AUTONOMIC NERVOUS SYSTEM-tf.pptx

AUTONOMIC NERVOUS SYSTEM: PHYSIOLOGY & PHARMACOLOGY Teddy S. Fabila, MD Department of Anesthesiology Ospital ng Maynila Medical Center Part One – Anatomy & Physiology Part Two - Pharmacology Anatomy & Physiology I. Functional Anatomy II. Neurotransmission III.Receptors IV.Molecular Pharmacology and Effector Response V. Reflexes ANESTHESIOLOGY IS THE PRACTICE OF AUTONOMIC NERVOUS SYSTEM (ANS) MEDICINE DRUGS USED DURING ANESTHESIA AS WELL AS PAINFUL STIMULATION & DISEASE STATES FREQUENTLY PRODUCE ANS-RELATED SIDE EFFECTS KNOWLEDGE OF ANS ANATOMY & PHYSIOLOGY IS A PREREQUISITE TO AN UNDERSTANDING OF PHARMACOLOGY OF DRUGS THAT ACT ON THE CNS Functional Anatomy  1921 – Langley divided ANS into two parts  sympathetic nervous system (SNS, adrenergic system)  parasympathetic nervous system (PNS, cholinergic system)  SNS & PNS produce complementary effects on the activity of various organ system Functional Anatomy  Central Autonomic Organization  Integration – all levels of the cerebrospinal axis  Cerebral cortex – highest level of CNS integration  Principal site of ANS organization – hypothalamus  SNS : nuclei in posterolateral hypothalamus  PNS : nuclei in midline and some anterior nuclei Functional Anatomy  Vital centers for hemodynamic & ventilatory control – medulla oblongata & pons  ANS hyperreflexia – spinal cord mediation of ANS reflexes w/o integration of function from higher inhibitory centers Functional Anatomy  Peripheral ANS Organization (efferent – motor)  Two complimentary parts  Cell body of preganglionic neuron originates in the CNS & synapses in an autonomic ganglion  Preganglionic fibers – myelinated (rapid conducting)  Preganglionic neurons arise from the autonomic ganglia & distributed to the effector organs  Post-ganglionic fibers – unmyelinated (slow conducting) Sympathetic : Anatomy Sympathetic Nervous System Thoracolumbar Divison  12 thoracic and first 3 lumbar  Three courses of preganglionic fibers  1. synapse with postganglionic fibers in ganglia at the level of exit  2. course upward or downward in the trunk of the SNS  3. collateral ganglion Sympathetic Nervous System Thoracolumbar Divison Sympathetic Nervous System Thoracolumbar Divison  Postganglionic neuronal cell bodies : located in ganglia of the paired lateral SNS chain or unpaired collateral ganglia  Three special paired ganglia  1. superior cervical  2. middle cervical  3. cervicothoracic ganglia (stellate ganglion) Characteristics of Nerve fiber types General Fiber Type and Example A-alpha Large a-motoneurons Sensory Fiber Type and Example Ia: Muscle spindle afferents Ib: Golgi tendon organs II: Secondary afferents of muscle spindles; touch and pressure Diameter Largest Largest Medium Conduction Velocity Fastest Fastest Medium A-beta Touch, pressure A-gamma Intrafussal fibers A-delta Touch, pressure, temperature and pain --III:Touch, pressure, temperature and fast pain Medium Small Medium Medium B: preganglionic autonomic fibers C: slow pain, postganglionic autonomic fibers --IV: pain and temperature Small Smallest Medium Slowest Anatomy SNS vs PNS Parameters Origin SNS T1 – 12, L1-3 PNS Brainstem (X, IX, VII, III)S2-S4 Longer Shorter or direct 1:1 to 3:1 Pre-ganglionic Postganglionic Postganglionic : preganglionic ratio Neurotransmitter in ganglion Receptor type in ganglion Neurotransmitter in the effector organs Shorter Longer 20:1 to 30:1 ACh Nicotinic NE and Ach ACh Nicotinic ACh Anatomy SNS vs PNS Parasympathetic Nervous System Parasympathetic Nervous System  Vagus nerve: most extensive distribution of all PNS, accounting for more than 75% of PNS activity  Mass reflex action is not a characteristic of the PNS Functional Anatomy Autonomic Innervation  Heart  SNS &PNS innervation of the heart (via