[PHARMA] Cholinergic Antagonists.pdf

PHARMACOLOGY 08/20/2024. MOD 1: CHOLINERGIC ANTAGONISTS Dr. Agnes Venes...

PHARMACOLOGY 08/20/2024. MOD 1: CHOLINERGIC ANTAGONISTS Dr. Agnes Venessa A. Carungcong, MD Trans Group: B.D. I. CHOLINERGIC ANTAGONISTS Acetylcholine receptor antagonists are divided into muscarinic and nicotinic subgroups on the basis of their specific receptor affinities for their classification. CHOLINERGIC ANTAGONISTS 1 Muscarinic Receptor Antagonist 2 G-Protein Coupled Receptors (GPCR) Ganglion blockers and neuromuscular junction (NMJ) blockers make up the anti-nicotinic drugs. Atropine’s mechanism of action, By being an antagonist in these receptor sites, these drugs are expected to REMOVE the predominant ACTION OF ATROPINE parasympathetic tone in tissues involved. Hence, also known as parasympatholytics. Atropine blocks muscarinic activity resulting in mydriasis or dilation of A. MUSCARINIC RECEPTOR ANTAGONIST the pupil, unresponsiveness to light Prevent the effects of acetylcholine by blocking its and cycloplegia which is the binding to muscarinic receptors on the effector cells inability to focus for near vision at parasympathetic and sympathetic cholinergic In patients with angle-closure neuroeffector junctions in peripheral ganglia and the 1 EYES glaucoma, intraocular pressure CNS. may rise dangerously Topical atropine – for patients TYPES OF MUSCARINIC RECEPTOR ANTAGONIST about to undergo ophthalmic surgeries for cataract extraction 1 Belladonna Alkaloids ○ Atropine is instilled ahead of Belladonna alkaloids are more commonly time to induce mydriasis. referred to as Tropane alkaloids, owing to the tropane found in their chemical structure. Atropine blocks muscarinic receptors in the salivary glands, producing dryness 2 Semi-synthetic or synthetic muscarinic antagonist of the mouth or xerostomia. Salivary glands are exquisitely sensitive to atropine. 1. BELLADONNA ALKALOIDS 2 Mouth Sweat and lacrimal glands are similarly affected. Naturally-occurring alkaloids Inhibition of secretion by sweat Example: atropine (prototypical drug), Scopolamine glands → elevated body temperature → dangerous in the 1.1 ATROPINE children and elderly Prototypical tertiary amine belladonna alkaloid High affinity for muscarinic receptors Atropine can be used as an Binds competitively and prevents acetylcholine from antispasmodic to reduce activity of binding to those sites the GI Tract. Acts both centrally and peripherally. Atropine and scopolamine are Its general actions last about 4 hours except when probably the most potent placed topically in the eye where the action may last antispasmodic drugs available. for days. Although gastric motility is reduced, Neuroeffector organs have various sensitivity to HCL production is not significantly atropine, the greatest inhibitory effects are on the 3 GI Tract affected. bronchial tissue and the secretion of sweat and ○ Thus, atropine is not effective saliva. for the treatment of peptic ulcer. ○ Pirenzepine, and M1 muscarinic antagonist reduce the gastric acid secretion at doses that do not antagonize other systems. Pharmacology- Mod 1 Cholinergic Antagonists 1 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Atropine produces divergent effects Massive doses of atropine depending on the dose. may be required over a long Low doses → predominant effect is period of time to counteract a slight decrease in heart rate. the poisons. ○ Results from blockade of the The ability of atropine to M1 receptors on the inhibitory enter the CNS is of 4 CVS pre-junctional neurons → particular importance in permitting increase in treating central toxic effects acetylcholine release of anticholinesterases. Higher doses → causes a progressive increase in heart rate by blocking the M2 receptors on the Atropine is necessary in pediatric patients before SA node. surgery as these patients tend to cry a lot. ○ Hypersalivation → bronchospasm during intubation. 3 ○ Prophylactic atropine is given to reduce salivation CNS and to prevent bradycardia caused by intubation. 