Cholinergic and Anti-cholinergic Drugs PDF

Cholinergic and Anti-cholinergic Drugs Maher Khdour Prof. Clinical Pharmacy AL-Quds University  Cholinergic System...

Cholinergic and Anti-cholinergic Drugs Maher Khdour Prof. Clinical Pharmacy AL-Quds University  Cholinergic System > "Parasympathetic * Acetyl-choline acts through 2 main group of receptors. 1) Muscarinic or "M" receptors : af M1 receptor > - C N S.. Stimulation and increase Stomach HCL Secretion. b) M ? receptor > - heart inhibion c )M? receptor. -> Smooth muscles stimulation "bronchi, intestinal and urinary bladder" and Stimulation of exocrine gland Secretion Sweat "Salivary and gland" Note : M3 receptor > - inhibition of sphincter. 2) Nicotinic Receptor :· at Nn receptor > - Stimulation of autonomic ganglion b) Nm receptor > - Stimulation of Skeletal muscles contraction. * Cholinomimetic drugs drugs With Cholinergic act" - the most famous group is the reservable "Anticholine esterase". Which preserve the acetylcholine release from cholinergic nerves to mediate their action. it includes Carbamates "physostigmine and neostigmine" · A Indication - therapeutic use > - 1) Due to their action on Nm receptor of Skeletal muscles (termination of newSubcotines-neostigmine. ) Due 2 to their action on M3 receptor (post operative paralytic ileus /'Subcotines-neostigmine a s i y s: -neostigmine m e d- %1000m 3) Due to their C N.. S actions : + Toxicity of atropine or atropine like drug "Subcotines-physostigmine brain :8 Atropine * Alzheimer dementia (donepezil) "Aricept" & Adverse effects > - 1) Muscarinic : Salivation , anorexia , nausea , vomiting , peptic ulcer , Colic , diarrhea : bronchospasm , urination , miosis , bardycardia 2) Nicotinci : fasciculation - ( Nm receptor 3) C N S.. : Irritability and Convulsion -) 15  Anti Cholinergic * Anticholinergic drugs "Atropine · Mechanism of action > - is the Competitive antagonist at the muscarinc receptors. · Therapeutic uses > - 1) C. N S. indications : as vomiting of motion Sickness Hyoscine Coral , perinteral , transdermal) b). Parkinsonism-benzatropine 2) Cardiac indications : Atropine is used in pre-anesthetic medication to abish the Veyal reflex that can lead to Cardiac arrest during surgical operation. 3) Smooth muscles indication : as Antispasmotic (Cholic , irritable bowel Syndrome) "hyoscine butyl bromide or dicyclomine" b) nocturnal nursis in childran · urinary urgency in adults buds Oxybutinin c) bronchodilator (generalized obstructive pulmonary diseases , bronchial asthma) Ipratropium. 4) treat. Exocrine gland indications : Hyperhidrosis n · Adverse effect and toxicity of Atropine - 1) C N S.. Stimulation is susceptible patients and madness in toxic closes 2) Cardiac - Tachycardia 2 , jsslis Mis 84 - 3) Smooth muscles > - a eye lthing , glaucoma in patient With shallow anterior chamber of eye : Complete blindness occurs in toxic closes b. Vesceral Smooth muscles (constipation ? bladdeck curine retention in male patients with prostatatic hypertrophy ( 9) Exocrine Gland > - a. Dry mouth b. complete dryness of Skin that can leads to hain toxic doses C. Dryin 5.1 -31.) 5 Vasodilation - flushing in toxic closes Summary of Neurohumoral Transmission: 54159 is 3 Comparison of Somatic and Autonomic Systems contracation Li adrenal Nil 4  Somatic Nerves Axon of the motor neuron leaves the spinal cord and travels without interruption to the skeletal muscle No gangila Faster response than in ANS Alpha Motor Neuron Innervated Muscle Fibers  1 - sty st Sympathetic Nerves Preganglionic fibers originate from the thoracic and lumbar region of the spinal cord (T1 to L2) Preganglionic nerve endings are highly branched Adrenal medulla Innervated by sympathetic preganglionic nerve and releases epinephrine, and little amounts of norepinephrine Ach NE Cord Ganglia Target Organ Short Preganglionic Long Postganglionic  di Parasympathetic Nerves The preganglionic nerves arise from 1. Cranial Nerves III (oculomoter), VII (facial), IX (glossopharyngeal), X (vagus) 1973 2. Sacral spinal cord (S2, S3, S4) The post ganglionic neurons innervate most of the organs in