the stellate ganglion) influences HR (chronotropism), strength of contraction (inotropism), & coronary blood flow  PNS cardiac vagal fibers – mainly to SA & AV nodes  chronotropic effect (strong vagal stimulation can arrest SA node firing & block impulse conduction to ventricles) Functional Anatomy Autonomic Innervations  Heart  SNS have stronger distribution to the ventricles  Paired stellate ganglion  Right : systolic duration and increase HR (anterior epicardial surface and interventricular septum)  Left : MAP and left ventricular contractility and HR (posterior and lateral surfaces of the ventricle)  (normal SNS tone maintains contractility about 20% above that in the absence of SNS stimulation) Functional Anatomy Autonomic Innervations  Peripheral Circulation  SNS is the most important regulator of peripheral circulation  Basal ANS tone maintains arteriolar diameter about 50% of maximum Functional Anatomy Autonomic Innervation  Peripheral Circulation  SNS may produce vasoconstriction and vasodilation  By functioning as a reservior for about 80% of the blood volume  small changes in venous capacitance produced by SNSmediated venoconstriction  large changes in venous return Functional Anatomy Autonomic Innervation  Lungs  SNS and PNS  Upper thoracic ganglion (stellate) pass to the lungs to innervate the bronchi and blood vessels  SNS: Bronchodilation and pulmonary vasoconstriction  PNS: vagus = bronchoconstriction, essential in reflex regulation, and pulmonary secretions Ans - neurotransmission  Transmission of impulses across the nerve terminal junction sites (synaptic cleft) of the peripheral ANS occurs through the mediation of liberated chemicals (neurotransmitters)  interact w/ a receptor on the end organ  biologic response Pns - neurotransmission  Acetylcholine (Ach) – neurotransmitter at preganglionic nerve endings of the SNS & PNS & at postganglionic nerve endings of the PNS  Ability of a receptor to modulate the function of an effector organ is dependent on rapid recovery to its baseline state after stimulation  Ach removal occurs by rapid hydrolysis by acetylcholinesterase (true cholinesterase) Sns - neurotransmission  Catecholamines – first messenger  Endogenous – any compound w/ a cathecol nucleus (benzene ring w/ 2 adjacent hydroxyl groups) & an amine containing side chain  dopamine, norepinephrine, epinephrine  Effects of endogenous or synthetic catecholamines on adrenergic receptors can be direct or indirect (little intrinsic activity but stimulate release of stored neurotransmitter) Sns - neurotransmission  Norepinephrine and Epinephrine – exclusive mediators of peripheral SNS  Norepinephrine – released from pre synaptic vesicles of postganglionic nerve endings of the SNS except in the sweat glands  ATP – released with norepinephrine  coneurotransmitter with synergistic action Sns - neurotransmission  Epinephrine –  principal hormone released by chromaffin cells (postganglionic neurons) as neurotransmitter hormone [ 85% in adrenal medulla]  Increases metabolic effect as much as 100%  Increases glycogenolysis in the liver  Dopamine  Coordinates motor function in the brain  Precursur of NE Phe Tyr Tyrosine hydroxylase DOPA Dopamine Ca + ATP β2 β1 α1 α2 Sns - neurotransmission  Inactivation  reuptake back into presynaptic nerve terminals  extra-neuronal uptake  diffusion reuptake back into presynaptic nerve terminals Phe Tyr Tyrosine hydroxylase DOPA Dopamine M α2 Ca + ATP β2 D2 β2 β1 α1 α2 extra-neuronal uptake VMA VMA VMA RECEPTORS  Protein macromolecules on cell membranes, when activated by agonist (Ach, norepinephrine) lead to a response by an effector cell  Antagonist – attaches to the receptor (prevents access of agonist) but does not elicit a response by the effector cell Molecular pharmacology & effector response  Agonist binding to the receptor is linked to activation of 1 or more distinct guanine nucleotide-binding regulatory proteins G-proteins  intermediaries between receptors and activation of cellular effector mechanisms Molecular pharmacology & effector response  Ligand binding to  and dopaminergic receptors activates stimulatory G proteins (Gs)  stimulates adenylate cyclase to produce cyclic adenosine monophospate (AMP) (second messenger) Molecular pharmacology & effector response  Ligand binding to 2 receptors activates inhibitory G proteins (Gi), thus decreasing cytoplasmic cyclic AMP concentrations  Coupling of the 2 receptors with Gi is linked to K channel activation (hyperpolarization) and Ca-channel activation Molecular pharmacology & effector response  Ligand binding to 1 receptors (also certain muscarinic and serotogenic receptors) activates Gq proteins  stimulates phospholipase C to produce diacylglycerol and inositol triphosphate  increase in cytoplasmic Ca responses is responsible for biologic responses, including cellular contraction and secretion of hormones Molecular pharmacology & effector response  Endothelial control of vascular smooth muscle function depends on production of endothelium dependent vasodilatory factor, which is believed to be Nitric Oxide (NO) Molecular pharmacology & effector response  NO is a free radical that diffuses out of endothelial cells and activates guanylate cyclase  production of cyclic guanosine monophosphate (GMP)  decrease in cytoplasmic Ca concentrations which inhibits contraction in vascular smooth muscle  In addition to its role as a vasodilator, NO release by endothelium inhibits platelet aggregation and adhesion. Molecular pharmacology & effector response  Rapid inactivation of cyclic AMP and cyclic GMP is a result of their hydrolysis by phosphodiesterase enzymes  Neurotransmitters and drugs trigger a series of events (ligand-triggered signaling cascades) culminating in cell’s biologic response  Receptors – first link in a communication series RECEPTORS  Cholinergic receptors  Muscarinic – postganglionic nerve endings  Nicotinic – autonomic ganglia, neuromuscular junction  Ach – neurotransmitter at cholinergic receptors  Atropine – specific antagonist at muscarinic receptors Characteristics of the most important cholinoceptors in the peripheral nervous system Receptor M1 Location Nerve endings Mechanism Gq-coupled Major Functions IP3, DAG cascade M2 M3 Heart, some nerve endings Effector cells: smooth muscle, glands, endothelium ANS ganglia Gi- coupled Gq-coupled cAMP, activates K channels IP3, DAG cascade Nn Ion channel Depolarizes, evokes action potential Depolarizes, evokes action potential Nm Neuromuscular end plate Ion channel Adrenoceptors Receptor α1 Location Effector tissues: smooth muscle, glands Nerve endings, some smooth muscle G Protein Gq Second Messenger IP3, DAG cascade cAMP Major function Ca, causes contraction, secretion Transmitter release, causes contraction α2 Gi β1 Cardiac muscle, juxtaglomelular apparatus Smooth muscle, cardiac muscle Adipose cells Gs cAMP Increase heart rate, force, renin release Relax smooth muscle: β2 Gs cAMP glycogenolysis and heart rate and force Gs cAMP Lipolysis β3 D1 D2 Smooth muscle Nerve terminals Gs Gs cAMP Relax renal vascular smooth muscle Inhibits adenylyl cyclase in peri. nerve Classification of adrenergic Receptor Synaptic site Anatomic site Action receptors Peripheral vascular smooth muscle Postsynaptic Constriction  1 Renal vascular smoothed muscle Epicardial coronary arteries Myocardium Renal tubules 2 Presynaptic Postsynaptic Peripheral vasc. smooth muscle Central nervous system Endocardial coronary arteries Central nervous system Constriction Constriction Positive inotropy Antidiuresis