Cholinergic Pharmacology PDF

CHOLINERGIC PHARMACOLOGY MATTHEW AIDOO Department of Pharmacolog y & Toxicolog y School of Phar macy and Pharmaceutical Sciences University for Development Studies, Tamale 1  OUTLINE ❑INTRODUCTION ❑ANABOLISM AND CATABOLISM OF...

CHOLINERGIC PHARMACOLOGY MATTHEW AIDOO Department of Pharmacolog y & Toxicolog y School of Phar macy and Pharmaceutical Sciences University for Development Studies, Tamale 1  OUTLINE ❑INTRODUCTION ❑ANABOLISM AND CATABOLISM OF ACETYLCHOLINE ❑TYPES AND LOCATION OF CHOLINERGIC RECEPTORS ❑EFFECT OF DRUGS ON CHOLINERGIC TRANSMISSION DRUG STRUCTURE ACTIVITY RELATIONSHIP THERAPEUTIC APPLICATION OF CHOLINERGIC AGENTS 2  INTRODUCTION ❑CHOLINERGIC PHARMACOLOGY The study of pharmacology of agents acting on the cholinergic system Cholinergic system: organized nerve cells that use the neurotransmitter acetylcholine in the transduction of action potentials. These nerve cells are activated by or contain and release acetylcholine during the propagation of a nerve impulse 3 CHOLINERGIC NERVE 4 5  ANABOLISM OF ACETYLCHOLINE 1. BIOSYNTHESIS ACh is synthesized within cholinergic neurons by the transfer of an acetyl group from acetyl CoA to the organic base choline. The enzyme choline-acetyltransferase (ChAT) catalyzes the reaction. 2. UPTAKE INTO STORAGE VESICLES The synaptic vesicles mainly accumulated at the nerve endings are the storage for greater part of neuronal ACh synthesized. Vesicular ACh transporter (VAChT) transport ACh into synaptic vesicles. 6  ANABOLISM OF ACETYLCHOLINE 3. RELEASE Influx of Ca2+ is essential to ACh release from the synaptic vesicles 4. NEUROTRANSMISSION (BINDING TO RECEPTOR) Once released from the nerve terminal, ACh diffuses across the synaptic cleft and acts on post synaptic ACh receptor(s). Activation (binding) of the post synaptic ACh receptor(s) leads to a physiological response. 7  CATABOLISM OF ACETYLCHOLINE 5. DEGRADATION (HYDROLYSIS) ACh is degraded by the enzyme acetylcholinesterase (AChE) located in the synaptic cleft to produce choline and acetate. 6. RECYCLING The choline derived from the hydrolyzed ACh is returned to the presynaptic nerve terminal by choline transporter (ChT) to form ACh (via a Na+-dependent transport process). The acetate is also returned to the presynaptic nerve terminal to form the acetyl portion of acetyl CoA used in another ACh biosynthesis. 8 9  AGENTS AFFECTING ACh ❑BIOSYNTHESIS ❖α-ketoacids, & Naphthoquinones Directly inhibit the enzyme choline acetyl transferase (ChAT), thus inhibiting biosynthesis of ACh via blocking transfer of acetyl group to choline. These have no clinical uses. ❑UPTAKE INTO STORAGE VESICLES ❖Vesamicol: blocks the specific transport i.e. VAChT which transport ACh into the synaptic vesicles. This compound is poisonous and has no clinical use. 10  AGENTS AFFECTING ACh ❑RELEASE ❖Botulinum toxin (a neurotoxin from Clostridium botulinum): inhibits ACh release from presynaptic nerve terminal. ❖Given as injection for: Spasticity (skeletal muscle stiffness or abnormal increase in muscle tone) Blepharospasm (persistent and disabling eyelid spasm) Urinary incontinence (inability to hold urine associated with bladder overactivity – intravesical injection) 11  AGENTS AFFECTING ACh ❑RELEASE ❖Botulinum toxin Strabismus/squint (misalignment of the two eyes; where the eyes do not look in the same direction at the same time) Sialorrhoea (excessive salivary secretion). Primary axillary hyperhidrosis (excessive sweating) Calcium: Agents that chelates & inhibits Ca2+ entry (e.g. Mg2+ and Aminoglycosides) will decrease ACh release, thus will occasionally produce muscle paralysis as side effects. 