Principles of Pharmacology of the Autonomic Nervous System (PDF) - knust.edu.gh

Principles of the Pharmacology of the Autonomic & Somatic Nervous Systems Veronica Amoah Entrance University of Health Sciences, Department of Pharmacology & Clinical Pharmacy Email: [email protected] www.knust.edu.gh  Learning Objectives 1. List the anatomi...

Principles of the Pharmacology of the Autonomic & Somatic Nervous Systems Veronica Amoah Entrance University of Health Sciences, Department of Pharmacology & Clinical Pharmacy Email: [email protected] www.knust.edu.gh  Learning Objectives 1. List the anatomical & cellular components of the ANS & SNS ANS Ganglia Subdivision Sympathetic Parasympathetic Somatic – single nerve, no ganglia www.knust.edu.gh  Learning Objectives 2. Discuss the key biochemical & cellular events that take place in autonomic (including ganglionic, postganglionic sympathetic and postganglionic parasympathetic nerves) or somatic nerve fibers upon stimulation 3. Summarize the points of potential pharmacological intervention in the synthesis, release, receptor binding and termination steps of the neurotransmitters acetylcholine and noradrenaline (norepinephrine) www.knust.edu.gh  Learning Objectives 4. Discuss the subtypes of adrenergic and cholinergic receptors Adrenergic Cholinergic Subtype:   M N Agonists Antagonists Location Importance www.knust.edu.gh  Learning Objectives 5. Identify prototype drugs that act to mimic, stimulate or block the a) synthesis b) release c) receptor binding d) removal of acetylcholine and noradrenaline at nerve terminals www.knust.edu.gh  Learning Objectives 6. Hypothesize the integrated physiological response of the autonomic nervous system to either abrupt or gradual changes in homeostasis with an emphasis on the baroreceptor reflex response Example: Baroreceptor Reflex  BP  BP www.knust.edu.gh  Learning Objectives 7. Recommend a strategy to pharmacologically treat pathological situations involving the autonomic or somatic nervous systems What general strategy using agents that alter either peripheral cholinergic or adrenergic nerves or target organs could be used to Treat hypertension Treat asthma Treat myasthenia gravis www.knust.edu.gh  Learning Objectives 8. Determine probable adverse responses What adverse effects would you predict with Ganglionic blockade Nicotinic agonist Muscarinic antagonist Adrenergic agonist AChE inhibitor Uptake I inhibitor www.knust.edu.gh Nervous System Pharmacology www.knust.edu.gh The Nervous System Nervous system Peripheral Central Nervous Nervous System System Efferent Afferent Brain Spinal Cord Autonomic Somatic Cholinergic Adrenergic www.knust.edu.gh  The Nervous System: A Review Overall functions – integration and homeostasis Divisions – CNS & PNS CNS consists of brain, brain stem, spinal cord motor and sensory neurons efferent fibers (exit CNS) & afferent fibers (enter CNS) PNS originates from hypothalamus, brain stem & spinal cord nerve endings located outside the CNS further divided into the Somatic NS & the Autonomic NS www.knust.edu.gh The Nervous System: A Review In the ANS, one neuron leaves the CNS and connects with a collection of nerve cells called a ganglion First neuron which innervates the ganglion is the preganglionic nerve The neuron leaving the ganglion and innervating the effector site is the postganglionic nerve ending In the somatic motor nervous system, the axon leaves the CNS but does not connect with a ganglion before innervating the effector cell www.knust.edu.gh  The Nervous System: A Review Somatic motor innervates one kind of neuroeffector cell - skeletal muscle cell ANS innervates three different neuroeffector sites or cells Smooth muscle Cardiac muscle Exocrine glands Somatic motor nervous system differs from the ANS in that the somatic is mainly under voluntary control whereas ANS is mainly under reflex control www.knust.edu.gh  The Autonomic Nervous System Two neuron chains Sympathetic Parasympathetic www.knust.edu.gh www.knust.edu.gh  The Sympathetic ANS  Has cell bodies of preganglionic neurons in the thoracic and lumbar regions of the spinal cord  These nerve fibers leave the spinal cord and enter the sympathetic ganglia  Acetylcholine: neurotransmitter between the pre- and post- ganglionic neurons  Noradrenaline: neurotransmitter released by postganglionic sympathetic fibers at the effector organ www.knust.edu.gh The Sympathetic ANS Sympathetic has its own neurohormones noradrenaline and adrenaline which are released from adrenal medulla into the circulation in response to sympathetic activation (i.e. "Fight or flight response") These neurohormones enable the sympathoadrenal system to discharge as a unit www.knust.edu.gh  The Parasympathetic ANS Ganglion near effector organ Long preganglionic neurons Short postganglionic neurons Postganglionic neurons are cholinergic Cranial and sacral nerves www.knust.edu.gh  The Parasympathetic ANS Neurotransmitters: Acetylcholine (ACh) is the neurotransmitter released from all pre- and postganglionic parasympathetic fibers (sites where ACh serves as the neurotransmitter are called cholinergic) Drugs can affect the biosynthesis, storage, release and inactivation (hydrolysis) of ACh www.knust.edu.gh The Autonomic Nervous System www.knust.edu.gh Physiological functions controlled by the ANS Both divisions help maintain homeostasis Adjustment to stress Adjustment to temp changes Protection of eyes against bright light Urination Defecation Digestion Salivation Accommodation for near vision Maintenance of blood pressure at optimal level Respiration www.knust.edu.gh Comparison of functions PARASYMPATHETIC NS SYMPATHETIC NS H.R. ↓, B.P. ↓ H.R. ↑, B.P. ↑ secretions ↑ secretions ↓ eyes adjust for light (miosis - eyes adjust for dark (mydriasis - constrict) dilate) emptying of bowel digestion slowed emptying of bladder airways constrict airways opened “rest and digest” response “fight or flight” response www.knust.edu.gh www.knust.edu.gh Cholinergic Pharmacology www.knust.edu.gh Goals & Objectives Cholinergic agonists To know the biosynthesis, storage, release and hydrolysis of acetylcholine To know the types and locations of different acetylcholine receptors To know the effects of cholinergic agonists on tissues To understand the relation between drug structure and function 