thoracic and abdominal cavity Ach Ach Cord or CNS Ganglia Target Organ Long Preganglionic Short Postganglionic 8  3 F & 18 Parasympathetic: craniosacral 1973 and s2 and s3, S4 Sympathetic : thoracolumbar T1-L2  Sympathetic System: Fight or Flight Sympathetic system is most active when the body needs to react to changes in the internal or external environment: Temperature regulation Regulation of glucose levels Rapid vascular response to hemorrhage Reacting to oxygen deficiency  Sympathetic Reaction: Fight or Flight During rage or fright the sympathetic system can discharge as a unit--affecting multiorgan systems. Increase heart rate Increase blood pressure Increase blood flow to skeletal muscles and heart Increase blood glucose Bronchioles dilatation Pupils dilatation Many of these effects are primarily due to epinephrine release from the adrenal medulla.  Parasympathetic Responses: Rest and Digest Parasympathetic system controls more discretely, reducing the level of resting organ function. Slows heart rate Lowers blood pressure Increases gastrointestinal motility Protects retina from excessive light (Pupil: constricts) Empties the bowel and bladder contraction Promotes absorption of nutrients 13 14  1- Synthesis 2- Storage 6- Recycling of choline 3- Release & release ACh 5- Degradation 4- Binding to of ACh the receptor Y - 1 s% S %. : choline-acetate n ACh i. 15 Botulinum toxin (Botox) is a neurotoxic protein produced by the bacterium Clostridium botulinum and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction and thus causes flaccid paralysis. Infection with the bacterium causes the disease botulism Is botulinum toxin the same as Botox? Botox is a drug that weakens or paralyzes muscle.... Botox is a protein made from botulinum toxin that the bacterium Clostridium botulinum produces. This is the same toxin that causes botulism. Botox is a toxin, but when people use it correctly and in small doses, it has a number of medical and cosmetic uses 16  Cholinergic Receptors Two types, determined by: Location Action once stimulated Nicotinic receptors xxxxx -1 Muscarinic receptors  Muscarinic Receptors Located postsynaptically: – Smooth muscle – Cardiac muscle – Glands of parasympathetic fibers – Effector organs of cholinergic sympathetic fibers (sweat glands) The five muscarinic receptor subtypes, M1 - M5, are associated with specific anatomical sites. For example: – M1: ganglia; secretory glands – M2: myocardium, smooth muscle – M3: bladder, smooth muscle, secretory glands Drugs affecting muscarinic receptors, at high concentration may show some nicotinic  Drug Effects of Cholinergic Agents: “Rest and Digest” “SLUDGE” Salivation Lacrimation (secretion and discharge of tears) Urinary incontinence Diarrhea Gastrointestinal cramps - Emesis ⑤-  DUMBBLESS: Diarrhea, urination, miosis, Bradycardia, bronchoconstriction, emesis, lacrimation, salivation, sweating 20  Effects of Cholinergic Agents Stimulate intestine and bladder – Increased gastric secretions – Increased gastrointestinal motility – Increased urinary frequency Stimulate pupil: Constriction (miosis) Increased salivation and sweating Cardiovascular effects – Decreased heart rate – Vasodilation Respiratory effects: Bronchial constriction 22 Cholinergic Agents: Direct-acting Choline Esters Alkaloids Acetylcholine Muscarine Bethanechol Pilocarpine Carbachol Methacholine  Major Contraindication to the Use Asthma: of Muscarinic Agonists Choline esters (muscarinic agonists) can produce bronchoconstriction. In the predisposed patient, an asthmatic attack may be induced. Hyperthyroidism: Choline esters (muscarinic agonists) can induce atrial fibrillation in hyperthyroid patients. Peptic ulcer. Choline esters (muscarinic agonists), by increasing gastric acid secretion, may exacerbate ulcer symptoms. Coronary vascular disease. Choline esters (muscarinic agonists), as a result of their hypotensive effects, can further compromise coronary blood flow INDIRECT-ACTING CHOLINERGIC AGONISTS: ACETYLCHOLINESTERASE INHIBITORS (REVERSIBLE) - ACh to acetate and choline and, thus, AChE cleaves terminates its actions. It is located both pre- and postsynaptically in the nerve terminal where it is membrane bound. & Inhibitors of AChE results in the accumulation of ACh in the synaptic space. The reversible AChE inhibitors can be classified as: – short-acting agents – intermediate-acting agents. 