12  AGENTS AFFECTING ACh ❑RELEASE β-Bungarotoxin (a component of the venom of krait snake), act presynaptically to cause initial inhibition of ACh (causing cessation of spasms), followed by excessive release of ACh causing prolonged muscle spasms Latrotoxin: (a toxin from the black widow spider) produces an explosive release of ACh, causing muscle spasms. ❑NEUROTRANSMISSION Atropine: inhibits muscarinic actions of ACh by blocking postsynaptic muscarinic ACh receptors. 13  AGENTS AFFECTING ACh ❑NEUROTRANSMISSION D-tubocurarine (a alkaloid known for its use as arrow poison): blocks presynaptic & postsynaptic nicotinic ACh receptors at the NMJ preventing nerve impulses from activating skeletal muscles thus causing relaxation of skeletal muscle (paralysis). α-Bungarotoxin: (a component of the venom of krait snake) irreversibly blocks the binding of ACh to postsynaptic nicotinic receptors at the NMJ causing muscle paralysis, respiratory failure and death. 14  AGENTS AFFECTING ACh ❑DEGRADATION Acetylcholinesterase inhibitors: inhibits acetylcholinesterases thus preventing degradation of ACh, increasing concentration of ACh in the synaptic cleft to rebind to muscarinic and nicotinic receptors. ❑RECYCLING Hemicholinium: blocks choline uptake, thereby blocking further synthesis of ACh. It is useful as an experimental tool but has no clinical applications. 15 RECEPTORS TYPES IN PHARMACOLOGY 16  CHOLINERGIC RECEPTORS ❑Cholinergic receptors are receptors on the surface of cells that are activated by the neurotransmitter acetylcholine Two (2) main types of cholinergic receptors 1. Nicotinic ACh receptors (nAChRs) – located on preganglion, ganglion, and post-ganglion. Excess acitivation of nicotinic receptors can lead to receptor desensitization 2. Muscarinic ACh receptor (mAChRs) – mainly postganglionic. Excess acitivation of muscarinic receptors do not lead to receptor desensitization 17 18 19 20  AGENTS ON NICOTINIC RECEPTORS AGENT NN RECEPTORS NG RECEPTOR NM RECEPTORS (neurons, CNS; (autonomic Ganglia; (skeletal muscle): pre and post- mainly postsynaptic mainly postsynaptic) synaptic AGONISTS Acetylcholine Acetylcholine Acetylcholine Nicotine Carbachol Carbachol Varenicline Nicotine Suxamethonium Varenicline ANTAGONISTS α-Bungarotoxin Hexamethonium α-Bungarotoxin Mecamylamine Trimetaphan Tubocurarine Mecamylamine Pancuronium Atracurium Vecuronium 21 22  MUSCARINIC RECEPTORS ❑Five (5) subtypes: M1, M2, M3, M4 and M5 ❖Activation of M1, M3 and M5 [Excitation] Activates phospholipase C →hydrolysis of Phosphatidylinositol biphosphate (PIP2)→ inositol triphosphate (IP3), and diacylglycerol (DAG) →DAG activates protein kinase C and causes calcium influx →IP3 causes sarcoplasmic reticulum to release stored calcium →↑ intracellular calcium → receptor activation (excitation); smooth muscle contraction and exocrine glandular secretion. 23  MUSCARINIC RECEPTORS ❑Five (5) subtypes: M1, M2, M3, M4 and M5 ❖Activation of M2, & M4 [Inhibition] Leads to inhibition of adenyl cyclase (catalyze formation of cAMP from ATP) → decrease↓ [cAMP] →↓ activation of protein kinase A → inhibition of calcium channels and activation of K+ channels (causes efflux of potassium → hyperpolarization) and reduction of action potential generation in the nodal cells (e.g. inhibition of AV conduction →slowing of heart rate & ↓ BP with activation of M2 receptors of the heart) 24  MUSCARINIC RECEPTORS RECEPTOR M1 (Neuronal, CNS) M3 (glands, smooth M5 (CNS) muscles, blood vessels) Location CNS: cerebral cortex Glands: gastric, sweat CNS: localized Glands: gastric, salivary, lacrimal expression in salivary, lacrimal Smooth muscle: GIT, substantia nigra eye, airways, bladder Blood vessels: vascular