3° vs. 4° drugs To know major therapeutic indications and contraindications www.knust.edu.gh Goals & Objectives Muscarinic antagonists To understand the relation between drug structure and function - 3° vs. 4° To know the key clinical uses of antimuscarinic drugs Side effects To know side effects of specific antimuscarinic drugs To recognize other drugs with anticholinergic side effects www.knust.edu.gh Goals & Objectives Cholinesterase inhibitors To understand the relation between drug structure and function 3° vs. 4° drugs Organophosphate vs. carbamate vs. alcohol drugs To know the mechanism of inhibition by different drug classes To know therapeutic uses of the different types of cholinesterase inhibitors www.knust.edu.gh Biosynthesis of Acetylcholine (ACh) ACh is synthesized within cholinergic neurons by the transference of an acetyl group from Acetyl CoA to the organic base choline. The enzyme choline-O- acetyltransferase (ChAT) catalyses the reaction. the enzyme choline-O-aceltyltransferase (ChAT) exists in multiple locations cytosol, surface of synaptic vesicles, and inner face of plasma membrane. www.knust.edu.gh Storage The vesicles are mainly accumulated at the nerve endings and inside these vesicles the greater part of neuronal ACh is stored. The vesicles combine with the membranes of nerve endings to discharge their content of ACh into the synaptic cleft. www.knust.edu.gh Release Ca2+ is essential to ACh release but exactly how it mediates release remains to be determined Drugs which chelate extracellular Ca2+ and prevent its influx (i.e Aminoglycoside antibiotics) will depress ACh release ACh is probably released from synaptic vesicles which are "docked" at the plasma membrane and in position to release it by exocytosis www.knust.edu.gh Neurotransmission Once released from the nerve terminal, ACh diffuses across the synaptic junction and acts on one post junctional receptor Activation of the postjunctional receptor leads to a physiological response www.knust.edu.gh Hydrolysis ACh is degraded by the enzyme acetylcholinesterase (AChE) to choline and acetate The choline derived from the hydrolyzed ACh is returned to the prejunctional nerve terminal by a Na+-dependent transport process to form ACh The acetate derived from ACh breakdown in the synaptic junction is also returned to the nerve terminal to form a portion of the acetyl CoA used in ACh formation. www.knust.edu.gh Factors(Agents) affecting ACh synthesis & release The inhibitions are competitive. Most of the drugs are NOT used clinically- they are experimental tools in studies concerned with the mechanism of ACh synthesis in cholinergic neurons. www.knust.edu.gh Factors(Agents) affecting ACh synthesis & release Hemicholinium α- ketoacids, naphthoquinones Vesamicol Latrotoxin Botulinum toxin Calcium Physostigmine Atropine d-Tubocurarine www.knust.edu.gh Factors(Agents) affecting ACh synthesis & release Hemicholinium blocks choline uptake, thereby blocking synthesis of ACh. α-ketoacids, naphthoquinones direct inhibition of the enzyme ChAT Vesamicol blocks the specific transport process of ACh into the vesicles so there will not be vesicular release of ACh. These compounds are poisonous and not used for any therapeutic purpose www.knust.edu.gh Factors(Agents) affecting ACh synthesis & release Latrotoxin (a toxin from the black widow spider) produces an explosive release of ACh, causing muscular spasm. Botulinum toxin (a toxin from Clostridium botulinum) is able to bind to the neuron and interferes with the trafficking proteins as they come together to promote the fusing of the vesicles to the membrane. www.knust.edu.gh Agents affecting cholinergic transmission Calcium is involved in the vesicular release. Its uptake is important in the fusion of vesicles to membrane of neuron. Physostigmine inhibits acetylcholinesterase causing ACh concentrations in the synaptic cleft to increase and rebind to muscarinic and nicotinic receptors. www.knust.edu.gh Agents affecting cholinergic transmission Atropine blocks muscarinic actions of ACh. D-Tubocurarine blocks the nicotinic actions, which are primarily at the endplate of the neuromuscular junction. Higher doses of this do tend to block nicotinic receptors at the autonomic ganglion. www.knust.edu.gh Cholinesterases www.knust.edu.gh Cholinesterases ChEs are not used as drugs but they are important. They interact with ACh. The ChE are a group of enzymes which share a common property of hydrolyzing ester bonds but they differ in their substrate specificity. The ChE found largely in the post synaptic membranes at the cholinergic synapses is called acetylcholinesterase (“True or specific” ChE) The function it performs there is to rapidly hydrolyze (terminate) the activity of ACh released from cholinergic nerve endings. A rich source of ChE is the RBC. www.knust.edu.gh Cholinesterases Another group of ChE that is collectively called non-specific or pseudocholinesterase is found in the plasma the intestine and to a lesser extent in the liver Their function is not clear but where the intestine is concerned, they are thought to regulate the action of ACh in controlling muscular motility. Amechol is hydrolyzed by AChE but not pseudo-ChE where as a drug known as succinylcholine (suxamethonium) is hydrolyzed by pseudo-ChE but not by AChE. www.knust.edu.gh Autonomic Receptors Two major types Cholinoceptors - receptors that respond to ACh Adrenoceptors - receptors that respond to Noradrenaline and related compounds such as Adrenaline and Dopamine www.knust.edu.gh Types of Cholinergic Receptors Cholinergic receptors at organ cells are either nicotinic (affects skeletal muscles) or muscarinic (stimulates smooth muscle and slows the heart rate) Two basic types - Nicotinic (N) Muscarinic(M) ACh has both muscarinic and nicotinic activity www.knust.edu.gh Nicotinic Receptors Two subtypes NN subtype is present on cell body of postganglionic autonomic neuron NM subtype is present at the endplate of the neuromuscular junction Differences? Hexamethonium competitively blocks the action of ACh at the ganglia but not at the NMJ D-tubocurarine is more selective in blocking the action of ACh at the NMJ. ?? www.knust.edu.gh Basic Functions of Nicotinic Receptors Nicotinic receptors are ionotropic - the proteins themselves form ion channels