26  Anticholinesterases: Reversible: Physostigmine, Neostigmine, Pyridostigmine, Edrophonium (Short –acting) Acht – It is used to stimulate the bladder and GI tract – An antidote for tubocurarine and other competitive neuromuscular- blocking agents – Used symptomatically to treat myasthenia gravis (MG) Rivastigmine, Galantamine, Donepezil (short) – Alzihimer – Delay progression Can NOT stop it 27  8 -je - · : Pralidoxime trimedoxime igg and obidoxime For OP and insecticide poisoning INDIRECT-ACTING CHOLINERGIC AGONISTS: ANTICHOLINESTERASES (IRREVERSIBLE) A number of synthetic organophosphate compounds have the capacity to bind covalently to AChE. The result is a long-lasting increase in ACh at all sites where it is released. Many of these drugs are extremely toxic and were developed by the military as nerve agents. Related compounds, such as parathion, are used as insecticides. E.g., Echothiophate , Parathion, diisopropyl 29  Organophosphate Antidote: Pralidoxime and/or Atropine Pralidoxime binds to organophosphates and breaks alkyl phosphate-cholinesterase bond to restore activity of acetylcholinesterase Use with atropine, which affects muscarinic receptors; pralidoxime's actions most striking at nicotonic sites (increase muscle strength 10-40 min) Pralidoxime administered as 15-30 min. IV infusion Summary 31 Anti-Cholinergic Drugs 32  Anticholinergics Mainly Anti-Muscarinic Most anticholinergic drugs interact with the muscarinic receptors in the brain, secretory glands, heart, and smooth muscle Mechanism of Action and Effects – Act by occupying receptor sites at parasympathetic nerve endings, thereby leaving fewer receptor sites free to respond to acetylcholine 33  2. Therapeutic uses of Atropine: a. Ophthalmic : madryasis a. Antispasmodic: used as an antispasmodic agent to relax the GI tract and bladder b. Cardio vascular : Bradycardia treatment 9 c. Bronchodilator and Antisecretory: Atropine used to block secretions in the upper and lower respiratory tracts prior to surgary d. Antidot for cholinergic agonists: Treatment of overdoses of: Cholinesterase inhibitor Ackfinares Insecticides and organophosphates Block effects of acetylcholinesterase (AChE) inhibitors such as physostigmine in the brain. Mine is low Hi  They are classified into: 1. Alkaloids – naturally occurring Atropine Neusea Scopolamine > - vomiting 9000.. $10 in 1. Tertiary amines Dicyclomine 361158 - Benztropine > - S.10 y 2. Quaternary amines - & 2- Ipratropium short acting Long acting Tiotropium (Spiriva) COPD  Atropine—prototype Atropine is a tertiary amine belladonna alkaloid with a high affinity for muscarinic receptors. It binds competitively and prevents acetylcholine (ACh) from binding to those sites  Ipratropium (Atrovent): Tiotropium (long act) bronchodilator. Asthma , COPD Scopolamine, similar to atropine. Depresses CNS and causes amnesia, drowsiness, euphoria, relaxation and sleep. Also good for motion sickness. Given parenterally, orally and transdermally. Benztropine : for tremor in Parkinson Trihexyphenidyl Neuromuscular Blocking Agents 40  Non-Depolarizing Agents Curare > - : , South American Indian arrow poison 5015. Crude material called curare Active principle is tubocurarine Polar, water soluble Prevents access of ACh to its receptor (competitive antagonist) Prevents depolarization of end-plate Relaxes skeletal muscles - I.V only. Very rapid onset 2min - First paralyze fast contracting muscle, Eyes, face, finger, then larg..neck.. Limbs and lastly Diaphragm - Recovery Diagphragm, Limbs, neck, fingers, face.eye - Agents selected depends on onset and duration Therapeutic uses: 1. Adjunct drugs in anesthesia during surgery; would act as skeletal muscle relaxants. 2. Used to facilitate intubation 3. During orthopedic surgery (for example, fracture alignment and dislocation corrections). 46