Cholinergic Drugs Flashcards
Bethanechol - uses
Urinary retention
GI stasis - p.o. Abdominal distention, gastric atony (but not the best), congenital megacolon (sometimes)
Diagnosis of atropine intoxication (but not the best)
Eye (but not the best)
Bethanicol - basics
Muscarinic agonist especially in GI and urinary tract smooth muscles
Totally resistant to ACE and BCE
Additive effects with ACE inhibitors, act independently
Orally or subcutaneous only - slowly taken up so vascular use can adapt
Quarternary amine
What are potential effects and contraindications for the use of muscarinic agonists?
Bronchoconstriction - asthma
Hypotension - coronary insufficiency, hypothyroidism
Gastric secretion - peptic ulcer, physical obstruction
Pilocarpine
Muscarinic agonist
Tertiary amine - effects in CNS, potent diaphoretic
Clinical uses - opthalmology treatment of acute glaucoma, limited oral admin for Sjögren’s syndrome, sweat test for CF
Sjögren’s syndrome
Autoimmune disease that attacks endocrine glands
Reduced saliva and tears
Treatment with pilocarpine or M3 selective agonist dependent on level of glandular survival
Atropine
Highly selective muscarinic antagonist
Competitive inhibitor
Tertiary amines - into CNS
Half life 2-4 hrs
Tropicamide
Synthetic muscarinic antagonist
Shorter half life
Tolterodine
Synthetic muscarinic antagonist
selectivity for M3 receptors
Used to treat incontinence
Tiotropium
Synthetic muscarinic antagonist
Quaternary compound - less CNS effect but additional nicotinic blocking activity
Utility of muscarinic antagonists
Equivalent to blocking PS tone
Specific use of atropine - treatment of cholineaterase poisoning
Can treat poisoning due to AchE inhibitors or muscarinic agonist
Muscarinic antagonists and the eye
Effect = mydriasis, cyclopegia
Use - optho (induce mydriasis during exam) - shorter acting tropicamide more useful
Damage of precipitating attack of narrow angle glaucoma - can block outflow of humor
Muscarinic antagonists and the heart
Effect = tachycardia, low dose can get bradycardia
Use - control of bradycardia during certain types of myocardial infarction
muscarinic antagonists and the GI and urinary tracts
Effect = reduce motility, reduce voiding, reduce gastric secretions
Use - M3 selective agents (tolteridine) to treat uninhibited detrussor contractions
Muscarinic antagonists and generic secretions
Effect = reduce salivation, inhibit sweating
Use - inhibit secretion in Parkinsonism of heavy metal poisoning, reduce hyperhidrosis, preanesthetic to inhibit secretions (scopolamine > atropine)
Muscarinic antagonists and the respiratory tract
Effect = bronchodilation, reduce secretions
Use - inhaled tiotropium can reduce constriction, COPD especially with vagally increased airway resistance (combo with beta adrenergic agonists), asthma but not as effective as adrenergics
Muscarinic antagonists and the CNS
Effect = low doses of atropine stimulate, high doses produce disorientation, delirium, hallucinations
Use - reduce tremor in Parkinsonism
Intoxication by muscarinic antagonists
Fatalities are uncommon
Symptoms are anything antiparasympathetic (cutaneous vasodilation, anhydrosis, delirium, urinary retention, etc)
Treatment - AchE inhibitor (physostigmine)
What do low doses and high doses of cholinesterase inhibitors do?
Low - can enhance endogenous stimulation
High - cause stimulation through natural leakage of Ach - can be poisonous
Uses of cholinesterase inhibitors
Myasthenia graves Alzheimer's Optho Atony of GI and urological tracts Termination of competitive cholinergic blocking drugs Insecticides and chemical warfare
Mechanisms of action of AchE inhibitors
Reversible - competitive antagonist (donepezil - longer acting tertiary amine that’s lipid soluble), carbamoylating agents - longer lasting and more effective (physostigmine - tertiary amine that’s lipid soluble, neostigmine - quaternary with selectivity at NMJ)
Irreversible - organophosphates phosphorylase active site (sarin)
Sites of action of AchE inhibitors
Postganglionic PS muscarinic junctions (increased)
Ganglionic nicotinic junctions (increased then decreased)
Neuromuscular nicotinic junctions (increased then decreased)
CNS junctions of both types (increased then N decreased)
Potentiation effects of Ach at muscarinic and nicotinic sites
M - stimulatory
N - post synaptic membrane remains depolarized and eventually no more APs possible
AchE inhibitors and the eye
Effect - miosis (dimming of vision and pinpointing of pupil)
Use - glaucoma (physostigmine for acute attacks, longer acting organic phosphates for wide angle)
AchE inhibitors and heart
Complex actions
Predominant bradycardia
AchE inhibitors and BP
No changes at low dose until ganglia and/or CNS affected
AchE inhibitors and GI and urinary tracts
Effect - gastric contraction and secretion, increased motility in bowels, involuntary voiding
Use - paralytic ileus (neostigmine for relief of abdominal distension), atony of bladder, gastric atony (not useful after vagotomy)
AchE inhibitors and general secretions
Induce salivation and other secretions
Characteristic runny nose of poisoning
AchE inhibitors and respiratory tract
Bronchoconstriction
Never really useful
AchE inhibitors and CNS
Effect - low dose causes stimulation, high dose causes inhibition
Use - Alzheimer’s (donepezil)
AchE inhibitors and skeletal muscle
Effect - facilitation followed by paralysis
Use - myasthenia gravis (antibodies to Ach receptors, neostigmine useful because quaternary selective for NMJ - also some stimulation at receptors)
What are two ways to differentiate between a myasthenia crisis and a cholinergic crisis?