Ligand gated ion channels and their activation causes a rapid increase in cell permeability to Na+ and Ca2+ Located on the motor endplate region of the neuromuscular junction, the adrenal medulla and on autonomic ganglia An excess of ACh or Nicotine (nicotinic agonist) at nicotinic receptor can cause receptor desensitization Receptor will no longer respond to agonist and physiological response does not occur www.knust.edu.gh Muscarinic Receptors Activated by Acetylcholine endogenously and Muscarine exogenously Blocked by atropine (non specific blocker) Location Smooth muscles Glands Heart www.knust.edu.gh Muscarinic Receptors Subtypes P/cologic types- M1, M2, M3, M4 Cloned receptors m1-m5 Pharmacologic receptors have been further sub classified into M1 (“neural”)- autonomic ganglia, CNS M2 (“cardiac”) and M3 (“glandular”)- peripheral gland tissue e.g. pancreas and smooth muscle www.knust.edu.gh Basic Functions of Muscarinic Receptors G-protein induced changes in membrane-bound effector Activation of certain muscarinic receptors activates a G- protein for stimulation of phospholipase C (M1, M3 and M5) Activation of other muscarinic receptors leads to an inhibition of adenyl cyclase and activation of K+ channels (M2 and M4) Muscarinic responses are typically slow, long lasting and may be either inhibitory or excitatory www.knust.edu.gh  The drugs atropine, hexamethonium, and d-tubocurarine are all competitive antagonists to the action of ACh at receptor sites If ACh reaches a sufficiently high enough concentration in their presence, it can override their blockade One way of increasing amount of ACh in the synaptic junction is to administer a drug which inhibits the degradative enzyme AChE www.knust.edu.gh Cholinergic Drugs www.knust.edu.gh  Cholinergic Drugs Drugs that mimic the effect of ACh – also known as cholinergic agonists/muscarinic stimulants - initiate a cholinergic response Cholinomimetics Parasympathomimetics Many cholinergic drugs are nonselective www.knust.edu.gh  Cholinergic Drugs Action: mimic the effects of stimulation of the parasympathetic system act on receptors that are activated by ACh in smooth muscle, cardiac muscle and some glands - Direct acting or inhibit the enzyme that breaks down acetylcholine – Indirect acting www.knust.edu.gh  Direct-Acting Cholinergic Drugs Drugs in this group include ACh Synthetic esters of choline bethanechol carbachol methacholine and Naturally occurring alkaloids such as pilocarpine www.knust.edu.gh Structure and mechanisms of cholinergic agonists www.knust.edu.gh  Acetylcholine (ACh) Positively charged quaternary nitrogen N+. the center of the cationic head and it is thought to fit into a depression in the receptor surface called the anionic site. Alterations in the molecule to reduce the charge on the quaternary N or increase the size of the cationic head will reduce the muscarinic receptor stimulating www.knust.edu.gh potency of the molecule.  Acetylcholine (ACh) The ester group in ACh is an excellent substrate for cholinesterase enzymes so ACh is broken down very quickly in vivo www.knust.edu.gh  Methacholine (Acetyl β–methylcholine) Synthetic parasympathomimetic More stable to hydrolysis by cholinesterase Virtually immune to hydrolysis by AChE More prolonged effect than ACh and is practically specific for muscarinic receptors www.knust.edu.gh  Carbachol (Carbamylcholine) Synthetic Immune to hydrolysis by both AChE and pseudocholinesterase More potent than acetylcholine Longer duration of action Administered orally Most active nicotinic drug among the commonly used parasympathomimetics though its nicotinic activity is less than that of ACh www.knust.edu.gh  Bethanechol (Carbamyl β–methylcholine) Reduced nicotinic potency Immune to hydrolysis by AChE Long-acting muscarinic stimulant drug almost devoid of nicotinic activity www.knust.edu.gh  Alkaloids- Pilocarpine Naturally occurring in the leaflets of a shrub Maranham jaborandi Difficult to account for the muscarinic activity in terms of structure because it bears no relationship to ACh No quaternary N (a major active center for ACh) but tertiary amine Has muscarinic receptor stimulating potency and much little nicotinic activity Particularly potent on glandular tissues e.g. sweat and salivary glands www.knust.edu.gh  Alkaloids- Muscarine Muscarine mimics the actions of acetylcholine at smooth muscles, cardiac muscles, and glands Muscarine is found in various mushrooms Amanita muscaria: content of muscarine is very low Inocybe sp: content of muscarine is high Clitocybe sp: content of muscarine is high www.knust.edu.gh  Physiological Responses Heart - The most prominent effect is bradycardia due to activation of the SA node (pacemaker). This is mediated by a hyperpolarization of SA node cells by an M2-receptor-mediated increase in potassium currents. Also, contractility in the atrium and conduction velocity in the AV node is reduced. GI tract - The GI tract is a major target of parasympathetic responses and muscarinic cholinergic agonists. Effects include increased acid secretion in the stomach, increased tone and amplitude of contraction and increased peristalsis in stomach and intestine. www.knust.edu.gh  Physiological Responses Urinary tract - A coordinated evacuation of the bladder occurs due to contraction of the detrusor muscle and relaxation of the sphincter. Glands - Many glands in the body respond to muscarinic stimulation. Lachrymal glands in the eye, bronchial secretory glands, salivary glands (parotid etc.), pancreas, and sweat glands are all activated by muscarinic agonists. www.knust.edu.gh  Physiological Responses Eye - Constriction of the pupil (miosis) and thickening of the ocular lens (accommodation) occur in response to muscarinic stimulation. Bronchial smooth muscle - Contraction of bronchial smooth muscle occurs and this can be very pronounced in asthmatic patients. www.knust.edu.gh  Physiological Responses Blood vessels – Vascular tissue represents a pharmacological "oddity"" in that it is not innervated by the parasympathetic nervous system but it does contain muscarinic receptors which are activated by exogenous agonists. The typical response is relaxation due to release of NO (endothelial-derived relaxing factor, EDRF) from endothelial cells. When endothelium is damaged or removed contraction is observed. ACh acts at M3 site, causing activation of nitric oxidase synthase. NO diffused to smooth muscle activating guanyl cyclase and changing GTP to cGMP to cause www.knust.edu.gh vasodilation.  