Download ANS Drugs - Cholinergic

Cholinergic Drugs: Agonists
Drug
Specificity
Cholinergic Agonists
Acetylcholine
M and N
Pilocarpine
Bethanechol
M only
Muscarine
Nicotine
N only
AChE Inhibitors
Alcohols
Edrophonium
Carbamates
- Physotigmine
- Neostigmine
- Pyridostigmine
Organophosphates
- Sarin, VX
- Malathion
- Parathion
- Diazinon
- Echothiophate
Pralodoxime
Donepezil,
Rivistigmine
Pharmacokinetics
Irreversibly
inhibit
AChE
Other properties
- Gets into CNS: not quaternary - Limited AChE susceptibility
- No CNS
- Limited AChE susceptibility
- Gets into CNS: not quaternary - Activates all autonomic ganglionic receptors: symp
- Absorbed well from mucus
& parasymp.
membranes, not from
o Symp: BP↑, HR↑; P-symp: Nausea, vomiting,
stomach
diarrhea, etc
- Biotransformed and excreted - Depolarization block  flaccid paralysis at high
in urine
doses
- Emesis since acts on CTZ in CNS
- Short acting: 5 – 15 minutes
- No CNS: Quaternary
ammonium
Reversibly
inhibit
AChE
©2009 Mark Tuttle
- Longer acting than
edrophonium because takes
longer to regenerate
carbamoyl enzyme
- Only Physotigmine  CNS
- Pyridostigmine is longestacting
- Hydrophobic, lipophilic – can
be absorbed through skin
- Recovery depends on
synthesis of new AChE
- Does not enter CNS
Regenerate - High doses block NM
AChE
- Oxime group has high affinity
for phosphate
Inhibit
- Rivistigmine somewhat
AChE
selective for CNS
- Myasthenia Gravis
- Assess effects of longer-acting AChE Inibitors
o If dose too low: will increase strength
o If dose too high: will decrease strength (via depol.
block)
- Myasthenia gravis, esp. pyridostigmine b/c long
acting
- Reversal of NMJ block after surgery (Neostigmine)
- Protection against nerve gas
- Treat Muscarine poisoning – Physotigmine b/c CNS
- Insecticides
- Used as nerve gases
- Treatment:
o Atropine, Diazepam for CNS effects
o Pralodoxime: help regenerate AChE
- Echothiophate used for glaucoma
- Parathion as insecticide – problem because not
inactivated in mammals. Malathion is better.
- Help regenerate AChE after AChE inhibitor overdose
- Less useful once aging of the OrganophosphateAChE has occurred and alkyl group is lost since it
becomes even more stable in inactivated form
- Treatment of Alzheimers
- Only useful in mild to moderate cases
©2009 Mark Tuttle
Cholinergic Drugs: Antagonists
Drug
Mechanism
Muscarinic Antagonists
Atropine
7-10 days
Scopolamine
All M
3-7 days
(competitive)
Benzotropine
Ipratropium
Pirenzepine
Tolterodine
M1 receptors
Only
~M3
Nicotinic Antagonists
Hexamethoniu
NN receptors
m,
(ANS ganglia)
Trimethaphan
Curare
(Tubocurarine) NM receptors
(NMJ)
(competitive)
(not 100% specif)
Succinylcholine
NM agonist –
depolarizing
block
Pharmacokinetics
Uses/Effects
- No fixed charge  gets into CNS
- Not very selective
- Gets into CNS better than atropine
-
-
Good ratio of CNS:peripheral
Quaternary  no CNS
Given by inhalation
No CNS availability
Salivation ↓, micturition ↓,
Heart rate ↑, eye paralysis
Sedation, amnesia, dreamless sleep
Effective for motion sickness
Parkinson’s Disease
Respiratory diseases: COPD, asthma for
bronchodilation ↑, secretion ↓
- Reduce Gastric acid secretion
-
- Relaxes detrusor m. in bladder
- Used for overactive bladder
- Quaternary: No CNS
- Not absorbed well from GI
(need IV)
- Quaternary: No CNS  need
another drug for anesthesia
- Not absorbed well from GI
(need IV)
- 50+ minute duration of action
(longest)
- Not hydrolyzed by AChE, and
AChE’s intensify effect (!)
- No CNS effect
- Rapid onset and brief duration of
action
- Hydrolyzed by
butyrylcholinesterase
-
Emergency treatment of hypertension
HR ↑ due to loss of vagal tone
No reflex tachy/bradycardia since both blkd
Non-depolarizing block at NMJ
Can be reversed with ACh↑ since competitive
Small muscles more sensitive than large
Diaphragm least sensitive
Can cause histamine release from mast cells
- Produces depolarizing block
- K+ released  hyperkalemia  heart problems
- Malignant hyperthermia
o Rapid onset of high fever w/muscle rigidity in
genetically-susceptible individuals with
abnormal butyrylcholinesterase