Cholinergic Drugs

Question 0

Bethanechol - uses

Answer 0

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)

Question 1

Bethanicol - basics

Answer 1

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

Question 2

What are potential effects and contraindications for the use of muscarinic agonists?

Answer 2

Bronchoconstriction - asthma
Hypotension - coronary insufficiency, hypothyroidism
Gastric secretion - peptic ulcer, physical obstruction

Question 3

Pilocarpine

Answer 3

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

Question 4

Sjögren’s syndrome

Answer 4

Autoimmune disease that attacks endocrine glands
Reduced saliva and tears
Treatment with pilocarpine or M3 selective agonist dependent on level of glandular survival

Question 5

Atropine

Answer 5

Highly selective muscarinic antagonist
Competitive inhibitor
Tertiary amines - into CNS
Half life 2-4 hrs

Question 6

Tropicamide

Answer 6

Synthetic muscarinic antagonist

Shorter half life

Question 7

Tolterodine

Answer 7

Synthetic muscarinic antagonist
selectivity for M3 receptors
Used to treat incontinence

Question 8

Tiotropium

Answer 8

Synthetic muscarinic antagonist

Quaternary compound - less CNS effect but additional nicotinic blocking activity

Question 9

Utility of muscarinic antagonists

Answer 9

Equivalent to blocking PS tone
Specific use of atropine - treatment of cholineaterase poisoning
Can treat poisoning due to AchE inhibitors or muscarinic agonist

Question 10

Muscarinic antagonists and the eye

Answer 10

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

Question 11

Muscarinic antagonists and the heart

Answer 11

Effect = tachycardia, low dose can get bradycardia

Use - control of bradycardia during certain types of myocardial infarction

Question 12

muscarinic antagonists and the GI and urinary tracts

Answer 12

Effect = reduce motility, reduce voiding, reduce gastric secretions
Use - M3 selective agents (tolteridine) to treat uninhibited detrussor contractions

Question 13

Muscarinic antagonists and generic secretions

Answer 13

Effect = reduce salivation, inhibit sweating
Use - inhibit secretion in Parkinsonism of heavy metal poisoning, reduce hyperhidrosis, preanesthetic to inhibit secretions (scopolamine > atropine)

Question 14

Muscarinic antagonists and the respiratory tract

Answer 14

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

Question 15

Muscarinic antagonists and the CNS

Answer 15

Effect = low doses of atropine stimulate, high doses produce disorientation, delirium, hallucinations
Use - reduce tremor in Parkinsonism

Question 16

Intoxication by muscarinic antagonists

Answer 16

Fatalities are uncommon
Symptoms are anything antiparasympathetic (cutaneous vasodilation, anhydrosis, delirium, urinary retention, etc)
Treatment - AchE inhibitor (physostigmine)

Question 17

What do low doses and high doses of cholinesterase inhibitors do?

Answer 17

Low - can enhance endogenous stimulation

High - cause stimulation through natural leakage of Ach - can be poisonous

Question 18

Uses of cholinesterase inhibitors

Answer 18

Myasthenia graves
Alzheimer's
Optho
Atony of GI and urological tracts
Termination of competitive cholinergic blocking drugs
Insecticides and chemical warfare

Question 19

Mechanisms of action of AchE inhibitors

Answer 19

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)

Question 20

Sites of action of AchE inhibitors

Answer 20

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)

Question 21

Potentiation effects of Ach at muscarinic and nicotinic sites

Answer 21

M - stimulatory

N - post synaptic membrane remains depolarized and eventually no more APs possible

Question 22

AchE inhibitors and the eye

Answer 22

Effect - miosis (dimming of vision and pinpointing of pupil)

Use - glaucoma (physostigmine for acute attacks, longer acting organic phosphates for wide angle)

Question 23

AchE inhibitors and heart

Answer 23

Complex actions

Predominant bradycardia

Question 24

AchE inhibitors and BP

Answer 24

No changes at low dose until ganglia and/or CNS affected

Question 25

AchE inhibitors and GI and urinary tracts

Answer 25

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)

Question 26

AchE inhibitors and general secretions

Answer 26

Induce salivation and other secretions | Characteristic runny nose of poisoning

Question 27

AchE inhibitors and respiratory tract

Answer 27

Bronchoconstriction | Never really useful

Question 28

AchE inhibitors and CNS

Answer 28

Effect - low dose causes stimulation, high dose causes inhibition Use - Alzheimer's (donepezil)

Question 29

AchE inhibitors and skeletal muscle

Answer 29

Effect - facilitation followed by paralysis Use - myasthenia gravis (antibodies to Ach receptors, neostigmine useful because quaternary selective for NMJ - also some stimulation at receptors)

Question 30

What are two ways to differentiate between a myasthenia crisis and a cholinergic crisis?

Answer 30

1. Ephronium test - myasthenic gets better, cholinergic worsens (eph is short acting) 2. Withhold cholinesterase inhibitor to see if weakness improves

Question 31

Toxicity of AchE inhibitors

Answer 31

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)

Question 32

Cholinesterase reactivators

Answer 32

Pralidoxime Only effective against phosphorylating agents Must be used early

Question 33

Nicotine - general

Answer 33

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

Question 34

Nicotine - toxicology

Answer 34

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

Question 35

Trimethaphan

Answer 35

Nicotinic ganglionic antagonist Quaternary Competitive antagonist Equate to withdrawal of sympathetic tone - Vasodilation, hypotension, tachycardia, mydriasis, reduced GI tone and motility

Question 36

What are the only three circumstances when nicotinic antagonists are considered useful?

Answer 36

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

Question 37

D-tubocurare and vecuronium

Answer 37

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

Question 38

Succinylcholine

Answer 38

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

Question 39

Clinical uses of neuromuscular blocking agents

Answer 39

Adjunct in surgical anesthesia Orthopedic procedures where muscle relaxation desired Facilitates intubation Electroshock therapy

Question 40

Drug interactions of neuromuscular blocking agents

Answer 40

Cholinesterase inhibitors - antagonize competitive agents and potentiated depolarizing agents Inhalation anesthetics Certain antibiotics can increase blockade Calcium channel blockers

Question 41

Disease interactions of neuromuscular blocking agents

Answer 41

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

Question 42

Treatment of overdose with neuromuscular blocking agent

Answer 42

Prolonged apnea - positive pressure artificial respiration and oxygen Cardiovascular collapse - sympathetic amines to support BP Histamine release - antihistamines