Physiological Responses CNS - Muscarinic receptors are very abundant in the CNS and muscarinic agonists lead to cortical arousal. There is evidence for reversal of memory deficits by muscarinic agonists or anticholinesterase drugs. www.knust.edu.gh  Pharmacokinetics Absorption - The quaternary choline esters are very poorly absorbed and must be given parenterally. Due to the dramatic cardiovascular effects of rapid bolus administration of choline esters, they should never be given intravenously, with subcutaneous administration being the preferred route. Pilocarpine is much better absorbed and is given either orally for systemic use or topically for ophthalmologic uses. Distribution - As expected, pilocarpine will reach the CNS while the quaternary choline esters have no CNS penetration. Clearance - Acetylcholine is cleared within minutes due to the activity of serum cholinesterase and its action is also reduced dramatically by the acetylcholinesterase present at the synaptic site of activity. Carbamylcholine and bethanechol are resistant to the action of cholinesterases so their clearance is somewhat slower though they are eliminated rapidly by the kidney t 1/2 < 1 hour. Pilocarpine has similar www.knust.edu.gh kinetics.  Clinical uses of muscarinic agonists Muscarinic agonists have relatively limited clinical utility at present, with ophthalmic uses being the most significant. However, knowledge of the actions of muscarinic agonists is important for the understanding of the actions of antagonists and in the understanding of pathophysiological processes mediated by over activity of parasympathetic responses. Glaucoma Gastric atony/Paralytic ileus Bladder dysfunction -nonobstructive Xerostomia www.knust.edu.gh  Specific uses of muscarinic agonists Acetylcholine (miochol™) ACh finds various clinical uses either by s.c, i.m, i.v, or i.a routes i.v for paroxysmal tachycardia (i.m preferred because of danger of cardiac depression) – 20- 200 mg i.m Topical miotic for treatment of acute glaucoma 1% ACh + 5% mannitol to constrict the pupil in cornea grafting operations www.knust.edu.gh  Specific uses of muscarinic agonists Amechol (provocholine™) Used mainly for its effects on the CVS Dilate constricted blood vessels in vasospastic conditions e.g. Raymond’s syndrome s.c 10- 25 mg Occasionally given as 0.1% or 0.5% aqueous solution by a process known as iontophoresis to produce vasodilatation in a restricted area in the body Xerostomia Glaucoma in 2.5-20% solution, orally, 200-600 mg (not very active orally) www.knust.edu.gh  Specific uses of muscarinic agonists Bethanechol (urecholine™) Functional gastric retention after vagotomy 30-120 mg orally, 2.5-30 mg s.c Abdominal distension Post operative urinary retention Xerostomia www.knust.edu.gh  Specific uses of muscarinic agonists Carbachol Mainly used for its effects in stimulating the intestine and bladder orally, 1-4 mg, s.c, 200-500 µg Postoperative intestinal atony Urine retention Simple glaucoma Tachycardia www.knust.edu.gh  Specific uses of muscarinic agonists Pilocarpine (ocusert™) Used as aqueous solution 1-5% Pilocarpine HCL Treatment of glaucoma Xerostomia www.knust.edu.gh  Contraindications ASTHMA  hyperactive airways CORONARY INSUFFICIENCY  drugs can cause fall in peripheral resistance, compounding the problem PEPTIC ULCER  HCl secretion would be increased ORGANIC OBSTRUCTION IN BLADDER OR G.I. TRACT  can’t force contraction of smooth muscle if something is present HYPERTHYROIDISM  may cause arrthymia www.knust.edu.gh  Side effects The side effects are mainly predictable based on the physiological function of acetylcholine and the parasympathetic nervous system. Cardiovascular effects of hypotension and bradycardia are common with systemic administration. Bronchoconstriction and wheezing Flushing, sweating, abdominal cramps, blurred vision, and salivation www.knust.edu.gh  Drug interactions Cholinesterase inhibitors greatly increase the duration and effect of acetylcholine and the muscarinic agonists Mushroom Poisoning ???? www.knust.edu.gh Anticholinergic Drugs www.knust.edu.gh  Concepts The cholinoceptor antagonists are grouped into subclasses on the basis of their spectrum of action i.e. whether the receptors they block are muscarinic or nicotinic www.knust.edu.gh  Anticholinergic drugs Antimuscarinic Antinicotinic M - selective Nonselective Ganglion Neuromuscular blockers blockers These drugs are pharmacological antagonists www.knust.edu.gh 79 Antimuscarinic drugs www.knust.edu.gh  Goals and Objectives  To understand the relation between drug structure and function  To know the key clinical uses of antimuscarinic drugs Side effects To know side effects of specific antimuscarinic drugs To recognize other drugs with anticholinergic side effects www.knust.edu.gh  Antimuscarinic drugs Drugs that selectively antagonise (block) the effects produced by either ACh or any other drug that stimulates ACh receptors of the muscarinic type www.knust.edu.gh  Antimuscarinic drugs Acetylcholine is an agonist at both muscarinic and nicotinic receptors M N www.knust.edu.gh 83  Antimuscarinic drugs The nicotinic actions of acetylcholine remain when muscarinic receptors are blocked Muscarinic receptor blockade M X N does not interfere with transmission at autonomic ganglionic sites, the adrenal medulla, or skeletal muscle fibers. Sympathetic adrenergic functions are not affected In dual innervated organs, muscarinic receptor blockade www.knust.edu.gh allows sympathetic dominance 84  Structural and pharmacological specificity Blockade caused by antimuscarinics is selective for muscarinic receptors: nicotinic receptors are not blocked, nor are adrenergic receptors Blockade is competitive i.e. blockade can be overcome by increasing the dose of the agonist (ACh or another parasympathomimetic/muscarinic agonist) www.knust.edu.gh  Pharmacological actions Largely predicted from the physiology of the PNS and the effects of muscarinic agonists Inhibit acetylcholine by occupying the muscarinic receptor sites By blocking the parasympathetic nerves, the sympathetic nervous system is