Pharmacology - Muscarinic Receptors Agonists & Antagonists PDF

PHARMACOLOGY MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS DR. COLLEEN M. ONGKINGCO-LUMANLAN | Sept. 10, 2024 Atropine...

PHARMACOLOGY MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS DR. COLLEEN M. ONGKINGCO-LUMANLAN | Sept. 10, 2024 Atropine OUTLINE ○ Competitively inhibits actions of ACh and congeners I. Acetylcholine & its III. Muscarinic receptor Muscarinic Receptor antagonists A. PROPERTIES AND SUBTYPES Target A. Structure-Activity Muscarinic – all are G Protein Coupled Receptors A. Properties and Relationships (GPCR) Subtypes B. Mode of Action → M1, M3, M5 B. PHarmacological C. Pharmacological ▪ Activate Gq-PLC pathway effects of Effects ▪ Hydrolysis of polyphosphoinositides and mobilization Acetylcholine D. ADME of intracellular Ca2+ II. Muscarinic Receptor E. Therapeutic Uses → M2 and M4 Agonist F. Toxicology ▪ Inhibit adenylyl cyclase A. ADME ▪ Regulate specific ion channels via coupling to B. Therapeutic uses pertussis toxin-sensitive Gi and Go C. contraindications, Muscarinic receptors precautions, & → M1: Important in modulation of nicotinic cholinergic adverse effects transmission in the ganglia D. Toxicology → M2: Predominant in the cholinergic control of the heart Abbreviations: IK-ACh: ACh- activated K current → M3: Smooth muscle, secretory glands, eyes Tx: Treatment ICa-L: L-type Ca current Classical (orthosteric) binding site CI: Contraindication If: cardiac pacemaker current → Consists a cleft formed by conserved amino acid NT: Neurotransmitter HCN: hyperpolarization-activated, chains located on seven TM helices (TM1-TM7) d/t: due to cyclic-nucleotide-gated channels Agonist binding to muscarinic receptor leads to Px: Patient IBS: Irritable Bowel Syndrome contractions of ligand-binding pocket A/E: Adverse effects → muscarinic agonists are smaller than muscarinic antagonists I. ACETYLCHOLINE & ITS MUSCARINIC Positive Allosteric modulators: enhance orthosteric activity Negative Allosteric modulators: inhibits orthosteric activity RECEPTOR TARGET Allosteric Agonists: allosteric agents that can directly Muscarinic activate muscarinic receptors ○ Actions of alkaloid muscarine on the same sites Additional information: produce the same qualitative effects as that of Ach. Muscarinic agonists Muscarinic (M) receptors are metabotropic (meaning ○ longer-acting congeners of Ach they primarily use GPCR for signal transduction) Muscarinic acetylcholine receptor: M receptors utilizes GPCRs therefore utilizing secondary ○ Found primarily on autonomic effector cells of messengers postganglionic parasympathetic nerves → so depending on type of receptor it may activate or ○ present in inactivate a receptor ▪ autonomic ganglia Ionotropic receptors ▪ on some cells (e.g., vascular endothelial cells) that → Ligand-gated ion channels mediating fast transmission receive little or no cholinergic innervation. → Ex: Nicotinic receptors ○ high densities in CNS: hippocampus, cortex, thalamus This is the segment that goes in depth about the muscarinic area of the ANS, which was Doc Corporal’s lesson. Recall Acetylcholine - has virtually no systemic therapeutic muscarinic receptors are PARAsympathetic/cholinergic, applications since its actions are diffuse Muscarinic receptors have to carry out their effects, and thus are ○ hydrolyzed by Acetylcholinesterase (AChE) and located POSTganglionically. butyrylcholinesterase (bAChE) rapidly Recall from Doc Corporal’s constant exercises that ACh is Muscarinic involved in both adrenergic and cholinergic. As a result, you can ▪ actions of ACh and related drugs at autonomic find cholinergic synapses in not just parasympathetic areas, but effector sites which produces same qualitative effect sympathetic ones as well. (One good example would be the as ACh innervation of the adrenal medulla) ACh is metabolized incredibly quickly thanks to the ○ Muscarinic agonists cholinesterases, both AChE and bAChE. As a result, unlike ▪ longer-acting congeners of ACh or natural alkaloids epinephrine, which one can administer systemically; ACh Cholinergic synapses occur at: doesn’t enjoy the same possibility (or else it gets metabolized 1. Autonomic effector sites innervated by away in literally seconds). It also doesn’t help that its chemical postganglionic parasympathetic nerves (by structure, being made of 4 ammonium ions (quat ammonium), postganglionic sympathetic nerves in sweat glands) means it can’t penetrate the BBB. 2. Sympathetic and parasympathetic ganglia and the The Muscarinic receptors go by the order of Q-I-Q-I-Q. Say it adrenal medulla out loud to remember them faster, and help you know which muscarinic receptor uses which GPCR. 3. Motor end plates in skeletal muscles 4. Certain synapses in CNS (either presynaptic or postsynaptic actions) ACh administered systemically: B. PHARMACOLOGICAL EFFECTS OF ○ Quaternary ammonium compound: penetration to ACETYLCHOLINE CNS is limited ○ Amount of ACh that reaches peripheral areas: limited 1. Cardiovascular system due to hydrolysis by plasma bAChE Four primary effects of ACh: Transcribed by: NMD 2027  MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS 1. Vasodilation 2. ⬇ heart rate (negative chronotropic) 3. ⬇ AV