[PHARMA] Cholinergic Agonists.pdf

PHARMACOLOGY 08/20/2024. MOD 1: CHOLINERGIC AGONISTS Dr. Agnes Vene...

PHARMACOLOGY 08/20/2024. MOD 1: CHOLINERGIC AGONISTS Dr. Agnes Venessa A. Carungcong, MD Trans Group/s: Volunteers I. REVIEW DIFFERENCES OF EFFECTS OF SYMPATHETIC AND PARASYMPATHETIC STIMULATION IN DIFFERENT ORGANS Effector Organ Sympathetic Parasympathetic Eye (Pupil) Dilation Constriction Heart Rate Acceleration Slowing Contractility Increased Decreased Arterioles Skin Constriction – Skeletal Dilation – Muscles Divisions of the Nervous System. Glands Salivary Viscid Secretions Watery Secretion Autonomic nervous system: the unconscious control Lacrimal – Secretion that branch out from the nervous system Sweat Secretion – ○ It is largely independent – its activities are NOT under direct conscious control Bronchial Relaxation Contraction ○ It is concerned primarily with visceral functions, Muscle such as: Cardiac output GI Tract Blood flow to various organs Muscle Wall Relaxation Contraction Digestion Sphincters Contraction Relaxation ○ The efferent portion is further divided to sympathetic, parasympathetic, and enteric division. Urinary Bladder The sympathetic division is related to the Fundus Relaxation Contraction “fight-or-flight” responses of the individual Trigone; Contraction Relaxation The parasympathetic normally functions for the “rest Sphincter and digest” responses of the body. Cholinergic neurons are primarily found in the Penis Ejaculation Erection parasympathetic nervous system, however they also participate in the sympathetic innervation of: Uterus Relaxation – ○ Sweat glands ○ Blood vessels Metabolism ○ Skeletal muscles Liver Gluconeogenesis – Kidney Glycogenolysis – Fat cells Renin secretion – Lipolysis Penis: “Point and Shoot” ○ Parasympathetic: Point = Erection ○ Sympathetic: Shoot = Ejaculation A. ACETYLCHOLINE Main neurotransmitter in cholinergic transmission Mediates transmission of nerve impulses across autonomic ganglia in BOTH sympathetic and parasympathetic nervous system Neurotransmission in cholinergic neurons involves 6 sequential steps Parasympathetic Nervous System. Critical functions are downregulated because the body does not need them. Pharmacology- Mod 1 Cholinergic Agonists 1 of 6 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ They are G-protein coupled receptors. Synthesis and Release of ACh from the cholinergic neuron. Acetylcholine Receptors. NEUROTRANSMISSION IN CHOLINERGIC NEURONS II. CHOLINERGIC AGONISTS Choline acetyltransferase Cholinergic agonists drugs mimic the effects of Synthesis of 1 catalyzes ACh synthesis from parasympathetic stimulation or activation, also known as ACh choline and acetyl-CoA parasympathomimetics. ACh is protected from A. PARASYMPATHETIC ACTIVATION Uptake into degradation in the vesicle, to Parasympathetic nerves operate when the body is at 2 storage vesicle be released later on and bind to rest, allowing energy assimilation and storage → “rest a receptor. and digest” Release is blocked by Release of botulinum toxin PARASYMPATHETIC RESPONSES 3 ACh Spider venom causes release of Ach ↓ heart rate Heart ↓ blood pressure Postsynaptic receptor is Decreased cardiac activity Binding to the 4 activated by binding of the receptor ↑ secretion neurotransmitter ↑ peristalsis Unbound ACh in the synaptic GI tract ↑ secretion of intestinal fluids Degradation of cleft is rapidly hydrolyzed by ↓ sphincter tone 5 Sped up transport of intestinal contents ACh acetylcholinesterase in the synaptic cleft ↑ secretion (copious, liquid) Choline is taken up by the Saliva Secretion of saliva and intestinal fluid Recycling of neuron again for recycling promotes the digestion of food. 6 choline This transport is inhibited by hemicholinium Constriction Bronchi ↑ secretion ↑ bronchomotor tone → ↓ tidal volume Acetylcholine is released → bind to a postsynaptic receptor → cholinergic response or a presynaptic ↑ wall tension via activation of detrusor receptor → inhibiting further release of acetylcholine → Bladder ↓ sphincter tone; relaxation negative feedback loop. Emptying of urinary bladder (micturition) B. ACETYLCHOLINE RECEPTORS Miosis Both nicotinic and muscarinic receptors are targets of Accommodation for near vision acetylcholine