1.

12 Cholinergic Drugs
DR. LUISA TAN-REYES | 09/05/2018
LE 1
OUTLINE • Cholinergic drugs are grouped into two categories based on
I. Cholinergic Drugs their mechanism of action.
B. Chemical Groups
II. Direct Acting
C. Pharmacokinetics Categories based on Mechanism of Action
Cholinergic Drugs
D. Mechanisms of Action
A. General 1. Direct – acting drugs (agonists): bind to and activate nicotinic
of AChE Inhibitors
Considerations receptors
E. Cholinesterase
B. Chemistry and
Reactivators • Alkaloids: may be in the naturally-occurring or synthetic forms
Pharmacokinetics
F. Important → Pilocarpine: a natural alkaloid derivative;
C. Pharmacodynamics ▪ used to treat glaucoma
Pharmacologic Effect
D. Mechanism of Action → Other examples:
G. Adverse Effects
E. Pharmacologic
V. Overall Therapeutic
Actions and Effects Receptor Drug
Uses Of Indirect
III. Overall Therapeutic Nicotinic Nicotine, Varenicline, Lobeline
Acting Cholinergic
Uses of Direct Acting - All indicated for smoking cessation
Drugs
Cholinergic Drugs Muscarinic Muscarine, Pilocarpine
A. Ophthalmologic
A. Clinical/ Therapeutic Mixed Arecoline (sounds like pareho-line lol)
B. Neuromuscular
Indication
C. Gastrointestinal and
B. Major Contraindication
Urinary System • Choline esters
C. Side Effects Receptor Drug
D. Anti-muscarinic Drug
D. Toxicology Muscarinic Bethanechol (indicated for urine retention; B for
Intoxication Bladder)
IV. Indirect Acting
E. CNS Mixed Methacholine (weak nicotinic), Acetylcholine,
Cholinergic Drugs
VI. References Carbachol
A. 2 types of
VII. Quiz Remember! MAC and cheese are mixed hehe
Cholinesterases
Note: For long outlines, use two columns to save space for main
content. For short outlines, just merge the two columns. 2. Indirect – acting (acetylcholinesterase inhibitors): drugs
produce their primary effects by inhibiting acetylcholinesterase
• Recall: Acetylcholinesterase (AchE) is an enzyme that
I. CHOLINERGIC DRUGS hydrolyzes acetylcholine to choline and acetic acid.
• Drugs that mimic the effects of acetylcholine → therefore also → Inhibiting this enzyme increases the endogenous
known as cholinomimetic agents; acetylcholine concentration in synaptic clefts and
→ have effects that mimic that of the parasympathetic nerve neuroeffector junctions.
discharge (parasympathomimetic) → As a result, effects of acetylcholine are observed
▪ [Katzung] alkaloid muscarine: action on muscarinic • Indirect-acting drugs are further classified as reversible or
receptors at effector cells (at autonomic neuroeffector irreversible
junctions), not on ganglia → Depends on the different characteristics such as
▪ [Katzung and also mentioned by Doc] Low concentrations pharmacokinetic properties, chemical structure of the drug,
of alkaloid nicotine: stimulated autonomic ganglia and and different activities on various tissues
skeletal muscle neuromuscular junctions → Ultimately depends on duration of action of drug
▪ Recall: Ganglion for cholinergic pathway only contains
nicotinic receptors; Effector cells (target organ) for Duration of action Drug
cholinergic pathway contains both nicotinic and muscarinic Short-acting: Edrophonium
receptors 2 to 10 or 15 min /
• [2020A trans] Stimulate cholinoreceptors, act primarily where Reversible
acetylcholine is physiologically released and thus amplify or (Simple alcohols)
imitate endogenous acetylcholine Intermediate-acting: -stigmine (Physostigmine, Neostigmine,
About 3-4 hr to 6 hr / Pyridostigmine)
→ [Katzung] Cholinoceptors- members of either G protein- Reversible Demecarium
linked (muscarinic) or ionic channel (nicotinic) families (Carbamates or Ambemonium
Carbamoyl esters)
Very long-acting: -thion (Malathion, Parathion)
> 24 to 48 hr / -phate (Isofluorophate, Echothiophate)
Irreversible Nerve gases: Sarin, Tabun, Soman
(Organophosphates)

▪ Reversible: some can cause spontaneous hydrolysis

but after some extent will liberate the enzyme
(acetylcholine can be removed from the enzyme after
duration of action)
− Simple alcohols (2 to 10 or 15 minutes): Edrophonium
− Carbamates or carbamoyl ester (about 3-4 hours to 6
hours)
▪ Irreversible: stability of phosphorylated (inhibited)
enzyme is of long duration
− Organophosphates
Figure 1. The major groups of cholinoceptor-activating drugs, receptors
and target tissues.