1.1.1 Pharmacokinetics of Atropine Rapidly absorbed Partially metabolized by the liver THERAPEUTIC USES OF ATROPINE Eliminated Atropine is primarily in urine Half life of about 4 hours. Topical atropine exerts both mydriatic and cycloplegic 1.1.2 Pharmacokinetics of Atropine effects. It permits the measurement Atropine can cause dry mouth, blurred vision or of refractive errors without sandy eyes, tachycardia, urinary retention, and interference with the constipation (depending on the dose) accommodative capacity of Effects on the CNS are restlessness, confusion, the eye. hallucination and delirium which may progress to Shorter acting depression, collapse of the circulatory and antimuscarinics respiratory systems and death. (Cyclopentolate and Low doses of cholinesterase inhibitors (e.g., 1 Ophthalmologic Tropicamide) have largely physostigmine) may be used to overcome atropine replaced atropine due to the toxicity. prolonged mydriasis Atropine may also include or induce troublesome urinary observed with atropine. retention. With atropine, it takes 7-14 May be dangerous in children because they are days vs. 6-24 hours with sensitive in its effects particularly to rapid increases in other agents. body temperature that it may elicit. Note that phenylephrine are similar α-adrenergic drugs 1.1.3 Atropine Toxicity are preferred for pupillary dilation if cycloplegia is not ATROPINE TOXICITY required. ↑ Temperature 2 Antispasmodic Atropine is used to relax the GIT. Hyperthermia “hot as a hare” ↓ Sweating Treatment for Atropine is used to treat ↓ Secretions 3 Bradycardia bradycardia of varying etiologies Dry mucosa “dry as a bone” Thirsty for the CVS. Flushed skin/face “red as a beet” Tachycardia Atropine is also an effective anti-secretory agent to block Dilated pupils “blind as a bat” secretions in upper and lower 4 Anti-Secretory respiratory tracts prior to “mad as a surgery and used to prevent Confusion/Delirium hatter” hypersalivation during intubation. 1. 2 SCOPOLAMINE Atropine is used as an Another muscarinic antagonist antidote for Tertiary amide, plant alkaloid organophosphate Produces peripheral effects similar to atropine poisoning coming from Scopolamine has greater action on the CNS and a Antidote for insecticides, for overdose longer duration of action, as compared to atropine 5 Cholinergic and clinically used One of the most effective anti-motion sickness drugs Crisis anticholinesterases such as available. physostigmine, and in It has an unusual effect of blocking short-term some types of mushroom memory. poisoning. In contrast to atropine, scopolamine produces sedation but at higher doses can produce excitement Pharmacology - Mod # Cholinergic Antagonists 2 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ May produce euphoria 2.4 Oxybutynin ○ Susceptible to abuse Atropine-like drug Used to treat overactive bladder or urinary frequency 1. 2. 1 Therapeutic Uses of Scopolamine By blocking muscarinic receptors in the bladder: Limited to prevention of motion sickness and ○ Lowered intravesical pressure post-operative nausea and vomiting ○ Increased bladder capacity For motion sickness, it is available as a topical patch ○ Reduced frequency of bladder contraction and provides effects for up to 3 days Side effects: dry mouth, constipation, and blurred ○ Effective as prophylactic vision which limits tolerability for this agents if used continually 1. 2. 2 Pharmacokinetics and Adverse Effects Available as transdermal system or topical patch Similar to atropine ○ Better tolerated ○ Less dry mouth than the oral formulation 2. SEMI-SYNTHETIC AND SYNTHETIC MUSCARINIC ANTAGONIST B. NICOTINIC RECEPTOR ANTAGONIST SEMI-SYNTHETIC AND SYNTHETIC MUSCARINIC NICOTINIC RECEPTOR ANTAGONIST ANTAGONIST 1 Ganglionic Blockers Semi-synthetic Belladonna alkaloids derivatives 2 Neuromuscular Blockers Synthetic Semi-Synthetic or synthetic derivatives muscarinic antagonist 1. GANGLIONIC BLOCKERS Specifically act on the nicotinic receptors of both Bronchodilators Ipratropium parasympathetic and sympathetic autonomic ganglia nonselectively Mydriatics Tropicamide Blocking the entire output of the ANS at the nicotinic receptor Parkinson’s Rarely used therapeutically Benztropine Disease Often serves as a tool for experimental pharmacology 2.1 IPRATROPIUM AND TIOTROPIUM Quaternary derivatives of atropine 1.1 Nicotine