conduction velocity (negative dromotropic) 2. Respiratory Tract 4. ⬇ force of cardiac contraction (negative inotropic) Bronchoconstriction → Less significant in ventricles than in atria ⬆ tracheobronchial secretions Cardiac glycosides, antiarrhythmic agents Stimulation of chemoreceptors of aortic and carotid bodies → Changes vagal stimulation of the heart Primarily by M3 receptors → Afferent stimulation of the viscera (surgical 3. Urinary tract interventions) reflexly ⬆ vagal stimulation Detrusor muscle contraction (M3 receptor) Small doses of ACh: ⬆ voiding → Transient hypotension → reflex tachycardia ⬆ ureteral peristalsis ▪ M3 receptors → Gq-PLC-IP → → Action of Ach is difficult to observe d/t of rapid Ca2+-calmodulin-dependent activation of eNOS → hydrolysis by plasma bAChE NO → stimulates guanylyl cyclase → M2 – cause bladder contractions indirectly by reversing β cGMP-dependent relaxation → Vasodilation → ⬇ BP receptor-cAMP mediated relaxation → Damaged endothelium → M3 receptors on underlying vascular smooth muscle → vasoconstriction Additional information: Larger doses of ACh than required for vasodilation: Drugs under this category are usually used for paralyzed → Mediated primarily by M2 (couple with Gi/Go) persons to induce voiding → Direct effect on cardiac function: If you ever forget what is the effect of AcH on the urinary ▪ ⬆ IK-ACh d/t Activation of K-ACh channels tract, just remember you don’t need to pee when you are ▪ ⬇ ICa-L d/t Inhibition of L-type Ca channels punching someone. ▪ ⬇If d/t Inhibition of HCN (pacemaker) → ACh via M2 → Gi mediated ⬇cAMP and inhibits 4. Gastrointestinal tract release of NE M3 – primarily responsible ▪ B1 adrenergic/Gs-mediated ⬆cAMP is counteracted M2 – also contributes ▪ M2 and M3 – mediates inhibition of NE release ⬆ amplitude of contractions In SA node ⬆ secretory activity of stomach and intestine → ⬇ rate of spontaneous depolarization → attainment of threshold potential is delayed →⬇ heart rate → Pace-making function for an intracellular Ca2+-“clock” 5. Secretory effects might mediate effects of ACh on heart rate ⬆ secretions in lacrimal, nasopharyngeal, salivary, and In Atria: sweat glands (M3) → Hyperpolarization & ⬇ action potential duration by ⬆ M1 receptors also contribute significantly to the cholinergic IK-ACh stimulation of salivary secretion → Inhibits cAMP and release of NE →⬇ contractility In AV node: → slows conduction and ⬆ refractory period by inhibiting 6. Eye calcium channel opening (ICa-L) Miosis – contracting pupillary sphincter muscle ▪ responsible for the complete heart block observed Accommodation (for near vision) by contracting ciliary with large quantities of cholinergic agonists muscle → ⬆ parasympathetic (vagal) tone → ⬆ refractory pd. Mediated primarily by M3 muscarinic receptors →⬇ freq. of aberrant atrial impulses → ⬇ ventricular rate during atrial flutter/fibrillation 7. CNS Effects Ventricle and His-Purkinje Muscarinic agonists crossing the BBB can cause arousal → receive only sparse vagal innervation or activation response Additional information: → Also produced by cholinesterase inhibitors and stimulation of brainstem reticular formation In the ATRIA → AcH causes hyperpolarization and → All five receptor subtypes are expressed decrease in action potential (by increasing the time of K channel opening) Additional information: → More negative The only thing to add is to help you in analysis, should you Small doses of ACh can cause vasodilation under normal forget. Secretion is an active process, and of course, must use conditions, while normal-large doses of ACh do well, some sort of muscles or channel to contract. Thus, we can use bradycardia, as we all know from normal parasympathetic Gq, the calcium and contraction receptor. If it’s a contractionary function. process (like miosis), of course it’s naturally Gq still. → Always remember that under normal conditions, AcH causes The only areas M2 may help contraction is both the GIT and the vasodilation (thus hypotension) but when endothelium is urinary tract. damaged, it causes VASOCONSTRICTION. (OPTIONAL)-What is a cardiac glycoside? It’s digoxin. Hopefully M3 is responsible for the vasodilation (and also vasoconstriction you remember that from our Physio. Cardiac glycosides are under pathological conditions), and it uses G1. When it comes special compounds one can extract from plants. You can use to Gq, always drill this into your head: Gq=Calcium=contraction. these to lower heart contraction strength. Recall from earlier that M3 uses the Gq mechanism. In this case, Calcium activates nitric oxide, a natural vasodilator. Damaging the endothelium also harms M3, which of course, will lead to constriction occurring. M2 meanwhile is responsible for the bradycardia. Again, when it comes to Gi, it is always an INHIBITING GPCR. Take doc corporal’s exercises to heart. Because it inhibits, that means it System Muscarinic Receptors inhibits many many types of ion channels, as well as also inhibiting cAMP, thus lowering NE levels. Recall from our Anatomy and Physio that the SA node is the Cardiovascular M3 and M2 main pacemaker. By using ACh slowing down its spontaneous contractions, of course, the entire heart’s rate thus slows down. Respiratory