Inhibit NE release Sedation Constriction Inhibition of insulin release Analgesia Natriuresis Diuresis Positive inotropy Positive chronotropy Dilation Renin release 1 Postsynaptic Myocardium Coronary arteries Kidneys 2 Presynaptic Postsynaptic Myocardium Peripheral vasc. smooth muscle Bronchial smooth muscle Renal vessel Accelerates NE release Dilation Positive inotropy Postivie chronotropy Dilation Dilation Autonomic Nerve Activity Effect of : Organ Eye Iris Radial Muscle(pupillary dilator) Sympathetic Action Receptor Parasympathetic Action Receptor Circular Muscle Ciliary muscle Heart Sinoatrial node Ectopic pacemakers Contractility Blood Vessels Skin, splanchnic vessels Skeletal muscle vessels Contracts … (Relaxes) Accelerates Accelerates Increases α1 … β β1, β2 β1, β2 β1, β2 … Contracts Con tracts Decelerates … Decreases(atria) … M3 M3 M2 … M3 Contracts Relaxes Contracts Platelet aggregation α1 β2 α1 α2 Endothelium … … … … Releases EDRF … … … … M3 RECEPTORS  Adrenergic receptors - , , dopaminergic   Receptors at Cardiovascular System  CORONARY ARTERIES. Postsynaptic 1 receptors predominate in the large epicardial conductance vessels (5% toal coronary artery resistance) while postsynaptic 2 receptors predominate in small coronary artery resistance vessels  Density of 2 receptors in coronary arteries increases in response to myocardial ischemia RECEPTORS  MYOCARDIUM. Postsynaptic 1 receptors exert a positive inotropic effect (phenylephrine increase myocardial contractility) & contribute to the development of cardiac dysrhythmias (1 antagonists such as prazosin & pentholamine exert dysrhythmic effect)  PERIPHERAL VESSELS. Presynaptic 2-vascular receptors mediate vasodilation; postsynaptic 1 & 2-vascular receptors mediate vasoconstriction RECEPTORS   Receptors in the Cardiovascular System  MYOCARDIUM. Postsynaptic 1 receptors & presynaptic 2 receptors play similar roles in the regulation of heart rate & myoicardial contractility  Increased circulating catecholamine levels associated w/ congestive heart failure result in down-regulation of 1 receptors w/ relative sparing of 2 & 1 receptors  PERIPHERAL VESSELS – predominantly 2 RECEPTORS  Actions attributed to postsynaptic 2 receptors:  Arterial & venous vasoconstriction  Platelet aggregation  Inhibition of insulin release  Inhibition of bowel motility  Inhibition of ADH release Effect of : Organ Bronchial Smooth Muscle Gastrointestinal Tract Smooth muscle Walls Sphincters Secretion Myenteric plexus Genitourinary Smooth Muscle Bladder wall Sphincter Uterus, pregnant Penis, seminal vesicles Sympathetic Action Relaxes Parasympathetic Action Contracts Receptor β2 Receptor M3 Relaxes Contracts … α2, α1 Contracts Relaxes Increases Activates M3 M3 M3 M1 Relaxes Contracts Relaxes Contracts Ejaculation Contracts β2 α1 β2 α α α Contracts Relaxes … Contracts Erection … M3 M3 … M3 M … Skin Pilomotor smooth muscle Sweat glands Thermoregulatory Apocrine (stress) Increases Increases M α … … … … Effect of : Organ Metabolic Functions Liver Liver Fat Cells Kidney Autonomic nerve endings Sympathetic Parasympathetic Sympathetic Action Gluconeogenesis Parasympathetic Action … … … … … Receptor Β2, α Β2, α β3 α2 β1 Receptor … … … … … Glycogenolysis Lipolysis inhibited by Renin Release … Decreases Ach release … α Decrease NE release … M1, M2 … Gluconeogenesis: B2 and A CO2 Biotin NAD NADH ATP Pyruvate Pyruvate carboxylase Glucose Glucose-6-phosphate G-6-P Phosphoglucoisomerase ADP OAA Malate dehydrogenase Malate F-6-P Fructose-1,6-biphosphate Malate NAD NADH Malate dehydrogenase F-1,6 BP Reverse glycolysis GTP GDP OAA PEP Phosphoenol Pyruvate carboxykinase + B3 - A2 Lipolysis RECEPTORS   Receptors in the Kidneys  1 receptors dominate in the renal vasculature (vasoconstriction regulates