and are therefore called cholinergic Activation of ocular parasympathetic receptors. Eyes fibers → narrowing of the pupil & ↑ Nicotinic cholinergic receptors are ligand-gated curvature of the lens → objects brought channels. into near vision ○ When acetylcholine binds to them, receptors undergo conformational change, allowing sodium ions to flow into the cells. Cholinergic agonist drugs that mimic the effect of Nm (muscle type): found in NMJ and are responsible acetylcholine are expected to produce responses for muscle contraction related to parasympathetic activation. Nn (neuronal type): found in the CNS and is mainly Maybe a good or bad thing. involved in the transmission of cholinergic signals. Muscarinic receptors: have a high affinity for muscarine. Pharmacology - Mod 1 Cholinergic Agonists 2 of 6 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 1. INDICATIONS FOR USAGE OF CHOLINERGIC AGONISTS ○ ↑ peristalsis Indications for the use of cholinergic agonists include Combined effect of ↑ bronchial conditions for which these responses would benefit the Lungs secretion and constriction can interfere patient. with breathing Example: ○ Atonic bladder → induce urination Such as that of urinary bladder, GI, and ○ Post-operative gastroparesis → promote bronchiolar smooth muscles peristalsis and facilitate digestion Smooth Contract in response to ACh or other ○ Glaucoma → facilitate movement of the aqueous muscle muscarinic agonist drugs humor to decrease intraocular pressure ↑ tone of detrusor muscle of urinary bladder → urination 2. CONTRAINDICATIONS FOR USAGE OF CHOLINERGIC AGONISTS ACh induces miosis or pupillary Contraindications that would not permit exaggerated constriction in response to ciliary parasympathetic activation in specific organ systems Eyes muscle contraction ○ e.g. mechanical obstruction in the GIT or Ophthalmic solution is sometimes used genitourinary tract → increasing peristalsis on top of to produce miosis during eye surgery. an obstruction → create more serious problems 2. BETHANECHOL WAYS CHOLINERGIC AGONIST DRUGS ENHANCE CHOLINERGIC TRANSMISSION CHARACTERISTICS OF BETHANECHOL Choline esters Strongly muscarinic DIRECT NO nicotinic agonist activity Activity Alkaloids Selectively stimulates urinary and GIT Reversible Acetylcholin-esterase Hydrolysis INDIRECT NOT hydrolyzed by AChE inhibitors Reaction Irreversible Commonly for atonia of the bladder Direct-acting cholinergic agonists mimic the effects of ○ e.g. in neurogenic cases, acetylcholine by binding to either muscarinic or nicotinic post-partum, or postoperative receptors. period with urinary retention Indirect-acting cholinergic agonists work by binding Uses Sometimes given orally or to Acetylcholinesterase (AChE). subcutaneously to treat urinary ○ The result is the buildup of acetylcholine in the retention or to treat gastrointestinal synaptic cleft and corresponding cholinergic effects. lack of muscular tone. III. DIRECT-ACTING CHOLINERGIC AGONISTS Drug-inducing increases in peristalsis are Increasing ACh release with choline esters or alkaloids contraindicated in the presence of an obstruction, as this may endanger rupture of a viscus A. ENDOGENOUS CHOLINE ESTERS 3. CARBACHOL 1. ACETYLCHOLINE Produces non-specific cholinergic effects. CHARACTERISTICS OF CARBACHOL Rapidly deactivated by Acetylcholinesterase. Very limited clinical use. Both muscarinic and nicotinic agonist Activity Prototypical direct-acting cholinergic agonist drug activity Expected to elicit majority of the responses expected of parasympathetic stimulation Hydrolysis NOT hydrolyzed by AChE Reaction SYSTEMIC EFFECTS OF ACETYLCHOLINE Commonly used for glaucoma treatment by local application in the Mimics vagal stimulation eye ○ ↓ cardiac rate ○ Carbachol facilitates draining of ○ ↓ AV node conduction velocity aqueous humor into the canal ○ ↓ force of contraction of Schlemm by realigning the Heart ○ ↓ SA node firing = ↓ stroke volume connective tissue trabeculae Normally regulated by vagal activity by Uses through which the canal of releasing ACh at the SA node Schlemm passes → decreasing ↓ blood pressure due to vasodilation is intraocular pressure also experienced with ACh Sometimes used for bladder and bowel atonia when systemically