Tract M3 For the rest of the heart, just remember that literally everything slows down from M3. Urinary System M3 and M2 2 of 11  MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS GIT M3 Resist hydrolysis; still has short Can cross BBB half-life d/t kidney elimination Secretory Effects M3 and M1 Muscarine ○ Still toxic when ingested and has CNS effects Eye M3 The natural alkaloids (pilocarpine, muscarine, arecoline) are primarily eliminated by the kidneys CNS M1 - M5 ○ Tertiary amines: Excretion can be accelerated by acidification of urine Additional information: Methacholine is basically a special form of acetylcholine that I. ACETYLCHOLINE & ITS MUSCARINIC resists AChE. But not IMMUNE to it, like the following… Which happen to be Carbachol and Bethanechol. To shorten RECEPTOR TARGET their specific receptors, remember CN and BM. Muscarinic Cholinomimetic alkaloids is fancy for “Plant compounds that induce cholinergic effects.” Table 1. Two Groups Of Receptor Agonist Areca nuts, or Betel nuts are a main source of arecoline. Have you ever heard of/seen old guys from indigenous groups here CHOLINE ESTERS CHOLINOMIMETIC chew something? It’s usually that. Arecoline is a partial nicotinic ALKALOIDS (Natural agonist, so yes, basically it’s kind of like nicotine, the main Alkaloid muscarinic addictive substance in cigarettes. agonists) Pilocarpine is from a plant. It’s mostly used for glaucoma and tx of Sjogren syndrome. METHACHOLINE MUSCARINE ○ β-methyl analog of ACh ○ Acts almost B. PHARMACOLOGICAL EFFECTS OF with added methyl group exclusively at which ⬆ resistance to muscarinic receptors ACETYLCHOLINE cholinesterases → greater ARECOLINE MUSCARINIC AGONIST duration of action ○ May also act on Tx of urinary bladder disorders & xerostomia (dry CARBACHOL AND nicotinic receptors mouth) BETHANECHOL (β PILOCARPINE Diagnosis of bronchial airway hyperreactivity METHYL ANALOG OF ○ Dominant muscarinic (Methacholine) through a bronchoprovocation test CARBACHOL) effect but is only → s/e: severe bronchoconstriction ○ Unsubstituted carbamoyl partial agonist Used as miotic agents esters ○ Sweat glands are Treatment of glaucoma ○ Almost completely resistant particularly sensitive M1 agonists - tx of cognitive impairments associated to hydrolysis by to this Alzheimer’s disease cholinesterases ○ used as sialagogue M2 & M3 receptors - regulation of cognitive function ○ long t1/2 (promotes salivary ○ Carbachol – nicotinic secretion) and miotic Additional information: Retains substantial agent Methacholine is given for bronchoprovocation test for nicotinic activity diagnosis of bronchial airway hyperreactivity with no ○ Bethanechol – muscarinic clinical apparent asthma actions; prominent effects on GIT and urinary bladder Table 3. Therapeutic use of muscarinic agonists Drug Use ACETYLCHOLINE 1% solution to induce miosis for ophthalmic surgeries CARBACHOL treatment of glaucoma, miosis BETHANECHOL Urinary tract: treating urinary retention; given 1-2 hours after meal to prevent nausea and vomiting Figure 1. Choline Esters and Natural Alkaloids GI Tract: stimulates peristalsis, Source: Goodman & Gilman’s, 13th Ed. increases motility and increases lower esophageal sphincter (LES) pressure METHACHOLINE Bronchial airway hyperreactivity testing / diagnosis of bronchial hyperreactivity A. ABSORPTION, DISTRIBUTION, METABOLISM AND ELIMINATION PILOCARPINE Used to treat xerostomia following head and neck radiation treatments Table 2. ADME associated with Sjogren’s syndrome used in treating glaucoma and as a QUATERNARY AMINES TERTIARY AMINES miotic agent Choline esters and Muscarine Pilocarpine and CEVIMELINE high affinity for M3 receptors Arecoline long sialogogic effect and fewer side Poorly absorbed in GIT effects than pilocarpine Does not cross BBB Readily absorbed Pilocarpine but better since it lasts 3 of 11  MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS longer, has less side effects (due to being III. MUSCARINIC RECEPTOR ANTAGONIST M3 selective) Naturally occurring alkaloids (SA) → ATROPINE and SCOPOLAMINE C. CONTRAINDICATIONS Semisynthetic derivatives of the alkaloids → differs from the parent compound in their disposition in Table 4. Contraindications & Adverse Effects the body or the duration of action CONTRAINDICATIONS ADVERSE EFFECTS Synthetic derivatives → has limited degree of selectivity for a certain receptor Asthma Excessive sweating subtypes COPD Diarrhea REMEMBER!!! Urinary or GIT obstructions Abdominal Cramps Table 5. Muscarinic Receptor Acid-peptic Diseases Nausea/ Vomiting Antagonists CV diseases accompanied with: sensation of tightness in the →bradycardia urinary bladder HOMATROPINE Shorter duration of action →hypotension (induction TROPICAMIDE visual disturbances of vasodilation) →hyperthyroidism hypotension METHSCOPOLAMINE Quaternary amines and (induce arrhythmias) IPRATROPIUM does not TIOTROPIUM cross the Blood Brain Additional information: Barrier (BBB) For easier remembering of contraindications, just remember that AcH causes bronchoconstriction, PIRENZEPINE M1 receptor-preferring increased secretion, increased peristalsis, vasodilation, antagonist hypotension and bradycardia. Inducing bronchoconstriction on asthma and COPD DARIFENACIN M3 