Autonomic Nervous System 3 and 4

Pharmacology Maria luisa d. delacruz, md SYNTHESIS OF NEUROTRANSMITTER

Enzymatic Termination of Neurotransmitter Action 1. Monoamine Oxidase (MAO) Metabolizes NE within the nerve terminal 2. Catechol-O-Methyltransferase (COMT) Metabolizes endogenous circulating and administered catecholamines particularly in the liver

METABOLISM OF CATECHOLAMINES

Note: The sympathomimetics arise from the amino acid tyrosine and are made at the terminal junction of the neuron. Tyrosine is converted to DOPA with the help of tyrosine hydroxylase. DOPA is converted to Dopamine using the enzyme DOPA decarboxylase. Dopamine is hydrolysed and is converted to Norepinephrine via Dopamine Betahydroxylase. When norepinephrine is methylated, it is converted to epinephrine. Norepinephrine is the primary neurotransmitter in postganglionic sympathetic fibers In the adrenal medulla, catecholamines are stored in the chromaffin granules 80% Epinephrine 10-20% Norepinephrine Glucocorticoid secreted by the adrenal cortex is a major factor that controls the rate of synthesis of Epinephrine Stress glucocorticoid secretion synthesis of Phenylethanolamine-Nmethyltransferase increase synthesis of epinephrine Note: Noradrenergic receptors may be found presynaptically (2 and 2) or postsynaptically (1, 1, 2)

ADRENERGIC RECEPTORS

TERMINATION OF NEUROTRANSMITTER ACTION

Reuptake of approximately 87% of released NE via NET 5% by ENT 8% by diffusion VMAT-2 has a higher affinity for NE than MAO Over 70% of recaptured NE is sequestered into storage vesicles

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Major Classification of Adrenergic Receptors Alpha Alpha 1 Alpha Alpha Alpha Alpha 2 Alpha

1A 1B 1D 2A

Alpha 2B Alpha 2C Alpha 3 Beta Beta 1 Beta 2 Beta 3 Dopaminergic (D1-D5)

PRESYNAPTIC ADRENERGIC RECEPTORS

Receptor 2 2 D2 Site CNS CNS CNS G protein Gi Gs Gi Second messenger system cAMP cAMP cAMP Action Inhibit NE release Stimulate NE release Stimulate Dopamine release

POSTSYNAPTIC ADRENERGIC RECEPTORS

Receptor 1 2 1 2 3 D G protein Gq Gi Gs Gs Gs Gi Enzyme Phospholipase C Adenylyl cyclase Adenylyl cyclase Adenylyl cyclase Adenylyl cyclase Adenylyl cyclase Second messenger IP3 and Ca2+ Cyclic AMP Cyclic AMP Cyclic AMP Cyclic AMP Cyclic AMP

ADRENERGIC AGONISTS
Neurotransmitters in the Sympathetic Nervous System Norepinephrine (Noradrenaline) Main neurotransmitter in postganglionic sympathetic fiber Epinephrine (Adrenaline) Main catecholamine secreted by the adrenal medulla Dopamine Main neurotransmitter in the nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular systems Structure Activity Relationship Phenylethylamine

Non-catecholamines Benzene ring Ethylamine side chain Absence of both OH group in carbon 3 and 4 of the benzene ring Orally active Resistant to COMT Longer duration of action Increase CNS distribution Note: The activity of the different sympathomimetics would vary depending on what is attached to the ethylamine side chain and in the benzene ring. The presence of hydroxyl group in the third and fourth carbon of the benzene ring identifies it as a catecholamine

CLASSIFICATION OF ADRENERGIC AGONISTS

A. Based on Structure 1. Catecholamines Norepinephrine Epinephrine Dopamine Isoproterenol Dobutamine 2. Non-Catecholamines Ephedrine Phenylephrine Phenylpropanolamine Amphetamine Tyramine salbutamol B. Based on Mode of Action 1. Direct-acting Norepinephrine Epinephrine Isoproterenol Phenylephrine Dobutamine Terbutaline