Approved as bronchodilators for maintenance Component of cigarette smoke treatment of bronchospasm associated with chronic Poison with many undesirable actions obstructive pulmonary disease (COPD) Without therapeutic benefit and deleterious to health Delivered via inhalation Depending on the dose, it depolarizes autonomic Has positive charges ganglia → stimulation → paralysis of all ganglia ○ Do NOT enter the systemic circulation or the CNS ○ Stimulatory effects are complex ○ Isolate their effects to the pulmonary system ○ Result from increased release of neurotransmitters due to effects of both parasympathetic and sympathetic ganglia IPRATROPIUM AND TIOTROPIUM Used for bronchospasm NEUROCHEMICALS RELEASED AS AN EFFECT OF Ipratropium management in asthma NICOTINE Requires dosing up to 4x daily Neurochemicals Effects Tiotropium Administered 1x daily Dopamine Pleasure, appetite suppression 2.2 TROPICAMIDE AND CYCLOPENTOLATE Norepinephrine Arousal, appetite suppression Used as ophthalmic solution to induce mydriasis and cycloplegia Acetylcholine Arousal, cognitive enhancement Shorter duration of action compared to atropine Glutamate Learning TROPICAMIDE AND CYCLOPENTOLATE Serotonin Mood, appetite suppression Tropicamide Produces mydriasis for 6 hours β-endorphin ↓ anxiety Cyclopentolate Produces mydriasis for 24 hours GABA Less anxiety 2.3 BENZTROPINE AND TRIHEXYPHENIDYL Useful adjuncts with anti-Parkinsonian agents to treat 2. NEUROMUSCULAR BLOCKING AGENTS Parkinson’s Disease and other types of Parkinsonian AKA “Paralytic agents” or “Muscle relaxants” syndrome including antipsychotic-induced extra Depolarizing and non-depolarizing neuromuscular pyramidal symptoms (EPS) blocking agents Pharmacology - Mod # Cholinergic Antagonists 3 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Block cholinergic transmission between motor nerve endings and the nicotinic receptors on the skeletal When after an initial opening, muscles → paralysis perijunctional sodium Clinically useful to facilitate to tracheal intubation and channels close and will not provide complete muscle relaxation during surgical reopen until the end plate is manipulation repolarized. Phase 1: Differ in mechanism by which they produce the Neural release of Depolarization relaxation or paralysis: acetylcholine results in the block binding of acetylcholine on an already depolarized end plate. NEUROMUSCULAR BLOCKING AGENTS This instance is potentiated by anticholinesterase agents Unaffected by such as neostigmine. acetylcholinesterase but NOT by plasma After administration of 7-10 cholinesterases. mg/kg or 30-60 minutes after It mimics the effects of exposure, train-of-four and acetylcholine at the tetanic fade becomes Depolarizing 1 nicotinic receptor sites Phase 2: apparent. muscle relaxants Induces persistent Desensitization Phase 2 block is reversed by depolarization → gradual block neostigmine or edrophonium repolarization → renders ○ However, it coincides with the receptor incapable of tachyphylaxis due to the transmitting further higher dose of impulses → paralysis succinylcholine required. Competitively block acetylcholine at the nicotinic receptors They compete with acetylcholine at the receptor Non-depolarizing 2 without stimulating it muscle relaxants Prevent depolarization of the muscle cell membrane Inhibit muscular contraction → relaxation and paralysis. Phases of Succinylcholine. Only specialized providers should deliver these drugs as neuromuscular blocking agents cause paralysis of all EFFECTS OF SUCCINYLCHOLINE ADMINISTRATION skeletal muscles, which includes muscles for respiration, THAT ARE IMPERATIVE FOR THE PROVIDER TO hence provision of ventilation support is mandatory KNOW for patients receiving these drugs. 