renal blood flow)  2 receptors predominate in the renal tubules, esp. the loop of Henle (which stimulate water & sodium excretion) RECEPTORS   Receptors in the Kidneys  1 receptors are more prominent & their activation results in renin release  Postsynaptic Dopamine1  Blood vessels (renal, mesentery, coronary) dilatation  Renal tubules – natriuresis, diuresis  Juxraglomerula cells – renin release RECEPTORS  Presynaptic Dopamine2  Postganglionic sympathetic nerves – inhibition of NE release  Postsynaptic Dopamine2  Renal & mesenteric vessels – constriction Adrenergic receptor numbers or sensitivity  Receptors are dynamically regulated by a variety of conditions (ambient concentration of catecholamine & drugs & genetic factors)  altered responses to catecholamine & ANS stimulation  Alteration in the number of density of receptors is referred to as up-regulation or down-regulation  Chronic treatment w/ clonidine or propranolol  up-regulation AUTONOMIC NERVOUS SYSTEM REFLEXES  Arterial baroreceptors located in the carotid sinus and aortic arch, react to alterations in stretch caused by changes in BP AUTONOMIC NERVOUS SYSTEM REFLEXES Volatile anesthetics (halothane>isoflurane) interfere with baroreceptor function; thus anesthetic-induced decreases in blood pressure may not evoke changes in HR AUTONOMIC NERVOUS SYSTEM REFLEXES  Venous baroreceptors located in the ® atrium and great veins  increased HR when ® atrium is stretched by increased filling pressure (Bainbridge reflex)  Slowing of heart rate during spinal anesthesia may reflect activation of baroreceptors as a result of decreased venous return Clinical ANS pharmacology Drugs that modify ANS activity can be classified by their site of action & the mechanism of action or pathology (antihypertensives) Ganglionic drugs  Agonists & antagonists  Not selective  affects SNS & PNS equally  have undesirable & un predictable side effects  Trimethaphan – ganglionic blockade by competition w/ Ach receptors  Rapid hydrolysis  continuous infusion  Tachyphylaxis & mydriasis Cholinomimetic (cholinergic) Drugs Direct Acting Indirect Acting Muscarinic Nicotinic Edrophonium Carbamates Choline esters Alkaloids Organophosphates cholinergic drugs  Anticholinesterases (neostigmine, pyridostigtmine, edrophonium) – inhibit activity of acetylcholinesterase, w/c normally destroys ACH by hydrolysis  Ach accumulation at muscarinic & nicotinic receptors  Simultaneous administration of anticholinergic drugs protects px against undesired muscarinic effects w/o preventing nicotinic effects of ACh anticholinergic drugs  Atropine, scopolamine, glycopyrrolate  Interfere in the muscarinic actions of Ach by competitive inhibition of cholinergic postganglionic nerves  Central anticholinergic syndrome – char. by symptoms from sedation to delirium, presumably reflecting inhibition of muscarinic receptors in the CNS  Tx - physostigmine anticholinergic drugs AM Drugs Atropine IV 15-30 mins 30-60 mins IM 2-4 hours 4-6 hours 6-8 hours Dose IV: 0.01 – 0.02 mg/kg IM: 0.4 – 0.6 mg/kg IV: 0.01 – 0.02 mg/kg IM: 0.4 – 0.6 mg/kg IV: 0.005 – 0.01 mg/kg IM: 0.2 – 0.3 mg/ kg in adults Scopolamine Glycopyrrolate 2-4 hours anticholinergic drugs Parameters Tachycardia Bronchodilation Sedation Antisialogogue CNS barrier Atropine +++ ++ + ++ ++ Scopolamine Glycopyrrolate + ++ + ++ +++ 0 +++ +++ ++ 0 Adrenomimetic Agonists Direct Acting Indirect Acting Alpha Agonists Beta Agonist Releasers Reuptake inhibitors Nonselective A1 A2 Nonselective B1 B2 Adrenergic drugs  Vasopressors (sympathomimetics) & inotropes (catecholamines)  Activate both  &  receptors  Changes in HR, cardiac contractility, conduction velocity of the cardiac impulses, cardiac rhythm, & systemic vascular resistance Hemodynamics  CO = HR x (inotropism : preload : afterload)  Preload  volume of venous return to the heart  Increase venous tone by a1 and a2  Decrease venous tone by B2, D1, D2  Afterload  Arterial resistance  Ohms law: blood flow directly related proportional to pressure and inversely proportional to resistance  Inotropism  Force and velocity of ventricular contraction  Characteristics of the ideal Positive Inotropic Agent  Enhances contractile strength  Lacks tolerance  Does not produce produce vasoconstriction  No Cardiac dysrhythmias  Does not affect Heart Rate  Controllability  Elevates perfusion pressure  Redistributes blood flow to vital organs  Direct acting  Compatible with other vasoactives  Effective orally or parentally Adrenergic drugs  Methoxamine – pure arterial vasoconstrictor that increases systemic vascular resistance & decreases cardiac output  Single IV dose can terminate paroxysmal atrial tachycardia reflexly through baroreceptor stimulation Adrenergic drugs  Phenylephrine – pure  agonist w/ greater venoconstriction than arterial constriction  venous return & BP  Excessive venoconstriction  baroreceptor-mediated bradycardia w/ systemic vascular resistance  CO & myocardial O2 requirements  Single dose 50-100mg IV – tx anesthesia-induced hypotension Adrenergic drugs  Norepinephrine – greater  than  effects  Venoconstriction tissue blood flow (renal)  myocardial O2 requirements  Continuous infusion via a central IV catheter to maintain systolic BP above 90mmHg requires invasive monitoring & attention to fluid management  During vasodilation & maldistribution of flow: improve renal & splanchnic blood flow by perfusion pressure provided the px has been volume resucitated Adrenergic drugs  Epinephrine -  effects predominate in renal & cutaneous vasculature to blood flow;  effects  blood flow to skeletal muscles  Cardiac dysrhythmias are a hazard of excess  stimulation  subcutaneous or submucosal dose administered during halothane anesthesia = 1g/kg Adrenergic drugs  Epinephrine  Treat asthma (0.3-0.5mg SQ)  Treat cardiac arrest or life-threatening allergic reactions (0.3-0.5mg IV)  Produce hemostasis (1:200,000 or 5g/ml SQ)  Prolong regional anesthesia (0.2mg for SAB; 1:200,000 conc. for epidural)  Provide bloodless arthroscopic field by large volume infusions Adrenergic drugs  Ephedrine – resemble effects of epinephrine; potency greatly decreased; duration of action 10x longer  Venoconstriction > arterial venous return & CO are improved   effects HR & further facilitate CO  Most commonly used vasopressor (5-10mg IV) Systemic perfusion out weighs vasopressors Adrenergic drugs  Dopamine – agonist at dopaminergic (0.52g/kg/min IV),  (2-10g), &  (>10g) receptors  Continuous IV infusion (2-10g/kg/min) for its inotropic & diuretic effects  Infusion rates >10g/kg/min  sufficient vasoconstriction to offset desirable dopaminergic &  receptor stimulation  Wide variability of individual responses Adrenergic drugs  Dopamine side effects  Tachycardia & cardiac dysrhythmias  Gangrene (extravasation)  pulmonary artery pressure (detract use in pxs w/ right- sided heart failure)  Insulin secretion inhibited  hyperglycemia Adrenergic drugs  Dobutamine – synthetic catecholamine derived from isoproterenol that acts directly on 1 receptors w/o norepinephrine release or stimulation of of dopamine receptors  Positive inotropic effects w/ minimal effects on HR & systemic vascular resistance  Most often administered (2-30g/kg/min IV) in pxs w/ poor myocardial contractility Adrenergic drugs  Dopamine side effects  automaticity of the SA node & conduction of impulses through the AV node & ventricles  caution in pxs w/ AF or other tachydysrhythmias  HR more than Epinephrine for a given  in CO Adrenergic drugs  Isoproterenol – nonspecific  agonist that lacks agonist