Catecholamines (O-Dihydroxybenzene) Benzene ring Ethylamine side chain, terminal amino group -OH group in positions 3 and 4

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2. Indirect acting Drugs that Displace NE from storage vesicles Enhances neurotransmission Amphetamine Tyramine

Drugs that Block NE Uptake Cocaine

Entacapone 3. Mixed acting Dopamine Ephedrine Clonidine C. Based on Receptor Activated 1. Nonselective and receptor agonists Norepinephrine Epinephrine Dopamine Ephedrine Pseudoephedrine Phenylpropanolamine 2. Nonselective receptor agonist Isoproterenol 3. Selective 1 agonists Nasal/conjunctival decongestants Methoxamine Phenylephrine Imidazoline derivatives: Naphazoline Oxymetazoline Tetrahydrozoline Xylometazoline 4. Selective 2 receptor agonist Clonidine Methyldopa Dexmedetomidine Guanfacine Guanabenz 5. Selective 1 agonists Dobutamine Prenalterol 6. Selective 2 receptor agonist Primarily used in bronchial asthma Terbutaline Salbutamol / Albuterol Metaproterenol Ritodrine Salmeterol Fomoterol 7. Dopaminergic Agonists Dopamine Fenoldopam bromocriptine

Drug/s that Oxidase Pargyline

Inhibit

Monoamine

Note: 1 agonists interacts with 1 receptors (Gq) and activates PLC to react with PIP2 and then it will be degraded to DAG and IP3 (both increasing calcium) and further elicits cellular response

Drug/s that Inhibit COMT

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REC

Signaling

Locations Vascular smooth mucle GUT smooth muscle Liver Radial muscles Salivary gland, sweat gland

IP3 and DAG Ca2+

Effects Contraction Contraction Glycogenolysis Gluconeogenesis Mydriasis Increase secretion

Rank order of potency for 1 receptors: Epinephrine Norepinephrine >> Isoproterenol Note: Adenylyl cyclase is inhibited by 2 agonist while 1 and 2 agonist induced it, therefore converting ATP to cAMP and elicits further cellular response

Bladder base, urethral sphincter, prostate urinary retention

REC

Signaling cAMP Ca2+ channels K+ channels

Locations Presynaptic nerve terminals Platelets Adipocytes Pancreatic cells Vascular smooth muscle

Effects Inhibition of NE and ACh release Aggregation Inhibition of lipolysis Decreased insulin secretion Contraction

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Prejunctional Action: 2 receptor Inhibition of Ach release in the GIT Relaxation of GIT smooth muscles Increase Na+ and water absorption Ciliary body decrease aqueous humour production REC 1 Signaling cAMP Ca2+ Locations Heart Juxtaglomerular cells Effects heart rate heart force AV conduction velocity renin release

Rank of order of potency at 1 receptor Isoproterenol > Epinephrine Norepineprine

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MECHANISM OF ACTION
1 and 2 activation

Interaction with Gs protein

Activation of adenylyl cyclase

Incdrease cyclic AMP

Intracellular Ca2+

Activation of protein kinase

Phosphorylation and inactivation of Myosin Light chain kinase Intracellular Ca2+

REC

Signaling

Locations Smooth muscle (vascular, bronchial, GI and genitourinary) Skeletal muscle

cAMP

Pancreatic cells Pancreatic cells Liver Uterine muscle

Effects Relaxation glycogenolysis K+ uptake insulin secretion glucagon secretion glycogenolysis gluconeogenesis Uterine relaxation (tocolysis) >>

Rank order of potency at 2 receptor Isoproterenol > Epinephrine Norepinephrine Other 2 receptor mediated action in the Respiratory Tract

Inhibits release of chemical mediators from mast cells Enhance mucociliary action Decrease bronchial secretions

MECHANISM OF ACTION
Dopamine1 receptor activation Dopamine2 receptor activation

Activation of adenylyl cyclase

Inhibition of adenylyl cyclase

Increase calcium influx

Decrease calcium influx open K+ channels

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AGONIST SELECTIVITY AT ADRENOCEPTORS