endothelium Clinical Improved memory Gastric secretion Not known Functional function (cognition) Smooth muscle response CNS excitation contraction Vasodilatation 25  MUSCARINIC RECEPTORS RECEPTOR M2 (Cardiac muscles) M4 (CNS) Location Heart: primarily in SA and CNS (hippocampus) atrioventricular nodal cells Clinical Cardiac inhibition Not known Functional ↓ heart rate response ↓ atrial contractility Central muscarinic effects (e.g. tremor, hypothermia) 26 AGENTS ON MUSCARINIC RECEPTORS AGENT M1 (Neural) M2 (Cardiac) M3 (glands /smooth muscle) AGONISTS Acetylcholine Acetylcholine Cevimeline (selective) Carbachol Carbachol Acetylcholine Pilocarpine Oxotremorine Carbachol Bethanechol Bethanechol Oxotremorine Pilocarpine Oxotremorine ANTAGONISTS Atropine Atropine Darifenacin (selective) Dicycloverine Dicycloverine Atropine Tolterodine Tolterodine Dicycloverine Oxybutynin Oxybutynin Tolterodine Ipratropium Ipratropium Oxybutynin Pirenzepine (selective) Gallamine (selective) Ipratropium 27  EFFECT OF DRUGS ON CHOLINERGIC TRANSMISSION ▪Muscarinic agonists ▪Muscarinic antagonists ▪Ganglion-stimulating agents ▪Ganglion-blocking agents ▪Neuromuscular-blocking agents ▪Anticholinesterases ▪Other agents that enhance cholinergic transmission 28 SAR OF MUSCARINIC AGONISTS 29  SAR OF MUSCARINIC AGONISTS ❑The key features important for activity: 1. Quaternary ammonium group (N+-4C), which bears a positive charge reduces penetration of the compound into the CNS 2. Ester group, which bears a partial negative charge, makes the compound susceptible to rapid hydrolysis by cholinesterase enzyme 3. Choline structure allows for relative affinity for both mAChRs and nAChRs. 30  SAR OF MUSCARINIC AGONISTS ❑The key features important for activity: A. Tertiary ammonium group (N-3C) enhances penetration into the CNS B. Variants of the ester group (e.g. carbamyl group) reduces the susceptibility of the compound to hydrolysis by cholinesterases C. Variants of the choline structure alters the relative affinity for mAChRs and nAChRs i.e. selective 31  MUSCARINIC AGONISTS Methacholine Nicotine 32 Compound Nicotinic receptor Muscarinic Hydrolysis by activity receptor activity Cholinesterase enzyme Acetylcholine +++ +++ +++ Carbachol +++ +++ - Methacholine + +++ ++ Bethanechol - +++ - Nicotine +++ - - Muscarine - +++ - Pilocarpine - +++ - Cevimeline - ++ - Oxotremorine + ++ - Arecoline - ++ - 33  MUSCARINIC AGONISTS ❑These agents, are also known as parasympathomimetics because their main effects resemble those of parasympathetic stimulation ❖Quaternary ammonium muscarinic agonists Acetylcholine, Carbachol, (non-selective muscarinic and nicotinic agonists), Methacholine, Bethanechol, Muscarine. ❖Tertiary ammonium muscarinic agonists Cevimeline*, Pilocarpine, Oxotremorine, Arecoline (non- selective muscarinic agonist except Cevimeline) 34  EFFECTS OF MUSCARINIC AGONISTS ORGAN EFFECT SMOOTH MUSCLES Bronchi smooth muscles Constriction M3 GI smooth muscles Motility ↑ M3 GI Sphincters (lower esophageal sphincter) ↑ LES Pressure M3 Bladder Contraction of detrusor muscles M3 Relaxation of urethral sphincter M3 EYE Pupil Constriction M3, eye accommodation Ciliary muscle Contraction M3, ↓ intraocular pressure 35  EFFECTS OF MUSCARINIC AGONISTS ORGAN EFFECT GLANDS Salivary glands ↑ Salivation M3 Lacrimal glands ↑ Lacrimation M3 Sweat glands ↑ Sweating M3 Bronchi glands ↑Secretion (mucus) M3 GI glands ↑Secretion M3 ↑Gastric acid secretion M1 BLOOD VESSELS Vasodilation M3 due to nitric oxide 36  EFFECTS OF MUSCARINIC AGONISTS ORGAN EFFECT HEART Sinoatrial node Heart Rate ↓ M2 (bradycardia) Negative Chronotropic effect Atrial muscle Force of contraction ↓ M2 Negative