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Cholinergic Drugs

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Direct
Acting Cholinergics
Reversible Direct
Acting Cholinergics
Inversible Direct
Acting Cholinergics
Cholinergic (Muscarinic) Effects
Decreased heart rate / AV conduction
Bronchoconstriction / inc secretions
Increased GI / GU
Eye - miosis, ciliary muscle contraction for near vision
Direct Acting Cholinergic- Acetylcholine
Ach is ester that is rapidly metabolized by Achesterase; short action (sec-min); muscarinic and nicotinic effects
Direct Acting Cholinergic- Bethanechol
A carbamate that resist Ach-esterase; longer action (few hrs); only muscarinic actions that mainly stimulate contraction of the bladder / GI tract after surgery or with bladder weakness
Direct Acting Cholinergic- Pilocarpine
An alkaloid with muscarinic effects, topical use in glaucoma, drops, gel, OCUSERT; PO to stim salivary secretions in dry mouth (SALAGEN), tablets
Indirect Acting Cholinergic Drug- Reverse Acetylcholinesterase Inhibitors
-Physiostigmine (ANTILIRIUM)
-Neostigmine
-Edrophonium
-Pyridostigmine
Physiostigmine (ANTILIRIUM)
IV, tertiary amine, penetrates BBB / CNS effects, antidote to anticholinergic overdosage/poisoning
Neostigmine
- quarternary, used as antidote to tubocurare-type skeletal muscle blockers
Edrophonium
quarternary, short acting, used IV for diagnostic testing myasthenia gravis
Pyridostigmine
quarternary, long-acting, used treatment of myasthenia gravis; PO, IM, IV
Sites of Direct Acting Drugs
Only stimulate the cholinergic (muscarinic) receptors.

-ACH is inactivated by acetylcholinesterase
Sites of Indirect Acting Drugs
-Cholinergic (muscarinic receptor)
-Nicotinic (Nn) receptor
-Nicotinic (Nm) receptor

-Indirect Acting Drugs inhibit Acetylcholinesterase, allowing ADH buildup at all sites.
Myasthenia Gravis
Autoimmune disease that affects Nm receptors, antibodies to Ach receptor
Progressive skeletal mus weakness; affects cranial muscles first (eyelids) eventualy oropharyngeal, limbs, respiratory muscles
Use of edrophonium to distinguish cholinergic crisis (too much Ach) from myasthenia crisis(too little Ach), review muscarinic vs nicotinic d-r curves
Treatment of Myasthenia Gravis
Treatment with long-acting reversible acetylcholinestease inhibitors, **pyridostigmine, ambenonium
Irreversible Acetylcholinesterase Inhibitors
-War gases / pesticides / insecticides
-Systemic overdosage (drown in ACH) causes irreversible acetylcholinesterase inhibition (aging), usu lethal without antidotes
-Antidote is atropine/blocks muscarinic receptors); pralidoxime (PAM) (reactivates enzyme)
-Military use: pyridostigmine adm prophylactically to reduce binding of war gases to enzyme (combat situation)