Norepinephrine Epinephrine Ephedrine Isoproterenol Phenylephrine Clonidine Salbutamol Dobutamine 1 +++ +++ +++ ++ + 2 +++ 1 +++ +++ +++ +++ + +++ 2 + +++ +++ +++ +++ +

Drug Epinephrine Norepinephrine Dopamine Dobutamine Isoproterenol Drug Epinephrine Norepinephrine Dobutamine Dopamine Isoproterenol

Receptor Selevtivity 1 = 2 > 1* = 2* 1 = 1 > 2 = 2 1= 2 > 1* 1 > 2 > 1 1 = 2

Action and Effects Low doses produce cardiac stimulation and vasodilation Vasoconstriction at high doses At high plasma concentrations, = selectiviry Reflex bradycardia mask direct stimulatory effects on sinoatrial node Net effect is cardiac stimulation with modest vasodilation At low doses, stimulates the heart and decreases systemic vascular resistance At high doses, produce vasoconstriction: dopamine binds to -receptors Also bins to D1 receptors in kidney, producing vasodilation Net effect is cardiac stimulation and vasodilation with little change in pressure

EFFECT ON BLOOD PRESSURE

Determinants of blood pressure: Cardiac output Total peripheral resistance

EFFECTS ON BP

Note: Norephinephrine gives a tremendous rise in BP due to the 1 and 1 effect. On the contrary, it lowers the heart rate, due to the baroreflex

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EPINEPHRINE REVERSAL
With administration of 1 antagonist Removal of the effect at the blood pressure There would still be a rise in BP Unmasking of 2 effects Decrease in BP is more profound due to unmasking Other Pharmacologic Actions Metabolic Actions: 2 receptor mediated Increase rate of glycogenolysis and gluconeogenesis in the liver and muscle Enhance uptake of K+ into the cells decreasing extracellular K+ levels 3 receptor mediated Increase lipolysis

Respiratory stimulation Appetite suppression Actions on the Central Nervous System Mild alerting to stimulation Improved attention Mood elevation Insomnia, euphoria Apprehension, restlessness Headache, tremors Psychotic behavior Aqueous humour secretion 2 inhibits secretion decrease IOP increase secretion increase IOP

EPINEPHRINE
Unstable in alkaline solution and in the presence of air and light Concentration for injection (subcutaneous and intravenous) is 1:1000 or 1:10,000 Concentration for inhalation is 1:100 Inadvertent injection of 1:100 solution can be fatal Pharmacokinetics: Not suitable for oral administration Administered topically, by inhalation and parenterally (subcutaneous, intravenous) Absorption from SC is slow Very short duration of action Not distributed to the brain

ACTIVATION OF 3 RECEPTORS
Fat cells Lipolysis

Increase activity of lipoprotein lipase Breakdown of triglycerides Free fatty acids Glycerol

NOREPINEPHRINE
Ineffective when given orally Poor absorption from subcutaneous sites Short duration of action Used in ICU for patients in shock or hypotension Necrosis and sloughing at site of IV injection due to extravasation

PHARMACOLOGIC ACTIONS
Actions on the Central Nervous System Mediated by both and receptor
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ISOPROTERENOL
Given by intravenous infusion and by inhalation Metabolized primarily by COMT Poor substrate for MAO Longer duration of action than Epinephrine May produce locked-lung syndrome

PHENYLEPHRINE
Pure 1 agonist Non-catecholamine Directly-acting, synthetic Commonly used as a Mydriatic, and nasal and conjunctival decongestant Poor oral bioavailability

DOPAMINE
Immediate metabolic precursor of Norepinephrine and Epinephrine Central neurotransmitter Ineffective when administered orally Inactivated by MAO and COMT Exogenous Dopamine has no central effects Agonist at a1, b1, and dopaminergic receptors Activation of specific adrenergic receptors is dose dependent Also enhance NE release from adrenergic neuron At low concentrations activate vascular D1 receptors in renal, mesenteric and coronary beds vasodilatation At high concentration activates 1 receptor positive Inotropic effect At higher doses activates vascular 1 vasoconstriction

