Drugs- Dementia (Kinder) Flashcards
(29 cards)
acetylcholinesterase
i) Provides immediate removal of ACh (hydrolysis to choline and acetate) to prevent lateral diffusion and sequential activation of adjacent nAChRs.
ii) Hydrolysis of ACh occurs in approximately 150 microseconds.
iii) Primarily found in cholinergic neurons (dendrites, perikarya, and axons) and is distributed more widely than BuChE.
iv) The primary target for cholinesterase inhibiting drugs.
v) Due to the distribution of AChE, nAChRs, and mAChRs, the pharmacologic effects of cholinesterase inhibitors are diffuse (cardiovascular system, gastrointestinal system, eye, respiratory tract, urinary tract, central nervous system, neuromuscular junction).
chemical subgroups of AChE inhibitors
alcohols
- edrophonium
(3) Binding to AChE is noncovalent and reversible, thus short-lived
(1) Contain an alcohol group and a quaternary ammonium group (positively charged)
carbamic acid esters
- bearing quaternary or tertiary ammonium groups (positively charged or neutral)
- neostigmine, pyridostigmine, physostigmine, carbaryl
(3) Binding to AChE is two-step process analogous to ACh hydrolysis; covalent bond of carbamoylated enzyme considerably more resistant to second step hydration
organophosphates
- echothiophate, insecticides, nerve gases
- highly lipid, charge neutral, CNS toxicity
- covalent binding and irreversible
what are some examples of quaternary and charged AChE inhibitors
neostigmine, pyridostigmine, edrophonium, echothiophate, ambenonium
clinical significance of quaternary and charged ACHe inhibitors
(1) Relatively insoluble in lipids and absorption from the conjunctiva, skin, and lungs is poor
(2) Parenteral administration is preferred; when given orally, larger doses are required
(3) No CNS distribution
(4) Duration of effect is determined by the stability of the inhibitor-enzyme complex rather than by metabolism or excretion
i) Quaternary AChE inhibitors are absorbed poorly from the GI tract or across the skin, are excluded from the CNS by the blood-brain barrier (at moderate doses), act preferentially at the NMJ of skeletal muscle, and have less effect at autonomic effector sites and ganglia
examples of tertiary and uncharged AChE inhibitors
donepezil
tacrine
rivastigmine
galantamine
well absorbed from all sites
CNS distribution
organophosphate AChE inhibitors
(1) Lipid-soluble and readily absorbed from the skin, lung, gut, and conjunctiva, which make them particularly dangerous to humans and highly effective as insecticides
(2) Distributed to all parts of the body including the CNS
(3) Organophosphate poisoning includes CNS toxicity
(4) Since the interaction between organophosphates and AChE is covalent and irreversible, there is virtually little metabolism and excretion via common biotransformation pathways
(6) Regeneration of AChE is required in order to reestablish the termination of ACh signaling at the neuromuscular junction (see below in ‘toxicology’ section)
which organophosphate is considered a “Safe” insecticide
(5) One exception, malathion, is rapidly metabolized to inactive products in mammals, and is therefore considered safe for use as an insecticide by the general public
effects of AChE inhibitors at LOW doses on the CNS
(1) Low concentrations: diffuse activation on the electroencephalogram and a subjective altering response
(2) High concentrations: generalized convulsions (may be followed by coma and respiratory arrest)
effects of AChE inhibitors on the eye, resp tract, GI tract, urinary tract
stimulation of the mAChR’s
eye- miosis, accomodation
resp tract - bronchial muscle contraction, bronchial glands stimulated
GI - increased motility, relax sphincters, stimulate secretion
urinary tract - contract detrusor and relax trigone/sphincter
effects of AChE inhibitors on the CV system
(1) AChE inhibitors can increase the activity of both sympathetic and parasympathetic ganglia supplying the heart and at mAChRs on cardiac cells
(2) Parasympathetic tone dominates and cardiac output decreases
(3) The net cardiovascular effects of moderate doses of AChE inhibitors is modest bradycardia, a fall in cardiac output (due to bradycardia, decreased atrial contractility, and some reduction in ventricular contractility), and modest increase in blood pressure
