PHAR 736 Final Exam (Filtz) Flashcards
N(N) Receptors
Neuronal Nicotinic receptors on post-gangliconic neurons and adrenal medulla
5 subunits forming a barrel with inner poor to allow cations to pass through
Required binding of 2 molecules of ACh
Nicotinic receptor antagonists
Non-depolarizing (flaccid paralysis)
Competitively blocks ACh binding sites (can be overcome by more ACh)
Nicotinic receptor agonists
Depolarizing blocker (spastic paralysis)
Persistent stimulation induced blockade, akin to desensitization
Blockade NOT to be reversed by excess ACh; must wait for resensitization
N(M) blockers cause paralysis of
voluntary, striated, skeletal muscle
Curare
Classic natural product paralytic agent
Used in South America to paralyze prey
No initial excitation, only blockade resulting in paralysis (80-120min)
Sequential order of paralysis: Eye, jaw, throat and neck, appendages, abdominal muscles, intercostal muscles and diaphragm
Dose can be titrated to avoid asphyxiation but produce waking paralysis
Poisoning treatable with AChE inhibitors
Problems with curare and curare-like drugs
Action terminated by excretion in urine so may have extended duration in patients with renal insufficiency
Histamine release also associated with curare, so be careful with asthmatics
Potentially dangerous synergism with antibiotics (streptomycin, tetracyclin)
> antibiotics chelate Ca2+ and contribute to muscle paralysis
Antibiotics prolong duration of action of curare-like drugs beyond expectations
Synthetic curare-like drugs
No histamine release
Drugs terminated by renal elimination are better for patients with liver disease, and vice versa
Cisatracurium, Pancuronium, Vecuronium, Rocuronium
Cisatracurium
Medium duration (30-40 minutes)
Nm selective because it cannot cross into the ganglionic space
Terminated by metabolism
Pancuronium, Vecuronium, Rocuronium
Greater selectivity for Nm over Nn receptors that cisatracurium
Pancuronium is long-lived (120-180 min), renal elimination (great for surgery and for those with liver disease)
Rocuronium and Vecuronium are of intermediate duration, liver metabolized, and can be chemically antagonized by sugammadex.
Succinylcholine
Depolarizing neuromuscular blocker; cheap, rapid acting and short duration
Nm selective
Opens ion channel, causing initial depolarization leading to contracting and twitching for 1 minute; persistent stimulation = eventual blockade (~5 minute paralysis)
Succinylcholine hydrolyzed by circulating plasma cholinesterases (pseudocholinesterases) and has short duration
Short term paralysis makes it useful for electroshock therapy, setting fractures and dislocations, endotracheal intubations)
Problems with succinylcholine
No chemical antidote for depolarizing blocker
May have muscle pain and soreness from initial twitching
Hyperkalemia due to affinity for K+ channels (problematic for those on digitalis or with electrolyte imbalances)
Duration may be dangerously extended in patients with liver disease or genetic defects resulting in low levels of circulating cholinesterase
May cause malignant hyperthermia when used in conjunction with inhalation anesthetics in some patients
Malignant Hyperthermia
Results from Succinylcholine + inhaled anaesthetic causing hypermetabolic response of muscle tissue due to excess calcium release
Treat with Dantrolene (blocks Ca2+ release from SR)
Tetrodotoxin
Bacterial toxin concentrated by marine organisms such as pufferfish
Na+ channel blocker that interrupts axonal conductance
Botulin toxin
From Clostridium botulinum of food-poisoning fame
Inhibits Ca2+ dependent binding of vesicles to plasma membranes thereby inhibiting neurotransmitter release
Predominant tone and effect of ganglionic blockade effect on Blood Vessels
Sympathetic; hypotension
Predominant tone and effect of ganglionic blockade effect on Bladder and GI sphincters
Sympathetic; Relaxation
Predominant tone and effect of ganglionic blockade effect on Heart
Parasympathetic; Tachycardia
Predominant tone and effect of ganglionic blockade effect on Eye
Parasympathetic; Mydriasis, blurred vision