receptor-preferring patients who already have increased tendency of SOLIFENACIN antagonist bronchoconstriction (for asthma) and retained secretions (for COPD) would only exacerbate their condition and can page. 213 Goodmans result to status asthmaticus (complete constriction of Mechanism: Muscarinic receptor antagonist airways). → prevents binding of ACh to the muscarinic receptor For GIT and urinary conditions, recall that AcH causes → It causes little blockade of nicotinic receptor increased activity on the two systems. Ultimately it can ▪ Quaternary ammonium antagonists have a greater lead to perforations in both systems. degree of blocking the nicotinic activity; so more likely to interfere with ganglionic transmission → Organs have varied sensitivity to muscarinic blockade D. TOXICOLOGY Doses of atropine that depress gastric secretion also Poisoning → exaggeration of parasympathomimetic affects salivary secretion, ocular accommodation, micturition, effects and GI motility Treatment: Atropine lacks selectivity in muscarinic subtypes ○ parenteral administration of Atropine ▪ doses sufficient to cross BBB and measures to A. STRUCTURE-ACTIVITY RELATIONSHIPS support the respiratory and CVS and to counteract pulmonary edema Intact ester of tropine and tropic acid → essential for the ANTIMUSCARINIC ACTION Note: For high (toxic) dose of atropine → Presence of free OH in acyl portion Red as a beet ▪ also important for the activity4 Dry as a bone Blind as a bat Quaternary Ammonium Derivatives of ATROPINE AND Hot as firestone SCOPOLAMINE are more potent and is Mad as a hatter → given parenteral route → poorly and unreliably absorbed when given in oral route B. MECHANISM OF ACTIONS Atropine competes with ACh for orthosteric Ach site competitive and surmountable by ACh (by ⬆ ACh concentration) Additional information: Figure 2. Effects of Atropine in Relation to dose Note that the quaternary amines listed, methscopolamine, Source: Goodman & Gilman’s, 13th Ed. tiotropium and ipratropium; happen to be mostly used for 4 of 11  MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS local purposes, like decongestion for ipra and tiotropium, Toxic doses: indirectly dilate cutaneous and limiting secretions in allergies and IBS. BV - especially in blush area (atropine All of the above are poorly absorbed orally, but are more flush) potent. → compensatory rxn to offset the rise in Atropine begins to be toxic around 2 mg. Going up temp that can accompany inhibition of carries risks. sweating. I used “Soli-Dari-3” to remember which antagonists prefer M3. 2. RESPIRATORY SYSTEM Also, do not be confused with the terms between Bronchodilation orthosteric and allosteric. Orthosteric site basically → inhibit bronchoconstriction caused by histamine, means it is the primary site in which the ligand binds to bradykinin, and the eicosanoids its receptor in general. On the contrary, allosteric site is ▪ basis for the use of muscarinic receptor where the ligand binds to the receptor other than the antagonists and β adrenergic receptor agonists primary site for Tx of asthma ⬇tracheobronchial secretion inhibits secretions of nose, mouth, pharynx, and bronchi → dries the mucous membranes of the respiratory tract C. PHARMACOLOGICAL EFFECTS → prevents irritating inhalational anesthetics (diethyl ether) from increasing bronchial secretion Note: → used to ⬇ rhinorrhea (runny nose) Listed are the effects of atropine (the prototypical Quaternary ammonium compounds (ipratropium, muscarinic antagonists), other drugs will be mentioned tiotropium, aclidinium, and umeclidinium) only when they differ significantly from the effects of → used exclusively for their effects on the respiratory tract atropine → side effect: dry mouth → Aclidinium - undergo rapid hydrolysis in plasma to inactive metabolites (reduces systemic exposure) 1. CARDIOVASCULAR SYSTEM → Ipratropium & Tiotropium - minimal inhibitory effect on mucociliary clearance relative to atropine ▪ minimizes the increased accumulation of lower Table 6. Cardiovascular Effects airway secretions encountered with atropine Heart Main effect: alter the rate Additional information: Dominant response: tachycardia Average clinical dose: 0.4 - 0.6 mg → In treating patients with COPD, Ipratropium and transient bradycardia Tiotropium are preferably given than atropine. You might modest slowing (4-8 beats/min) wonder why since they both decrease bronchial → occurs with no accompanying secretions. The reason is although atropine inhibits changes in BP or cardiac output bronchial secretions, it ALSO INHIBITS MUCOCILIARY → d/t the block of presynaptic M1 CLEARANCE. For COPD patients, one of the receptors manifestations of the disease is retained secretions in the SA node because of vast amounts of secretions in their airways. Larger doses: progressive tachycardia by Inhibiting it would further exacerbate their conditions and blocking of M2 on the nodal pacemakers you might induce mucus plugging. Tiotropium and cells Ipratropium is the go-to-drug since it only inhibits Maximal HR (e.g. d/t exercise) → not bronchial secretions and does not affect mucociliary altered by atropine clearance which is helpful for COPD patients. Infants, elderly & Px w/ heart failure - even large doses