1 Rapid onset of action (1 minute): useful for rapid NCRare (NON intubation DINSux (DEPOLARIZING) DEPOLARIZING) 2 Short duration of action: useful relaxant agent for brief Depolarizing Non-depolarizing procedures Irreversible Competitive Non-competitive Reversible 3 Due to the persistent depolarization at the nicotinic Suxamethonium (a drugs that are receptor muscle fasciculations are observed → drug similar to derivatives of curare. reported as painful by most patients after the procedure succinylcholine)/ E.g. –curium and Succinylcholine –curonium 4 Increases potassium release from intracellular stores into the plasma → causes dangerous hyperkalemia in 2.1. Depolarizing susceptible patients (i.e. with burns, massive tissue injury) 2.1.1. Succinylcholine 5 Can potentiate malignant hyperthermia in susceptible patients Succinylcholine is the single depolarizing agent available in clinical use. 6 Due to fasciculations, it can increase: NOT destroyed by acetylcholinesterases → Intraocular pressure (IOP) accumulate at high concentrations in the synaptic Intragastric pressure (IGP) cleft → attached to the receptor for a relatively longer Intracerebral pressure (ICP) time → persistent depolarization of the receptors → gradual repolarization → paralyzed muscle fiber 2.2. Non-Depolarizing CAPABLE OF DUAL BLOCK Non-depolarizing neuromuscular blockers competitively block acetylcholine at the nicotinic Pharmacology - Mod # Cholinergic Antagonists 4 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  receptors at the motor end plate → prevent binding of Laudanosine: degradation product acetylcholine and depolarization of muscle cell membrane → inhibits muscle contraction. 2.2.2. Pancuronium ONLY neuromuscular blocker with: COMMONLY USED NON-DEPOLARIZING MUSCLE ○ Direct (+) vagolytic / sympathomimetic RELAXANTS properties as a muscarinic antagonist activity ○ ↑ BP, ↑ HR, ↑ CO 1 Atracurium High incidence of residual block in the post anesthesia care unit because of its known long duration 2 Cisatracurium of action 3 Rocuronium 2.2.3. Rocuronium Among the intermediate acting neuromuscular blockers, 4 Vecuronium it exhibits the fastest onset of action (1.5 - 3 minutes) An ideal substitute to succinylcholine for the purpose 5 Pancuronium of immediate intubation For rapid-sequence induction, rocuronium can be used at higher doses if there is contraindication to use CLASSIFICATION OF NON-DEPOLARIZING succinylcholine NEUROMUSCULAR BLOCKERS (NMB) II. SUMMARY Non- Cholinergic antagonist drugs can either be: Depolarizing Onset Duration ○ Anti-muscarinics: action is parasympatholytic NMB ○ Anti-nicotinics: action revolves around ganglionic or neuromuscular blockade Short Acting Mivacurium 3-4 mins 15-20 mins Antimuscarinics has atropine as its prototypical agent Atracurium 3-4 mins 35-45 mins Intermediate Cisatracurium 5-7 mins 35-45 mins Effects of Antimuscarinic Drugs Acting Rocuronium 2-4 mins 35-45 mins Vecuronium 1.5-3 mins 30-40 mins Dry Mouth Urinary retention DUCT Long Acting Pancuronium 3-5 mins 60-90 mins Constipation Tachycardia Non-depolarizing neuromuscular blockers are classified based on their onset and duration of action. Effects of Anti-Nicotinic Drugs CLASSIFICATION OF NON-DEPOLARIZING 1 Ganglionic blockers NEUROMUSCULAR BLOCKERS (NMB) 2 Neuromuscular Produce paralysis by way of (+) Histamine Release (-) Histamine Release blockers two mechanisms ○ Depolarizing by Atracurium Rocuronium mimicking acetylcholine Cisatracurium Vecuronium and persistently (at a lesser degree) Pancuronium depolarizing the end plate for depolarizing Non-depolarizing neuromuscular blockers can also be neuromuscular blockers classified based on their histamine releasing capacity. ○ Non-Depolarizing by competing with acetylcholine at the POSSIBLE EFFECTS RELATED TO HISTAMINE receptor site for RELEASE non-depolarizing neuromuscular blockers 1 Skin flushing Another way of memorizing the effects of cholinergic 2 Hypotension antagonists is by memorizing the effects of cholinergic agonists, which is the famous mnemonic DUMBBELS, 3 Airway hyperreactivity and reversing them. ○ Diarrhea → Constipation ○ Urination → Urinary Retention 2.2.1. Atracurium & Cisatracurium ○ Miosis → Mydriasis Independent of the liver and the kidneys for ○ Bradycardia, Bronchoconstriction → Tachycardia, elimination Bronchodilation Undergo: ○ Emesis → Ⓧ Emesis ○ Hoffman elimination: a non-enzymatic ○ Lacrimation → Ⓧ Lacrimation degradation ○ Sialorrhea → Xerostomia ○ Ester hydrolysis: distinct from plasma cholinesterase or acetylcholinesterase degradation Pharmacology - Mod # Cholinergic Antagonists 5 of 5 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.