allowed to dominate anticholinergic and adrenergic drugs produce many of the same responses www.knust.edu.gh  Pharmacological actions SALIVARY GLANDS RESPIRATORY TRACT  salivation  secretions bronchodilatation CVS primary expected effect is reversal GI TRACT of vagal tone and acceleration of  motility (smooth muscle relaxation) heart rate  acid secretion  A-V impulse conduction other mediators prevent full  contractile force (only slight inhibition of these processes effect) URINARY TRACT  micturition speed and urinary retention at higher doseswww.knust.edu.gh  Pharmacological actions EYE CNS dilatation of pupil excitation leading to (mydriasis) restlessness and paralysis of accommodation hallucinations (moderate (cycloplegia) doses) followed by generalized depression and  lachrymal secretions coma (high doses) SWEAT GLANDS inhibition of sweating can lead to increased core temp. www.knust.edu.gh  Atropine & Other Tertiary Amines Atropine is found in the Atropa Belladonna plant (deadly nightshade) and in Datura stramonium (thorn apple). Bella donna = Italian for “beautiful lady” Hyoscine (Scopolamine) occurs in Hyosciamus niger (henbane) www.knust.edu.gh  Pharmacokinetics Atropine and hyoscine (scopolamine) are readily absorbed orally and through mucosae. They penetrate the blood-brain barrier easily. The plasma half-life of atropine is approximately 4 hours but the duration of action of these two compounds is very long - in part due to very tight binding to the muscarinic receptor. Local application of atropine or hyoscine to the eye leads to very prolonged action; up to 7 days. Because of this shorter acting agents are used for diagnostic dilatation (e.g. Tropicamide, MYDRIACYL™) www.knust.edu.gh  Quaternary compounds In contrast, charged molecules are more polar and therefore less likely to penetrate a lipid barrier like the blood-brain barrier or the cornea of the eye. Only 10-30 % of a dose is absorbed after oral administration If an intense effect is needed they should be administered parenterally. These drugs are used for their antisecretory or antispastic actions in the gut (anticholinergic action) and the bronchi. Ipratropium bromide (ATROVENT ) used by inhalation for bronchial dilatation Propantheline bromide (PROBANTHINE ) are given orally where limited systemic absorption is desirable www.knust.edu.gh  Clinical indications (Antimuscarinics) HEART EYE Atropine & hyoscine - Mainly used for premedication to general Ophthalmologic anaesthesia (prevent diagnostic dilatation excessive vagal slowing of (homatropine preferred?) heart rate-Bradycardia) Hence used to reduce the GIT risk of cardiac arrest GI hypermotility syndromes (not common diarrhoea)-spasms of the pylorus and bile Peptic ulcer disease www.knust.edu.gh  Clinical indications (Antimuscarinics) CNS (BRAIN) Treatment of Parkinson’s disease objective- (ACh and  dopamine) treatment of maniac states (withdrawal of drugs of dependence or alcoholism) hyoscine preferred? Motion sickness www.knust.edu.gh  Side effects and adverse reactions of Anticholinergics Think opposite of DUMBBELS  Dry mouth  Dry skin  Decreased perspiration  Blurred vision  Tachycardia  Constipation  Urinary retention  Photophobia (“day blindness” from dilated pupil)  Seizures  Delirium  Abdominal distention www.knust.edu.gh  Atropine Toxicity 1. Peripheral (Autonomic) signs & symptoms ‘Dry as a bone’ Absence of secretions, no defecation or urination ‘Red as a beet’ (‘the atropine flush’) Reflects vasodilatation ‘Blind as a bat’ Cycloplegia, pupillary dilation and impaired lens accommodation www.knust.edu.gh  Atropine Toxicity 2. Central (CNS; Brain) responses ‘Mad as a hatter’ Hallucinations, delusions, delirium etc. ‘Hot as a furnace’ Fever can be severe Suppression of rigidity (in Parkinson’s) and prevention of motion sickness www.knust.edu.gh  Treatment of Atropine Poisoning Physostigmine Symptomatic/supportive care No antipyretic drug should be used www.knust.edu.gh  Contraindications Glaucoma Pyloric stenosis Prostate hypertrophy www.knust.edu.gh  Indirect-Acting Cholinomimetics/Acetylcholinesterase Inhibitors (AChEIs)/Anticholinesterases www.knust.edu.gh  Acetylcholinesterase Inhibitors These are drugs which prevent the hydrolysis of ACh by cholinesterase, and they do this by forming stable complex with the ChE and therefore compete with ACh for the active sites of the ChE enzyme - esteratic and anionic sites. Anti-cholinesterases by delaying the destruction of ACh means ACh will survive in synaptic cleft and re-stimulate neurotransmission. www.knust.edu.gh  Acetylcholinesterase Inhibitors These drugs modify transmission in Autonomic ganglia Post-ganglionic parasympathetic nerve endings (neuroeffector junction) Neuromuscular junction Cholinergic synapses in the CNS www.knust.edu.gh  Classification 1. REVERSIBLE anticholinesterase Physostigmine Neostigmine Pyridostigmine Edrophonium Ambenonium Distigmine www.knust.edu.gh  Classification 2. IRREVERSIBLE - Organophosphates Echothiophate (PHOSPHOLINE) Di-isopropylfluorophosphate (DFP) www.knust.edu.gh  Pharmacological actions Actions of anticholinesterases are like the combined action of nicotinic and muscarinic stimulation Muscarinic - There is massive activation of parasympathetic target organs, which has been described as the DUMBBELSS syndrome Nicotinic - The nicotinic effects of cholinesterase inhibitors are complex and may show an initial activation of nicotinic receptors - with muscle tremors or fasciculations - followed by paralysis due to desensitization of the nicotinic receptors. The primary mode of death in poisoning by cholinesterase inhibitors is due to respiratory paralysis. www.knust.edu.gh  Therapeutic uses of reversible anticholinesterase Paralytic ileus or bladder atony (Neostigmine preferred?) Glaucoma Alzheimer's disease (Donepezil) Myasthenia gravis (pyridostigmine preferred to neostigmine) Atropine poisoning (physostigmine preferred?) www.knust.edu.gh  Myasthenia Gravis Progressive autoimmune disorder that blocks the ACh receptors at the neuromuscular junction The more receptors are damaged the weaker the muscle (as the disease progresses). More common in women 20-40 yrs with possible line to thymus gland tumors Begins with double vision, swallowing difficulties and progresses to paralysis of respiratory