may fail to accelerate the heart Prevents or abruptly abolishes bradycardia 3. EYE or asystole caused by: Dilate the pupil (mydriasis) leads to: → choline esters → photophobia → AChE inhibitors → lens fixed for far vision: near objects are blurred, and → parasympathomimetic drugs, objects may appear smaller than they are → cardiac arrest from electrical → normal pupillary reflex constriction to light or stimulation convergence of the eyes is abolished of the vagus paralyze accommodation (cycloplegia) Shortens the functional refractory period For systemic doses: of → Scopolamine causes evident mydriasis and loss of the AV node and can ⬆ ventricular rate in accommodation as compared to equal dose of atropine patients who have atrial fibrillation or flutter If applied locally, lasts 7-12 days Second-degree AV block - Atropine may Pilocarpine & choline esters (carbachol) - reverse the lessen the degree of block ocular effects of atropine (sufficient conc.) Px w/ complete AV block - idioventricular 4. GI Tract rate may be accelerated by atropine MUSCARINIC RECEPTOR ANTAGONIST For Px with inferior or posterior wall MI: → antispasmodic agents for GI disorders relieves severe sinus or nodal bradycardia → reduce gastric acid secretion in treatment of Peptic or AV block ulcer Disease Circulation Clinical doses: completely counteracts Table 7. GI Tract Effects the peripheral vasodilation and sharp fall Motility Large doses: prolonged inhibitory effect in BP caused by choline esters on 5 of 11  MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS motor activity of stomach, duodenum, → Limited absorption from intact skin jejunum, Quaternary muscarinic receptor antagonists ileum and colon → ⬇ in tone, amplitude → limited systemic abs. for inhaled and orally ingested and Atropine: t1/2 - 4 h frequency of peristaltic contractions Ipratropium: Atropine → aerosol or solution for inhalation; lasts for 4-6 h → can completely abolish the effects of Tiotropium: exogenous mus. agonists on GI → dry powder; slower onset than ipratropium; lasts for 24 motility and secretion hrs → incompletely inhibit the GI responses Additional information: ▪ because GIT has other synapses and plexuses that is noncholinergic As mentioned, Doc Corporal should have drilled every in origin basic concept of what an ANTIcholinergic does in your head already. I will just be making note of what isn’t obvious. Gastric acid Atropine A 0.4-0.6 mg dose of Atropine is enough to cause its secretion → only partially inhibits the gastric acid beneficial clinical effect of tachycardia, starting with M1 secretory responses blocking. Larger doses will block M2 instead, and of course, ▪ because gastric secretions are has a more dangerous tachycardia. also mediated by gastrin-releasing Scopolamine tends to be quite stronger compared to its peptides (GRP) [not by ACh] cousin Atropine. Not only does it have more intense ▪ Gastrin Releasing Peptide → mydriasis, it can even cause CNS depression due to it gastrin release from G cells → acid crossing the BBB far better secretion by parietal cells → than Atropine can. histamine release by ECL cells Tiotropium lasts quite long, for 24 hrs compared to its → parietal cells also secrete acid in brother Ipratropium. As a result, it’s quite preferred for long response to 3 hormones: gastrin, term chronic COPD. histamine, ACh Secretions completely abolish the copious, watery secretion → dry mouth, difficulty swallowing and talking E. THERAPEUTIC USES Pirenzepine Muscarinic Antagonists → inhibits gastric acid secretion at doses → Inhibits parasympathetic activity in the respiratory that have little effect on salivation or tract, urinary tract, GIT, eye, and heart heart rate → Used for Tx of: → primary target: M1 receptors ▪ Parkinson’s ▪ mgt of extrapyramidal side effects of antipsychotics ▪ prevention of motion sickness 5. OTHER SMOOTH MUSCLE → selectivity is achieved by local administration Urinary Tract: → Ureter and Bladder: ⬇normal tone and amplitude Note: → eliminate drug-induced enhancement of ureteral tone Refer to Table 8 in the Appendix for the full and specific → ⬇ salivation and lacrimation and blurred vision list of therapeutic uses Biliary tract: → exerts mild antispasmodic action on the gallbladder Additional information: and bile ducts in human Respiratory Ipratropium-NONSELECTIVE M 6. SWEAT GLANDS AND TEMPERATURE BLOCKER small doses: inhibit the activity of sweat glands; skin Tiotropium and Aclidinium- M1 and M3 becomes hot and dry selective BLOCKER 7. CNS Tiotropium and Umeclidinium-for Atropine maintenance → minimal effects purposes → toxic dose leads to central excitation (restlessness, provide COMPLETE PROTECTION irritability and disorientation) Eyes Homatropine, Cyclopentine, Tropicamide → larger doses = depression, circulatory collapse, All have SHORTER half lives than Atropine respiratory failure, period of paralysis and coma and Scopolamine Cause mydriasis and Scopolamine cycloplegia (paralysis of ciliary muscle) → even at low therapeutic dose: prominent central effects CVS Atropine- for acute MI where vagal nerve → has greater permeation across the BBB is stimulated and you need an → therapeutic doses: CNS depression (drowsiness, anticholinergic