AUTONOMICS MA. JANETTH B. SERRANO, M.D. DPBA

Site and Mode of Action: Site and Mode of Action: 1. Direct Acting –Epinephrine- Dobutamine –Phenylephrine- Norepinephrine –Isoproterenol- Clonidine 2. Indirect Acting –Tyramine, Amphetamine, Cocaine 3. Mixed Acting Agonists –Dopamine- Ephedrine –Amphetamine- Phenylpropanolamine –Metaraminol SYMPATHETIC DRUGS

Sympathetic Agonists SYMPATHOMIMETICS

α1α1α1α1 α2α2α2α2 α and β β1β1β1β1 β2β2β2β2 α 1 and α 2 β 1 and β 2 Sympathetic Agonists (Sympathomimetics) EPINEPHRINE NOREPINEPHRINE DOPAMINE IBOPAMINE AMPHETAMINE METHAMPHETAMINE EPHEDRINE PSEUDOEPHEDRINE DOBUTAMINE ISOPROTERENOL

α1α1α1α1 α2α2α2α2 α and β β1β1β1β1 β2β2β2β2 α 1 and α 2 β 1 and β 2 Sympathetic Agonists (Sympathomimetics) PHENYLEPHRINE METHOXAMINE MEPHENTERMINE METARAMINOL MITODRINE

α1α1α1α1 α2α2α2α2 α and β β1β1β1β1 β2β2β2β2 α 1 and α 2 β 1 and β 2 Sympathetic Agonists (Sympathomimetics) METHYLDOPA CLONIDINE GUANABENZ GUANFACINE

α1α1α1α1 α2α2α2α2 α and β β1β1β1β1 β2β2β2β2 α 1 and α 2 β 1 and β 2 Sympathetic Agonists (Sympathomimetics) NAPHAZOLINE TETRAHYDROZOLINE OXYMETAZOLINE XYLOMETAZOLINE

α1α1α1α1 α2α2α2α2 α and β β1β1β1β1 β2β2β2β2 α 1 and α 2 β 1 and β 2 Sympathetic Agonists (Sympathomimetics) METAPROTERENOL TERBUTALINE, ALBUTEROL RITODRINE ISOETHARINE, PILBUTEROL BITOLTEROL, FENOTEROL FORMOTEROL, SALMETEROL PROCATEROL

Special sympathomimetics: Special sympathomimetics:COCAINE –Local anesthetic –Inhibits uptake 1  Peripheral sympathomimetic action –CNS  inhibits reuptake of dopamine into neurons in the “pleasure centers” of the brain Sympathetic Agonists (Sympathomimetics)

Special sympathomimetics: Special sympathomimetics:TYRAMINE –Normal by-product of tyrosine metabolism –Fermented foods  cheese, red wine –Metabolized by MAO –Release of stored catecholamines  indirect sympathomimetic action Sympathetic Agonists (Sympathomimetics)

Sympathetic Antagonists SYMPATHOLYTICS

1. Adrenergic Neuron Blockers (ANB) -Guanethedine, Reserpine 2. Adrenergic Receptor Blockers (ARB)  Reversible – Prazosin, Phentolamine, Tolazoline, Labetalol, Ergot alkaloids  Irreversible – Phenoxybenzamine, Dibenamine Sympathetic Antagonists (Sympatholytics)

α1α1α1α1 α2α2α2α2 α and β β1β1β1β1 β2β2β2β2 α 1 and α 2 Β 1 and β 2 YOHIMBINE BUTOXAMINE LABETALOL CARVEDILOL

α1α1α1α1 α2α2α2α2 α and β β1β1β1β1 β2β2β2β2 β 1 and β 2 α 1 and α 2 Sympathetic Antagonists (Sympatholytics) PRAZOSIN, TERAZOSIN DOXAZOSIN, TRIMAZOSIN INDORAMIN, URADIPIL KETANSERIN, ALFUZOSIN BUNAZOSIN, TAMSULOSIN

α1α1α1α1 α2α2α2α2 α and β β1β1β1β1 β2β2β2β2 α 1 and α 2 Β 1 and β 2 Sympathetic Antagonists (Sympatholytics) PHENOXYBENZAMINE PHENTOLAMINE ERGOT ALKALOIDS NEUROLEPTIC DRUGS

PHENOXYBENZAMINE irreversible noncompetetive blockade (14-48 hrs) inhibits NE reuptake Blocks H 1, Ach and serotonin receptors Blocks catecholamine-induced vasoconstriction Epinephrine- reversal Cl. Indication:pheochromocytoma male erectile dysfunction peripheral vascular diseases Adv. Eff: postural hypotension, tachycardia

