Drugs- Dementia (Kinder)

Question 1

acetylcholinesterase

Answer 1

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).

Question 2

chemical subgroups of AChE inhibitors

Answer 2

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

Question 3

what are some examples of quaternary and charged AChE inhibitors

Answer 3

neostigmine, pyridostigmine, edrophonium, echothiophate, ambenonium

Question 4

clinical significance of quaternary and charged ACHe inhibitors

Answer 4

(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

Question 5

examples of tertiary and uncharged AChE inhibitors

Answer 5

donepezil
tacrine
rivastigmine
galantamine

well absorbed from all sites
CNS distribution

Question 6

organophosphate AChE inhibitors

Answer 6

(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)

Question 7

which organophosphate is considered a “Safe” insecticide

Answer 7

(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

Question 8

effects of AChE inhibitors at LOW doses on the CNS

Answer 8

(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)

Question 9

effects of AChE inhibitors on the eye, resp tract, GI tract, urinary tract

Answer 9

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

Question 10

effects of AChE inhibitors on the CV system

Answer 10

(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

Question 11

effects of AChE inhibtors at the NMJ

Answer 11

(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)

Question 12

why do AChE inhibitors work for dementia

Answer 12

i) Patients with progressive dementia (Alzheimer type) are found to have a deficiency of intact cholinergic neurons

Question 13

why was tacrine pulled off market

Answer 13

AChE inhibitor

causes hepatotoxicity

Question 14

combination of mivacurium and AChE inhibitor

Answer 14

ii) Exception: mivacurium (metabolized by plasma AChE), neuromuscular blockade is prolonged

Question 15

what is the typical DDI of nondepolarizing neuromuscular blocking agents and AChE inhibitor

Answer 15

i) Combination with AChE inhibitors will diminish neuromuscular blockade

Question 16

succinylcholine and AChE inhibitors

Answer 16

b) Succinylcholine

i) Combination with AChE inhibitors may increase serum concentration of succinylcholine, prolonging neuromuscular block

Question 17

b-blockers plus ACHe inhibitor

Answer 17

i) Combination with AChE inhibitors may enhance bradycardic effects

Question 18

systemic corticosteroids and AChE inhibitors

Answer 18

i) Co-administration with AChE inhibitors may enhance muscle weakness seen in patients with myasthenia gravis

Question 19

miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea

Answer 19

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

Question 20

what is the treatment protocol for AChE inhibitor intoxication/overdose

Answer 20

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

Question 21

pralidoxime

Answer 21

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!

Question 22

memantine

Answer 22

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.

Question 23

donepezil

Answer 23

tertiary uncharged

t1/2 life of 70 hours

used for mild to mod AD
severe AD dementia

CYP2D6 and CYP3A4 metabolism

Question 24

ADR’s of donepezil

Answer 24

GI (N/v/d) especially on initiation dose

• Urinary incontinence, vivid dreams, bradycardia, syncope have occurred

Question 25

Galantamine

Answer 25

CYP2D6 and CYP3A4 metabolism

tertiary uncharged CNS distribution

used for mild to moderate AD

Question 26

ADR’s of galantamine

Answer 26

• GI (nausea, vomiting, diarrhea, anorexia), dizziness, weight loss, mostly during dose escalation
• Bradycardia and syncope
• Depression, fatigue, somnolence reported

Question 27

ADR of tacrine

Answer 27

hepatotoxicity - not on market anymore

Question 28

Rivastigmine

Answer 28

• Oral form rapidly absorbed,

short plasma t1/2 1.5 hours but actions of AChE inhibition in CNS 10 hours

• Metabolized via esterase hydrolysis

used for
Mild-to-moderate AD
Severe AD dementia (transdermal patch)
Parkinson’s related dementia

Question 29

ADR’s of rivastigmine

Answer 29

• High incidence of nausea, vomiting, diarrhea (oral form)
• GI effects substantially less with transdermal formulation
• Bradycardia and syncope