amnesia, fatigue, dreamless sleep, and ⬇ REM) effect to counter the bradycardia ▪ causes euphoria → subject to abuse → used w/ anesthetic agents or preanesthetic medication GUT For overactive bladder → if Px has severe pain → can cause excitement, Oxybutynin - oldest in the class, high risk restlessness, hallucinations, or delirium of s/e → prevents motion sickness by blocking neural pathways Trospium-quaternary amine, less risk of in the vestibular apparatus of the inner ear CVS s/e compared to others in its class, excreted mostly renally D. ADME Tolterodine-binds to all with similar affinity Darifenacin and Solifenacin-Binds to M3 Belladonna alkaloids, tertiary synthetic and specifically semisynthetic derivatives GIT for IBS, diarrhea → Absorbed rapidly from GIT → Enter the circulation when applied locally to mucosal surfaces 6 of 11  MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS Pirenzepine- Imipramine analog, as good Cognitive impairment (if it as an H2 antagonist for healing, M1 crosses the BBB) selective Telenzepine- pirenzepine but better, recommended for acid peptic disorder F. TOXICOLOGY Glycopyrrolate- Quat amine, does NOT Belladonna Alkaloids: cross the BBB, less S/E → major cause of poisoning Dicyclomine- for diarrhea dominant IBS Phenothiazine And Tricyclic Antidepressants Drugs → H1 receptor blocker and muscarinic blocker (in CNS for Prophylaxis of Motion Sickness sufficient doses) Scopolamine- best 4-6 hrs → can cause syndromes with features of atropine Parkinson’s Disease- M1 and M4 blockage intoxication can help, especially if early stage → Protriptyline & Amitriptyline (Tricyclic Antidep.) Benztropine, Trihexyphenydyl, ▪ most potent muscarinic receptor antagonist Biperiden - for EPS of antipsychotics ▪ given in therapeutic doses higher than the effective dose of the atropine Saliva Glycopyrrolate-for drooling in Parkinson’s Newer “Atypical” Drug are potent muscarinic blockers AChE Atropine -for organophosphate poisoning, → CLOZAPINE → increases salivation and drooling d/t Toxicity as well as counteracting toxicity of partial agonist effect pyridostigmine, an anticholinesterase used DIPHENOXYLATE-ATROPINE for MG. → used in the tx of diarrhea in children Anesthesia Atropine can be used to lower vagal → poisoning is extensively reported reflexes during surgery TRANSDERMAL SCOPOLAMINE Administered to counteract neostigmine → can cause toxic psychoses especially in children and s/e after surgery elderly Misc. Methscopolamine- does not act on CNS Berries or seeds with BELLADONNA ALKALOIDS → like scopolamine, used for allergic rhinitis can cause serious intoxication (prevent excessive mucus) Homatropine- JIMSON WEED → can cause poisoning better at ganglionic blocking than atropine, Atropine Poisoning but less antimuscarinic, used as antitussive → In full blown poisoning, syndrome may last 48h or (suppress cough) more → Physostigmine ▪ anticholinesterase agent which may be used for Additional information: confirmation of atropine poisoning READ ME IF YOU DON'T KNOW WHAT AN EPS IS: In ▪ If salivation, sweating or bradycardia and intestinal psychosis, one of the main problems the doctor must deal hyperactivity occurs = atropine poisoning is with is the abundance of dopamine. As a result, confirmed antipsychotics must of course inhibit dopamine. However, ▪ slow IV relieves delirium and coma this means their side effects are SIMILAR to that of → Benzodiazepine Parkinson’s, a disease where your dopamine levels in the ▪ most suitable for sedation and control of brain are low. Anticholinergics can help relieve EPS convulsions if the specific tx is unavailable or symptoms, and are often partnered with main antipsychotic marked excitement is present drugs. → Phenothiazines READ ME IF YOU DON’T KNOW WHAT AN MG IS ▪ should not be used for Tx Myasthenia Gravis is an autoimmune condition where ▪ intensifies toxicity antibodies bind to the end plate receptor, thus leading to muscle weakness. Anticholinesterases basically inhibit the Additional information: inhibitor (AChE), leading to increased amounts of ACh for The toxidrome of anticholinergics has been mentioned the body to use, lessening the effects of MG. over and over again by dear ol’ Doc Corporal. I’m not READ ME IF YOU WANT TO KNOW WHY YOU USE gonna explain them already. NEOSTIGMINE AND ATROPINE TOGETHER In surgery, What the hell is a phenothiazine? A tricyclic one must use skeletal muscle paralyzers (ACh blockers) to antidepressant? Phenothiazines are first generation make sure the patient’s muscles hold still and no unfortunate antipsychotics that inhibit the dopamine receptor. Tricyclic anatomic structure gets slashed. However, we must of antidepressants, or TCA as I will now call them, are course reverse this after the operation by allowing ACh to SNRIs (serotonin norepinephrine reuptake inhibitors), return to the muscles. Neostigmine is favored for this used for depression, as depression involves a lack of both purpose, but has a high risk of unwanted cholinergic effects. 