Inotropic effect Atrioventricular node Conduction velocity ↓ M2 Negative Dromotropic effect Blood pressure ↓ arterial pressure CNS Improved cognition M1 Excitation M1 37 Compound Clinical uses Acetylcholine None Methacholine Diagnosis of asthma Carbachol Glaucoma, inhibit post operative ↑ of intraocular pressure Bethanechol Urinary retention, Post-operative ileus, Gastro Esophageal Reflux Disease (GERD) Pilocarpine Xerostomia; Sjögren’s syndrome (immune system disorder with dry eyes and dry mouth). Used for Glaucoma Cevimeline Xerostomia; Sjögren’s syndrome Oxotremorine Investigation of antiparkinosin drugs (it produces ataxia, tremor and spasticity similar to the symptoms of Parkinson's disease) Muscarine (toxic alkaloid in certain mushrooms) 38  MUSCARINIC AGONISTS ❑UNWANTED EFFECTS (DUMBBELSS) Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia Excitation of skeletal muscle and CNS, Lacrimation Sweating, Salivation ❑CONTRAINDICATION Asthma or Chronic Obstructive Pulmonary Disease (COPD) Peptic Ulcer Coronary vascular disease Hyperthyroidism 39  MUSCARINIC ANTAGONISTS ❑These agents are also known as parasympatholytics, they are competitive antagonists at muscarinic receptors. ❖Tertiary ammonium muscarinic antagonist Lipid-soluble; readily absorbed from the gut or conjunctival sac and, penetrate the CNS. E.g. Atropine (Atropa belladonna) and Scopolamine/Hyoscine (Datura stramonium) ❖Quaternary ammonium muscarinic antagonists They have peripheral actions, lack CNS actions. E.g. Hyoscine butylbromide, Dicycloverine, Propantheline, Ipratropium, Cyclopentolate, Tropicamide, Gallamine, Pirenzepine, Oxybutynin, Tolterodine, Darifenacin, Glycopyrrolate 40  EFFECTS OF MUSCARINIC ANTAGONISTS ORGAN EFFECT SMOOTH MUSCLES Bronchi smooth muscles Bronchodilatation M3 GI smooth muscles Motility ↓ M3 GI Sphincters (Lower Esophageal ↓ LES Pressure Sphincter) Bladder smooth muscles Relaxation of detrusor muscles M3 Contraction of urethral sphincter M3 Biliary tract smooth muscles Relaxation 41 EFFECTS OF MUSCARINIC ANTAGONISTS ORGAN EFFECT GLANDS Salivary glands ↓Salivation M3 Lacrimal glands ↓Lacrimation M3 Sweat glands ↓Sweating M3 (innervated by sympathetic nerves) Bronchi glands ↓Secretion (mucus) M3 GI glands ↓Secretion M3 ↓Gastric acid secretion M1 42  EFFECTS OF MUSCARINIC ANTAGONISTS ORGAN PARASYMPATHETIC EFFECT HEART Sinoatrial node Heart Rate ↑ M2 (tachycardia) Atrial muscle Force of contraction↑M2 * ↑ arterial pressure * EYE Pupil Dilatation (mydriasis) M3 Ciliary muscle Relaxation M3, ↑ Intraocular pressure 43 EFFECTS OF MUSCARINIC ANTAGONISTS ORGAN EFFECT CNS At low doses, Atropine causes mild restlessness At low doses, Scopolamine causes marked sedation Higher doses of both cause agitation and disorientation Atropine poisoning causes marked excitability and irritability which result in hyperactivity and hyperthermia, which is accentuated by the loss of sweating (blockade of M3 receptors on the sweat glands) 44 EFFECTS OF MUSCARINIC ANTAGONISTS Compound Pharmacological Clinical uses properties Atropine Inhibits action *Sialorrhoea (excessive salivation) (Non-selective of ACh on *Pylorospasm (spasm of pyloric sphincter) smooth muscles, *Adjunct in anaesthesia secretory glands *Organophosphate/carbamate poisoning *Sinus Bradycardia CNS stimulant *Mydriasis/Cyclopegia (eye examination) *Diarrhea (atropine/diphenoxylate) Hyoscine CNS Depressant *Motion sickness (Prevent motion-induced [scopolamine] nausea and vomiting by blocking Non-selective transmission of cholinergic impulses to the vomiting center in the CNS) 45 EFFECTS OF MUSCARINIC ANTAGONISTS Compound Pharmacological properties Clinical uses Hyoscine ↓GI motility *Antispasmodic