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53 Cards in this Set
- Front
- Back
What are the 3 categories of cholinergic agonists?
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Choline esters
New M3 specific agonists Natural alkaloids |
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What is an example of a choline ester?
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Bethanechol
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What is an example of an M3 specific agonist?
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Cevimeline
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What is an example of a natural alkaloid?
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Pilocarpine
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Why isn't Ach used clinically?
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As soon as you ingest it, it gets broken down?
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What is the main difference between Ach and metacholine?
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Metacholine has more muscarinic effects than nicotinic effects. (also a little less hydrolyzed by acetylcholinesterase)
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Carbachol is used in treatment of what, seldomly?
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Glaucoma
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Bethanechol is used in treatment of what?
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Bladder and GI hypotonia
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Pilocarpine is used in treatment of what?
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Glaucoma
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Cevimeline is used in treatment of what?
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dry mouth in patients with Sjogren's Syndrome
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Bethanechol
1. Clinical Uses 2. MOA |
1. Clinical Uses:
Disorders associated with decreased parasympathetic tone - Postoperative (d/t anesthetics) & postpartum urinary retention and/or inadequate emptying of the bladder - Postoperative abdominal distension or GI tract atony or paresis 2. MOA: Acts at the muscarinic receptors - To contract detrusor muscle of urinary bladder, usually enough to initiate micturition - To increase GI motility |
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Pilocarpine
1. Clinical Uses 2. MOA |
1. Clinical Uses:
Clinical Uses: Topical formulations are used - To reduce intraocular pressure (IOP) in certain types of Glaucoma (Better tolerated than AChE inhibitors) - To treat dry mouth (xerostomia) - To reverse the effects of atropine, which is commonly used for dilation of the pupil during eye exams MOA: - Reduces IOP by improving drainage. Contracts the sphincter pupillae (M3 receptors) and reduces angle block (mydriasis can cause angle block) *Warning! It is a tertiary amine and can cross the conjunctiva leading to systemic effects* - Xerostomia: Acts at the M3 receptors on the salivary gland to increase secretion |
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Cevimeline
1. Clinical Uses 2. MOA |
Cevimeline
1. Clinical Uses: - Treatment of Xerostomia following head & neck irradiation - Xerostomia associated with Sjogren’s syndrome - Enhances lacrimal secretions in Sjogren’s syndrome *Sjogren's syndrome destroys lacrimal and salivary glands 2. MOA: - Newer M3 receptor specific agonist - More selective, potent action at the salivary glands & lacrimal glands *Fewer side effects than pilocarpine |
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What are some side effects of muscarinic agonists (aka cholinergic agonists)?
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- Diarrhea
- Diaphoresis - Miosis - Nausea - Salivation - Urinary urgency *With drugs that cross the BBB (ex: pilocarpine) you may see CNS disturbances |
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Why is asthma a contraindication for muscarinic agonists?
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Muscarinic agonists can cause bronchoconstriction and increase mucous secretion
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Why is heart disease a contraindication for muscarinic agonists?
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Slowing conduction of cardiac action potential through AV node may precipitate arrhythmias.
IV drugs can also cause hypotension & reduce coronary blood flow. The hypotension can then trigger reflex increase in sympathetic activity to the heart leading to arrhythmia. decrease HR, decrease SV, decrease CO, decrease BP |
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What inhibits transport of choline in the neuron?
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Hemicholinium
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What toxin blocks release of Ach from the neuron?
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Botulinum Toxin
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What toxin CAUSES release of Ach from the neuron?
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Spider venom
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What are 2 examples of pseudo cholinesterases?
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Plasma cholinesterase
Butyryl cholinesterase |
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What are potential sites of action for Ach esterase inhibitors?
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- At all effector organs innervated by parasympathetic system such Eye, GI, urinary bladder
- Neuromuscular junction (NMJ) - All autonomic ganglia |
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What is a short (~10 min), reversible AChE inhibitor?
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Edrophonium
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What are some intermediate, reversible AChE inhibitors?
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- Physostigmine
- Neostigmine - Pyridostigmine - Rivastigmine - Galantamine - Ambenonium - Donepezil - Tacrine |
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What are some synthetic organophosphate, irreversible (long) AChE inhibitors?
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- Ecothiophate
- Isofluorophate |
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What are some nerve gas, irreversible (long) AChE inhibitors?
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- Sarin
- Soman |
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What AChE inhibitors are used for myasthenia gravis?
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- Edrophonium (diagnostic test only)
- Neostigmine - Pyridostigmine - Ambenonium |
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What AChE inhibitor is used for hypotonia of bladder and GI?
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Physostigmine
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What AChE inhibitors are used for Glaucoma?
