PHTH1011 003 Autonomic Drugs - Francis.pdf

AUTONOMIC DRUGS Ms. Shamonia Francis Objectives 1. To understand the role of the sympathetic nervous system in controlling heart rate and blood pressure. 2. To understand the role of the parasympathetic nervous system in controlling heart rate and blood pressure. Autonomic Nervous System CO – Cardia...

AUTONOMIC DRUGS Ms. Shamonia Francis Objectives 1. To understand the role of the sympathetic nervous system in controlling heart rate and blood pressure. 2. To understand the role of the parasympathetic nervous system in controlling heart rate and blood pressure. Autonomic Nervous System CO – Cardiac output BP - Blood pressure SV – Stroke volume Autonomic Nervous System: Functions Regulation of heart rate and force of contraction Constriction and dilatation of blood vessels Contraction and relaxation of smooth muscle in various organs Visual accommodation, pupillary size and secretions from exocrine and endocrine glands Sympathetic Nervous System Sympathetic Nervous System Fight, fright or flight response Arousal responses Release of Neurotransmitters: Norepinephrine (NE) from postganglionic sympathetic fibres Epinephrine (E) from adrenal medulla Sympathetic Nervous System: Receptors a1– blood vessels, smooth muscles, bronchi, GIT, uterus, bladder, iris a2 – mainly on GIT, pancreas, blood vessels (minimally) 1 – mainly on the heart, kidneys, salivary glands 2 – Blood vessels, bronchi, GIT, uterus, bladder, iris, ciliary muscle Adrenergic Agonists Epinephrine/Adrenaline Epinephrine is a non-selective adrenergic ( and β) agonist. CVS Effects  HR and force of contraction, 1 Blood pressure (biphasic response) ✓ Vasodilation   BP (low doses), 2 & 2 ✓ Vasoconstriction   BP (high doses), 1 Epinephrine/Adrenaline Low dose Epinephrine Vasodilation (2)   BP  reflex  HR Reflex  HR + stimulation of heart (1)   HR   CO  Potent  BP Epinephrine/Adrenaline High dose Epinephrine (iv doses) Vasoconstriction (1)   BP  reflex  HR Reflex  HR + direct stimulation of heart (1)  net  HR   CO  Potent  BP  BP on 1 overshadows the fall in BP on 2 Epinephrine/Adrenaline Sympathetic Nervous System: Receptors a1– blood vessels, smooth muscles, bronchi, GIT, uterus, bladder, iris a2 – mainly on GIT, pancreas, blood vessels (minimally) 1 – mainly on the heart, kidneys, salivary glands 2 – Blood vessels, bronchi, GIT, uterus, bladder, iris, ciliary muscle Epinephrine/Adrenaline Other Effects Relaxation of bronchial muscles (2) Relaxation of smooth muscles (2) and constriction of sphincters (1) in GIT Relaxation of pregnant uterus (2) Relaxation of bladder smooth muscle (2) and contraction of sphincter (1)  urinary retention Contraction of iris radial muscle  Dilation of pupil (mydriasis) (2)  insulin,  glycogenolysis (2)  hyperglycemia Epinephrine/Adrenaline Clinical uses Adverse effects Cardiac arrest Cardiac arrhythmias Cerebral hemorrhage Nasal decongestion Acute Asthma Hypersensitivity reactions (type 1) To reverse low blood pressure (e.g. in anaphylactic shock) Headache Anxiety Tremor Palpitations Epinephrine/Adrenaline Administration: Ineffective orally Absorbed slowly from subcutaneous tissue Faster from intramuscular (IM) site Inhalation is locally effective (unless in emergencies) Not usually given IV Rapidly inactivated in Liver by Monoamine Oxidase (MAO) and Catechol-o-methyltransferase (COMT) Norepinephrine/Noradrenaline Non-selective adrenergic ( and 1) agonist Endogenous neurotransmitter Effects similar to epinephrine, however NE primarily affects alpha receptors on blood vessels It also acts on 1 receptors NE does not have significant effect on 2 receptors ✓ NE is not likely to cause vasodilation Norepinephrine/Noradrenaline Vasoconstriction (1)   BP  reflex  HR Reflex  HR + direct stimulation of heart (1)  net  HR   CO   BP Vasoconstriction   TPR,  stroke volume   systolic & diastolic BP,  mean pressure,  pulse pressure Norepinephrine/Noradrenaline Other effects Increases coronary blood flow Hyperglycemia at large doses Contracts pregnant uterus Rarely used clinically Use: vasopressor agent in treating hypovolemic shock and other hypotensive states – Noradrenal bitartrate by slow IV infusion at the rate of 2-4 mg/minute Norepinephrine/Noradrenaline PHARMACOKINETICS