5-HT and NE. TCAs have had significant s/e though, so Atropine ensures there’s less Neostigmine toxicity. these days SSRIs are mostly used for depression instead. Clozapine is an Atypical antipsychotic. Atypical antipsychotics are basically antipsychotics who have a much lower EPS risk, leading to much safer and ADVERSE EFFECT AND CONTRAINDICATION consistent use (EPS means you should discontinue the Table 9. Adverse Effects and antipsychotic under normal circumstances) Diphenoxylate-Atropine is Lomotil. You can buy this at Contraindications Watsons usually. Diphenoxylate is an opioid, and Atropine is an anticholinergic. Basically, since both opioids and ADVERSE EFFECT CONTRAINDICATION anticholinergics stop gastric motility, this is for when you Xerostomia (dry mouth) Urinary tract obstruction really, really don’t want to go to the bathroom anytime Constipation (⬇ the GI tone GI obstruction soon.The atropine also helps by lowering the amount of and secretion) Uncontrolled angle diphenoxylate needed, as to reduce the chance of Blurred Vision (mydriasis) closure glaucoma (⬇ addiction (yes you can get addicted to any kind of opioid, Dyspepsia (⬇ peristalsis outflow of the humor) even just Tramadol.) and secretion) BPH (benign prostatic Jimson Weed is Datura stramonium. Want some hyperplasia entertainment if you have the time? Search “datura trips” 7 of 11  MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS and begin reading some of the most insane cases of hallucinations you’ll ever read. Seriously. Datura is an incredibly potent hallucinogen, manifesting entire alternate realities and universes as part of its toxidrome. DO NOT SMOKE/INGEST THIS PLANT. Just as you use Atropine for physostigmine poisoning, it cuts the other way too, you can use Physostigmine for Atropine poisoning FREEDOM WALL kupal review notes: M2, M4 - inhibit adenylyl cyclase Gi Go M1, M3, M5 -activation of Gq and PLC Positive allosteric modulators(PAMs) - enhance orthosteric activity Negative allosteric modulators - inhibit it Cevimeline - activates M1 and M3 receptors Primary Target of Pirenzepine(MRA) - M1 receptors Parietal cells - express M3 receptors Quaternary ammonium derivatives - does not cross BBB it means good - less/no CNS effects eg. methscopolamine, ipratropium, tiotropium, aclidinium and umeclidinium. Oxybutynin(MRA) - metabolized by CYP3A4 Solifenacin(MRA) - metabolized by CYP3A4 -avoid CYP3A4 inhibitors grape fruit juice, ritonavir, conazoles, clarithromycin, cipro., erythro., aprepitant. -reduce the dose if taken with drugs that inhibit their CYP Tolterodine(MRA)- metabolized by CYP2D6 Solifenacin and Darifenacin - metabolized by CYP2D6 and CYP3A4 Most common reason for discontinuation of Muscarinic receptor agonist - Xerostomia -page 216 goodmans -(MRA) Muscarinic receptor antagonist 8 of 11  MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS APPENDICES Table 3. Therapeutic Uses of Muscarinic Receptor AGONISTS ACETYLCHOLINE CARBACHOL used topically for the induction of miosis during ophthalmic surgery Topically for the tx of glaucoma instilled into the eye as 1% solution induction of miosis during surgery METHACHOLINE BETHANECHOL administered by inhalation primarily affects the urinary and GI tracts diagnosis of bronchial airway hyperreactivity Urinary tract: available as: powder diluted with 0.9% NaCl administered via ○ Tx of urinary retention and inadequate emptying of nebulizer bladder when organic obstruction is absent; given Asthmatic Px Response: 1-2 hours after meal to prevent nausea and ○ intense bronchoconstriction vomiting ○ reduction in vital capacity ○ Chronic use: Methacholine + adrenergic antagonists = prolonged response ▪ 10-50mg; given orally 3-4x daily Contraindications to methacholine testing: GI tract: severe airflow limitation ○ stimulates peristalsis recent myocardial infarction or stroke ○ ⬆ motility uncontrolled hypertension ○ ⬆ resting lower esophageal sphincter pressure pregnancy PILOCARPINE CEVIMELINE Tx of xerostomia that follows head and neck radiations associated long-lasting sialogogic action on lacrimal & salivary with Sjogren syndrome glands Enhances salivary secretion, ease of swallowing, and subjective fewer side effects and better px compliance than improvement in hydration of the oral cavity pilocarpine Side effects: preferentially activates M1 and M3 receptors (high ○ cholinergic stimulation (sweating - most common complaint) affinity for M3 receptors) Usual dose: ○ 5-10 mg, 3x daily; Lower dose in Px with hepatic impairment Also used topically for Tx of glaucoma and as a miotic agent Table 8. Therapeutic Uses of Muscarinic Receptor ANTAGONISTS RESPIRATORY TRACT GENITOURINARY TRACT Ipratropium, tiotropium, aclidinium & umeclidinium: Tx for overactive urinary bladder ○ tx for COPD (inhaled metered dose) ○ ⬇ intravesicular pressure, ⬆ capacity, ⬇ frequency of ○ often used with B2 agonists contractions of the urinary bladder IPRATROPIUM Tx of enuresis (loss of bladder control) in children 9 of 11  MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS ○ blocks all M receptors For overactive bladder ○ Nasal Inhalation: Tx for rhinorrhea with allergic or - oxybutynin - tolterodine non-allergic perennial rhinitis - darifenacin - trospium chloride TIOTROPIUM - solifenacin - fesoterodine ○ selective M1 and M3 receptor blocker Most common A/E: ○ has lower affinity for M2 which minimizes the presynaptic - Xerostomia - Blurred vision effect enhancing Ach release - GI