Predominant tone and effect of ganglionic blockade effect on GI Tract
Parasympathetic; Decreased motility
Predominant tone and effect of ganglionic blockade effect on Urinary Bladder
Parasympathetic; Urinary retention
Predominant tone and effect of ganglionic blockade effect on Salivary glands
Parasympathetic; dry mouth
Non-depolarizing and depolarizing ganglionic blockers have __________________ clinical use
very-limited
No antidote for depolarizing, induce vomiting
Nicotine
Some selectivity for Nn over Nm
At high dose, Nm receptor effects cause muscle twitching
Most noticeable effect is initial EPI release following excitation of adrenal medualla Nn receptors (increase in HR, BP)
Nicotine dependency/addictive properties based on CNS effects
Special effects include: concentrated nicotine is lethal; analgesia following through blockade of pain sensory nerves; nausea and vomiting from activation of vomiting reflex center; respiratory distress and hyperventilation (activation of chemosensory nerves); and may have neuroprotective, anxiolytic or GI protective effects
Varenicline
Partial agonist at (a4)2(b2)3 and full agonist at (a7)5 nicotinic receptors
Predominant CNS nicotinic receptor subtypes
Nicotine withdrawal symptoms due to elevated receptor levels - irritability, insomnia, restlessness, aches and pains, constipation, increased appetite, sugar cravings
As a partial agonist, will reduce withdrawal symptoms without activating dependency pathways (doubles abstinence rate compared to placebo over 52 weeks)
Draw graph of verenicline by itself and in presence if nicotine
…
ACHe inhibitors that do not pass the BBB and ganglionic barriers will increase ACh levels to
Affect muscarinic receptors on PNS target organs
Affect Nm receptors on skeletal muscle
Inhibitors of AChE that DO pass the BBB and ganglionic barriers will
Affect Nn receptors in autonomic ganglia
Affect Nn receptors on adrenal medulla
Affect Nn and muscarinic receptors in the CNS
Pseudocholinesterase
Produced by the liver and in the circulation
AKA butyryl cholinesterase
Indications for AChE inhibitors
Nm effects, Nn (ganglionic) effects, muscarinic (M) effects, CNS effects
Describe Nm effects of AChE inhibitors
For Myasthenia Gravis (antibodies attack and destroy Nm, not Nn, receptors)
> diagnosis can be made with AChE inhibitors which have no effect on other muscle diseases characterized by weakness
symptoms treated by increasing ACh levels at neuromuscular junction
longterm treatmnet may involve thymectomy or immune suppression
Also used to reverse effects of non-depolarizing (competitive) Nm blockers
AChE inhibitors ganglionic (Nn) effects
Orthostatic hypotension
Prolongs ganglionic transmission leading to increased basal tone
AChE inhibitors muscarininc effects
Glaucoma (increases miosis through MI and M3 receptor activation on iris sphincter; increased aqueous humor flow through contraction of ciliary muscle)
Antidote to poisoning by deadly nightshade (atropine) or other muscarinic antagonist (competitive antagonist actions overcome by excess agonist)
GI and Bladder atony-limited use (increased GI motility and bladder emptying through activation of muscarinic receptors in gut and bladder, smooth muscle and sphincters)
Paroxysmal atrial tachycardia-very limited use (decrease heart rate through M2 receptor activation on cardiac muscle)
AChE inhibitors CNS effects
Treatment of Alzheimer’s disease (increasing ACh levels in CNS have short term therapeutic benefit; longterm loss of cholinergic neurons eventually render AChE inhibitors impotent)
Side effects with AChE inhibitors
Secretory, cardiac, bronchiol, and GI effects same as with a muscarinic receptor agonist (may decrease over time, can be controlled by concurrent admin of muscarinic antagonist, and at toxic levels hypoxia activates chemosensory reflexes to increase HR)
Actions on the vasculature (No ACh to release at vascular endothelium so vascular muscarinic receptor not affected; AChE inhibitors may have unpredictable effects on BP depending on degree of ganglionic stimulation, basal tone of blood vessels, age and level of excitement)