PHENTOLAMINE Competetive antagonist (4 hrs) Competetive antagonist (4 hrs) Epinephrine- reversal Epinephrine- reversal reduce PVR reduce PVR Cardiac stimulation  baroreflex & ↑ NE release Cardiac stimulation  baroreflex & ↑ NE release Inhibits serotonin responses Inhibits serotonin responses Indic: Pheochromocytoma, male erectile dysfunction Indic: Pheochromocytoma, male erectile dysfunction Adv. Eff: severe tachycardia, arrhythmia, myocardial ischemia, GI stimulation Adv. Eff: severe tachycardia, arrhythmia, myocardial ischemia, GI stimulation

Beta-Adrenergic Blocking Agents BETA - BLOCKERS

α1α1α1α1 α2α2α2α2 α and β β1β1β1β1 β2β2β2β2 α 1 and α 2 Β 1 and β 2 Sympathetic Antagonists (Sympatholytics) METOPROLOL ATENOLOL ACEBUTOLOL BETAXOLOL CELIPROLOL ESMOLOL

α1α1α1α1 α2α2α2α2 α and β β1β1β1β1 β2β2β2β2 α 1 and α 2 Β 1 and β 2 Sympathetic Antagonists (Sympatholytics) PROPRANOLOL NADOLOL, TIMOLOL PINDOLOL, LEVOBUNOLOL CARTEOLOL, BISOPROLOL

Beta- blockers Pharmacokinetics: Pharmacokinetics: – oral: peak in 1-3 hrs – extensive first-pass metabolism – half- lives: 3 to 10 hrs * Esmolol – 8 – 10 min * Nadolol – 24 hrs

PHARMACODYNAMICS: PHARMACODYNAMICS: – CVS: (-) chronotropic, (-) inotropic effects – Respiratory: bronchoconstriction – Eye: reduce IOP – Metabolic & Endocrine:  inhibits lipolysis  partial inhibition of glycogenolysis  ↑ VLDL and ↓ HDL  ↓ HDL: LDL ratio – ISA; MSA Beta- blockers

Properties of Beta-receptor blocking agents: Partial Agonist Activity ( ISA) Local Anesthetic Activity (MSA) Lipid Solu- bility EliminationHalf-life Approxi- mate Bioavai- lability Selective β 1 blockers Acebutolol++Low 3-4 hrs 50 Atenolol--Low 6-9 hrs 40 Betaxolol-SlightLow hrs 90 Esmolol--Low 8-10 min 0 Celiprolol+- No data 4-5 hrs 70 Metoprolol-+Mod 3-4 hrs 50

ISA (Partial Agonist Activity ) MSA (Local Anesthetic Activity) Lipid Solu- bility Elimina-tionHalf-life Approxi- mate Bioavai- lability NonSelective β 1 Blockers Propranolol-+High hrs 30 Carteolol+-Low 6 hrs 85 Carvedilol-- No Data 6-8 hrs Labetalol++Mod 5 hrs 30 Nadolol--Low hrs 33 Pindolol++Mod 3-4 hrs 90 Timolol--Mod 4-50 hrs 50 Properties of Beta-receptor blocking agents:

CLINICAL INDICATIONS: CLINICAL INDICATIONS:  Hypertension  Cardiac arrhythmias  Angina  CHF: Metoprolol, Bisoprolol, Carvedilol  Glaucoma: Timolol, Betaxolol, Carteolol, Levobunolol, Metipranolol  Neurologic: Migraine, somatic mgt. of anxiety, alcohol withdrawal  Misc: reduce portal vein pressure in cirrhosis Beta- blockers

Clinical toxicities: Clinical toxicities: 1.Drug allergy – rare 2.CNS effects – sedation, sleep disturbances, depression, psychotic rxns 3.Worsening of preexisting asthma & airway obstruction 4.Depress myocardial contractility & excitability 5.Hypoglycemic episodes Beta- blockers

DRUG INTERACTION: DRUG INTERACTION: – Calcium- channel VERAPAMIL  Severe hypotension  Bradycardia  CHF  arrhythmia Beta- blockers

“A heartfelt apology can’t change the past, but it can brighten the future.”

QUIZ 1. Major neurotransmitter of the Sympathetic Nervous System Write A if Agonist or B if Antagonist: 2. Epinephrine7. Phentolamine 3. Labetalol8. Cocaine 4. Clonidine9. Phenylephrine 5. Prazosin10. Ephedrine 6. Terbutaline