Pharmacology & Therapeutics Of Drugs Auto-Nervous System PDF

1 Pharmacology & Therapeutics of drugs related to the autonomic nervous system Prof. Kannan Sridharan Department of Pharmacology & Therapeutics CMHS, AGU. 2 Rest and digest 3 ...

1 Pharmacology & Therapeutics of drugs related to the autonomic nervous system Prof. Kannan Sridharan Department of Pharmacology & Therapeutics CMHS, AGU. 2 Rest and digest 3  > ach exception : sweat gland - Sympathetic Short ganglion : -pre ganglion long : ve-post Parasympathetic ganglion longshort : am-pre am-post ganglion : -function happen when binding to a receptor 4  Nicotinic Preganglionic SNS & PNS Nn Acetylcholine muscurinic Postganglionic Neurotransmitters PNS M in the ANS 5 types Postganglionic Norepinephrine SNS α, β Alpha & beta 5  Nature of ANS receptors 95 % receptors in body are G-protein GS : increase camp GI : decrease camp GQ : Increase calium 6  Gs – Increase cAMP Gi – Decrease cAMP/Open potassium channel Gq – Increase intracellular calcium concentration Muscarinic receptors Alpha & Beta receptors nicotinic Its not available in receptors. - > ligand gated 7  Nicotine receptors – Ligand-gated ion channels – Allows Na+ entry : G-protein all muscurinic and Alpha-beta receptors Nicotinic receptors : ligand 8  memorize 22 Miosis 14 not significant in Pharmacology The most important muscarinic receptors are M1, M2, and M3. increase calcium - odd numbers are GQ-so they - calcium in muscle - even numbers : GI camp decreased 9  memorize Bronchodilation Uterine relaxation not used in Pharma Alpha-2: Two – Terminal All B's haveGs Weaning off To help you remember the adrenergic receptors and their functions more effectively, we can break it down into simpler patterns and mnemonics: 1. Key Concepts to Focus On: α₁ (Think: Constriction): Causes vasoconstriction and sphincter contraction. α₂ (Think: Inhibition): Inhibits neurotransmitter release. β₁ (Think: Heart): Increases heart rate and force of contraction. β₂ (Think: Relaxation): Causes relaxation in bronchioles, vessels, uterus, and bladder. β₃ (Think: Fat & Bladder): Helps in fat breakdown (lipolysis) and bladder relaxation. α₁ – “Arteries Tighten**”**: Gq increases Ca²⁺ → vasoconstriction (think “tightening” of blood vessels and sphincters). Example: Skin and gut vessels constrict. α₂ – “Autoregulatory Inhibition**”**: Gi decreases cAMP → less Ca²⁺ → inhibition of neurotransmitter release. Example: Keeps things calm by preventing too much neurotransmitter release. β₁ – “Beats Increase**”**: Gs increases cAMP → more Ca²⁺ → stronger and faster heartbeats. Example: Increased cardiac output. β₂ – “Breathe Easy, Muscles Relax**”**: Gs increases cAMP → muscle relaxation in bronchi (bronchodilation) and vessels. Example: Smooth muscle relaxation like bronchodilation. β₃ – “Burn Fat, Empty Bladder**”**: Gs increases cAMP → lipolysis and bladder detrusor relaxation. Example: Adipose tissue lipolysis and bladder relaxation. 4. Visualization: Picture each receptor as a switch: α₁ turns on the “tightening” (vasoconstriction) switch. α₂ turns off the “release” switch (inhibits neurotransmitter release). β₁ turns on the “beat faster and stronger” switch. β₂ turns on the “relax” switch in your lungs and muscles. β₃ turns on the “burn fat and relax bladder” switch 10 True or False… Nicotinic receptors are Gs type. false - they are ligand gated (NA) Neurotransmission at the ganglion is mainly mediated by muscarinic receptors for parasympathetic nervous system.True Muscarinic receptors are of three types.false > - S M1 receptor is in the Heart. false -GIT M3 receptor mediates Bronchodilation. false - > m3 constriction Alpha-1 receptor is Gq type.True Alpha-2 receptor is located post-synaptically. false -> Pre-synaptically Beta-1 receptor is Gi type. falsee all beta areGS Beta-2 receptor stimulation leads to bronchodilation. True 11  Mechanisms of termination of action of Ach & NE reuptake Broken down The primary transmitter acetylcholine (ACh) is rapidly hydrolysed by a specific enzyme acetylcholinesterase (AChE) located strategically on the synaptic membrane. The primary transmitter noradrenaline (NA) is largely taken back into the neurone by membranebound norepinephrine