Cholinergic Pharmaclogy Flashcards
Eye sympathetic targets (ST)
Iris - contraction of radial muscle: alpha1.
Ciliary muscle - relaxation (minor effect): Beta
Eye parasympathetic targets (PT)
Iris - contraction of circular muscle and ciliary muscle: M2
Heart sympathetic targets (ST)
SAN - Accelerates: Beta1 and 2
Contractility - increases: Beta1 and 2
Heart parasympathetic targets (PT)
SAN - Decelerates: M2
Contractility - Decreases: M2
suppresses AV conduction
Blood vessels ST
Skin/splanchnic - contracts: alpha
Skeletal muscle - relaxes: Beta2, M
Renal - Relaxes: D1
Blood vessels PT
Endothelium - EDRF release: M3
Note: not directly innervated, responds to exogenously administered muscarininc agonist
Bronchiolar smooth muscle ST
Relaxes: Beta2
Bronchioloar smooth muscle PT
Contracts: M3
GI tract smooth muscle ST
Walls and Esophageal sphincter - relaxes: Alpha2 and Beta2
Other sphincters - contracts: alpha1
GI tract smooth muscle and secretions PT
Walls and Esophageal sphincter - contracts: M3, M
Other sphincters - relaxes: M3
Gastric/other secretions - increase: M1 and M3
Genitourinary tract ST
Bladder - relaxes: Beta2
Sphincter - contracts: alpha1
Uterus - relaxes/contracts: Beta2 and alpha respectively
Penis - ejaculation: alpha
Genitourinary tract PT
Bladder - contracts: M3
Sphincter - relaxes: M3
Uterus - contracts (minor effect): M3
Penis - erection: M but mediated through NOx
Skin pilomotor smooth muscle and sweat glands ST
SM - contracts: alpha
Apocrine: alpha
Eccrine: M
Metabolism ST
Liver gluconeogenesis and glycogenolysis: Beta2 and alpha
Fat lipolysis: Beta3
Kidney - Renin release: Beta1
Synthesis of acetylcholine
Cytosolic catalysis of acetyl CoA (from glucose metabolism in mitochondria) and choline (quaternary amine pumped from ECF). Rate is dependent on availability of choline. Packaged into vesicle/quanta. 100 or more quanta released per action potential
Release of acetylcholine at neuromuscular junction
Triggered by AP, specifically increase intracellulary Ca++ (antagonized by Mg++)
Additionally background release of ACh to produce small transient depolarizations of the motor endplate (MEPP) that do not initiate contraction by may serve trophic function
Muscarinic receptors
Muscarin is an alkaloid that mimics ACh at AChR in:
Visceral smooth muscle of GI tract, lower urinary tract, uterus and bronchis
Heart and Vascular tissue
Secretory glands
Central nervous system
Autonomic Ganglia
Antagonized by Atropine - alkaloid from belladonna
Work via G proteins - Gi (M2) results in increased K+ conductance and decreased cAMP slowing heart rate. Gq (M1 and M3) activates phospholipase C, resulting in increased intracellular Ca++ causing contraction of SM or secretion in glands or NOx release from endothelium
Nicotinic receptors
Receptor is cation channel. Found at ganglionic and neuromuscular junction and are slightly different. Blocked by d-turbocurarine. CNS agents - first to be approved is varenicline (Chantix - partial agonist, note negative neuropsychiatric side-effects
Acetylcholine esterase
Very rapid, 2 primary sites - anionic and esteratic site. The anionic electrostatically attracts the choline quaternary amine. The esteratic site is composed of a serine residue with an exposed OH held in place by histidine. The enzyme transfers the acetyl group from choline to the serine - covalently modified. Water recharges enzyme by hydrolysis.
Presynaptic cholinoceptor
Regulate the evoked release of ACh, usually muscarinic - M2. Inhibit the release of ACh, thus atropine can cause increased release of ACh - paradoxical bradycardia at low doses of atropine and reliable tachycardia with moderate or high doses of atropine.
Sodium-dependent choline transporter
inhibited by hemicholinium drugs
Vesicle-associated transporter
inhibited by vesamicol
VAMP and SNAP associated exocytosis
Inhibited by botulinum toxin
Aminoglycoside Antibiotics
streptomycin, kanamycin, neomycin and gentamicin inhibit calcium movement through cholinergic nerve terminal the reducing exocytotic ACh release
Depolarizing blockade
Excessive cholinergic agonist stimulation of the nicotinic receptors at the motor end plate result in depolarization without excitation coupled contraction resulting in paralysis (ex. succinylcholine - therapeutic or nicotinic/organophosphate toxicity)
Acetylcholine
Direct acting agonist, rapid hydrolysis in plasma by pseudocholinesterases. Direct intracoronary injection in diagnostic angiography - in patients with vasospastic angina pectortis ACh induces spasm of CA. Normal response would be vasodilation
Atropine
(hyoscyamine or Levsin) prototype anti-muscarinic drug. Natural alkaloid. Well absorbed orally, parenterally and topically. Competitive antagonist at AChR, surmountable with agonist
Red as a beet, dry as a bone, blind as a bat, mad as a hatter.