effects  CO by virtue of HR as well as myocardial contractility; systemic vascular resistance contribute to afterload  Continuous IV infusions for tx of congestive heart failure w/ bradycardia, asthma, or pulmonary HPN  Chemical cardiac pacemaker during complete heart block Adrenergic drugs  Isoproterenol side effects  Myocardial ischemia in vulnerable pxs (myocardial O2 requirements due to tachycardia & myocardial contractility paralleled by coronary O2 delivery due to diastolic BP)  CO may be diverted in nonvital tissues such as skeletal muscles Adrenergic drugs  Tocolytics (Ritodrine) – predominant 2-agonist effects on the myometrium (relaxation) via IV to stop prematuer labor  Side effects: hyperglycemia, hypokalemia, tachycardia  Tachycardia may be sufficient enough to produce congestive heart failure manifesting as pulmonary edema in some parturients Nonadrenergic sympathomimetic drugs  Adenosine – endogenous by-product of ATP when administered IV has negative chronotrophic effects on the SA node as well as negative dromotrophic effects on the AV node  Prinicipal clinical use: termination of paroxysmal supraventricular tachycardia (6mg IV) Nonadrenergic sympathomimetic drugs  Digoxin – principally treat CHF & control supraventricular tachydysrhythmias such as AF  Therapeutic effect w/in 10min (0.25-1.0mg IV)  Digitalis toxicity: cardiac dysrhythmias, GI disturbances – inquired during preop evaluation enhanced by hyperkalemia or injection of Ca  Continuation preop esp when being administered for HR control  Antagonists  Produce orthostatic hypotension, tachycardia, miosis  Phentolamine – nonselective & competitive antagonist at 1 & 2 receptors  Administered 2-5mg IV until control of BP is achieved  Tachycardia reflects continued presynaptic release of norepinephrine owing to 2 receptor blockade  Antagonists  Prazosin – selective postsynaptic 1 antagonist that leaves intact the negativre feedback mechanism for norepinephrine release that is mediated by presunaptic 2 activity  Useful in preop preparation of pxs w/ pheochromocytoma  Antagonists  Side effects include: heart block, worsening of CHF, bronchospasm, vasoconstriction (of coronary arteries), & inhibition of insulin release  Excessive SNS activity (HPN, angina) may accompany abrupt withdrawal presumably reflecting prior up-regulation of  receptors caused by chronic suppression of agonist activity  Antagonists  1 selectivity (cardioselectivity) – greater safety in tx of pxs w/ obstructive pulmonary dse, DM, or peripheral vascular dse because 2 agonist effects (bronchodilation & vasodilation) are maintained  Antagonists  Propranolol – none selective 2 antagonist administered in single IV doses of 0.1-0.5mg (max of 2mg) to slow HR during anesthesia  Additive negative inotropic & chronotropic effects w/ inhaled or injected anesthesia are likely to occur  Antagonists  Timolol – topical preparation for the treatment of glaucoma  Sufficient systemic absorption to cause bradycardia & hypotension that are resistant to reversal w/ atropine  Antagonists  Esmolol – cardioselective 1 antagonist as sinlge IV bolus (0.5mg/kg) or continuous IV infusion (50200g/kg/min) to produce rapid & short-duration decreases in HR & BP  Unique feature is rapid hydrolysis by plasma esterases allowing precise control of drug effect during continuous IV infusion  Antagonists  Labetalol – mixed antagonist produces selective 1 & nonselective -antagonists effects  Single dose (0.5-0.15mg/kg IV over 2min)  Useful in controlling HPN & tachycardia  Worsening of CHF or bronchospasm w/ less magnitude than  antagonists Calcium entry blockers  Interact w/ cell membranes to interfere w/ movement of calcium into cells through ionspecific-channels (slow channels)  Heterogenous group of drugs  Most