agent butylbromide (Non-selective) Dicycloverine ↓ GI motility *Antispasmodic agent (Non-selective) Propantheline ↓ GI motility *Antispasmodic agent (Non- selective) ↓ Gastric acid secretion *Peptic ulcer Relaxation of smooth muscles *Urinary incontinence of bladder *Spasms of the bladder ↓LES pressure (exacerbate *Hyperhidrosis (excess GERD) sweating) 46 EFFECTS OF MUSCARINIC ANTAGONISTS Compound Pharmacological properties Clinical uses Pirenzepine Inhibits gastric acid secretion *Peptic ulcer (Selective M1) ↓ motility of GIT, and bladder *Antispasmodic agent *Bladder spasms Oxybutynin Relaxation of detrusor muscles of *Urinary incontinence (Non-selective bladder → (Overreactive bladder) Contraction of urethral sphincter Tolterodine ↓Frequency and urgency to *Urinary incontinence (Non-selective) urinate (void) (Overreactive bladder) Darifenacin Relaxation of bladder *Urinary incontinence (Selective M3) ↓frequency and urgency to void (overreactive bladder) 47 EFFECTS OF MUSCARINIC ANTAGONISTS Compound Pharmacological properties Clinical uses Tropicamide Dilation of the pupil (mydriasis) *Refraction (Non-selective) Relaxation and paralysis of ciliary (Mydriasis) muscles (cyclopegia) *Fundoscopic exam Cyclopentolate Relaxation of the ciliary muscle block (cyclopegia) (non-selective) the trabecular meshwork which obstructs the outflow of aqueous humour (↑ intraocular pressure) Ipratropium Bronchodilatation *Asthma (non-selective) (Relaxation of bronchial smooth *COPD muscles) Tiotropium *Asthma (non-selective) Bronchodilatation *COPD 48 EFFECTS OF MUSCARINIC ANTAGONISTS Compound Pharmacological Clinical uses properties Benzhexol Affect the *Adjunct in Parkinson’s disease (Non-selective) extrapyramidal system, reducing the involuntary *Adjunct with antipsychotic drugs Benztropine movement and rigidity (Counter extrapyramidal side (Non-selective) of patients with effects of antipsychotic drugs) Affinity for M1 Parkinson’s disease in the CNS Glycopyrrolate Decreases↓; salivation, *Used with Neostigmine to (Non-selective) lacrimation, diarrhea, minimize its SE in the reverse of Bradycardia non-depolarizing blocking agents *Used with Atropine to induce bronchodilatation in refractory bronchospasm 49  MUSCARINIC ANTAGONISTS ❑Atropine toxicity Overdose can lead to ↑ antimuscarinic effects; dilated pupils, warm dry skin, tachycardia, tremor, ataxia, delirium, and coma In extreme toxicity, circulatory collapse secondary to respiratory failure may occur after paralysis and coma. ❑Treatment of atropine toxicity Physostigmine is as an antidote to treat delirium and coma of atropine toxicity. It inhibits the degradation of ACh in the brain →↑ACh to antagonize the action of atropine. Short-acting barbiturate or diazepam as needed to abate convulsions or excitations. 50  MUSCARINIC ANTAGONISTS ❑UNWANTED EFFECTS Dry mouth (xerostomia), Nasal dryness Fever, Anhidrosis, Tachycardia Increased intraocular pressure, Angle closure glaucoma Constipation, Delayed gastric emptying, decreased LES pressure (exacerbate GERD) Blurred vision (dilatation of pupils), Dry eyes Drowsiness, insomnia, hallucinations, confusion, delirium, coma Urinary hesitancy and retention 51  MUSCARINIC ANTAGONISTS ❑CONTRAINDICATIONS Dry mouth (xerostomia) Paralytic ileus Narrow-angle glaucoma Myocardial infraction GERD Benign prostatic hyperplasia Urinary retention Myasthenia gravis 52  GANGLION AGONISTS ❑Agonist of nAChRs at autonomic ganglia Both sympathetic and parasympathetic ganglia are stimulated, so effects are complex, including Tachycardia and increase in blood pressure; Variable effects on GI motility and secretions; Increased bronchial, salivary and sweat