EPHEDRINE
Has been used in China for almost 200 years Introduced to western medicine in 1924 Herbal preparation Ma-huang contains ephedrine-like alkaloids An ingredient in dietary supplements that promote appetite suppression First orally active sympathomimetic drug Poor substrate for COMT and MAO CNS stimulant An ingredient of anti-asthma preparation Weak base; renal excretion is enhanced by urine acidification

OXYMETAZOLINE
Prototype for Imidazoline Direct-acting 1 agonist Used as topical mucosal decongestant Larger doses produce hypotension due to central Clonidine-like effects Selectivity is not absolute for 1, it may activate 2 and cause the inhibition of release of NE that will cause the hypotension

AMPHETAMINE
Not used as a drug Important primarily because of misuse and abuse as a CNS stimulant Impairs memory Similar pharmacokinetic profile as Ephedrine Marked CNS stimulant effects Marked appetite suppressant effects

Given only intravenously During IV infusion, monitor myocardial function, perfusion of vital organs such as the brain and urine output Short duration of action

METAMPHETAMINE
N-methyl amphetamine SHABU, poor mans cocaine Compared with Amphetamine, has higher central than peripheral effects CNS actions attributed to release of Dopamine and Norepinephrine

DOBUTAMINE
Synthetic catecholamine Direct acting Relative selectivity for b1 receptors Positive inotropic effect Positive chronotropic effect More prominent inotropic effects Less effect on heart rate Half-life is 3 minutes Given intravenously by continuous infusion Steady state is attained within 10 minutes after start of infusion Can only be used up to 72 hours Tolerance to its effects occur with prolonged use Worsen long term outcome with chronic use in patients with heart failure
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METHYLPHENIDATE
An amphetamine variant Evidences show that it is a more potent Dopamine transport inhibitor than Cocaine Proven efficacy in children with attention deficit hyperactivity disorder (ADHD) One of most prescribed drugs for children

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PHENYLPROPANOLAMINE
Non selective adrenergic receptor agonist Can induce release of NE from adrenergic nerve ending Used as a nasal decongestant and appetite suppressant Common component of over-the counter Cold preparations and weight reducing pills A five year study by scientists at Yale University, reported that it was associated with a small but significant increase in risk of stroke among young women In the New England Journal of Medicine women aged 19-49 who took the drug, as much as 15 times are more likely to suffer hemorrhagic stroke

Concomitant administration with MAO Inhibitors will greatly intensify its effect Note: Tyramine should not be taken by patients under medication with MAO inhibitors due to its sympathomimetic effect. Patients can go to hypertensive crisis due to markedly increase in the blood pressure

CHARACTERISTICS OF ADRENERGIC RECEPTORS

Selectivity Preferential affinity for a specific receptor type/subtype Relative rather than absolute Higher drug concentration decreases selectivity Receptor regulation Desensitization Decrease responsiveness with continuous exposure to the agonist Tolerance, tachyphylaxis, refractoriness

CLONIDINE
Presynaptic 2 agonist Postsynaptic effects in blood vessels similar to a1 agonist Well absorbed after oral administration, almost 100% bioavilability Maximal hypotensive effect in 1-3 hours Mean half-life 12 hours

MECHANISMS FOR DESENSITIZATION OF RECEPTORS

Sequestration of receptors Down regulation Decrease in the number of receptors Receptor phosphorylation resulting to inability of the receptor to couple with Gprotein

TERBUTALINE
With other selective 2 agonist, useful in: Bronchial asthma Premature labor Poor substrate for COMT

COCAINE
Binds to the monoamine reuptake transporter and prolongs CNS and peripheral action of monoamines Readily enter the CNS and produce CNS stimulation Used as a local anesthetic for surgical procedures in the eye, ear, nose and throat Heavily abused drug Smoked, snorted in the nose and injected for rapid onset of effect Produce, euphoria, hallucinations, delusions and paranoia Causes of death from over dosage: Convulsion, coma Fatal cardiac arrhythmias Myocardial infarction Hyperthermia Respiratory depression