side effects (constipation and dyspepsia) ○ same effect with ACLIDINIUM CNS RELATED EFFECTS (problematic in elderly) Tiotropium & Umeclidinium: used for maintenance therapy ○ drowsiness, dizziness, confusion via dry powder inhaler in Px with moderate to severe disease ○ less likely to appear with: In normal px: ▪ trospium (quaternary amine) ○ complete protection against bronchoconstriction produces ▪ selective M3 receptors (darifenacin & solifenacin) by subsequent inhalation of irritants →minimal effects on M1 (plays important role in memory ○ Px with atopic asthma and bronchial hyperresponsiveness and cognition) are less protected OXYBUTYNIN Drug formulation ○ it the oldest antimuscarinic ○ DPI (dry powder inhaler) and Inhaled metered dose are ○ high incidence of side effects (esp. xerostomia) for px with respiratory problem (COPD) ○ oral administration EYES → higher doses are required due to enteric and hepatic Topical application: produces cycloplegia and mydriasis CYP3A4 which causes and extensive metabolism ○ Mydriasis is necessary in the Tx of iridocyclitis and keratitis TOLTERODINE Agents used in ophthalmological practice: ○ binds to all M receptors with similar affinity ○ homatropine hydrobromide* ○ metabolized by CYP2D6 to 5-hydroxymethyltolterodine ○ cyclopentolate hydrochloride* ○ CYP3A4: alternative for CYP2D6 in tolterodine elimination ○ tropicamide* FESOTERODINE *has shorter duration of action than atropine or scopolamine ○ prodrug that is rapidly hydrolyzed by esterases CARDIOVASCULAR SYSTEM ○ less variable source of 5-hydroxymethyl metabolite For coronary care units for short term intervention or in TROSPIUM surgical settings only ○ quaternary amine ATROPINE ○ as effective as oxybutynin but has better tolerability ○ initial Tx for Px with Acute MI whose excessive vagal tone ○ only antimuscarinic used for overactive bladder eliminated causes sinus bradycardia or AV node block primarily by kidneys How it works: SOLIFENACIN → reduces bradycardia and syncope associated with ○ selective M3 receptor antagonist hyperactive carotid sinus reflex ○ metabolized by CYP3A4 → may eliminate premature ventricular contractions DARIFENACIN → may reduce AV block when increased vagal tone is the ○ selective for M3 receptor major factor ○ metabolized by CYP2D6 and CYP3A4 ○ doses is reduced in Px that inhibit CYP’s GIT CNS used for diarrhea with irritation of the lower bowel BELLADONNA ALKALOIDS (DIARRHEA IBS) ○ 1st drug used for prevention of motion sickness PIRENZEPINE *all agents used to combat motion sickness should be given ○ selective M1 receptor to a limited degree prophylactically ○ a tricyclic drug similar with IMIPRAMINE SCOPOLAMINE ○ produces same rate of healing of duodenal and gastric ○ most effective for short (4-6h), severe motion sickness ulcers as H2 receptor antagonists ○ it applied in postauricular mastoid region TELENZEPINE (analogue of pirenzepine) ▪ one 0.5mg of scopolamine transdermal can last 72h ○ has higher potency than pirenzepine ○ A/E: xerostomia, blurred vision, mydriasis and cycloplegia ○ tx: for acid-peptic dse (by transfer of the drug to the eyes), severe psychotic ○ s/e is much lower that pirenzepine episodes BELLADONNA ALKALOIDS PARKINSON’S DISEASE (PD) (⬇dopamine) ○ used for tx GI spasticity or motility ○ Effects of muscarinic antagonists: ○ ⬇ tone and motility in max doses ▪ M1 & M4 blockage ➡ activation (for M1) or inhibition (for GLYCOPYRROLATE M4) of specific striatal neuronal subpopulation ○ also used to reduce the GI tone and motility ○ effective in early stages if tremor is predominant ○ a quaternary amine - does not cross the BBB Tx for the extrapyramidal symptoms of antipsychotics ▪ less likely to cause a/e in CNS Drugs used for PD and extrapyramidal symptoms are the ff. DICYCLOMINE HYDROCHLORIDE (all are tertiary amines: crosses the BBB) ○ weak muscarinic receptor ▪ BENZTROPINE MESYLATE ○ nonspecific direct spasmolytic effects ▪ TRIHEXYPHENIDYL HCL ○ For the tx of diarrhea-predominant IBS ▪ BIPERIDEN SALIVARY SECRETIONS ANTICHOLINESTERASE POISONING Belladonna alkaloids and synthetic substitutions are effective in ATROPINE (in large doses) ⬇ excessive salivation ○ tx of poisoning by anticholinesterase organophosphorus insecticides GLYCOPYRROLATE: ○ antagonize the parasympathomimetic effects of ○ ⬇ drooling especially in px with parkinson’s disease PYRIDOSTIGMINE or other anticholinesterases administered in the tx of myasthenia gravis ANESTHESIA OTHER THERAPEUTIC USES ATROPINE METHSCOPOLAMINE BROMIDE ○ block the responses to vagal reflexes induced by surgical ○ a quaternary ammonium derivative of scopolamine manipulation of visceral organs ○ it lacks central action of scopolamine 10 of 11  MUSCARINIC RECEPTOR AGONISTS & ANTAGONISTS ATROPINE OR GLYCOPYRROLATE ○ used in combination for the relief of allergic rhinitis , ○ block parasympathomimetic effects of neostigmine sinusitis and common cold ATROPINE + NEOSTIGMINE (cholinergic drug) HOMATROPINE METHYLBROMIDE ○ can cause severe cardiac arrhythmias d/t initial ○ 4x more potent than atropine as ganglionic blocking agent bradycardia produced ○ less potent in antimuscarinic activity than atropine ○ combination with HYDROCODONE - used as antitussive combination (for cough) 11 of 11