(4) Toxic doses of AChE inhibitors cause more marked bradycardia, decreased cardiac output, and hypotension
effects of AChE inhibtors at the NMJ
(1) Therapeutic concentrations of AChE inhibitors prolong and intensify the actions of ACh, which increases the strength of contraction
(2) Fibrillation of muscle fibers and fasciculations result with high concentrations
(3) Continued inhibition of AChE results in the progression of depolarizing neuromuscular blockade to nondepolarizing blockade (as seen with succinylcholine)
(4) Some quaternary carbamate AChE inhibitors have additional direct nicotinic agonist effects at the NMJ (e.g., neostigmine)
why do AChE inhibitors work for dementia
i) Patients with progressive dementia (Alzheimer type) are found to have a deficiency of intact cholinergic neurons
why was tacrine pulled off market
AChE inhibitor
causes hepatotoxicity
combination of mivacurium and AChE inhibitor
ii) Exception: mivacurium (metabolized by plasma AChE), neuromuscular blockade is prolonged
what is the typical DDI of nondepolarizing neuromuscular blocking agents and AChE inhibitor
i) Combination with AChE inhibitors will diminish neuromuscular blockade
succinylcholine and AChE inhibitors
b) Succinylcholine
i) Combination with AChE inhibitors may increase serum concentration of succinylcholine, prolonging neuromuscular block
b-blockers plus ACHe inhibitor
i) Combination with AChE inhibitors may enhance bradycardic effects
systemic corticosteroids and AChE inhibitors
i) Co-administration with AChE inhibitors may enhance muscle weakness seen in patients with myasthenia gravis
miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea
acute AChE inhibitor intoxication
iii) With poisoning from lipid-soluble agents, CNS involvement follows rapidly (confusion, ataxia, generalized convulsions, coma, and respiratory paralysis)
iv) Time of death after a single acute exposure may range from
what is the treatment protocol for AChE inhibitor intoxication/overdose
iii) The mAChR antagonist atropine is the antidote recommended for cholinergic poisoning in combination with maintenance of vital signs (respiration in particular) and decontamination (removal of clothing and washing of the skin in cases of exposure to dust and spray pesticides)
iv) Atropine is ineffective against the peripheral neuromuscular stimulation (nAChRs)
v) To regenerate AChE at the NMJ, cholinesterase re-activator (pralidoxime) can be administered
vi) Therapy often also includes benzodiazepines for seizures
pralidoxime
regenerating active enzyme from the organophosphorus-cholinesterase complex via removal of the phosphorous group from the active site of the enzyme (the oxime group, NOH, has a high affinity for the phosphorus atom)
ii) Must be given before aging has occurred between the organophosphate and cholinesterase (the time-dependent process of aging further strengthens the phosphorus-enzyme bond, making the complex even more difficult to break)
iii) Does not reverse central effects of organophosphate poisoning as pralidoxime does not enter CNS –> need atropine too!
memantine
a) Glutamate, the primary excitatory amino acid in the CNS, may contribute to the pathogenesis of Alzheimer’s disease (AD) by over-stimulating various glutamate receptors leading to excitotoxicity and neuronal cell death
b) MOA: antagonist of the N-methyl-D-aspartate (NMDA) type of glutamate receptors
i) Under normal physiologic conditions, the (unstimulated) NMDA receptor ion channel is blocked by magnesium ions, which are displaced after agonist-induced depolarization
ii) Pathologic or excessive receptor activation, as postulated to occur during AD, prevents magnesium from reentering and blocking the channel pore resulting in a chronically open state and excessive calcium influx
iii) Memantine binds to the intra-pore magnesium site, but with longer dwell time, and thus functions as an effective receptor blocker only under conditions of excessive stimulation
iv) Does not affect normal neurotransmission.
donepezil
tertiary uncharged
t1/2 life of 70 hours
used for mild to mod AD
severe AD dementia
CYP2D6 and CYP3A4 metabolism
ADR’s of donepezil
GI (N/v/d) especially on initiation dose
• Urinary incontinence, vivid dreams, bradycardia, syncope have occurred