useful in tx of supraventricular tachydysrhythmias & coronary artery vasospasm Calcium entry blockers  Exhibit additive myocardial depressant effects w/ volatile anesthetics  Augment the effects of both depolarizing & nondepolarizing MR Calcium entry blockers  Verapamil – drug of choice for termination of supraventricular dysrhythmias & effective in slowing the HR in pxs w/ AF & atrial flutter  Dose dependent increase i the PR interval on ECG & a delay in conduction of cardiac impulses through the AV node  Caution when treating pxs w/ Wolff-Parkinson-White Syndrome – verapamil  conduction velocity in the accessory tract Calcium entry blockers  Nifedipine – more effective than nitroglycerin for tx of angina pectoris due to coronary artery vasospasm  Vasodilation & afterload reduction  compensatory tachycardia & CO  Useful during anesthesia when there is evidence of myocardial ischemia associated w/ HPN Calcium entry blockers  Diltiazem – effective artery vasodilator but poor peripheral vasodilator; may produce bradycardia  Nicardipine – vasodilation of coronary arterioles w/o altering the activity of the sinus node or conduction of cardiac impulses through the AV node  1 amp + D5W in soluset to complete 100 cc to run initially at 10 ugtts/min then titrate sympatholytics  Block the central SNS outflow or norepinephrine release from presynaptic neurons  antihypertensive effect  Decrease ensthetic requirements for inhaled & injected drugs sympatholytics  Clonidine – stimulates 2 receptors in the vasomotor center of the medulla oblongata   SNS activity &  PNS tone  Administered preop (5g/kg PO) attenuates SNS reflex responses & greatly  anesthetic requirements (40% or more) for volatile drugs or opioids  Subarachnoid or epidural: produces analgesia w/ sedation & bradycardia but no depression of ventilation sympatholytics  Clonidine side effects  Sedation, bradycardia, & dry mouth  Rebound HPN after abrupt discontinuation  Life-threatening hypertension after withdrawal may be treated w/ nitroprusside Angiotensin-converting inhibitor  Captopril, enlapril, lisinopril enzyme  Prevent the conversion of angiotensin I to angiotensin II  Effective for tx of CHF & essential HPN as well as renovascular & malignant HPN  Side effects are minor, w/ the principal cardiovascular effect being systemic vascular resistance vasodilators  Decrease blood flow pressure by dose-related direct effects on vascular smooth muscle independent of  or  receptors  May evoke baroreceptor-mediated increases in HR combination w/  antagonist may be necessary to offset this reflex tachycardia (maintain HR <100beats/min) vasodilators  Hydralazine – (5-10mg IV q10-20min) to control periop HPN  Nitroprusside – continuous infusion (0.25- 0.5g/kg/min IV) using an infusion pump w/ continuous BP monitoring  Dose increased slowly as needed to produce controlled HPN  Acute HPN responses can be treated w/ single IV doses of 50-100g vasodilators  Nitroprusside hypotensive effects reflects direct relaxation of arterial & venous smooth muscle  preload & afterload potentiated by volatile anesthetics & blood loss  Side effect: ferrous iron of nitroprusside reacts w/ sulfhydryl groups in RBC releases cyanide reduced to thiocyanate in the liver high doses (>10g/kg/min IV) cyanide toxicity  Diagnosis: tachyphylaxis, venous oxygen tension, & metabolic acidosis  d/c infusion immediately vasodilators  Tx of cyanide toxicity: Na thiosulfate (150mg/kg IV in 50ml water) over 15min to speed the conversion of cyanide to thiocyanate vasodilators  Nitroglycerin – continuous infusion (0.25- 3.0g/kg/min IV) to treat myocardial ischemia  Predominant action is on venules  venous capacitance &  venous return  No cyanide toxicity  control HPN associated w/ pregnancy Thank you & good day!!!