Widely distributed metabolized in the liver, some excreted unchanged in the urine.
Uses: motor symptoms of parkinsons (bentropine). pupilary myadrisis and fixed resting lens (loss of near vision). Treatment of sinus bradycardia post MI. Treatment of diarrhea
Scopolamine
Similar to atropine, also from atropa belladona. 100 times more depressive than atropine in ascending reticular core. Used in adhesive patch to treat motion sickness, hypnotic, anxiolytic
Anti-cholinergic burden
Anti-histamine, anti-depressants, and anti-psychotics have significant atropine like activity. Cumulative effects can reduce cognition and be confused with dementia
Pilocarpine
Tertiary amine - plant source. Muscarinic agonist applied topically to eye to induce miosis (pupilary contraction). Used to treat chronic and DOC for acute glaucoma. Given orally for xerostomia in patients receiving radiotherapy for head-and neck cancer or with Sjogren’s Syndrome
Carbachol (carbamylcholine)
Synthetic quaternary amine, agonist to muscarinic and nicotinic receptors. Not metabolized by cholinesterases. Used as miotics during eye surgery such as lens replacement
Tropicamide (Mydriacyl)
Muscarinic antagonist used to dilate pupil for ophthalmologic assessment
Bethanechol (carbamylmethylcholine, Urecholine)
Synthetic quaternary amine with muscarinic long lasting action due to resistance to hydrolysis by psuedo and acetylcholine esterases. Direct acting. Acts in GI and bladder when administer orally or sub-Q. Treats post-partum and post surgical stasis of bladder and GI. Contraindicated if obstruction is suspected.
Propantheline (Pro-benthine)
Quaternaty amine used as a spasmolytic to treat GI hypermotility
A note on Quaternary Amines
possess some ganglionic blocking actions when distributed systemically, which seems to increase their effectiveness as spasmolytic agent on visceral smooth muscle
Neostigmine
Muscarinic agonist, indirect acting inhibitor of AChE. Synthetic quaternary amine analog of physostigmine. Charged quaternary amine - more effective in the management of myasthenia gravis, no significant CNS side effects. Additional uses - augment motility of GI or lower urinary tract, and reverse neuromuscular blockade by competitive antagonists. Contraindicated in GI obstruction and oral administration requires a very large dose. MG now usually treated with pyridostigmine which has a longer duration
Oxybutynin (Ditropan)
Tertiary amine, weak muscarinic antagonist metabolized by liver CYP3A4. Treats bladder spasm, urinary urgency. Available as transdermal patch (oxytrol)
Tolterodine (Detrol)
Bladder relaxant for overactive bladder. tertiary amine, administered orally, muscarinic antagonist. CYP2D6 metabolism
Festerodine (toviaz), trospium (sanctura), Solifenacin (vesicare), darifenacin (enablex)
Muscarinic antagonists approved by FDA to treat over-active bladder.
Methacholine
Synthetic quaternary amine acts as mAChR agonist to suppress atrial tachycardias, now available as aerosol form to diagnose bronchial airway hyper-reactivity. Do not use unless prepared for acute respiratory distress. Slowly hydrolyzed by AChE only
Ipratropium (Atrovent)
Aerosol muscarinic antagonist, quaternary amine. treats COPD
Triotropium (Spiriva)
longer half-life that ipratriopium. Less antogonist activity at M2 - less feedback regulation.
Cevimeline (Exovac)
Synthetic muscarinic agonist for xerstomia - may have beneficial selectivity for M1 and M3 receptors. Metabolized by CYP2D6 and 3A3/4
Nicotine
Principle alkaloid of nicotiana plants, liquid. Lipid soluble. Crosses placenta and into breast milk. Nicotine is an agonist of all nicotinic receptors in the C and PNS. Prolonged action can lead to depolarizing blockade. pharmacological use for nicotine to treat nicotine withdrawal symptoms, may improve cognition in Alzheimer’s patients and decrease the incidence of Parkinson’s disease
D-tubocurarine
Competitve nicotinic antagoinist at motor endplate. Reduces number of available AChR’s for physiologically release ACh to bind and activate. Reversible. Neostigmine or edrophonium or by tetanic stimulation of motor nerves.
60% metabolized, 40% excreted unchanged by the kidney.
Side-effects: rapid and transient decrease in blood pressure from ganglionic blockade of sympathetic vascular tone and release of Histamine from mast cells. Note: histamine can produce salivation, increased bronchial secretions and may precipitate and asthmatic-like action
Cisatruacurium (Nimbex)
Synthetic isomer of atracurium. Competitive antagonist of nAChR with only mild hypotensive actions. Inactivated by spontaneous breakdown - can be used safely in hepatic and renal failure. Breaks down to laudanosine which can cause seizures but so potent less is needed so less laudanosine.
Note: Doxacurium and Mivacurium were in this family but are no longer in production in the US
Pancuronium (Pavulon)
Steroid-based competitive nAChR antagoinst with long duration of action. Renally eliminated. Produces tachycardia due to blockade of M2 receptors. Prolonged use in ICU may be associated with persistent weakness.