- Ephronium test - myasthenic gets better, cholinergic worsens (eph is short acting)
- Withhold cholinesterase inhibitor to see if weakness improves
Toxicity of AchE inhibitors
Usually includes muscarinic, nicotinic, and CNS effects
Muscarinic effects = SLUDGE (salivation, lacrimation, urination, defecation, GI distress, emesis), bronchoconstriction, miosis
NMJ effects = muscle weakness, twitching, eventual paralysis
CNS effects = confusion, respiratory paralysis (death can occur within 5 min), slurred speech
Treatment - atropine, supportive measures, cholinesterase reactivators (pralidoxime)
Cholinesterase reactivators
Pralidoxime
Only effective against phosphorylating agents
Must be used early
Nicotine - general
Nicotinic ganglionic agonist
Excites, then blocks at high doses
Stimulates receptors at NMJ and CNS
Higher doses give dual response
Effects unpredictable
Repeated usage - minor effects dissipate while cardiovascular (increased HR and BP) persist
Sharpening of attention and development of dependence
Nicotine - toxicology
Larger doses give stimulation followed by depression and eventual central and peripheral paralysis of respiratory muscles
Therapy - empty stomach, avoid basic solutions, give respiratory assistance
Trimethaphan
Nicotinic ganglionic antagonist
Quaternary
Competitive antagonist
Equate to withdrawal of sympathetic tone - Vasodilation, hypotension, tachycardia, mydriasis, reduced GI tone and motility
What are the only three circumstances when nicotinic antagonists are considered useful?
Hypertensive crisis in patient with acute dissecting aortic aneurism (lower BP without making heart work too hard to compensate)
Controlled hypotension in surgery
Control of autonomic hyperreflexia with injuries to upper spinal cord
D-tubocurare and vecuronium
Non polarizing competitive inhibitors - neuromuscular blocking a agents
Bulky and nonflexible
Produce flaccid paralysis
Antagonized by AchE inhibitors
Small rapid muscles, then limbs and neck, then intercostal muscles, then diaphragm last
No effect on ganglia or in CNS
Sometimes cause release of histamine
Succinylcholine
Depolarizing neuromuscular blocking agent
Long slender molecule
Flaccid paralysis
Dual phase response (phase 1 is depolarization block with potential loss of K+ from muscle, phase 2 is desensitization of receptors - slower recovery)
Initial effects potentiated by AchE inhibitors
Limbs, neck and smaller rapid muscles, then diaphragm
Little effect on ganglia or CNS with normal doses
Fast action - IV infusion gives paralysis in .5 - 1 min, rapidly hydrolyzed by butyryl cholinesterase
Clinical uses of neuromuscular blocking agents
Adjunct in surgical anesthesia
Orthopedic procedures where muscle relaxation desired
Facilitates intubation
Electroshock therapy
Drug interactions of neuromuscular blocking agents
Cholinesterase inhibitors - antagonize competitive agents and potentiated depolarizing agents
Inhalation anesthetics
Certain antibiotics can increase blockade
Calcium channel blockers
Disease interactions of neuromuscular blocking agents
Reduced plasma cholinesterase - genetic deficiency
Malignant hyperthermia - combo of mutations in ryanodine receptor and succinylcholine can lead to muscle rigidity and temp rise
Patients with extensive soft tissue damage - electrolyte imbalance can exacerbate hyperkalemia
Muscular disorders
Treatment of overdose with neuromuscular blocking agent
Prolonged apnea - positive pressure artificial respiration and oxygen
Cardiovascular collapse - sympathetic amines to support BP
Histamine release - antihistamines