CHARACTERISTICS OF ADRENERGIC RECEPTORS

Receptor Regulation Supersensitivity Enhanced responsiveness May produce exaggerated response i.e. hypertensive crisis

MECHANISMS FOR SUPERSENSITIZATION OF RECEPTORS

Pharmacologic sympathectomy Guanethidine Prevents release of neurotransmitter from the sympathetic nerve ending Reserpine Inhibits monoamine transport into storage vesicles and leads to depletion of catecholamines from sympathetic nerve endings and in the brain Up regulation Increase in the number of receptors

TYRAMINE
Normal by-product of tyrosine metabolism in the body Not clinically useful Also found in high concentrations in fermented food (cheese, beer, red wine, etc.) Cause release of stored catecholamines Enters the nerve terminal and displaces stored NE Direct actions are similar to Norepinephrine Readily metabolized by MAO
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ADVERSE EFFECTS
Due to 2 receptors: Dry mouth, sedation Depression Marked bradycardia Sexual dysfunction

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Rebound hypertension upon withdrawal Due to 1 receptors: Hypertension Hypertensive crisis, stroke Rebound congestion Urinary retention Due to 1 receptors: Palpitation Cardiac arrhythmias Premature ventricular contractions Ventricular arrhythmias Angina Myocardial infarction Due to 2 receptors: Skeletal muscle tremor Tachycardia Hypokalemia Pulmonary edema Near death or death with prolonged use Due to and receptors in the CNS: Depression/stimulation Psychotic symptoms Euphoria Restlessness, apprehension Convulsion

E. Others Hypersensitvity reaction - Epinephrine Anaphylactic shock By physiologic antagonism Weight reduction Amphetamine and its variants Narcolepsy Amphetamine Dextroamphetamine Attention Deficit Hyperactivity Disorder Methylphenidate Pemoline

ADRENERGIC ANTAGONISTS

Selective a1 receptor antagonists Selective a2 receptor antagonists receptor antagonists Non b selective antagonists 1 selective antagonists

receptor antagonists Non Selective Receptor Antagonists

ALPHA RECEPTOR ANTAGONISTS

Adrenergic Antagonists 1. Non Selective Receptor Antagonist Phenoxybenzamine Phentolamine Tolazoline Ergot derivatives Ergotamine Dihydroergotamine Ergonovine Methysergide 2. Selective 1 Receptor Antagonist Prazosin Terazosin Doxazosin Tamsulosin Alfuzosin 3. Selective 2 Receptor Antagonist Yohimbine

CLINICAL USES OF ADRENERGIC AGONISTS

A. Due to 1 receptor activity Vasoconstrictor Adjunct to Local Anesthetics Epinephrine Local Hemostatic - Epinephrine Topical application in epistaxis, dental extractions, ophthalmic surgery, etc. Decongestant (nasal and conjunctival) Shock Norepinephrine, Dopamine Ophthalmologic Mydriatic Paroxysmal atrial tachycardia BP reflex vagal discharge B. Due to 2 receptor activity Antihypertensive - Clonidine Decrease central sympathetic outflow Inhibition of NE release Clonidine Diarrhea in diabetic patients with autonomic neuropathy Decrease intraocular pressure in patients with glaucoma C. Due to 1 receptor activity Congestive heart failure (+) inotropic effect Complete heart block Cardiac arrest Redistributes blood flow during CPR to the coronary beds and the brain D. Due to 2 receptor activity Bronchodilator Bronchial asthma COPD Tocolytic Delay premature labor Prevent abortion
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PRAZOSIN
Selective 1 receptor antagonist Affinity for a1 receptors is 1000x greater than affinity for 2 receptors Affects both arterioles and vein Pharmacologic Actions 1. Cardiovascular System Vasodilatation Decrease afterload Decrease preload Decrease blood pressure Dilatation of arterial smooth muscles Decrease total peripheral resistance Dilatation of venular smooth muscles Decrease venous return