Trans Group #20: Second Line Cruzes EDITOR: Almira 1 of 15

 1.12 Cholinergic Drugs
Carbamoyl Esters
• Contains amino group (carbamoyl) → not hydrolyzed by AchE
→ However, still degraded by liver and plasma esterases
• Bethanechol: more selective in activating muscarinic receptors
(mAchRs) than carbachol;
→ Can be more advantageous than carbachol as a smooth
muscle stimulant since it is not hydrolyzed by AchE
→ Since it also stimulates muscarinic receptors, it can be blocked
by atropine

Natural Alkaloids
• Pilocarpine: more of a muscarinic receptor stimulant but in
some readings, it may have some actions on nicotinic receptors
• Muscarine: no drug preparation but found in mushrooms (eg.
Amanita muscaria)
Figure 2. Classification of cholinergic stimulants. → Blocked by atropine

II. DIRECT ACTING CHOLINERGIC DRUGS A. GENERAL CONSIDERATIONS

• Divided into groups based on their chemical structure: • Cholinergic agonists vary in
→ Choline Esters: e.g. acetylcholine, methacholine, carbachol, → Muscarinic/nicotinic activity (duration, selectivity)
bethanechol → Susceptibility to cholinesterase (see Table 1)
→ Alkaloids: e.g. muscarine and nicotine ▪ Note: Only acetic acid esters are susceptible to hydrolysis
• Binds and directly activates receptors (muscarinic and nicotinic) by AChE, because their acetyl group is not substituted with
• Have affinity (tenacity to bind to a receptor) and intrinsic a carbamyl group (contains amine)
activity (interaction between receptor and drug and produce the
corresponding effects) • Key features of choline esters:
→ Permanently charged quaternary ammonium group →
Table 1. Structure activity relationships relatively lipid insoluble
Antagonized → Poor absorption and distribution in the CNS
Drugs by Atropine
Receptor Specificity Hydrolysis
(Directly (anti-
Acting)
by AchE
Muscarinic
• Key features of cholinomimetic alkaloids:
activity) → Tertiary amine (eg. pilocarpine, lobeline, nicotine): well-
Muscarinic Nicotinic absorbed; unionized or uncharged, lipid soluble;
A. Choline Esters ▪ Stays longer in the body
Acetic Acid Esters Remember:
Acetylcholine PILOcarpine, ILO for ileus (part of small intestine) → absorbed in small
+++ +++ +++ +++
intestine charot
Methacholine .
+++ + + +++
→ Quaternary amine (muscarine): less completely absorbed
Carbamoyl Esters from GIT than tertiary amines
Carbachol ++ +++ - + ▪ In contrast to tertiary amines, these are positively
Bethanechol +++ - - +++ charged; generally ionized → poor lipid solubility
B. Natural Alkaloids ▪ Not in oral preparations as it is not absorbed in gut mucosa
Pilocarpine ++ - - +++ ▪ Has difficulty traversing body membranes including the
Muscarine +++ - - +++ CNS