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- Physostigmine
- Ecothiophate |
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What AChE inhibitors are used for Alzheimers?
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- Donepezil
- Rivastigmine - Tacrine - Galantamine *All these drugs cross the BBB to increase cholinergic effects in the brain! |
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Neostigmine
1. Clinical Uses 2. MOA 3. Adverse effects |
1. Clinical Uses:
- Effect at NMJ is greater than that of physostigmine, hence used in myasthenia gravis 2. Synthetic compound that cannot enter the brain 3. Adverse effects: - Effects of generalized cholinergic stimulation and drop in blood pressure (usually not a problem) - Overdose can cause cholinergic crisis & muscle paralysis (too much ACh, desensitizes it -> flaccid paralysis) |
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Physostigmine
1. Clinical Uses 2. MOA 3. Adverse effects |
1. Clinical Uses:
- Antidote for overdoses of atropine & other anticholinergic drugs. Especially useful in reversing the CNS side effects - Reduces intraocular pressure in Glaucoma. Similar mechanism as pilocarpine 2. MOA: - Plant alkaloid & tertiary amine that CAN cross the BBB - Potentiates Ach effects at Muscarinic & Nicotinic receptors of the ANS and also nicotinic receptors at the NMJ 3. Adverse effects: - Diarrhea, nausea, sweating, miosis, urinary urgency - At high doses physostigmine can cause convulsions , bradycardia & hypotension |
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a) How might someone get organophosphate poisoning?
b) What symptoms does it cause? c) MOA? |
a) Many insecticides and pesticides contain cmpds that are long acting AChE inhibitors. Accidental or intentional poisoning gives rise to a slew of symptoms that involve activation of muscarinic & nicotinic receptors. Also from nerve gases!
b) First 4 symptoms: S: SALIVATION L: LACRIMATION U:URINATION D: DEFECATION *Also increased are GI motility, emesis/vomiting, miosis c) These compounds phosphorylate AchE thereby inactivating the enzyme. The organophosphate- enzyme complex undergoes an “aging” process which inactivates AChE permanently. Depending on the agent it can take 2 min or hrs. |
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How is organophosphate poisoning treated prophylactically?
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Pyridostigmine (during chemical warfare)
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How is organophosphate poisoning treated post-exposure?
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High doses of muscarinic antagonist atropine or Scopolamine followed by an injection of Pralidoxime can reverse the effects of poisoning
*Pralidoxime reactivates acetylcholinesterase. However, pralidoxime therapy is ineffective once “aging” has occurred |
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What are 2 subcategories of muscarinic receptor antagonists?
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Belladona Alkaloids
Synthetic & Semi-synthetic Derivatives |
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What are examples of Belladona alkaloids?
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Atropine
Scopolamine |
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What are some commonly used examples of synthetic and semi-synthetic derivatives (muscarinic receptor antagonists)?
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Ipratropium
TiotropiumI Tolterodine |
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Atropine
1. Clinical Uses. 2. MOA 3. Side Effects |
1. Clinical Uses:
- Reversal of severe bradycardia - To produce mydriasis and cycloplegia ( loss of accomodation) for examination of the eye - Antispasmodic - To suppress respiratory secretions prior to surgery - To treat organophosphate (AChE inhibitors) insecticide poisoning - To treat mushroom poisoning 2. MOA: - Belladonna alkaloid, it is a tertiary amine & can cross the BBB ( but not at therapeutic doses) - Non selective muscarinic antagonist - Eye- Blocks all parasympathetic effects on the eye & causes mydriasis (dilation of pupil), Cycloplegia (loss of accomodation) - GI- Reduces GI motility - Reduces salivary, sweat & lacrimal secretions 3. Side Effects: - Dry mouth - Constipation - Dilated pupils (Mydriasis) - Blurred vision due to cycloplegia - Hot, dry flushed skin - Tachycardia - Fever - CNS disturbances |
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Scopolamine
1. Clinical Uses 2. MOA 3. Side Effects |
1. Clinical Uses
- Prophylactic for motion sickness (~ 4 hrs before travel) - Adjunct drug in anesthesia to produce sedation & amnesia - Opthalmic use 2. MOA: - Scopolamine crosses BBB much more than atropine at clinical doses 3. Side effects: Similar to side effects seen with Atropine except that CNS effects are more prominent Eg: Drowsiness, amnesia, fatigue, loss of REM sleep |
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Ipratropium Bromide
1. Clinical Uses 2. MOA 3. Side Effects |
1. Clinical Uses:
- Used in asthma & Chronic obstructive pulmonary disorder (COPD) to cause bronchodilation as an adjunct to albuterol - It is also be used alone as an alternative to albuterol in patients who are unable to take adrenergic agonists 2. MOA: - Blocks muscarinic receptors and reduces bronchoconstriction mediated by parasympathetic activity - Minimal inhibitory effect on mucociliary clearance when compared to atropine 3. Side Effects: - Less CNS effects |
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At very low doses, what is unique about atropine?
