely to increase serum TG and decrease HDL-colesterol
• Maybe preferred in diabetic and possibly in patients with bradycardia
• NOT for angina, after MI, or in heart failure

Some have membrane-stabilizing effect-as antiarrhythmics - block Ca current into cell - (e.g. propranolol, acebutolol)

Fatigue and "Sexual dysfunction"

• Carvedilol, Labetalol: Vasodilation due to alpha-AR blockade
• Nebivolol: Vasodilation via generation of NO

• Drug profules of beta blockers may differ due to differences in physiochemical and pharmacologic properties
• "Heterogeneous drug class"

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

• Heart Block: decreased AV conduction may convert partial to complete block
• Severe Bradycardia:
• Asthma and active obstructive airway disease: because they increase airflow resistance
• Raynaud's syndrome: Exacerbate alpha-AR vasoconstriction
• Withdrawal syndrome with abrupt discontinuation:
• Rebound HTN
• Exacerbate anginal attacks
• Supersensitivity to exogenous Beta-AR agonists

• Arrhythmias
• Angina pectoris
• Essential HTN
• Post-MI
• Hyperthyroidism
• Migraine prophylaxix
• Benign essential tremor
• Peri-operative
• Congestive Heart Failure
• Adverse myocardial remodeling
• Toxix effects of catecholamines on myocardium primarily via Beta-AR

• 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 flutter
• Terminate reentrant arrhythmias involving AV node:
• because increases refractory period so arrhythmia comes around and hits tissue in refractory period

Sotalol: Nonselective Beta blocker that also blocks K+ channels

• 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

• 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

• Decreases mortality: with administration of drugs during early MI and continued long-term
• Mechanism:
• Decreased O2 demand and therefore decreases ischemia
• Redistribution of myocardial blood flow
• Anti-arrhythmic action

Management of peripheral symptoms: tachycardia, tremor

• Uses of Beta-AR Blockers
• Migraine prophylaxis: decreases frequemcy which may lead to suppression
• Benign 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 bradycardia
• Peri-operative Beta-blockers for patient already on Beta-blocker therapy

• Activation of sympathetic and renin-angiotensin aldosterone systems are compensatory for acure myocardial inadequacy:
• Direct action on hear to increase CO
• Vasoconstriction to maintain BP and allow organ perfusion
• Venous constriction to increase venous return and increased cardiac filling
• Volume expansion due to H2O and Na+ retention

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

• Adverse myocardial remodeling:
• Increased apoptosis: increased Ca++ leads to Ca++ overload which uncouples mitochondrial oxidative phosphorylation with decreased ATP

Hypertrophy of myocytes and fibroblast growth --- increase the risk of ischemia

• Fetal gene expression:
• Remodeling also leads to electrophysiological heterogeneity which can promote re-entry arrhythmias
• Desensitization of Beta-1 and Beta-1 BUT not Beta-3

• Toxic effects of catecholamines on myocardium promarily via Beta-AR but also involve alpha-AR
• Carvedilol: (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:

nonselective Beta-1 and Beta-2 blocker

"selective" beta-1 blocker

selective Beta-1 blocker; limited CNS penetration - ADVANTAGE

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

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

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

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

Beta-1 selective blocker + NO generator