muscles Treatment includes steroids that reduce antibodies that bind to ACh receptors and acetylcholinesterase inhibitors www.knust.edu.gh  Irreversible anticholinesterase The irreversible anti-ChEs R2 are mainly compounds of O organic sources and they P contain pentavalent R1 X phosphorus. R1/R2-alkyl chains X=halogen (Cl,F,Br,I) www.knust.edu.gh  Irreversible anticholinesterase These compounds are referred to as organophosphorus anti- ChEs or phosphostigmines. The reaction between the irreversible anti-ChE and the enzyme ChE is similar to the reaction between the reversible anti-ChE and the enzyme. The only difference is that many of the organophosphorus compounds do not have a quaternary N atom and for this reason cannot react with the cationic site of the enzyme. They react only with the esteratic site of the enzyme. www.knust.edu.gh  Irreversible anticholinesterase Initially the irreversible anti-chE reacts with the enzyme to form a complex, which is capable of dissociation at the initial stage. The “X” in the molecule is split off from the inhibitor- organophosphorus complex what is left is extremely stable so that the removal of the phosphoryl group from the complex may take several weeks or months for practical purposes the reaction is regarded as irreversible. www.knust.edu.gh Irreversible anticholinesterase www.knust.edu.gh  Uses of irreversible Anti-ChE The very long duration of action of these compounds together with their high potency makes them extremely toxic substances. Their toxicity is further increased by the fact that they are lipid soluble and therefore they can be absorbed by inhalation and even by contact with the skin. Their lipid solubility makes them easily penetrate the CNS. www.knust.edu.gh  Uses of irreversible Anti-ChE Their actions promoting accumulation of ACh at the Nm nicotinic receptor is the basis for their toxicity, but actions at the muscarinic receptors can contribute to their toxic actions as well In general, they are too toxic for use as therapeutic agents but occasionally their long duration of action is desirable for the treatment of conditions such as glaucoma. Their action promoting accumulation of ACh at the nicotinic and muscarinic receptor of the ciliary muscle www.knust.edu.gh  Toxicity of organophosphate cholinesterase inhibitors in man While cholinesterase inhibitors have some clinical uses, they are of major toxicological importance Both insecticides and chemical warfare agents (humanicides) often contain the highly irreversible organophosphorus type of cholinesterase inhibitor www.knust.edu.gh  Toxicity of organophosphate cholinesterase inhibitors in man Nicotinic receptors - DEPOLARIZING BLOCKADE Target: Neuromuscular junction muscle weakness, respiratory failure , DEATH Muscarinic receptors - HYPERACTIVITY Target-peripheral parasympathetic nervous system bradycardia, arrhythmias/arrest, excessive airway secretion/constriction, asphyxiation, DEATH Target 2: central nervous system decreased respiratory drive, respiratory failure, generalized seizures, convulsions, DEATH www.knust.edu.gh  Treatment of Anti-ChE Poisoning Reversible anti-ChE Autonomic effects can be controlled by using Atropine Organophosphate anti-ChE Can be treated with substances that are able to regenerate the inhibited cholinesterase by removing the phosphoryl group. These compounds are strongly basic and have positively charged quaternary N atom. The best known of these compounds is Pralidoxime (2 Pyridine aldoxime methyl chloride (2-PAM)) and it is generally called REACTIVATOR www.knust.edu.gh  Treatment of Anti-ChE Poisoning Pralidoxime was designed to optimally reactivate acetylcholinesterase by incorporating the positive charge in the ring along with the highly nucleophilic oxime to displace the covalently bound organophosphorus inhibitor. Early treatment is essential as “aging” of the enzyme-inhibitor complex renders pralidoxime ineffective. Inhibition by agents that undergo rapid “aging” is not reversed. Atropine can be used to take care of the autonomic effects of organophosphorus poisoning www.knust.edu.gh  Nicotinic Pharmacology (Ganglion stimulants & blockers) www.knust.edu.gh  Goals and objectives Ganglion stimulants & blockers 1. Describe ganglionic transmission and the respective roles of the nicotinic, muscarinic and dopaminergic receptors at certain ganglia. 2. State that nicotine stimulates ganglionic transmission at low doses and inhibits it at high doses. 3. Summarize nicotine toxicity and how to treat it. 4. State which division of the ANS dominates over the other in controlling a particular body function. www.knust.edu.gh  Drugs which affect autonomic ganglia Ganglion Stimulants These have no therapeutic uses but have useful pharmacological activities. www.knust.edu.gh  Nicotine Alkaloid obtained from Nicotina tobaccum A tertiary amine that can act as an agonist at nicotinic receptors in autonomic ganglia including the adrenal medulla at the neuromuscular junction on sensory nerve endings in the CNS It is a partial agonist Exhibits tachyphylaxis www.knust.edu.gh  Nicotine CVS CNS ­ blood pressure Can cause emesis by acting at chemoreceptor trigger zone ­ HR ­ ADH release Respiratory System GIT  respiration  G.I. tract motility and HCl release Neuromuscular junction stimulates the NMJ www.knust.edu.gh  Nicotine Effects of nicotine receptor agonists may reflect stimulation or blockade Produces a variety of pharmacological effects in the body and most of these effects are antagonistic to each other and therefore the effects of nicotine are generally very difficult to analyse www.knust.edu.gh  Other stimulants Tetramethyl ammonium (TMA) Dimethylphenylpiperazinium (DMPP) www.knust.edu.gh  Drugs which affect autonomic ganglia Ganglion blockers These are drugs used in the management of hypertension. Their uses have been replaced by other drugs and are now widely used in experimental pharmacology. These drugs produce blockade without stimulating the ganglia. Since ganglion blockers inhibit both sympathetic and parasympathetic output the major factor that determines the net effect of a ganglion blocker is the predominant tone in the tissue affected. www.knust.edu.gh  Hexamethonium (C6) CVS effects Heart  BP by preventing the effects on the heart are variable passage of nerve impulses