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Effects on BP

2. Metabolic effects Decrease LDL cholesterol and triglycerides Increase HDL Decrease hepatic glucose output 3. Genitourinary tract Decreases tone of smooth muscles in the prostate and bladder neck Inhibit ejaculation Pharmacokinetics: Well absorbed after oral administration 50-70% bioavailability Peak plasma conc. attained in 1-3 hours Highly bound to plasma proteins (primarily to a1-acid glycoprotein) 5% as free drug Extensively metabolized in the liver Plasma half-life is approx. 2-3 hours but duration of action is 7-10 hours Small fraction of the drug is excreted unchanged in the kidneys Adverse Effects: First dose phenomenon Marked postural hypotension and fainting 30-90 minutes after the first dose Associated with syncopal attacks Measures: Start with the least effective doses Administer drug at bedtime

ERGOT ALKALOIDS
Were the first adrenergic blocking agents to be discovered Ergot is a fungus which grows on rye Both Ergotamine and Dihydroergotamine are structural derivatives of a compound isolated from ergot which have potent competitive alpha antagonist effects. General Therapeutic Uses (1 antagonists) 1. 2. 3. 4. Hypertension Pheochromocytoma Congestive heart failure Peripheral vasospastic disease e.g. Raynauds disease 5. Benign Prostatic Hypertrophy

1 ADRENERGIC ANTAGONISTS ADVERSE EFFECTS

1. Orthostatic hypotension 2. Reflex cardiac stimulation tachycardia, cardiac arrhythmias angina, myocardial infarction 3. Nasal congestion 4. Sexual dysfunction

TERAZOSIN
Structural analog of Prazosin Higher oral bioavalability (>90%) Longer plasma half-life (approx. 12 hours) Induces apoptosis in prostate smooth muscles Limits cell proliferation in the prostate Not related to a1 antagonism

YOHIMBINE
Competitive a2 antagonist An indolealkylamine alkaloid from bark of Pausinystalia yohimbe and in Rauwolfia root Limited use May improve sexual performance Pharmacologic Action: Increase Blood pressure Enhanced release of NE Increase central sympathetic outflow Activation of b1 receptors in the heart Activation of a1 receptors in the blood vessels

PHENOXYBENZAMINE
Binds covalently to alpha adrenergic receptor Non-competitive, irreversible blocker Slight selectivity for a1 receptor than for a2 receptor Mainly used in the control of high blood pressure prior to surgery for Pheochromocytoma

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BETA RECEPTOR ANTAGONISTS (BETA BLOCKERS)

Adrenergic Antagonists 1. Non-subtype Selective Receptor Antagonist (First Generation) Propranolol (prototype) Nadolol Timolol Pindolol 2. Selective 1 Receptor Antagonist (Second Generation) Cardioselective Beta Blocker Atenolol Acebutolol Metoprolol 3. Non-subtype Selective Receptor Antagonist (Third Generation) with additional CVS Actions Labetalol Carvedilol Carteolol Bucindolol 4. Selective 1 Receptor Antagonist (Third Generation) with additional CVS Actions Betaxolol Celiprolol Nebivolol PHARMACOLOGIC ACTIONS (BETA BLOCKERS) 1. Cardiovascular system Decrease heart rate (-) chronotropic effect Decrease myocardial contractility (-) inotropic effect Attenuate the expected rise in heart rate during exercise or stress Negative dromotropic effect Slows conduction in the atria and A-V node Decrease the spontaneous rate of depolarization of ectopic pacemakers Increase refractory period in the AV node Decrease blood pressure due to: Decrease cardiac output (1 in the heart) Decrease renin secretion (1 in the JGA) - BB without ISA Decrease central sympathetic outflow (presynaptic 2 receptor)

2.

3.

4. 5. 6.