secretions. Ganglion stimulation may be followed by depolarization blockade E.g. Varenicline*, Nicotine* (act on NN in the CNS; effect is adjunct in smoking cessation), Lobeline, Epibatidine 53  GANGLION BLOCKERS ❑Antagonist of nAChRs at autonomic ganglia Inhibit transmission between preganglionic and postganglionic neurons in the ANS. Their effects are complex: Decrease in blood pressure, bradycardia. Inhibition of secretions, GI paralysis, impaired micturition. Interfere with the postsynaptic action of ACh, blocking nAChRs or the ion channels (Na+), causing non- depolarization blockade E.g. Tetraethyl ammonium, Hexamethonium, Trimetaphan, Mecamylamine, D-tubocurarine, Pentamine etc. 54  NEUROMUSCULAR BLOCKERS ❑Drugs that block neuromuscular transmission either 1. Act presynaptically to inhibit ACh synthesis or release (E.g. botulinum toxin) 2. Act postsynaptically, this being the site of all the clinically important NMBs (except d-tubocurarine) ❑The drugs that act postsynaptically, act either by 1. Blocking nAChRs (or Na+ ion channel) and thus causing non- depolarizing block of the motor endplate of skeletal muscles 2. Activating nAChRs and thus causing persistent depolarization and then blockade of the motor endplate 55  NEUROMUSCULAR BLOCKERS ❑Clinical uses of neuromuscular blocking agents 1. Adjunct in general anaesthesia (skeletal muscle relaxants) 2. Endotracheal intubation to facilitate mechanical ventilation ❖Apart from suxamethonium all of the neuromuscular blockers used clinically are non-depolarizing blockers NMBDs lack analgesic or anesthetic properties So they should not be used WITHOUT anxiolytic or sedation agents or in inadequately anesthetized patients (due to increased risk of awareness during general anesthesia). 56  NON-DEPOLARIZING BLOCKERS ❑Postsynaptic competitive antagonists at the NM receptors on the motor endplate (neuromuscular junction) of the skeletal muscles. Thus they block the binding of ACh to NM receptors, so that motor endplate cannot depolarize (non-depolarizing). This leads to skeletal muscle paralysis (skeletal muscle relaxation) SHORT ACTING INTERMEDIATE ACTING LONG ACTING Mivacurium Atracurium Pancuronium Vecuronium Pipecurium Rocuronium Doxacurium Cisatracurium D-tubocurarine* 57  NON-DEPOLARIZING BLOCKERS ❑ADVERSE EFFECTS Hypersentivity reactions and anaphylaxis reactions Elevations in blood pressure, Skeletal muscle weakness or paralysis Respiratory insufficiency or apnea ❑CONTRAINDICATIONS A prior history of anaphylaxis to one Non-depolarizing NMBD Uncontrolled hypertension, Inadequate sedation Neuromuscular disease (e.g. myasthenia gravis) Absence of ventilator support 58  DEPOLARIZING BLOCKERS ❑Agonists on NM nAChRs on motor endplates of the skeletal muscles and generate an action potential (depolarization by influx of Na+ ions) followed by blockade (due to receptor desensitization) The persistent depolarization of the skeletal muscles, results in muscle fasciculations (spontaneous muscle spasticity) Depolarizing blockers are resistant to hydrolysis by acetylcholinesterases (synaptic cleft), and thus remain bound to the receptor for a longer period. Hydrolyzed by psuedocholinesterases. After persistent depolarization, the skeletal muscles are no longer receptive to ACh released by the motor neurons (receptor desensitization) and this causes depolarizing blockade. 59  DEPOLARIZING BLOCKERS ❑Suxamethonium (Succinylcholine) and Decamethonium Suxamethonium is the clinically useful depolarizing agent (muscle relaxant in anaesthesia) It is the agent of choice in obstetric anesthesia due to its rapid onset and short duration of action It is rapidly metabolized by plasma psuedocholinesterases Also, because it is highly ionized and poorly lipid soluble, only small amounts may cross the placenta. 