and depend on the initial level across sympathetic ganglia of the vagal tone. If the initial rate is high then fall in BP is mainly due to these drugs will reduce the reduced peripheral resistance heart rate. the more usual effects are Cardiac output bradycardia. reduce BP better in the upright produce variable effects but position – cause orthosthatic generally they lower the hypotension cardiac output because they produce postural hypotension reduce venous return www.knust.edu.gh  Uses of ganglion blockers Treatment of hypertension (rarely used now) Produce controlled hypotension during surgery in order to reduce bleeding www.knust.edu.gh  Adverse effects Eye Glandular secretions Incomplete mydriasis – ↓ secretions of digestive blockade of sympathetic juices from the stomach nerve supply to the iris and intestine by blocking Cause partial paralysis of the parasympathetic accommodation and so ganglion patients may suffer from ↓ saliva and sweat and blurred vision and therefore patients may difficulty in focusing the complain of dry mouth eye www.knust.edu.gh  Adverse effects GIT Sex organs ↓ tone and motility on all Serious consequence in the parts of the GIT sexual performance of the results in slowing of gastric male, often producing emptying after meals complete impotence – ejaculation and erection are constipation affected paralytic ileus in very high doses Urinary bladder Blockade of the parasympathetic ganglia produce difficulty in emptying of the bladder and this may www.knust.edu.gh lead to serious urinary retention  Other blockers Mecamylamine (Inversine®) Pentolinium Pempidine Trimethaphan www.knust.edu.gh Nicotinic Pharmacology (Neuromuscular blockers) www.knust.edu.gh  Learning objectives Describe neurotransmission at the neuromuscular junction State that there are two distinct types of neuromuscular blocking agents which are used as surgical adjuncts during general anesthesia to produce skeletal muscle relaxation -competitive antagonists which compete with endogenous ACh and include d-tubocurarine (prototype), Pancuronium and Vecuronium. -persistent blockers e.g. succinylcholine (suxamethonium) www.knust.edu.gh  Learning objectives Recognize that these agents primarily differ in how they affect the cardiovascular system and how much histamine they release. Assess how various drugs such as aminoglycoside antibiotics and certain general anesthetics can interact with competitive neuromuscular blockers. List the particular reversible AChE inhibitors used to treat an overdose of a competitive blocking drug. www.knust.edu.gh  Learning objectives Specify that the drug Dantrolene acts directly on skeletal muscle to produce relaxation; also, that it is used to treat malignant hyperthermia, multiple sclerosis and stroke. Cite that the cholinergic toxin (botulinum toxin) is now used to treat blepharospasm and to cosmetically reduce facial aging and to treat cerebral palsy spasms. Recognize that the centrally acting drug cyclobenzaprine is used to treat muscle spasms and may have a lower abuse potential than other drugs used to treat muscle spasms. www.knust.edu.gh  Why neuromuscular blockers? Neuromuscular blocking drugs are used to induce complete skeletal muscle relaxation in surgery www.knust.edu.gh  General properties of neuromuscular blockers Paralyze skeletal muscle by interfering with the normal skeletal muscle activation or reactivation (i.e. depolarization by ACh and /or subsequent depolarization) via the nicotinic receptors found on skeletal muscle at the neuromuscular junction. Used specifically (and commonly) to paralyze skeletal muscle e.g. for surgery, some diagnostic procedures. Virtually all skeletal muscles in the body are paralyzed when therapeutic doses are given www.knust.edu.gh  General properties of neuromuscular blockers Do not affect sensory function/sensory nerves (e.g. sensation of pain), nicotinic receptors in autonomic ganglia, or muscarinic receptors on any structures Have no major direct autonomic effects (they act only on structures innervated by the somatic nervous system) Do not affect the CNS or alter level of consciousness (assuming patient’s ventilation, cardiovascular functions are supported at normal levels) www.knust.edu.gh  General properties of neuromuscular blockers 1º cause of death from over dosage or improper use is ventilatory impairment/apnea (asphyxiation) 1º treatment for (and prevention of) this is mechanical support of ventilation (+ cardiovascular function as needed) All of these drugs can have an adverse effect on respiration Can cause respiratory paralysis by either antagonizing action of ACh at motor endplate region of diaphragm and intercostal muscles or by causing receptor desensitization. www.knust.edu.gh  Persistent Depolarization Blockers (Prototype-succinylcholine) Mechanism of action: These drugs produce contraction of skeletal muscles (quickly, intensely activates nicotinic receptors on skeletal muscles by acting sort of like a “super ACh”) but they are not destroyed immediately as ACh is and therefore the depolarization persists and it is this persistent depolarization that blocks the neuromuscular junction (agonists which initially cause persistent depolarization followed by receptor desensitization) www.knust.edu.gh  Persistent Depolarization Blockers Effects NOT surmountable: cannot overcome or reverse effects (paralysis) i.e. administering AChE-Inhibitor does not reverse drug effects and may actually prolong/intensify them. Normal muscle function restored naturally and rapidly as effects of drug wear off due to metabolism by plasma ChE. When used clinically, they initially produce muscle fasciculation prior to muscle relaxation These drugs elevate plasma K+ levels www.knust.edu.gh Succinylcholine (Succinyldiacetylcholine – Suxamethonium) Anectine™ Short acting depolarization neuromuscular blocker Typical dose of 1mg/kg iv produces complete neuromuscular blockade. Occasionally it may be given i.m/s.c 50% blockade recovery occurs within 10min Muscle fasciculation occurs prior to paralysis www.knust.edu.gh  Succinylcholine Patients receiving drug often complain of muscular pain about 1-3 days after the operation (because of the intense contractile effects of the drug) ↑ intra ocular pressure A second dose of suxamethonium inj. shortly after