Does not lower blood pressure in normal individuals Reduce blood pressure in hypertensive patients Chronic prophylactic therapy with a beta blocker in patients who have had a myocardial infarct appears to help prevent the recurrence of a second fatal myocardial infarct Net effect in patients with coronary artery disease is to decrease oxygen demand Improves exercise tolerance in patients with angina Long term use decrease total peripheral resistance Respiratory system Negligible effects on pulmonary function in normal persons Bronchoconstriction in predispose patients Cardioselective beta blockers less likely to cause respiratory problems in patients with bronchospastic diseases Precaution still to be observed Metabolic Nonselective beta blockers Mild impairment of glucose tolerance Inhibition of beta-receptor dependent glucose-mobilization from the liver. Mild elevation of plasma triglyceride and VLDL (less significant with drugs having ISA) Decrease intraocular pressure Decrease aqueous humor production by the ciliary body Block catecholamine induced tremor Block catecholamine-induced inhibition of mast cell degranulation

PHARMACOLOGIC CHARACTERISTICS OF BLOCKERS

Selectivity Relative rather than absolute Non-selective Equal affinity for both b1 and b2 receptors Cardioselective Selective 1 Greater affinity for 1 At therapeutic doses only block b1 At higher doses may become nonselective Lipid solubility Increases the ability to enter the CNS Affects presynaptic receptors to block release of Norepinephrine Decrease central sympathetic outflow e.g. Propanolol, Pindolol Intrinsic sympathetic activity blockers can activate receptors in the absence of catecholamines Partial agonist activity Intrinsic activity are less than that of the full agonists

PRESYNAPTIC ADRENERGIC RECEPTORS

Receptor 2 2 D2 Site CNS CNS CNS G protein Gi Gs Gi Second messenger system cAMP cAMP cAMP Action Inhibit NE release Stimulate NE release Stimulate Dopamine release

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Prevent bradycardia and decrease in force of myocardial contraction in the resting heart e.g. Pindolol, Acebutolol Membrane stabilizing action Local anesthetic action Inhibits Phase 0 of action potential resulting in:

Impaired spontaneous firing of SA and AV node (bradycardia) Decreased AV node conduction (1,2,3 degree heart block) Decreased ventricular conduction (prolonged QRS) e.g. Propranolol, Acebutolol, Carvedilol

COMPARATIVE PROPERTIES OF BETA BLOCKERS

Drug Propranolol Pindolol Acebutolol Metoprolol Carteolol Labetalol Betaxolol MSA ++ + + + 0 + + ISA 0 +++ + 0 ++ + 0 Lipid solubility High Low Low Mod Low Low Mod Oral bioavailability 30% ~100% 20-60% 40-50% 85% ~33% ~80% Half-time (hours) 3-5 3-4 3-4 3-7 6 3-4 15 Protein binding 90 40 26 12 23-30 ~50 50

Dilatation of blood vessels due to: 2 agonist effects 1 antagonism

Ca+ entry blockade Nitric oxide production

ADDITIONAL CVS ACTION OF THIRD GENERATION BETA BLOCKERS

Drug Carteolol Carvedilol Labetalol Betaxolol NO production + 2 agonist effect + 1 receptor antagonist + + Ca+ entry blockade + + Antioxidant action +

PROPRANOLOL
Pharmacokinetics: Highly lipophilic Almost completely absorbed after oral administration Undergoes extensive first pass metabolism in the liver 25% bioavailability from oral route Metabolized to 4-hydroxypropranolol, an active metabolite 90% of the drug in the circulation is bound to plasma proteins Plasma half-life 3-5 hours Well distributed As antihypertensive agent, the full response on the blood pressure is not observed until after several weeks of administration

10% of the unchanged drug is recovered in the urine

LABETALOL
Competitive antagonist to alpha and beta receptors More (5-10x) receptor antagonism than 1 receptor antagonism Pharmacokinetics: Completely absorbed from the GIT Presence of food in the stomach will increase absorption 20-40% bioavailability Extensive metabolism in the liver by oxidation and glucuronidation Elimination half-life 8 hours Small fraction of the drug is excreted unchanged in the kidneys

METOPROLOL
Equipotent to Propranolol in affinity to the b1 receptor 50-100x less affinity to b2 receptor Pharmacokinetics Almost completely absorbed after oral administration Only 40% bioavailability due to first pass hepatic metabolism Primarily metabolized by CYP2D6 Half-life is 3-4 hours
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BETAXOLOL
Pharmacokinetics: Completely absorbed from the GIT Presence of food or alcohol in the stomach does not affect absorption 80% bioavailability Approx. 50% bound to plasma proteins Elimination half-life 15 hours 15% of the drug is excreted unchanged in the kidneys