60  DEPOLARIZING BLOCKERS ❑ADVERSE EFFECTS It ↑ cation permeability of the motor endplates causes a net loss of K+ from muscle, and thus cause rise in plasma K+ levels It can cause malignant hyperthermia (treated with Dantrolene) Muscle fassiculation may result in postoperative pain. Hypotension due to bradycardia, Increased intraocular pressure ❑CONTRAINDICATIONS Severe hyperkalemia Malignant hyperthermia or history of malignant hyperthermia Cardiac dysrhythmias 61  NUEROMUSCULAR ENHANCERS ❑CHOLINESTERASES Enzymes which hydrolyzes ACh and other related compounds in the neuromuscular junction and in other cholinergic synapses to terminate neuronal transmission. There are two (2) distinct types of cholinesterases: 1. Acetylcholinesterase (AChE) 2. Butyrylcholinesterase (BuChE) also known as psuedocholinesterases or plasma cholinesterases 62  CHOLINESTERASES Description Acetylcholinesterase Plasma cholinesterase Location Soluble form in Soluble form in Plasma cerebrospinal fluid, Insoluble form in Cytosols: cholinergic nerve terminals liver, skin, brain and GI Red blood cells smooth muscles Natural Acetylcholine Fatty acyl esters substrate Aromatic esters Test substrates Acetylcholine Acetylcholine (less rapidly) Methacholine Butyrylcholine (more rapidly) Suxamethonium Procaine 63  CHOLINESTERASES ❑Cholinesterase enzyme have two (2) active sites: 1. Anionic site: binds the basic choline moiety (positive quaternary amine of ACh) 2. Esteric [catalytic] site: binds to the acetyl group (ester of ACh). Here, ACh is hydrolyzed to acetic acid and choline. 64  ANTICHOLINESTERASES ❑Cholinesterase/Acetylcholinesterase Inhibitors Inhibit cholinesterase enzyme, thus block the normal breakdown of ACh (and other related compounds) and increase both the levels and duration of action of ACh found in the CNS & PNS. ❑CLINICAL USES Most commonly, used in treating neurogenerative diseases such as Alzheimer disease, and Parkinson disease. Treating patients with psychiatric disorders (schizophrenia) Diagnosis and treatment of patients with myasthenia gravis 65  ANTICHOLINESTERASES ❑CLINICAL USES Reversal of non-depolarizing NMBDs at the end of surgeries (mostly Neostigmine) Antidote in anticholinergic poisoning (mostly physostigmine) Treatment of glaucoma (physostigmine) ❑CLASSIFICATION OF ANTICHOLINESTERASES Short acting Intermediate acting Long acting/irreversible 66  ANTICHOLINESTERASES ❑SHORT ACTING ANTICHOLINESTERASES EDROPHONIUM: a quaternary ammonium compound that binds to the anionic site of the enzyme only. The ionic bond formed is readily reversible, and the action of the drug is very brief, thus it used mainly for diagnostic purposes. It is used for diagnosis of myasthenia gravis, because it improves muscle strength in myasthenia gravis, which does not occur when muscle weakness is due to other causes. Main site of action is the NMJ of skeletal muscles by increasing and prolonging action ACh, but it is too short for therapeutic purposes 67  ANTICHOLINESTERASES ❑INTERMEDIATE ACTING ANTICHOLINESTERASES NEOSTIGMINE, PYRIDOSTIGMINE (quaternary ammonium) and PHYSOSTIGMINE (tertiary amine) They all have carbamyl groups (as compared to acetyl group in ACh) that binds to the esteric site and all possess basic groups that bind to the anionic site Transfer of the carbamyl group to the esteric site (as occurs with acetyl group of ACh), but carbamylated enzyme is very much slower to hydrolyze taking minutes (intermediate duration of action) rather than microseconds with Ach. 68  ANTICHOLINESTERASES ❑INTERMEDIATE ACTING ANTICHOLINESTERASES Neostigmine: Reversal of non-depolarizing NMBDs. It is used in diagnosis and treatment of myasthenia gravis. Pyridostigmine: Reversal of non-depolarizing NMBDs. It is used in treatment of myasthenia gravis, better absorbed and has longer duration of action than neostigmine. Physostigmine: act at the postganglionic parasympathetic junction, as an antidote for anticholinergic (atropine) poisoning. It is used as eye drops in treatment of glaucoma. 