Speeds up digestion administered GI tract ○ ↑ salivary secretion Sometimes used locally to constrict ○ ↑ intestinal secretion the pupil during eye surgery. Pharmacology - Mod 1 Cholinergic Agonists 3 of 6 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. B. ALKALOIDS REVERSIBLE INDIRECT-ACTING ACETYLCHOLINESTERASE INHIBITORS ALKALOIDS 1 Edrophonium 1 Pilocarpine 2 Physostigmine 2 Muscarine 3 Neostigmine 3 Arecholine 4 Pyridostigmine 1. PILOCARPINE 5 Tacrine CHARACTERISTICS OF PILOCARPINE 6 Donepezil Structure Tertiary amide 1. EDROPHONIUM Hydrolysis Stable to hydrolysis by AChE Reaction CHARACTERISTICS OF EDROPHONIUM Activity Muscarinic Prototypical short acting AChE Function inhibitor Primarily for ophthalmology The drug of choice for emergency Quaternary amine – actions are Structure lowering of intraocular pressure in both limited to the periphery open- and closed-angle glaucoma Extremely effective in opening Reversibly binds to the active center trabecular meshwork around the MOA of AChE and inhibits it, consequently Uses canal of Schlemm → an immediate preventing hydrolysis of ACh drop in intraocular pressure as a result of increased drainage of aqueous Rapidly absorbed humor PK Short duration of action (10 - 20 mins) Very useful in treating acute Rapid renal elimination glaucoma attack Mainly used for the diagnosis of Occurs within a few minutes Myasthenia Gravis (MG) Action Lasts 4-8 hours ○ Improvement of muscle Can be repeated strength by anticholinesterase is characteristic of MG, but does Treatment of xerostomia (dry mouth) not occur when muscle weakness following head and neck radiation is due to other causes therapy. Other uses: Other uses Uses Sjogren’s syndrome ○ Assess cholinesterase inhibitor ○ CEVIMELINE: preferred drug therapy over pilocarpine ○ Differentiate between cholinergic vs. myasthenic crisis Blurred vision ○ Reversing the effects of A/E Night blindness non-depolarizing Brow ache neuromuscular blockers after surgery Exaggerated parasympathetic effects whose clinical manifestation includes 1.1 MYASTHENIA GRAVIS Pilocarpine profuse sweating (diaphoresis) and Poisoning increased salivation Autoimmune disease caused by antibodies to the Antidote: atropine (muscarinic nicotinic receptor at the NMJ causing nicotinic receptor antagonist drug) degradation making fewer receptors available for interaction with ACh. Intravenous (IV) injection of edrophonium → rapid IV. INDIRECT-ACTING CHOLINERGIC AGONISTS increased in muscle strength Inhibits cholinesterase enzymes that would result in Caution: excessive edrophonium → cholinergic crisis increasing the pool of ACh by preventing its degradation ○ Antidote: Atropine by such enzyme The treatment for Myasthenia Gravis is Pyridostigmine, AChE-inhibitors can provoke responses to both and Edrophonium is solely used for its diagnosis. nicotinic or muscarinic receptors and can either be reversible or irreversible 1.2 CHOLINERGIC VS. MYASTHENIC CRISIS A. REVERSIBLE INDIRECT-ACTING CHOLINERGIC MYASTHENIC ACETYLCHOLINESTERASE INHIBITORS CRISIS CRISIS Effects are all cholinergic or one that mimics parasympathetic stimulation Pharmacology - Mod 1 Cholinergic Agonists 4 of 6 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ NOT used to stop the progression of Alzheimer’s Excess ACh at the disease neuromuscular Causes of junction, producing Muscle depolarization ACh deficiency 3. CHOLINERGIC CRISIS Weakness blockade similar Adverse effect of reversible cholinesterase inhibitors to one produced (parasympathomimetics) by succinylcholine Neuromuscular junction is overstimulated due to excessive ACh or cholinesterase inhibitors Increase ACh Muscle stops responding due to ACh bombardment Effect of Worsen muscle levels resulting in leading to: Edrophonium weakness increased muscle ○ Flaccid paralysis and respiratory failure with or strength without myosis ○ ↑ sweating and salivation 1.3 TENSILON TEST ○ ↑ bronchial secretions To determine muscle weakness due to Myasthenia B. IRREVERSIBLE INDIRECT-ACTING Gravis CHOLINESTERASE INHIBITORS ○ 2 mg of IV Edrophonium is given initially ○ Dose is repeated every 2 minutes for a total of 8 mg ○ Wait for improvement in muscle strength over 2 Extremely toxic minutes Developed by the 1 