Orally ineffective and poor subcutaneous (SC) absorption SIDE EFFECTS Anxiety, palpitation, respiratory difficulty IV administered Headache Metabolized by MAO, COMT Extravasations causes necrosis, gangrene Short duration of action Severe hypertension, anginal pain Adrenergic Antagonist Propranolol Non-selective  antagonist (beta blocker) CVS Effects Decreases heart rate (less pronounced on resting heart) Reduces coronary blood flow and oxygen consumption Reduce secretion of renin from juxtaglomerular cells of kidneys (reninangiotensin pathway increases BP) Propranolol Therapeutic uses Adverse effects Hypertension Myocardia infarction Angina pectoris (prophylaxis) Arrhythmias (prophylaxis) Migraine (prophylaxis) Stage fright May induce heart failure Fatigue Depression Hypoglycemia (especially in patients insulin) Bradycardia on Parasympathetic Nervous System Parasympathetic Nervous System Release Acetylcholine (ACh) as neurotransmitter Control of restorative/vegetative/housing responses REST & DIGEST SYSTEM Parasympathetic Nervous System: Receptors MUSCARINISC (M) NICOTINIC (N) M1 – mainly at autonomic ganglia, Locations include autonomic M1 – M5 in CNS and on presynaptic nerves of the ANS ganglia, NMJ of skeletal muscles, CNS M2 – mainly on the heart (nodes), GIT, CNS M3 – on glands, vasculature, smooth muscles *NMJ - Neuromuscular junction Muscarinic Receptors: Subtypes Parasympathetic Regulations of the Heart The parasympathetic innervation of the heart is via the vagus nerves (cranial division – nerve X) It innervates the SA node, AV node and atrial myocardium The parasympathetic neurotransmitter is acetylcholine (Ach) The major cholinergic receptors in the heart are M2 muscarinic receptors Parasympathetic Activity on Blood Vessels Note: Parasympathetic system does not contribute to normal control of the tone of blood vessels, but there are M3 receptors on these vessels. M3 receptors on the vasculature respond to circulating Ach (after release from other sites) or injected M3 agonists Examples of agonists: acetylcholine (non-selective) Parasympathetic Activity on Blood Vessels ✓VASODILATION and reduction in BP Note: the vascular effects of the M3 agonists are not exploited clinically, however they occur as side effects when these drugs are used for other purposes Cholinergic Agonist Acetylcholine (ACh) Non-selective Muscarinic & Nicotinic agonist CVS Effects Decrease in heart rate and force of cardiac contraction of the heart (M2) Vasodilation via NO pathway on vascular endothelium   BP (M3) Acetylcholine (ACh) Other Effects (M3) Increased contraction of smooth muscles (M3) Increase in motility and secretory activity of GIT Increase in uterine contractility Increase in tone of bronchial muscles Increase in contractility of bladder Constriction of pupil (miosis) Contraction of ciliary muscles (accommodation) Stimulation of salivary, sweat and lacrimal glands Acetylcholine (ACh): Therapeutic Uses Miotic in ophthalmic surgery (given intraocular not topical) Diagnosis of vasospastic angina pectoris ✓ ACh injected in coronary artery  coronary artery spasm on M2 receptors  vasoconstriction  dramatic  of coronary blood flow Acetylcholine (ACh): Pharmacokinetics ACh is rapidly hydrolyzed by cholinesterase Has short duration of action The effects are also non-specific (due to M and N receptor stimulation), hence the agent does not have much clinical application Cholinergic Antagonist Atropine Non-selective muscarinic antagonist Atropine competitively inhibits the actions of ACh at muscarinic receptors M2 and M3 Cardiovascular Effects Block effects of vagal nerve on heart (M2)   HR and  conduction If atropine is administered IV there is initial transient bradycardia at low dose. Atropine Other Effects Relaxation of smooth muscles Relax bronchial muscles and  secretions Reduction in motility of GIT Relaxation of smooth muscle in bladder Relaxation of ciliary muscle (cycloplegia) Relaxation of sphincter pupillae (mydriasis)  salivary, gastric and sweat gland secretions Atropine Therapeutic uses Adverse effects Sinus bradycardia Heart block Ophthalmology Pre-operative medication ( secretions) Prophylaxis of motion sickness Tachycardia Constipation Blurred vision Dry mouth Urine retention