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 ADRENERGIC ANTAGONISTS THERAPEUTIC USES

1. Coronary artery disease Reduce myocardial workload and oxygen demand Angina Reduce the frequency of angina attacks Acute myocardial infarction Decrease mortality in about 25% of patients Prevents recurrent MI in those with an initial attack 2. Hypertension (mild to moderate) Cardiac Output renin secretion central sympathetic outflow 3. Congestive Heart Failure Recent evidence that beta blockers decrease mortality in patients with CHF Caution is necessary in initiating therapy due to risk of worsening CHF blockers currently approved for treatment of CHF: Metoprolol Carvedilol Bisoprolol 4. Anti-arrhythmic Drugs with Membrane Stabilizing Action e.g. Propranolol, Metoprolol, Acebutolol 5. Glaucoma Decrease the rate of synthesis of aqueous humour e.g. Timolol 6. Reduce signs and symptoms of hyperthyroidism Blocks enhanced responsiveness to catecholamines Inhibit peripheral conversion of T4 to T3 7. Migraine prophylaxis 8. Essential tremor 9. Control signs and symptoms of alcohol withdrawal 10. Acute panic and anxiety symptoms

Block counter regulatory effects of catecholamines secreted during hypoglycemia 1 selective blockers improve serum lipid profile and are less likely to interfere with hypoglycemia-induced counterregulatory mechanisms

ADRENERGIC NEURON BLOCKERS

1. False Transmitter Methyldopa 2. Prevents storage of Norepinephrine in granules Reserpine 3. Prevents release of Norepinephrine from vesicles Guanethidine Bretylium

RESERPINE
An alkaloid obtained from Rauwolfia plant Slow onset but long duration of action Also cause depletion of other biogenic amines (serotonin, dopamine) Mainly used as Antihypertensive Mechanism of action: Very low concentration, blocks the transport of norepinephrine and other amines into synaptic vesicles, by blocking the vesicular monoamine transporter (VMAT2) Norepinephrine accumulates in the cytoplasm, where it is degraded by MAO Adverse Effects: Central nervous system Mental depression Lassitude, sedation, nightmares Parkinsonian syndrome Gastrointestinal Abdominal cramps Increase gastric acid secretion Mild diarrhea

ADRENERGIC ANTAGONISTS ADVERSE EFFECTS

1. Cardiovascular system Bradyarrhythmias (may be life threatening) Abrupt withdrawal after chronic therapy can produce rebound hypertension or angina May exacerbate or cause heart failure 2. Central nervous system Lethargy, fatigue, nightmares Insomnia and depression 3. Respiratory system Negligible effects in normal persons Life threatening bronchoconstriction in patients with bronchospastic diseases 4. Metabolic (Non-selective blockers) Dyslipidemia Blunts perception of hypoglycemic symptoms (tachycardia, tremors, nervousness)
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GUANETHIDINE
Mechanism of action: Inhibit the release of norepinephrine from sympathetic nerve terminals Causes a gradual and long-lasting depletion of norepinephrine in sympathetic nerve endings Reduce or abolish the response of tissues to sympathetic nerve stimulation Large doses lead to accumulation in the nerve terminal that may cause structural damage to noradrenergic neuron No longer used clinically, now that better antihypertensive drugs are available Associated with severe adverse effects due to loss of sympathetic reflexes Adverse Reactions: Orthostatic hypotension Bradycardia Nasal congestion

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Failure of ejaculation Diarrhea PSNS activity on GIT Denervation supersensitivity Marked BP response to sympathomimetics may lead to hypertensive crisis END

Read at your own risk. This now marks the end of the ANS module. Remember the concept by heart because the entire module will help you a lot in understanding future concepts in Pharmacology. Some diagrams/pictures are not explained due to the fact that they are already discussed to us in first year. Good luck and God bless 2016!

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