The following points emphasized by lecturer in the table: B. CHEMISTRY AND PHARMACOKINETICS
• Acetylcholinesterase (AChE) causes hydrolysis of
acetylcholine; continuously released
Choline Esters (from 2020A trans and Katzung)
• Atropine: prototype drug of muscarinic antagonists (anti-
Acetic Acid Esters
muscarinic drug)
1. Acetylcholine
NOTES: • The endogenous neurotransmitter at the cholinergic nerve
Both muscarinic and nicotinic receptors are present in the brain and ending
spinal cord. But there are more muscarinic receptors in the brain and • Acts on nicotinic and muscarinic receptors
there are more nicotinic receptors in the spinal cord.
• Rapidly hydrolyzed by acetylcholinesterase (>10,000
molecules are degraded per second in a single active site;
Acetic Acid Esters short half-life)
• Acetylcholine: stimulates the abovementioned receptors at the • Therefore, large amounts must be infused intravenously to
neuromuscular junction and the ganglia achieve concentrations sufficient to produce detectable
→ Readily degraded by AChE for about 2 milliseconds effects
 Atropine is an anti-muscarinic drug that prevents
• Methacholine: has selectivity towards muscarinic receptors acetylcholine from binding with muscarinic receptors by
(weak nicotinic receptor activator) competitive inhibition
→ Has some resistance to hydrolysis by AChE compared to ACh
→ But since it stimulates muscarinic receptors, it is antagonized
by atropine
▪ Note: Atropine is a competitive muscarinic antagonist
PHARMACOLOGY 2 of 15
 1.12 Cholinergic Drugs
2. Methacholine
• With methyl group substitution (makes the drug more selective
towards muscarinic receptors)
→ Recall: More selective to muscarinic receptors = more
antagonized by atropine
Carbamoyl Acid Esters
3. Carbachol (Miostat)
• Binds to muscarinic and nicotinic receptors (non-selective)
• According to Table 1, it shows more selectivity towards
nicotinic receptors (have more neuromuscular side effects)
• Has amino group substitution: provides increased resistance
to hydrolysis by acetylcholinesterases
4. Bethanechol (Urecholine)
• Has methyl substitution (makes the drug more selective to
muscarinic receptors)
• Has amino group substitution: provides increased resistance
to hydrolysis by acetylcholinesterases
• Muscarinic smooth muscle stimulant
• Has a greater effect on smooth muscles of the GIT while
exhibiting a lesser effect on the CVS
• Used in acute postoperative and postpartum non-obstructive
urinary retention and neurogenic atony of the bladder
Rule of Thumb! Structure-Activity Relationship
Carbamic acid esters (carbachol, bethanecol) have amino group that
makes them more resistant to hydrolysis by acetylcholinesterase and
have correspondingly longer durations of action
Methacholine and bethanechol have β-methyl group that reduces the
potency of these drugs at nicotinic receptors → selective to muscarinic
Drugs with higher muscarinic activity are more susceptible to
antagonism by atropine
Figure 3. Molecular structure of 4 choline esters.
• Acetylcholine and methacholine are acetic acid esters of
choline & β-methylcholine, respectively. Carbachol and
bethanechol are carbamic acid esters of the same alcohols.
Notice the substitution by the methyl groups (-CH3).
Cholinomimetic Alkaloids (from 2020A trans and Katzung)
Natural Cholinomimetic Alkaloids
• The tertiary structure of some of these drugs (pilocarpine,
nicotine, lobeline) renders them lipid soluble; therefore, these
are well absorbed in most sites of administration
• Excreted chiefly by the kidneys; acidification of the urine
accelerates clearance of tertiary amines
PHARMACOLOGY
Figure 4. Structures of some Cholinomimetic Alkaloids
1. Pilocarpine
• For treatment of glaucoma but not the 1st line drug
• Selective to the muscarinic receptors; to some extent, can
also affect nicotinic site especially at the sympathetic ganglia
• Well-absorbed
• Sialagogue: increases salivary secretions
2. Muscarine
• Quaternary amine, chiefly muscarinic in action
• Less absorbed in GIT than tertiary amines due to positive
charge
• Not commercially available; found in certain mushrooms, toxic
and fatal when ingested
• No therapeutic use
• May penetrate the CNS
3. Arecoline
• Component of betel nut (Areca catechu)
• Commonly chewed by elders which causes increased
salivation
• Mixed nicotinic and muscarinic action
4. Lobeline
• Plant derivative similar to nicotine
• Used for smoking cessation
• Act on nicotinic receptor
5. Nicotine
• Tobacco; cigarettes
• Act on nicotinic receptors
→ Low concentrations of this alkaloid will stimulate autonomic
ganglia and skeletal muscle neuromuscular junctions but
not autonomic effector cells
▪ Recall: Nicotinic receptors are found on autonomic
ganglia and muscle cells
• If in liquid form, sufficiently lipid-soluble to be absorbed across
the skin
→ Available as patches for smoking cessation
Synthetic Cholinomimetic Alkaloids
1. Oxotremorine: produces effects such as tremor, hypothermia,
and antinociception; used in research for Parkinson’s Disease
• Recall: Nociceptors are pain receptors
2. Dimethylphenylpiperazinium (DMPP)
• Nicotinic receptor agonist, specific for ganglion receptors
3. Cevimeline
• Newer drug; very selective for M3 receptors
• Quinuclidine derivative of acetylcholine
• Sialogogue
• Remember: C is the 3rd alphabet; Acts on M3 receptors
3 of 15
 1.12 Cholinergic Drugs
C. MECHANISM OF ACTION ▪ Activation of G-protein regulated K+ channels →
hyperpolarization
Muscarinic Receptors: G protein-coupled type
▪ Inhibit release of NE from sympathetic nerve endings
− Note: Receptors that regulate ligands that is not its own
Mnemonic: “KISS and KICK” = QISS and QIQ are called heteroceptors
“I’ll be including the sympathetic ANS receptors just so the mnemonic → Larger dose of ACh may elicit bradycardia and block of AV
would be more memorable lol”
Sympathetic/Adrenergic Parasympathetic/Cholinergic
nodal conduction
α1 = Q M1 = Q
α2 = I M2 = I NOTE:
β1 = S M3 = Q Principle of Accentuated Antagonism (Katzung)
β2 = S Parasympathetic innervation of the ventricles is much less
• Recall: G protein-coupled receptors may be stimulatory via cAMP extensive than the atria. However, effects of muscarinic agonists on
synthesis increase (Gs), inhibitory via cAMP synthesis reduction ventricular function are clearly evident during sympathetic nerve
(Gi), or stimulatory via Phospholipase C activation (G q) stimulation due to sympathetic modulation of sympathetic effects