**Echothiophate only one available (eyedrops) used in glaucoma
Cholinergic Adverse Effects at Muscarinic Sites
n-v-d, blurred vision, sweating, muscular tremors, bradycardia, hypotension , bronchoconstriction / secretions
Cholinergic Adverse Effects at Nicotinic Sites
caused by indirect-acting drugs, @ high doses/toxicity: skeletal muscular weakness (Nm) > paralysis; ganglionic blockade (Nn) that will block all autonomic nerve transmission
Alzheimer's Disease
Progressive dementia/memory loss due to loss of neurons, esp cholinergic
Associated with plaques / tangles
No cure yet, centrally-acting reversible acetylcholinesterase inhibitors adm to inc ACH / cholinergic transmission
Treatment of Alzheimer's Disease
Tacrine (COGNEX), *donepezil (ARICEPT), galantamine (REMINYL), *rivastigmine (EXELON), usu for mild to moderate disease
Cholinergic side effects; tacrine associated with hepatotoxicity
Memantine (NAMENDA) blocks glutamate
Cholinergic Receptors
-Muscarinic
-Nicotinic-neutral
-Nicotinic- muscle
Muscarinic Receptors
receptor at post-ganglionic nerve ending, activated by ACH and similar drugs.
Nicotinic-Neutral Receptors
Nn receptor at sympathetic and parasympathetic ganglionic site, activated by ACH and nicotine, very few ganglionic drugs/blockers
Nicotinic-Muscle Receptors
Nm receptor at skeletal muscle, the neuromuscular junction, activated by ACH
and nicotine, agonist drugs used to stimulate contraction in certain diseases, blockers to relax/
paralyze skeletal muscle during surgical procedures
Cholinergic Drug Types
-Direct Acting
-Indirect Acting
-Irreversible Inhibitors
Direct-Acting Cholinergic Drugs
bind directly to muscarinic receptors, activated by ACH
Examples of Direct-Acting Cholinergic Drugs
-Bethanechol
-Pilocarpine
Bethanechol (Urecholine)
-direct acting cholinergic drug
-used to treat urinary retention
-used to treat postoperative ileus
Pilocarpine (Isopto carpine)
-Treatment of glaucoma
Indirect- acting cholinergic drugs (Anticholinesterases)
-The anticholinesterases that inhibit acetylcholinesterase; allow the accumulation of ACH AT ALL 3 CHOLINERGIC RECEPTOR SITES

-Includes both reversible and irreversible inhibitors
Reversible Indirect-acting cholinergic drugs
used clinically to treat myasthenia gravis, Alzheimer's disease, glaucoma, urinary retention, intestinal stasis and as antidotes to skeletal muscle blockers and overdosage
with anticholinergic drugs
Neostigmine (Prostigmin)
-Reversible Indirect-acting cholinergic drug
-Treatment of myasthenia gravis, postoperative ileus, and urinary retention; antidote to excessive cholinergic blockade with anticholinergic and skeletal muscle blockers.
Physostigmine (generic)
-Reversible Indirect-Acting Cholinergic Drug
Treatment of glaucoma, antidote to excessive cholinergic blockage with anticholinergics and skeletal muscle blockers.
Pyridostgmine (Mestinon)
-Reversible Indirect-Acting Cholinergic Drug
-Treatment of Myasthenia Gravis
Drugs for Treatment of Alzheimer's Disease- Reversible Indirect-Acting Cholinergic Drugs
-Donepezil (Aricept)
-Galantamine (Remiyl)
-Rivastigmine (Exelon)
-Tacrine (Cognex)
-Memantine (NAMENDA)