transporter (NET) and recycled. A minor fraction diffuses away. Parasympathetic ach breaken down by acetylcholine esterase Sympathetic Noredraneline - reuptake from where taking It back Its released by (NET) 12  Drugs acting on the ANS Drugs related Drugs related to PNS to SNS 13 Drugs related to acetylcholine synthesis not for memorization with drugs that interfere Synthesis and release of acetylcholine Botulinum toxin : Botox & inhibits ach so muscles can relax Botulinum +n - Botox 14  Cholinergic drugs Cholinergic Cholinomimetics - mimics produce similar effect antagonists will bind to receptor antagonist but won't have any intrinsic activity on the receptor I h L anticholine cholinergic cholinergic I esterase antagonist esters cholinergic alkaloid 15  Cholinomimetics Anticholinesterases These are drugs which produce actions similar to that of ACh, either by directly interacting with cholinergic receptors (cholinergic agonists) or by increasing availability of ACh at these sites (anticholinesterases). Cholinergic agonists are called directly acting cholinomimetics while anticholinesterases are called indirectly acting. cholinomimetics bind to cholinergic Cholinergic agonist receptor and stimulate them. called directly because they directly bind in receptors made for Ach and stimulate them anticholinesterase cholinergic they inhibit the indirectly actingagonistsa acting - anticholinestrates , ACH enzyme acetycholinestrase ; thus accumulatesaenzyme responsible for degradation thus more ACH : indirectly acting 16  Acetylcholine Highly sensitive to AchE and so very short acting. Binds to all the cholinergic receptors in the body and so non-selective. - One small change can give us another molecule -don't memorize this Ach is degraded quickly · Ach is non-selective it produce foot. effects from head to lot of adverse - can produce a Cunwanted effect)- bouz If for It's given eye problem , It can affect organs other than the eye 17 Drugs Hydrolysis by Actions on Actions on Indications AchE Muscarinic Nicotinic receptors receptors Acetylcholine +++ + + No specific indication due to non-selectivity Methacholine + + (More selective + Cardiac to M2) indications Carbachol - + ++ GIT, Urinary bladder Bethanechol - + - GIT, Urinary bladder Post-operative urinary retention Methacholine is a synthetic choline ester that differs from ACh chiefly in its greater duration of action (the added methyl group increases its resistance to hydrolysis by cholinesterases) and its predominantly muscarinic selectivity. Carbachol and bethanechol are completely resistant to hydrolysis by cholinesterases; their t1/2 are thus sufficiently long that they become distributed to areas of low blood flow. Carbachol retains substantial nicotinic activity, particularly on autonomic ganglia. Bethanechol has mainly muscarinic actions, with prominent effects on motility of the GI tract and urinary bladder. 18  Cholinergic agonists Alkaloids end With INE I has muscurinic receptora Xerostomia ~ MI responsible for salivation , here theres no M1 , no salivation Alkaloids are nitrogenous compounds of plant origin. Pilocarpine has a dominant muscarinic action; the sweat glands are particularly sensitive to pilocarpine. Its used as a sialagogue (to increase salivation) in xerostomia, and mitotic drug (in glaucoma – a condition with increased pressure in the eyes). cholinergic antagonist h I cholinergic cholinergic esters allealolds pilocarpine interferes with m1 , m3 m1 > Increase Saliva m2-causes Mlosis 19  Cholinomimetics drugs on eyes Radial muscles (alpha-1 receptors) dilation Circular muscles (M3 receptor) constriction (miosis) M3 Pilocarpine stimulates m3 receptor > miosis - mosis : causes reduction in pressure of eye used for condition called glacoma 20 True or False. Botulinum toxin inhibits the formation of Acetylcholine. True Acetylcholine is an indirectly acting cholinomimetic. false directly acting Pilocarpine increases the size of the pupil. false > - constricts 21  Inhibit M achase Indirect Cholinomimetics Anticholinesterases 22  Anticholinesterases (Acetylcholinesterase inhibitors) Reversible Irreversible Physostigmine Ecothiophate Neostigmine Malathion Pyridostigmine Tabun Organophosphates Rivastigmine Sarin Galantamine Soman Donepezil Edrophonium Normal catalytic reaction of acetylcholine to acetyl choline will be very rapid. With reversible AchE inhibitors – Slow reaction; With irreversible – Extremely slow anticholinesterase & h reversible Irreversible inhibition - enzyme binds and never leaves - will last for the enzyme few his - enzyme is lost forever - Slow slow extremely prob organophosphate (consumed by in the - girl Is Irreversible - anything ends with 'stigmine' are reversible reversible : ends with stigmine Irreversible : organophosphate 23  Anticholinesterases Lipid soluble Lipid insoluble If soluble , it will have drug is lipid they distribution because high drug can easily pass cell membrane 24  Anticholinesterases Lipid soluble Lipid insoluble Marked Muscarinic effects Muscarinic effects less Marked CNS effects prominent. Action on skeletal muscles less Do not enter CNS. prominent. Marked effects on skeletal muscles. Imuscurin drugs highly are soluble the body in - If a drug has to cross brain barrier and reach the brain It must have high lipofilicity · in acctycholinesterase , the liped soluble drugs can cross the blood brain barrier and inhibit the brain and increase Ach achesterase in In the brain low (neuromuscular junction) muscurinic in muscles is very - - receptor for muscles : Nicotinic M recepter - lipid soluble acetylcholinesterase will have poor Penetration on distribution lipid Insoluble - low drug effect of lipid Insoluble have a good in neuromuscular enzyme Inhibiting cholinesterase Junction receptors lipid soluble can activate all muscurinic and cross blood brain barrier and In the body Increase Ach in brain 25 Anticholinesterases PI(Y)NE Lipid soluble Lipid insoluble PYNE Physostigmine eye Pyridostigmine Rivastigmine alzheimer Neostigmine muscle Donepezil Edrophonium for diagnosing Organophosphates 26  derived from Plant and end WithiHe so alkaloid N Physostigmine Topical application in eyes Used in glaucoma Physiotigmine - cause mosis by activating m3 receptor inhibits acetylcholinesterase Physiotigmine So increases Ach -> causes miosis for drugs eye better topically So other don't get organs affected Physiostigmine is lipid soluble, When put in It can cross eye multiple layers to target the right tissue of the eye. 27  Rivastigmine, Donepezil, Galantamine are used in Alzheimer’s disease Decrease in brain acetylcholine (ACh) levels is implicated in the pathophysiology of cognitive dysfunction occurring in Alzheimer's disease (AD). To treat : Increase Ach better to be lipid soluble low levels of Ach cause dementia 28 Anticholinesterases Lipid soluble Lipid insoluble Physostigmine Neostigmine Rivastigmine Pyridostigmine Galantamine Edrophonium Donepezil Organophosphates relaxed muscles have to be otherwise there will during surgery be spasm> is used to relax muscle neostigmine , cuz its a neuromuscular blocker 29  In addition to AchE inhibition, neostigmine also stimulates nicotinic receptor. Neostigmine is preferred for treating myasthenia gravis. Used for cobra snake Used for reversal of bite neuromuscular blockade used in major surgeries neuromuscular blockers are muscle relaxant Systemic administration neostigmine : treats myasthenia gravis edrophonium : diagnosing myasthenia gravis 30  Lipid insoluble Short acting – 10 Used for diagnosis of Edrophonium to 20 minutes myasthenia gravis Tensilon test Short duration used for diagnosing newly encountered Patients with symptoms of myasthenia gravis. - administer edrophonium , If or not , If theres theres recovery recovery Its myasthenia gravis b called tensilon test This is a drug used for diagnosis, not treating or prophylaxis 31 True or False… Neostigmine crosses blood-brain barrier. false > - its lipid insoluble Physostigmine has a poor muscarinic activity. false -> Its lipid soluble , has high affinity for muscurin receptors Lipid insoluble anticholinesterases are used for treating Alzheimer’s disease. false they , have to be soluble to pass blood brain barrier Edrophonium is used for treating myasthenia gravis. false used for , diagnosis 32 Questions/Clarifications: Office @ 2-063; Student office hours: Sunday 8-10 AM. Email: [email protected] Telephone: 17239794 33