• block AChE, resulting in increased ACh levels in the synapse
• examples
  • edrophonium
  • neostigmine
  • physostigmine
  • rivastigmine
  • galantamine
  • donepezil
  • sarin

• diagnosis of myasthenia gravis
• paralytic ileus

duration- 5-15 min

• myasthenia gravis
• ileus

Duration- 0.5-2 hrs

Alzheimer's

• rivastigmine, galantine last 12 hrs
• donepezil lasts 24 hrs

• at low doses, major effect to enhance ACh action at muscarinic R's
• unlike direct agonists, there is little effect on vascular smooth muscle and bp due to the fact they have no cholinergic innervation
• at high conc., we activate both muscarinic and nicotinic R's
  • increased muscular contraction
  • fasciculations
  • CNS effects (ex: convulsions)

physostigmine (its lipid soluble)

neostigmine (only difference from physostigmine)

• loss of cholinergic function (muscarinic and nicotinic) seen in Alzheimers due to cholinergic neuron damage and death, leading to impaired congition and memobry

• cross BBB
• block AChE (decrease activity by 40%)
• for Alzheimer's

• donepezil
• rivastigmine
• galantamine

• binds to allosteric site on nicotoinic R and enhances its activation
• block AChE

• patch (pill caused GI upset)

• mech
  • NMDA receptor antagonists
  • reduce Glu activation of NMDA receptors
  • decreasing potentially harmful excess entry of calcium into neurons that can cause excitotoxic damage and cell death
• use- Alzheimers

nausea

diarrhea

insomnia

• mech.
  • IRREVERSIBLE AChE
  • very lipid soluble
  • lead to progressive sympstoms of excessive exposure
• compostion- volital liquids readily aerosolized and extremely toxic
• effects (SLUD)
  • salivation
  • lacrimation
  • urination
  • defication
• initial effects (muscarinic)
  • pulm. edema
  • hypotension
  • bradycardia
  • sweating
  • miosis
  • bronchoconstriction
• later effects (nicotinic)
  • resp. paralysis
  • twitching
• terminal effects
  • ataxia
  • confusion
  • convulsions
  • coma

• atropine (muscarinic antagonist)
• pralidoxime (reactivates AChE)

Injected

• mechanism of action
  • bind
  • endocytosed
  • cleave SNAP 25
  • block release of ACh
• FDA aproved use
  • local IM injection in blepharospacm
  • hemifacial spasm
  • spasm of muscular disease
  • cosmetic (frown lines, crow's feet)
• side effects- excessive muscle paralysis
• duration- several months, but wear off

• heart- tachycardia, blunted reflex
• eye- prolonged mydriasis
  • contraindicate- acute angle glaucoma
• glands- inh. secretion
• GI, urinary- constipation, antispasmodic, urinary retention
• CNS- excitement, possible hallucination
• blood vessels- little to no effect
  • NO ACh INNERVATION

atropine

ipratropium

• cross BBB
• uses
  • preanesthetic medication
    • reduce secretion
    • relax bronchi
  • antispasmodic
  • antidiarrheal

• chem structure- quarternary amine, so it does not enter BBB
• use
  • bronchodilation in COPD
    • marked reduction in wheezing and breathing difficulties
• preparation as suspended inhalation aerosol
  • very limited absorption to keep effects in the lungs

• hexamethonium
• trimethaphan (only one clinically available as ganglionic blocker)

• accute disecting aortic aneurysm
  • rapidly control bp
  • block baroR reflex

• tubocurarine (non depolarizing blocker)
• succinylcholine (depol., then blocks channel)
• vecuronium (non depolarizing blocker)

• chemical comp.- highly charge, so it wont cross BBB
• mech of action
  • block muscle nicotnic R, leading to long acting (2 hr) muscle paralysis
  • no analgesia w/any skel musc. blocker
• use
  • elim. muscle movt during surgery
• effects
  • hypotension
    • stimulates mast cells to release histamine
    • some blockade on neuronal nicotinic R's in autonomic ganglia

• mech. of action- same as tubocurarine
• duration of action 1-1.5 hrs (much less than tubocurarine)
  • less histamine release, so less hypotension problems
• use- FREQUENTLY used in surgery

• rapid onset (less than a minute) and short acting (5-10 minutes)
• metabolized by cholinesterase (you cant reverse this with neostigmine
• use
  • rapid sequence induction endotrachial intubation in emergency condition
    • reduce risk of gastric aspiration
    • no increase in intracranial pressure
• side effecs
  • during activation phase, muscle fasciulations
  • malignant hyperthermia (treat with dantrolene- block calcium release from SR)
  • hyperkalemia leading to cardiac arrhythmias
• contraind.
  • those w/atypical cholinesterase (cant metabolize drug, so prolonged effects)
  • renal failure
  • burn patients
  • multiple trauma
  • large areas of denervated muscle

• inhaled anesthetics and aminoglycoside antibiotics- augment blockade in nondepol. blockers
• neostigmine- reverses blockade of nondepolarizing drugs

• rocuronium (nondepol. blockers)
  • same onset time
  • longer duration than
  • can reverse with neostigmine