-Treatment of Alzheimer's disease- blockers excitatory glutamate receptors in the brain.
Irreversible Indirect-Acting Cholinergic Drugs
-organophosphates used as pesticides, insecticides, and chemical warfare agents; form irreversible bonds with acetylcholinesterase enzyme,**
- echothiophate only one
used clinically (eyedrops) for glaucoma.
-Severe toxicity leads to respiratory paralysis and death,lifesaving antidote atropine and pralidoxime (PAM) which reactivates acetylcholinestease
enzyme.
Adverse/Side Effects of Cholinergic Drugs
1. Excessive parasympathetic stimulation: n-v-d, blurred vision, sweating, muscular tremors,
bronchoconstriction, bradycardia, hypotension
2. toxic overdosage: Nm and Nn: respiratory and skeletal muscular paralysis, death
3. antidote: atropine
Anticholinergic Drugs (parsympatholytics)
-Bind to muscarinic receptors and competitively antagonize ACH
Pharamacologic Actions of Anticholinergic Drugs (Parsympatholytics) on Respiratory System
Inhibits Secretions and Causes Bronchodilation
Pharamacologic Actions of Anticholinergic Drugs (Parsympatholytics) on Cardiovascular System
Increased HR/ AV conduction
Pharamacologic Actions of Anticholinergic Drugs (Parsympatholytics) on GI tract
-Decrease salivary/ GI secretions, decrease motility/antispasmodic action
Pharamacologic Actions of Anticholinergic Drugs (Parsympatholytics) on GU system
inhibit voiding of urine in over active bladder, contraindicated in males with BPH
Pharamacologic Actions of Anticholinergic Drugs (Parsympatholytics) on CNS
sedation, especially scopolamine (OTC sleep aid); high dose CNS stimulation/delirium, profound CNS depression and respiratory arrest
Pharamacologic Actions of Anticholinergic Drugs (Parsympatholytics) on CNS
antiemetic action, treatment of motion sickness
Pharamacologic Actions of Anticholinergic Drugs (Parsympatholytics) on Ocular Effects
mydriasis, cycloplegia (loss of accommodation, used eye exams, contraindicated in glaucoma
Atrophine (generic)
-Anticholinergic Drug
-Antidote for cholinesterase inhibitor poisoning, anticholinergic effects
Scopolamine (Generic) (Transderm Scop)
-Anticholinergic Drug
-Used to treat intestinal disorders, diarrhea, IBS
Hyoscyamine (Anaspaz)
-Anticholinergic Drug
-Used to treat intestinal disorders, diarrhea, IBS
Ipatropium (Atrovent)
-Anticholinergic Drug
Used for bronchodilation, asthma, COPD
Tolterodine (Detrol, Detrol LA)
-Anticholinergic Drug
-Used for relief of urinary spasms, urgency, incontinence.
Adverse and Toxic Effects of Anticholinergic Drugs (Parsympatholytics)
1. dry mouth, visual disturbances, urinary retention, constipation, dry skin, flushing, fever,
tachycardia, both CNS stimulation and depression, delirium, hallucinations
2. atropine/scopolamine found in many plant berries, can lead to death in few hours; treat with
physiostigmine
Ganglionic Drugs
Ganglionic stimulants: stimulate nicotinic neural (Nn) receptors
Examples of Ganglionic Drugs
-Bupropion
-Varenicline
Bupriopion
-Ganglionic Drug
-Antidepressant drug used to reduce nicotine cravings
Varenicline
-Ganglionic Drug
-Blocks effect of nicotine on CNS receptors
Ganglionic Blockers
block Nn receptors.** Mecamylamine (INVERSINE)
Mecamylane
-Used for treatment of severe HTN when other drugs have not been effective.
Adverse Effects of Ganglionic Blockers
-Result is a combination of anticholinergic and antiadrenergic drugs, which usually include decreased GI activity (dry mouth and constipation), visual disturbances (mydriasis and cyclopegia), decreased cardiovascular function (hypotension and decreased cardiac output) and decreased GU function (urinary retention and impotency.)

The ganglionic blockers are contraindicated in patients with glaucoma because the mydriatic effect increases intraocular pressure.
Peripherally-Acting Skeletal Muscle Relaxants
-Depolarizing and Non-Depolarizing Drugs
Depolarizing Peripherally-Acting Skeletal Muscle Relaxants
Depolarizing blockers: **Succinycholine (2 ACH molecules back to back)
1. Initially brief stimulation of Nm get muscle fasciculations
2. followed by inactivation of Nm receptor
3. drug rapidly metabolized by plasma cholinesterase, often adm by IV infusion
4. genetic atypical enzyme does not metabolize drug > respiratory arrest
5. no antidote, need artificial respiration till drug wares off
6. unusual toxicity: malignant hyperthermia, increased body temp, acidosis, shock,
usually occurs in combo with anesthesia and patient calcium hyperreactivity,
patient goes into rigor mortis, antidote is dantrolene, blocks release calcium .
Non-Depolarizing Peripherally-Acting Skeletal Muscle Relaxants
1) do not initially stimulate Nm receptors
2). provide longer durations of action, usu 30-60 minutes
3). main ADRs: histamine release: inc secretions/bronchospasm; also paralysis
of respiratory muscles, antidote usu neostigmine
Example of Depolarizing Peripherally-Acting Skeletal Muscle Relaxants
Succinycholine
Examples of Non-Depolarizing Peripherally-Acting Skeletal Muscle Relaxants
-Atracurium besylate (Tracrium)
-Pancuronium bromide
-Tubocurarine/Curare
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