Vecuronium (Norcuron)
Steroid-based competitive antagonist with good selectivity fro nmj nAChR with little effect on cardiovascular system. Structure identical to pancuronium except one of two amines is tertiary rather than quaternary. Eliminated mostly unchanged by liver (15% unchanged elimination by kidney)
Rocuronium (Zemuron)
Steroid based agent with fastest onset. Can be used in a series for rapid-sequence intubation. Low dose used prior to SuCh to prevent fasciculations (pre-curarization). Biliary excretion. Minimal cardiovascular effects, but rare allergic reactions have been reported.
Competitive neuromuscular blocking agents are potentiated by:
General anesthetics, aminoglycoside antibiotics, electrolyte imbalances, polypeptide antibiotics (polymyxins, colistin and lincomycin) and Advanced age.
Note Mayasthenia gravis will greatly increase block, while severe burns, upper motor neuron disease or spinal injury will have resistance to curare-type drugs.
Succinylcholine (Anectine)
agonist at the neuromuscular junction, very rapid onset of action and short duration (5 min.) Metabolized by plasma pseudocholinesterases (note polymorphism may result in decreased or absent metabolism requiring transfusion with normal plasma to clear SuCh). Mild histamine release counteracted with mild gangiolinc blockade - result mild bradycardia with increase in peripheral resistance. Significant potassium release into blood stream can result in cardiac arrest, particularly in patients with extensive burns, trauma, neuromuscular disorders, on diuretics or digitalis for congestive heart failure, have renal failure or children are particularly susceptible.
Depolarizing Blockade
Phase 1 blockade - gradual depolarization past threshold resulting in the inability of release ACh to generate enough potential change to excite adjacent sarcolemma. Cannot be antagonized by neostigmine or edrophonium or anything else. If SuCh overdose, all you can do is support breathing until it is cleared.
Phase 2 blockade - mixed or dual blockade, occurs when SuCh is given over 20 minutes or more. some motor endplates become repolarized but transmission failure is still present. Can be partially reverse by edrophonium or neostigmine. Don’t need to know mechanism.
Note the effect of skeletal muscle blockade is monitored by transdermal stimulation
Dantrolene (dantrium)
Depresses skeletal muscle contraction by blocking release of calcium from the sarcoplasmic reticulum. Uses limited to spasticity type disease (UPN lesions where patient is already required to be in a wheel chair as dantrolene causes significant muscle weakness) and as an adjunct during anesthesia to treat malignant hyperthermia
Baclofen
Agonist at GABA-B receptors, activation leads to hyperpolarization, likely works pre-synaptically to decrease excitatory neurotransmission in the brain and spinal chord. Effective antispasmodic, non-sedating with less weakness than dantrolene
Tizanidine
Atypical agonist at alpha2 adrenoceptors, increases pre and post-synaptic inhibition
Riluzole
Inhibitor of glutaminergic signalling that has limited anti-spasmodic activity but does modestly prolong life in ALS
Cyclobenzaprine
Used to treat acute muscle spasms after trauma. Structurally similar to tricycline antidepressants with significant anti-muscarinic and sedative activities. Method of action unknown
Hexamethonium
Classic gangionic blocking drugs, used first to treat hypertension, selective and competitive antagoinist of nAChR on postganglionic cell. Significant undesirable side-effects - orthostatic hypertension
Mecamylamine (inversine)
Secondary amine, predictable absorption and wide distribution. Ganglionic blocker. Some residual use in hypertensive emergencies or to produce hypotension during neurosurgery. Under trial in nicotine sensitive CNS disorders - Tourett’s
Phygostigmine (antilirium)
Plant based, prototype, tertiary amine methyl carbamate - acts at both muscarinic and nicotinic receptor junctions. Reversible anticholinesterase agent. Still empoyed topically as a miotic in glaucoma treatment. Can cause seizures. Metabolized by ester hydrolysis in the plasma compartment.
Edrophonium (tension)
Synthetic quaternary amine, only occupies the anionic site on AChE. Very brief action, used as a diagnostic agent for Myasthenia gravis
Alzheimer treatments
Tacrine - first approved, now little used due to side effects.
Donepezil - piperdine based, little ability to improve cognitive function, milder side-effects without hepatotoxicity
Rivastigmine - carbamate, less plasma protein binding, less drug interactions
Galantamine - tertiary alkaloid from the snowdrop, now maufacture synthetically
Memantine - glutamate receptor antagonist
Organophosphates
echothiophate - used medically, but uses decreasing, topically in eye for sustained miosis lasting 3 days or longer.
Malathion and parathion are insecticides
Sarin Gas
Organophosphate poisoning
Marked GI motilty, hypotension, bradycardia, reflex tachycardia, bronchial constriction with increased secretions, involuntary micturition, CNS - convulsions, depression, and finally coma, depressed respiratory rate, muscle fasciculations, then depolarizing blockade and paralysis
Organophosphate poisoning treatment
Must be rapid, begin with decontamination, atropine to control the muscarinic actions, pralidoxime to recharge AChE. Supportive measures.