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It causes slight cardiac slowing, because every nerve terminal regulates its own release. The M2 presynaptic reduces release of ACh.
(M1 increases, M2 decreases ACh release) |
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Tiotropium Bromide
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- Clinical uses: COPD and Asthma
- Much more selective action at the bronchioles - Greater affinity for M3 vs M2 |
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Tolterodine
1. Clinical Uses 2. MOA |
1. Clinical Uses:
Treatment of overactive bladder - Reduce the number of incontinent episodes - Increase the amount of urine, the bladder can hold - Reduce frequency of urination - Decrease urgency 2. MOA: - Blocks M3 receptors on detrusor muscle reducing parasympathetic mediated contraction of the bladder & helps diminish urge incontinence during the initial stages of filling - Also blocks parasympathetic tone to the sphincter and prevents leaks |
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What is a contraindication to M3 antagonists?
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Slows Voiding: Not appropriate in individuals with urinary retention (eg Benign prostatic Hyperplasia (BPH)
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What makes tolterodine different from the other M3 antagonists (Fesoterodine,
Solifenacin, Darifenacin, Oxybutynin)? |
The others don't favor M3 much more than M2
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What are some contraindications to muscarinic antagonists?
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- Glaucoma (b/c of mydriasis)
- Benign prostatic Hyperplasia (BPH) or any urinary condition , or kidney condition with urination problems - Myasthenia Gravis (don't want to block ACh effects!) - Excessive constipation |
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T/F
Very few ganglionic blockers are used clinically. |
True!
Hexamethonium bromide and Trimethopham are examples. |
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What are some non-depolarizing NMJ blockers?
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Atracurium*
Cistracurium Vecuronium Rocuronium Pancuronium Tubocurarine curiums and curoniums |
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What is an example of a depolarizing NMJ blocker?
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Succinyl choline
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What is the MOA of non-depolarizing NMJ blockers?
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They block the nicotinic receptor at the NMJ & prevent the actions of acetylcholine.
aka: Surmountable or Competitive blockers: Blocking effect CAN be overcome by increasing the amount of Ach available in the synaptic cleft For example, with a AchE inhibitor |
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What is the molecular structure of succinylcholine?
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2 ACh molecules linked end to end
*It is metabolized by plasma cholinesterase (pseudo cholinesterase, butyryl cholinesterase), but NOT by AChE. So it has to diffuse out of the tissues to get broken down. THEREFORE: Rapid onset, short duration of action (minutes for a single dose). Duration may be prolonged in patient with genetic variants of pseudocholinesterase |
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What is the MOA for succinyl choline? (Both phase 1 and phase 2)
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PHASE 1:
- Succinylcholine is an agonist at nicotinic receptors & initially depolarizes the muscle membrane, releases Ca2+ & causes fasiculations - The Ca2+ is removed from the cytosol back into sarcoplasmic reticulum , muscle relaxes, and the patient is paralyzed (Flaccid paralysis) *AchE inhibitors will worsen Phase 1 (b/c you activate more receptors) PHASE 2: Upon continued exposure to succinylcholine, the phase I block changes to phase II block - i.e the membrane is repolarized but the muscle is resistant to further activation by ACh being released at the NMJ In more detail... Unlike the acetylcholine, succinylcholine is not subject to hydrolysis by acetylcholinesterase and therefore remains in the junction longer. Soon after administration of the drug, some receptors are desensitized and, although occupied by an agonist, they do not open to allow current to flow to depolarize the area. If succinylcholine is applied in high concentration and allowed to remain at the neuromuscular junction for a long time, other effects occur, including entry of the drug into the channel to obstruct it or to pass through it into the cytoplasm. Succinylcholine also has effects on prejunctional structures, and the combination of prejunctional and postjunctional effects plus secondary ones on muscle and nerve homeostasis results in the complicated phenomenon known as phase II blockade |
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What are side effects of succinyl choline?
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- Muscle pain postoperatively (damaged muscle due to fasciculations (?))
- Hyperkalemia (from prolonged use, K+ is kicked out of cells into the ECF) - At high doses can also block ganglionic nicotinic receptors - Decreased heart rate - Increased IOP Serious side effects: MAKE SURE they don't have genetic variant! - Malignant hyperthermia (ryanodine receptor, increase in Ca2+ release from SR, can happen suddenly) ---> Treat with Dantrolene |