Organophosphates ○ (+) result: rapid improvement (30-45 seconds) in military as nerve facial muscle strength agents Diisopropyl 2 Fluorophosphate (DFP) Forms covalent bonds with AChE leading to a very strong cholinergic stimulation Use is restricted to 3 Echothiophate open-angle glaucoma only. Result of Tensilon Test. Rarely used today due to the side 2. OTHER REVERSIBLE CHOLINESTERASE INHIBITORS effects associated with cholinergic OTHER REVERSIBLE CHOLINESTERASE stimulation INHIBITORS 4 Malathion DRUG INDICATIONS 5 Nerve Gases PHYSOSTIGMINE Intestinal / Bladder atony 1. ORGANOPHOSPHATES NEOSTIGMINE Neuromuscular blockade reversal CHARACTERISTICS OF ORGANOPHOSPHATES PYRIDOSTIGMINE Myasthenia gravis Formulation Generally dispersed as aerosols or dust TACRINE Improve cognitive function Structure Highly Lipid soluble = HIGHLY TOXIC in Alzheimer’s disease DONEPEZIL Rapidly absorbed in ○ Skin, mucus membranes Physostigmine stimulates both nicotinic and muscarinic following contact with moisture receptors. ○ Lungs after inhalation ○ Intermediate-acting (duration of action: 30 mins - 2 Kinetics ○ GI tract after ingestion hrs) Metabolized by both plasma and ○ Used in treatment of overdoses of anticholinergic liver esterases drugs such as atropine Excreted in urine as hydrolysis Neostigmine is an intermediate-acting agent. products ○ Used for myasthenia gravis ○ Stimulates bladder and gastrointestinal tract Pyridostigmine is similar to neostigmine. V. CHOLINERGIC INTOXICATION Donepezil, Rivastigmine, and Galantamine relieve “DUMBBELS” symptoms of Alzheimer’s disease by enhancing ○ Diarrhea cholinergic effects, leading to somewhat improved ○ Urination cognitive function. ○ Miosis & Muscle Weakness ○ Bronchorrhea Pharmacology - Mod 1 Cholinergic Agonists 5 of 6 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ Bradycardia ○ Some central muscarinic effect of excessive ○ Emesis cholinergic stimulation ○ Lacrimation Has NO EFFECT against peripheral neuromuscular ○ Salivation compromise Procedure: Initial 2-4 mg administered IV / IM A. TYPES (Intravenous or Intramuscular), then 2 mg IV every 5 to 10 minutes until muscarinic symptoms disappear. 1. SEVERE ACUTE INTOXICATION 2. PRALIDOXIME Often seen in organophosphate poisoning Includes a mix of muscarinic and nicotinic excess Reverses both muscarinic and nicotinic effects on with generalized cholinergic stimulation the NMJ of skeletal muscles such as: Presents with: ○ Fatigability ○ Extreme salivation and sweating ○ Generalized weakness ○ Involuntary urination ○ Involuntary twitching ○ Hypotension ○ Fasciculation ○ Bradycardia ○ Paralysis of respiratory muscles BUT NOT that ○ Paralysis of motor function → induce difficulty in of CNS effects breathing to respiratory paralysis Procedure: Administer 1-2 g IV infusion over 5 mins ○ Muscle twitching then repeated every 20-60 minutes until desired effect ○ Convulsions is reached ○ Intense miosis VI. SUMMARY 2. CHRONIC INTOXICATION Cholinergic agonist drugs enhance cholinergic Slowly progressive peripheral nerve demyelination transmission in two ways Presents with: ○ DIRECTLY: by increasing acetylcholine release ○ Progressive muscle weakness ○ INDIRECTLY: by targeting the enzyme that ○ Sensory loss normally degrades it (cholinesterase enzyme) Both processes increase the amount of acetylcholine that binds the receptor sites: B.DIAGNOSIS ○ Muscarinic receptor Get a complete history of exposure including certain ○ Nicotinic receptor agents In acetylcholine or cholinergic agonism, expect Look for characteristic signs and symptoms parasympathetic effects in the eyes, GI tract, muscles, Confirmatory: determination of cholinesterase activity and the lungs. in erythrocytes and plasma Indications for use of these drugs depend on the Respiratory failure is a common cause of death in needed parasympathetic stimulation for a particular cholinergic intoxication, and is often heralded with: patient. ○ Laryngospasm Adverse effects are expected with drug-induced ○ Bronchoconstriction overstimulation of the parasympathetic nervous system. ○ Increased tracheobronchial and salivary secretions with compromised voluntary control of the diaphragm, intercostal muscles and latter central respiratory paralysis Time of death: