Autonomic Pharmacology Cholinergic Agonists Notes - PDF

AfraTafreeh.com Last edited: 9/9/2022 AUTONOMIC PHARMACOLOGY | CHOLINERGIC AGONISTS Auto...

AfraTafreeh.com Last edited: 9/9/2022 AUTONOMIC PHARMACOLOGY | CHOLINERGIC AGONISTS Autonomic Pharmacology | Cholinergic Agonists Medical Editors: Aldrich and Jona OUTLINE I) THE CHOLINERGIC SYSTEM II) CHOLINERGIC RECEPTORS AND AGONISTS CLINICAL INDICATIONS AND IV) REFERENCES (A) CHOLINERGIC PATHWAYS – CRANIAL NERVES & SPINAL (A) NICOTINIC RECEPTORS ADVERSE EFFECTS OF CORD (PARASYMPATHETIC FIBERS) (B) MUSCARINIC RECEPTORS CHOLINERGIC AGONISTS (B) CHOLINERGIC PATHWAY – SYMPATHETIC NERVOUS SYSTEM (A) DIRECT AGONISTS CLINICAL INDICATIONS (C) CHOLINERGIC PATHWAY – SOMATIC NERVOUS SYTEM (B) INDIRECT AGONISTS CHOLINERGIC CRISIS III) REVIEW QUESTIONS I) THE CHOLINERGIC SYSTEM Cholinergic system is the system where the neurons are particularly releasing acetylcholine (Ach) o Refer to the Cholinergic Receptors and Autonomic Nervous System lecture video for better understanding of the physiology (A) CHOLINERGIC PATHWAYS – CRANIAL NERVES & SPINAL CORD (PARASYMPATHETIC FIBERS) When we talk about cholinergic pathway o We have bunch of different cranial nerves  Some of them have parasympathetic fibers What Professor Zach wants us to remember o Is that these parasympathetic fibers innervate particular target organs (1) CN III (2) CN VII (facial nerve) Supplies eye, particularly extraocular muscles Supplies these structures o It even supplies some of the structures inside of the o Lacrimal glands eye like ciliary and pupil muscle o Salivary glands We have parasympathetic fiber that’s supplying the pupil  Submandibular salivary gland o It causes pupillary constriction → miosis  Sublingual salivary gland  It contracts the ciliary muscle and helps to be able It plays a role in lacrimation (production of tears) and to play a role with accommodation salivation  Changes in our vision like distance There’s another nerve that also plays a role within salivation → glossopharyngeal nerve (CN IX) o CN IX also plays a role with salivation, primarily via parotid glands Autonomic Pharmacology | Cholinergic Agonists PHARMACOLOGY: NOTE #8. 1 of 13 (3) CN X (vagus nerve) Has lots of cholinergic fibers that actually work particularly on some of our viscera (i) Heart (ii) Smooth muscle of bronchioles Acts as negative chronotropic agent Helps to be able to slow down the conduction of the When we have the smooth muscle of our bronchial heart, working on the AV node o Generally the parasympathetic nervous system want o This basically decrease the heart rate them to constrict o We may see bradycardia o It actually induces bronchoconstriction One of the things that we know is  Kind of make the actual airways a little bit smaller o With us slowing down our heart rate, we could  Narrowing the amount of air getting in potentially lower our cardiac output Because when we’re in the resting, digesting kind of o Because we know that relaxing type of state Cardiac output = heart rate x stroke volume o We don’t want to be utilizing a lot of energy and doing So, we can see both decrease in heart rate and a lot of things subsequent drop in our cardiac output o That’s why we don’t really need a ton of airflow when we’re resting and digesting (iii) Upper parts of the GI tract Works on stomach and duodenum o GI secretions  It helps to be able to promote secretion  It helps to stimulate HCl production by the stomach  Secretions of particular molecules within the intestines o Contraction of the smooth muscle of the GIT  Increased motility of the GIT (peristalsis) Parasympathetic fibers from spinal cord We have parasympathetic fibers from the sacral part of our spinal cord, generally S2-S4 o And then go and deliver parasympathetic or cholinergic fibers to other target organs in our actually lower part of abdomen and pelvis  Lower parts of the GIT To be able to increase motility and defecation  General urinary tract Works on the bladder especially detrusor muscle to be able to cause an increased motility of the detrusor muscle → to be able to empty urine AfraTafreeh.com (B) CHOLINERGIC PATHWAY – SYMPATHETIC NERVOUS SYSTEM For some recap, watch Cholinergic Receptors and Autonomic Nervous System lecture video We have another type of cholinergic pathway but it’s NOT Quick recap a part of the parasympathetic nervous system Cholinergic pathway (autonomic nervous system) o It’s actually part of the sympathetic nervous system (1) Eye In the sympathetic part which is like T1-L2, we have Causes pupillary constriction sympathetic fibers Change in the actual vision like near or far vision What these sympathetic fibers do is these actually go and supply Lacrimation o So there’s acetylcholine that’s actually released in our (2) Salivatory gland preganglionic fibers Salivation o But we know in all pre-ganglionic synapses acetylcholine is released (3) Heart In all of these postganglionic synapses acetylcholine is Causes lower heart rate (bradycardia) released for this part of the parasympathetic nervous (4) Lungs system (craniosacral outflow) Bronchoconstriction Sympathetic part of the spinal cord (T1-L2) o This is where the sympathetic outflow is (5) GI tract o The preganglionic fibers releases acetylcholine Increase in GI secretions and motility  And generally the postganglionic release NE Inducing defecation o In this case, it’s not (6) Urinary tract And this sympathetic fiber actually goes to the skin Causes increased motility or contraction of the bladder causing urination o This is one of the few examples where the postganglionic (7) Skin and preganglionic fibers of the sympathetic nervous system release acetylcholine Sweating o Act on the skin → this will induce sweating Cerebrum There’s also cholinergic pathways that act with particularly within the cerebrum o There’s also cholinergic pathways that play a role in cognitive function So, as we have patients who get older or suffer from very specific diseases o They may have a decrease in acetylcholine pathway within their central nervous system o And potentially develop called Alzheimer’s disease or decreased memory 2 of 13 PHARMACOLOGY: NOTE #8. Autonomic Pharmacology | Cholinergic Agonists  AfraTafreeh.com (C) CHOLINERGIC PATHWAY – SOMATIC NERVOUS SYTEM Last function of the actual cholinergic system The cholinergic pathway is also involved with our somatic nervous system o We’ve talked about our autonomic nervous system  Some of the actual central nervous system o But we also have acetylcholine particularly released from these somatic motor neurons  What happens is this acetylcholine that we actually release can act on skeletal muscles Quick recap Target organ o Smooth muscle o Cardiac muscles o Glands o Types of neurons in central nervous system o Skeletal muscle What we need to know is that this helps to be able to produce skeletal muscle contraction II) CHOLINERGIC RECEPTORS AND AGONISTS CHOLINERGIC RECEPTORS When we’re talking about the cholinergic system o The drug that we’re going to be giving people particularly working at these target sites We’ll zoom in on this o But imagine we’re going to release acetylcholine and acetylcholine is going to have work on this pupil or ciliary muscle o How does it do that?  It has to have a particular receptor  What happens is certain drugs that we give can act on the receptor and potentially Act like acetylcholine → stimulating the receptor o Causing all of the same mimicking type of effects Or we can have another drug that can actually work to increase acetylcholine levels NOT by directly stimulating the receptor o They can just increase acetylcholine levels by preventing a particular enzyme from breaking it down → acetylcholinesterase We’ll actually go into a little bit more detail about how acetylcholine particularly works on these target organs o Because what we need to understand is there’s different types of receptors in order for acetylcholine to exert its effect We know based upon the concept of pharmacodynamics that a drug will potentially need some type of receptor to be able to bind to produce it’s type of cellular response o In this situation for these skeletal muscles  These receptors are called nicotinic receptors  These are ligand-gated ion channels o For the autonomic nervous system  They have receptors called muscarinic receptors  These are G-protein coupled receptors o Generally nicotinic receptors are located in 2 particular places  Skeletal muscles → neuromuscular junction  Preganglionic sites The point where between we have our preganglionic neuron and postganglionic neurons o But generally at all these target organ sites (outside skeletal muscle), they’re going to be muscarinic receptors Autonomic Pharmacology | Cholinergic Agonists PHARMACOLOGY: NOTE #8. 3 of 13  (A) NICOTINIC RECEPTORS Zoom in and imagine we have a target organ (skeletal muscle) o We have somatic neuron releasing acetylcholine on the actual skeletal muscle cells How does this actual acetylcholine process work? o What we need to understand is when we have acetylcholine particularly being released o All of this acetylcholine acting on the receptor and producing its response (1) Acetylcholine production (4) Acetylcholine binds to nicotinic receptor How do we make acetylcholine? Once it’s out there We have molecule called choline that we get from our diet o Acetylcholine will come and bind onto little pockets on o We have special transporters that will bring the these little receptors called nicotinic receptor choline into the actual synaptic neurons We have mitochondria that are important because they o That nicotinic receptors are called ligand-gated ion channel actually have these very special molecules called acetyl- o So, they’re protein channel CoA  They have a little pocket where acetylcholine will bind What we’ll do is we’ll take acetyl -CoA and combine it with (5) Acetylcholine exerts its effect – depolarization & choline muscle cell contraction o When we do, we use an enzyme called choline acetyl transferase Normally these channels are kind of closed because there’s no ligand bound to it (2) Acetylcholine stored in vesicle o But once acetylcholine binds with the actual little What we’re going to do is we’re going to make pocket, it opens up the gate acetylcholine and we’re going to put this into vesicles o Na+ ions will start rushing into the actual muscle cell o From this enzyme, we’re going to make acetylcholine and put them into these vesicles AfraTafreeh.com As Na ions rush into the muscle cell + o It starts making the inside of the muscle cell positive (3) Acetylcholine release to synaptic terminal o Depolarizing the actual muscle cell and we’ll activate sarcoplasmic reticulum Now what happen is once there’s some particular  Release Ca2+ and cause the crossbridge stimulus  It will induce a muscle contraction o This neuron becomes activated, an action potential moves down the somatic neuron (6) Muscle relaxation – breakdown of acetylcholine When action potential moves down the somatic neuron After we’ve stimulated the muscle to contract o It opens up voltage-gated calcium channel o What has to happen is we need to relax o What happens is Ca2+ will rush into this particular o How do we get muscle cell to relax? synaptic neuron  Get acetylcholine out of there  It will help to be able to stimulate the fusion of the In order for acetylcholine not to be present vesicles containing acetylcholine with the actual o We got this enzyme called acetylcholinesterase membrane of the synaptic terminal  It will actually break down the acetylcholine into And then via exocytosis we will release our acetylcholine choline and acetyl groups molecule out into the synapse  Now it’s rendered ineffective; we can’t utilize it anymore So, the acetylcholine levels within the synapse drop o And then now the muscle will no longer contract Significance That’s an important concept because we can utilize drugs to potentially work at this actual nicotinic receptor (i) Drugs that act like acetylcholine (ii) Drugs that inhibit acetylcholinesterase We have drugs potentially can act like acetylcholine and Or we can have drugs particularly that work to inhibit bind that little pocket acetylcholinesterase Open up these channels and have ions flood in, induce Remember acetylcholinesterase works to be able to contraction break down acetylcholine If we want to give drugs that act like acetylcholine o What we want to do is we want to indirectly increase our acetylcholine levels by inhibiting acetylcholinesterase If we inhibit acetylcholinesterase, will we break down acetylcholine? No o The level of acetylcholine level in the synapse will increase o It will act just as though we’re stimulating the actual receptor 4 of 13 PHARMACOLOGY: NOTE #8. Autonomic Pharmacology | Cholinergic Agonists  AfraTafreeh.com (B) MUSCARINIC RECEPTORS (1) Acetylcholine production We bring choline into the actual synaptic terminal o It combines with acetyl-CoA o Whenever it combines with the choline, acetyl-CoA Muscarinic receptor overview will be converted into acetylcholine via this enzyme Generally, the muscarinic receptors are inhibitory called choline acetyltransferase So we’re going to have inhibitory receptors (2) Acetylcholine is put in vesicle and get released o They’re going to be able to slow things down, inhibit things Put into the synaptic terminals o This means it will work through a very special type of Action potential moves down the axon, activates special G-protein coupled pathway called G-inhibitory channels called voltage-gated calcium channels pathway o Calcium channels open → Ca2+ flood into the actual synaptic terminal and stimulate synaptic vesicle In the primary, there are lots of muscarinic receptors fusing with the actual cell membrane o But the primary ones that Professor Zach wants us to  And releasing the actual acetylcholine via remember that inhibits is M2 receptor exocytosis o And in some degree M4 receptors (3) Acetylcholine binds to muscarinic receptor Once acetylcholine is released via exocytosis o It can act on receptors In the same way as it acts on the nicotinic receptor  We can have it act on muscarinic receptors Autonomic Pharmacology | Cholinergic Agonists PHARMACOLOGY: NOTE #8. 5 of 13 Inhibitory muscarinic receptor (1) G-inhibitory protein stimulation Gi protein subunit – K+ channela ctivation Acetylcholine will come and bind onto this receptor There are 3 subunits of Gi protein o When it binds onto this G-protein coupled receptor o 𝛼𝛼, 𝛽𝛽, 𝛾𝛾 subunits  It changes its shape o What happens is these Gi subunits o It activates a protein called G-inhibitory protein (Gi  𝛽𝛽, 𝛾𝛾 subunits can actually bind onto K+ channels protein) When it binds onto these K+ channels  This will release GDP and be stimulated by GTP o It opens up these channels and allows for K+ ions to  GTP will actually bind to this and becomes active leave the cell (2) Adenylate cyclase inhibition If K+ ions leave the cell G-protein Moves along the cell and works on an enzyme o Inside of the cell becomes negative called adenylate cyclase If we make the inside of the cell negative o It will inhibit adenylate cyclase o It will decrease its actual activity  It’s normally supposed to take ATP and convert it o Now we won’t be able to generate action potentials into cAMP (cyclic AMP)  We want to slow things down the AV node to lower Which helps to be able to activate protein heart rate kinase  Protein kinase is supposed to phosphorylate Significance proteins to perform specific actions If we give a particular drug that act like as direct agonist But what we’re going to do here is we’re inhibiting on that muscarinic receptor this enzyme o The overall response will inhibit the particular cell o It’s not going to make ATP into cAMP functioning o We’re not going to get protein kinase A If we gave a drug that inhibit acetylcholinesterase o And therefore because of that o It cause an increase in acetylcholine  We’re going to get decrease in the o Increase in acetylcholine will stimulate an increase in phosphorylation of particular proteins particular pathway causing the inhibition of that cell o So all this phosphorylation reactions that are supposed to work on particular proteins, we’re not going to get Example – nodal cell of the heart This is a great example because in our actual heart muscle or particularly the actual nodal cells of our heart AfraTafreeh.com o This is important because we want to phosphorylate to be able to open up and allow for ions to flow in like Ca2+ or Na+ o These are supposed to be phosphorylated in order to do that If we don’t phosphorylate these o They’re not going to open up and allow for ions to be able to flood into them o We won’t be able to stimulate this actual nodal cell, AV node 6 of 13 PHARMACOLOGY: NOTE #8. Autonomic Pharmacology | Cholinergic Agonists  AfraTafreeh.com Stimulatory muscarinic receptor In the other types of cells, we’re going to have receptors that are stimulatory (stimulatory receptors) o These are usually coupled to Gq protein  Some degrees Gs protein Primary one that Professor Zach wants us to remember is M3 receptor o Technically M1, M3, M5 receptors but M3 is the most important one Quick recap Most important inhibitory receptor is M2 receptor Most important stimulatory receptor is M3 receptor (1) Gq protein stimulation (2) Phospholipase C stimulation → PIP2 → DAG & IP3 Acetylcholine binds onto this receptor When it becomes stimulated, activates an enzyme called o Changes its shape phospholipase C o Activates G protein so it gets rid of GDP, binds GTP Phospholipase C will break down parts of the cell membrane → a molecule called PIP2 and break it down to o DAG (diacylglycerol)  Which activates protein kinase C o IP3  Which works to be able to increase the Ca2+ outflow from sarcoplasmic reticulum The whole concept is that if we have an increase in protein kinase and Ca2+ o We’ll be able to cause a lot of phosphorylation of particular types of proteins  And increase the activity of these particular proteins o Increasing the response of the cell Example – smooth muscle cell of GIT Acetylcholine gets released M3 receptor increase the activity of the phospholipase C o Increase diacylglycerol (DAG)and IP3 If we increase DAG, they’re going to activate protein Significance kinase C o Increase Ca2+ level If we gave a direct agonist to act on this muscarinic o Protein kinase phosphorylates particular receptor channels to bring more positive ions into the cell o It produced the same response  If we bring more positive ions into the cell Or if we gave a drug that inhibit this acetylcholinesterase  We make the inside of the cell to become very o It would increase acetylcholine indirectly positive o And give the same type of response We make it depolarize and then subsequently contract Remember what happens to the acetylcholine o That would increase the GI motility o It gets broken down into choline and acetyl group product and gets recycled via acetylcholinesterase Autonomic Pharmacology | Cholinergic Agonists PHARMACOLOGY: NOTE #8. 7 of 13  CHOLINERGIC AGONISTS (PARASYMPATHOMIMETICS) Overview What are the drugs that we can actually give to work as o Direct agonist on either muscarinic receptor or o Direct agonist on the nicotinic receptor and What are the drugs we can give to inhibit the acetylcholinesterase to increase the acetylcholine and still produce the same type of effect? (A) DIRECT AGONISTS Drugs Mechanism of action Bethanechol AfraTafreeh.com These drugs are particularly working to stimulate o May work heavily on M3 receptor o Muscarinic receptors o Because it loves to cause an increase in GI motility  G-protein coupled receptors and detrusor activity o Nicotinic receptors Methacholine  Ligand-gated ion channel o Acts on M3 receptors and cause bronchoconstriction Bethanechol, methacholine, pilocarpine Pilocarpine o They work on muscarinic receptors only o May act on some of the M3 receptors All works on the muscarinic receptors except carbachol Carbachol which acts on our nicotinic receptor and muscarinic o Work on both muscarinic receptor and nicotinic receptor receptors o Never be used again 8 of 13 PHARMACOLOGY: NOTE #8. Autonomic Pharmacology | Cholinergic Agonists  AfraTafreeh.com (B) INDIRECT AGONISTS The ones that are working on inhibiting acetylcholinesterase Drugs Edrophonium Physostigmine Neostigmine Pyridostigmine Donepezil Rivastigmine Echothiophate Reversible acetylcholinesterase inhibitors Irreversible inhibitor - echothiophate Important concept to understand is which one will actually Similar drug class this particular enzyme to where it’s reversible o Sarin o Meaning if we inhibit this enzyme, there’s a possibility  Nerve gas that it will stop inhibiting o Organophosphate o If we can’t reversibly uninhibit that enzyme  Any kind of pesticide  Then we’re going to have some serious problems Once utilized in glaucoma Reversibility determines the onset or length of action o But we don’t utilize it anymore because of this severe o Edrophonium side effect profile  Very short-acting o We have better drugs for this o Physostigmine and neostigmine Fearful thing of these types of drugs especially things like  Those are relatively short acting sarin or pesticides (organophosphates) o Pyridostigmine o These are irreversible inhibitors of the  Relatively one of the longer lasting acting acetylcholinesterase enzymes Physostigmine, donepezil, rivastigmine and galantamine o We won’t be able to uninhibit them are called tertiary amines What happens is o Meaning they are very lipid soluble o They will put alkyl group on the enzyme o These can penetrate into the central nervous o It prevents from being able to perform its function system o What happens is certain other enzymes may come in  Increased blood-brain-barrier penetration and remove that alkyl group o For cognitive function types  That’s a problem  Example Alzheimer where they have a decreased o If a patient gets a drug like sarin or organophosphate in cognitive function due to decreased or echothiophate and they start developing toxicity acetylcholine pathway because of it o If we increase the acetylcholine within those  Cholinergic crises type of effects actual central nervous system pathways  We could improve some of their cognitive function If we give them the antidote like pralidoxime at this stage  Donepezil and rivastigmine would be good drugs when they have the alkyl group on them Physostigmine is not necessarily that good o They would actually be able to reverse this But what happens is these special types of phosphorylating enzymes come in and lay down some phosphates onto this and remove a piece of the actual alkyl group o So, we give them pralidoxime but it will not work  This is an important concept they may ask us in our exam  This is called aging If we give the actual antidote whenever the enzyme is in the aging stage o It will not be reversed and continue with the cholinergic crisis  Meaning that we’ve removed a piece of the alkyl group and it has a phosphorylated group on it If we give the antidote in the point where the alkyl group is added, there’s no phosphorylation o There’s no actual piece that’s actually removed off of the alkyl group o Then we can actually reverse the underlying toxicity Autonomic Pharmacology | Cholinergic Agonists PHARMACOLOGY: NOTE #8. 9 of 13  CLINICAL INDICATIONS AND ADVERSE EFFECTS OF CHOLINERGIC AGONISTS CLINICAL INDICATIONS (1) Increase motility of the GI and the bladder (3) Glaucoma Post-operation ileus There’s a problem in the drainage of the aqueous humor Postpartum urinary retention into the Canal of Schlemm Gastroparesis in Diabetes mellitus Improves the drainage by o Due to decrease in nerve stimulation (Figure 1) o Pulling the ciliary muscle opening the angle, hence Drugs can be given are: improving the drainage o Constricting the pupillary sphincter, tightening the iris, (i) Bethanechol decreasing the volume of iris tissue in the angle, and (ii) Neostigmine pulling the peripheral iris away from the trabecular meshwork (Figure 3)  Short-acting agent Drugs (iii) Pyridostigmine (i) Pilocarpine  Neostigmine and pyridostigmine are safer options than physostigmine  More superior than carbachol (ii) Carbachol  More side effects (iii) May add physostigmine Figure 1. Increasing Motility. AfraTafreeh.com Figure 3. Glaucoma. (2) Bronchial Provocation Test In patients who have asthma, their bronchial smooth muscles are hyperresponsive. (4) Sjogren Syndrome and Radiation-induced o It doesn’t take much to cause these smooth muscles Destruction of the Lacrimal and Salivary Glands to go into intense contraction (Figure 2) Drug/s To increase lacrimation and salivation (Figure 4) Drugs (i) Methacholine (i) Pilocarpine  Causes increase bronchospasm → decreases (ii) Carbachol FEV1 by >20% Figure 2. Bronchial Provocation Test. Figure 4. Sjogren Syndrome and Radiation-Induced Destruction of the Lacrimal and Salivary Glands. 10 of 13 PHARMACOLOGY: NOTE #8. Autonomic Pharmacology | Cholinergic Agonists  AfraTafreeh.com (5) Myasthenia Gravis (i) Definition (iii) Drugs An autoimmune disease where autoantibodies block the nicotinic receptors → Ach cannot (a) Acetylcholinesterase Inhibitors bind to the receptors → Weakness (Figure 5) (i) Edrophonium o Short-acting o Helps in diagnosing myasthenia gravis in a test called Tensilon Test (ii) Neostigmine o Treatment for myasthenia gravis o Duration of action is significantly less than pyridostigmine (iii) Pyridostigmine o Longer duration o Used as treatment in chronic cases (iv) Do not give Physostigmine in myasthenia gravis o Due to its CNS TOXICITY (b) Cholinergic drugs (i) Physostigmine o Can be given in anticholinergic toxicity such as TCA toxicity (ii) Neostigmine o Can be given in neuromuscular blockage reversing the paralytic effect of the drug Figure 5. Myasthenia Gravis. (ii) Mechanism of Action o Inhibition of acetylcholinesterase  Acetylcholinesterase degrades acetylcholine into choline  If acetylcholinesterase is inhibited, there will be more Ach available to compete with the autoantibodies for the receptors.  There will be an improvement in ion influx resulting to a contraction and reduced weakness. o Cholinergic Drugs  Displaces anticholinergic drugs in the receptors (TCAs, atropines) (Figure 6) Figure 6. Cholinergic Drugs for Anticholinergic Crisis. (iv) Myasthenic Crisis vs Cholinergic Crisis (a) Myasthenic Crisis (c) Edrophonium o More antibody attack of nicotinic receptors o Inhibits acetylcholinesterase → increasing Ach → o Normal dose of pyridostigmine is not enough hence increasing ion influx → contraction of muscle → weakness continues decrease weakness o In Myasthenic Crisis (b) Cholinergic Crisis  Edrophonium decreases weakness o Overdose of pyridostigmine causing excessive  Increase pyridostigmine dose stimulation of the muscle leading to weakness (Figure o In Cholinergic Crisis 7)  Edrophonium increases weakness  Decrease pyridostigmine dose Since both myasthenic crisis and cholinergic crisis present with weakness but with different management, we should be able to differentiate the two through administration of Edrophonium. Figure 7. Myasthenic Crisis and Cholinergic Crisis. Autonomic Pharmacology | Cholinergic Agonists PHARMACOLOGY: NOTE #8. 11 of 13 (6) Alzheimer’s Disease N UCLEUS OF MEYNERT o Has cholinergic fibers that provide cortical stimulation o Important in our cognitive function In Alzheimer’s, there is a reduction in Ach within the pathway causing the reduction in cognitive function (Figure 8) Drugs (Acetylcholinesterase Inhibitors) (i) Donepezil (ii) Rivastigmine (iii) Galantamine These drugs only slow down the progression of Alzheimer’s. They do not cure them. Figure 8. Alzheimer's Disease. CHOLINERGIC CRISIS (7) DUMBBELLS (8) DRUGS D IARRHEA, U RINATION , MIOSIS, BRADYCARDIA, B RONCHOCONSTRICTION , EMESIS, LACRIMATION , (i) Atropine LETHARGY, SALIVATION (Figure 9) (ii) Pralidoxime Should be given before aging occurs Ineffective after 24-48 hours after exposure (i) Pupils [Katzung, 2018] Miosis – pinpoint fuels (ii) Lacrimal glands Increase in lacrimation (iii) Salivary glands Increase in salivation AfraTafreeh.com (iv) Heart Decrease in heart rate Decrease in cardiac output Drop in blood pressure (v) Lungs Increase in bronchospasm (vi) GI Increase in defecation Diarrhea (vii) Bladder Increase in urination (viii) Skeletal muscle Weakness (ix) Sweat glands Increase in sweating (x) Agitation, restlessness, convulsion Figure 9. Cholinergic Crisis. 12 of 13 PHARMACOLOGY: NOTE #8. Autonomic Pharmacology | Cholinergic Agonists  AfraTafreeh.com III) REVIEW QUESTIONS IV) REFERENCES 1) CN III, CN VII, CN IX, CN X are the cranial nerves that Tao and Bhushan, Vikas. First Aid for the USMLE Step 1 2022, Thirty second edition. New York: McGraw-Hill Education, 2022. have sympathetic fibers a) True Raffa, Robert B, Scott M. Rawls, Elena P. Beyzarov, and Frank b) False H. Netter. Netter's Illustrated Pharmacology. 2013. 2) Bethanechol, methacholine, and pilocarpine works Ritter, James. Rang and Dale's Pharmacology. Ninth edition. Edinburgh: Elsevier, 2020. on both muscarinic receptors and nicotinic receptors a) True Brown, Morris J., Pankaj Sharma, Fraz A. Mir, and Peter N. b) False Bennett. Clinical Pharmacology. 12th ed. Philadelphia: Elsevier [Imprint] Elsevier - Health Sciences Division, 2018. 3) When acetylcholine binds to muscarinic receptor (M3) in the smooth muscle, it will cause relaxation of Goodman & Gilman's: The Pharmacological Basis of the muscle Therapeutics, 13e Brunton LL, Hilal-Dandan R, Knollmann BC. a) True Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.), Eds (2018) b) False 4) Indirect cholinergic agonists’ mechanism of action is Lippincott Illustrated Reviews: Pharmacology. 6th ed. Philadelphia, PA: Wolters Kluwer, (2015) the inhibition of acetylcholinesterase a) True Katzung BG. Katzung B.G.(Ed.), Ed Bertram G. Katzung: Basic b) False & Clinical Pharmacology, 14e. McGraw Hill (2018) 5) Which drugs below are classified as indirect cholinergic agonists? (May choose more than one) a) Bethanechol b) Carbachol c) Edrophonium d) Neostigmine e) Pilocarpine f) Pyridostigmine g) Rivastigmine 6) Which of the following is NOT a part of the cholinergic crisis? a) Miosis b) Constipation c) Lacrimation d) Bradycardia 7) What is the is used for Tensilon Test? a) Neostigmine b) Edrophonium c) Rivastigmine d) Atropine 8) What is the drug of choice for glaucoma? a) Pilocarpine b) Carbachol c) Physostigmine d) Any of the above Autonomic Pharmacology | Cholinergic Agonists PHARMACOLOGY: NOTE #8. 13 of 13