the first dose leads to bradycardia or even cardiac arrest mainly due to vagal stimulation. Atropine can prevent/block this cardiac arrest www.knust.edu.gh  Pharmacokinetics Rapidly eliminated by metabolism via plasma ChE For normal person 2 other routes are important: Alkaline hydrolysis - 5% inj. drug destroyed in 1 hr. Renal excretion – 2% excreted unchanged www.knust.edu.gh  Pharmacokinetics Patients with genetic deficiency of ChE have these 2 other routes as the only means of eliminating the drug and in such patients the duration of action of the drug is very much prolonged. If the duration of action lasts for hours, there is no effective way of eliminating the drug and hence artificial respiration or passive pressure ventilation is initiated. The diaphragm is the last skeletal muscle to be attacked by the drug www.knust.edu.gh  Pharmacokinetics Muscle relaxation is first seen in the eyelids of patients Paralysis in normal patients lasts for about 2-6 min AntiChE e.g. Tacrine is used to potentiate the effect of suxamethonium www.knust.edu.gh  Important Adverse Reactions & Considerations Contra-indicated when there is ocular trauma or glaucoma – risk of damage to the eye. Succinylcholine can elevate intraocular pressure and should not be used in patients with narrow-angle glaucoma High plasma K + - develop dysrhythmia www.knust.edu.gh  Important Adverse Reactions & Considerations Death mainly from ventilatory failure Complicated by cardiac arrhythmias from hyperkalaemia – intense muscle contractions damage muscle cells which then leak large amounts of K+ in circulation Succinylcholine releases vasodilator histamine and tends to slow heart rate. May be unwise to use in patients taking digitalis-like drugs that compete with K+ to increase ventricular contraction or diuretics that lower plasma K+ levels www.knust.edu.gh  Important Adverse Reactions & Considerations Mainly used for short-term procedures such as endotracheal intubation and to protect skeletal muscle during electroshock therapy Releases histamine so will reduce blood pressure No drug antidote for succinylcholine overdose www.knust.edu.gh  Management Anticipate potential for reaction –monitor closely Body temp. must be reduced with physical means NOT with antipyretics –toxic if high doses are used in attempt to lower temp. Administer Dantrolene – helps to restore normal skeletal muscle function (blocks Ca2+ release from the SR, reduces heat production and muscular tone) Symptomatic/support- focus on ventilation, CV status, correct electrolyte imbalance. www.knust.edu.gh  Others Deccamethonium www.knust.edu.gh Non-depolarization (competitive, curare inhibitors) Blockers prototype- d-tubocurarine Mechanism of action Competitively block nicotinic receptors on skeletal muscle that are normally activated by ACh released from the somatic nerve. This prevents depolarization (activation) of skeletal muscle cells by ACh and leads to paralysis (compete with ACh at nicotinic receptor and act strictly as ACh antagonists when producing skeletal muscle relaxation) These drugs have affinity for the receptor sites at the motor end plate and they bind to the receptor loosely. Since these drugs do not have intrinsic activity, they do not stimulate the muscle Release of ACh goes on normally but the released ACh comes to www.knust.edu.gh find the receptor site already occupied.  Non-depolarization Blockers Effects are surmountable: can overcome effects (paralysis) and restore normal muscle function (before effects of the blocker wear off normally) by making more ACh available to activate the nicotinic receptors. Clinically accomplished by injecting ChE-inhibitor e.g. neostigmine or edrophonium Just before receiving AChEI, patient is pretreated with atropine to prevent unwanted parasympathomimetic effects of AChEI that will arise due to stimulation of muscarinic receptors simultaneously by ACh. www.knust.edu.gh  D-tubocurarine (curare, d-tc) No CNS effect Rarely used because it causes more cardiovascular difficulties than others and also releases more histamine Is broken down if given orally Only used as a surgical adjunct during general anesthesia Reversed by anti-ChE Onset of action not preceded by muscle fasciculation www.knust.edu.gh  D-tubocurarine When inj. effect is maximal in about 4min Has some ganglion blocking activity Hypotension follows the inj. of the drug d-tubocurarine lowers b.p. by releasing histamine and causing some blockade of ganglionic transmission through sympathetic division of ANS Effect on muscle is entirely peripheral www.knust.edu.gh  Pharmacokinetics Principal route of excretion by kidney (unmetabolized drug). Liver and biliary systems provide alternate route of excretion (important in renal failure) Does not affect the fetus and can therefore be used in caesarean sections Given im/iv (may be dissolved in oil and given by deep im to prolong the effect of the drug. Usual iv dose 30mg produces muscle paralysis lasting for about 30 min www.knust.edu.gh  Others Gallamine (flaxedil™) Pancuronium (pavulon™) Vecuronium Alcuronium (alloferin™) www.knust.edu.gh  Drug interactions Certain general anesthetics stabilize postjunctional membrane (i.e., halothane) and make depolarization at nicotinic receptor more difficult. Therefore, dose of a d-tubocurarine-like competitive blocker should be reduced when using one of these anaesthetics Aminoglycoside antibiotics (i.e., neomycin, kanamycin) and tetracycline reduce prejunctional release of ACh by chelating Ca2+. Less ACh arrives at nicotinic receptor for d-tubocurarine- like drug to block. Reduce dose of competitive blocker www.knust.edu.gh  Contraindications Asthma - d-tubocurarine and succinylcholine Narrow-angle glaucoma - succinylcholine Hyperthyroid condition - d-tubocurarine and vecuronium Hyperkalaemia www.knust.edu.gh  Distinction between the two classes Avian skeletal muscle (Day old chick) Results Spastic paralysis – Persistent blockers Flaccid paralysis – Competitive blockers www.knust.edu.gh  Caution Neuromuscular blockers should NEVER be administered for any reason, by anyone who is not extremely familiar with their safe use and who can provide rapid intervention in case “something wrong” occurs. -only anaesthesiologists and nurse anaesthetists not the average doctor or nurse www.knust.edu.gh