69  ANTICHOLINESTERASES ❑REVERSIBLE LONG ANTICHOLINESTERASES ❖DONEPEZIL, RIVASTIGMINE, GALANTAMINE Reversible acetylcholinesterase inhibitor; increases acetylcholine levels in the brain, which inturn enhances cholinergic transmission effect on M1 (improving memory). Elimination half life: 70 hours Indicated for dementia of Alzheimer’s disease (memory loss in AD is associated with cholinergic deficit due to the reduced activity of choline acetyltransferase) 70  ANTICHOLINESTERASES ❑IRREVERSIBLE ANTICHOLINESTERASES Pentavalent phosphorus compounds containing a labile group such as fluoride (DYFLOS) or an organic group (PARATHION AND ECOTHIOPHATE) Irreversible anticholinesterases are mostly organophosphate compounds, used in pesticides and biowarfare (war gases) Pseudo irreversible compounds have clinical indications The pentavalent PO4 group is transferred to the esteric site of the enzyme, causing the esteric site to be phosphorylated which is extremely slow or irreversible to hydrolyzes 71  ANTICHOLINESTERASES ❑IRREVERSIBLE ANTICHOLINESTERASES ❖Pseudo-irreversible anticholinesterases (Ecothiophate): It is used as eye drop in treatment of glaucoma. It has pentavalent phosphorous group that binds to the esteric site and a quaternary nitrogen group that binds to the anionic site. ❖Irreversible anticholinesterases (Dyflos and Parathion): they only have the pentavalent phosphorous group that binds to the esteric site of the enzyme leaving the anionic site unbound. Dyflos: highly toxic with very prolonged action (biowarfare) Parathion: Used as pesticide but causes poisoning in humans 72  CHOLINESTERASE REACTIVATION ❑Spontaneous hydrolysis of phosphorylated cholinesterase is extremely slow or irreversible, a fact that makes poisoning with organophosphates very dangerous. The extent of potential reactivation of organophosphate- inhibited cholinesterases decreases with time, within few hours the phosphorylated enzyme undergoes a chemical change known as “Ageing” Ageing is due to dealkylation of the alkyl group of the compound bound to the enzyme. 73  CHOLINESTERASE REACTIVATION ❑Pralidoxime (2-PAM) reactivates the phosphorylated enzyme by binding to the anionic site of the enzyme and bringing it’s oxime group into close proximity with the esteric site The oxime in 2-PAM is a strong nucleophile and attracts the phosphate group away from the esteric site of the enzyme The main limitation to the use of 2-PAM as an antidote for organophosphate poisoning is due to “ageing” that renders the enzyme no longer susceptible to reactivation. Pralidoxime must be given early in order to work Not approved for treatment of carbamate poisoning, and inorganic phosphates (do not involve cholinesterase activity) 74  CHOLINESTERASE REACTIVATION ❑Pralidoxime does not enter the brain, and thus has no effect on the central actions of organophosphate poisoning. Pralidoxime is also used to reverse anticholinesterases toxicity (e.g. Neostigmine, Pyridostigmine) Pralidoxime relieves neuromuscular weakness (nicotinic receptors NM at skeletal muscles), and Atropine are used concomitantly for the treatment of organophosphate poisoning. Benzodiazepines may sometimes be used when there are convulsions. 75 76 THANK YOU 77