CNS effects may cause confusion, convulsions and coma at toxic doses
Skeletal muscle activation of twitching, eventual paralysis and death by asphyxiation at toxic doses
Physostigmine
AChE inhibitor
Natural plant alkalpoid and prototype
Penetrates peripheral ganglia and CNS - proposed use to treat orthostatic hypotension
Used topically to treat glaucoma
Neostigmine
AChE Inhibitor
Does not cross BBB
Most used for management of myasthenia gravis
Useful for atropine poisoning
Useful for GI and bladder atony
Edrophonium
AChE inhibitor
Short duration of action
Used to diagnose myasthenia gravis because it washes away quickly
Pyridostigmine bromide
AChE inhibitor
Approved for prophylactic use by military to potentially block effects from a feared nerve gas attack
never been clinically tested for this use
Rivastigmine
AChE inhibitor for Alzheimer’s
Crosses BBB
Approved for mild to moderate dementia in Parkinson’s; may target AChE isoenzymes that are more prominent in the CNS; fewer reported side effects than donepezil, particularly less bradycardia
Donepezil, Galantamine
AChE inhibitors used in Alzheimer’s
Cross BBB
Huperzine A
AChE inhibitor used in Alzheimer’s treatment
Cross BBB
Herbal product
Organophosphates
Irreversible AChE inhibitors
Aging of phosphorylated AChE (in 1 hour) leads to permanently phosphorylated enzyme that can NOT be reactivated
Very lipid soluble and readily cross the BBB, pulmonary and intestinal membranes
Echothiophate, Nerve gases (Sarin, Tabun, Soman, VX), Insecticides (Malathion, Parathion)
Echothiophate
Very long duration of action
Used topically to treat glaucoma
Decreased lipid solubility and limited systemic absorbance
Nerve Gases (Sarin, Tabun, Soman, VX)
Airborne organophosphates
Rapidly cross membranes and barriers
Death from asphyxiation may result in minutes
Insecticides (Malathion, Parathion)
Can be detoxified rapidly by mammals
Over-exposure is similar to nerve gas poisoning
Treatment of organophosphate poisoning
Support respiration plus atropine + Pralidoxime
- give atropine within seconds to minutes to reverse muscarinic effects
- *pralidoxime, an oxime reactivator of AChE must be given within minutes to hours of exposure
- **support respiration to avoid patient asphyxiation or drowning in secretions
No antidote available if sufficient time has passed for aging of phosphorylated AChE to occur
Acute Glaucoma
Closed angle
Characterized by an abnormal lodging of the iris against the lens, impeding the flow of aqueous humor, leading to increased intraocular pressure
Chronic Glaucoma
Open angle
Characterized by excess aqueous humor, from either overproduction or impaired absorption by the Canal of Schlemm
Treatment of closed angle glaucoma
Best treated by pupillary constrictors
Cholinomimetics (problems with far and night vision)
Constrict the iris sphincter and dislodge the iris, opening a pathway for aqueous humor flow
Contraction of the ciliary muscle increases space for aqueous humor flow through the ciliary ligaments
Treatment for chronic open angle glaucoma
Use agents that inhibit production of aqueous humor
B-adrenergic receptor antagonists (problems with concurrent airway disease)
a2 adrenergic receptor agonists (problems with drug reactions through alkylation)
Carbonic anhydrase inhibitors, dorzolamide and brinzolamide (carbonic anhydraw is required enzyme for aqueous humor production; systemic administration of inhibitors can cause metabolic acidosis, leading to kidney stones and allergic reactions)
May also be treated with agents that increase aqueous humor drainage (prostaglandin analogues - latanoprost, bimatoprost, travoprost, tafluprost)
Prostaglandin analogues side effects
Irreversible increase in pigmentation of the iris, eyelid, and lashes
Cosmetically will increase eye lash growth (bimatoprost = Latisse)
Alternative glaucoma remedies
Cannabinoids, medical marijuana, including delta9-tetrahydrocannabinol
MOA to reduce intraocular pressure not well understood
Tolerance develops
Take systemically due to no topical penetrance