• Activation of M1 and M3 receptors:

→ Utilizes stimulatory GPCR pathway via PLC • Vascular effects (mediated by M3 receptors)
→ Activation of phospholipase C (PLC) → formation of IP3 and → Intact vascular endothelium: generalized relaxation or
DAG and mobilization of stored Ca+2 vasodilation
→ Increase in sodium conductance → Mechanism of action:
▪ Opening of Na channels causes depolarization → ▪ Stimulation of endothelial Nitric Oxide (aka EDRF:
smooth muscle contraction Endothelial Derived Relaxing Factor) production →
stimulation of guanylyl cyclase → increased cGMP
• Activation of M2 receptors
(responsible for the vasodilation)
→ Utilizes inhibitory GPCR pathway via cAMP reduction
▪ Indirect inhibition of NE release from adrenergic nerve
→ Inhibition of adenylyl cyclase → reduced intracellular cAMP→
endings by ACh (heteroreceptors are also present)
increased cellular cGMP
→ Note: Absence of intact endothelium → contraction of
→ Increase in cGMP: parasympathetic effect in Beta receptors vascular smooth muscle (also via M3 receptors)
and alpha 2 receptor
→ IV dose (20-50 mcg) of ACh produces a transient fall in BP
→ Activation of K+ channels or inhibition of L-type Ca++ due to generalized vasodilation (due to M3 in vascular
(inward) channels endothelium), accompanied by reflex tachycardia
▪ Activation of K+ channels causes hyperpolarization
▪ Recall: Baroreceptor Reflex: If the BP goes down, the
baroreceptors in your carotid sinus and aortic arch will try
D. PHARMACOLOGIC ACTION AND EFFECTS to offset the change → decrease in firing of neurons of
vagus nerve to the glossopharyngeal nerve → inhibition of
cholinergic effect → reflex tachycardia
Location and Effect of Receptors:
Receptor Location Effect
• Biphasic Effects
M1 Stomach Stimulate parietal cells (Gq): → Larger dose of Ach (50mg) injected after atropine
+
Increase H secretion administration
Brain Improved cognition and locomotor ▪ Atropine: blocks all muscarinic receptors (competitive)
activity via Gq − Muscarinic receptors are located in the exocrine glands,
M2 Heart Inhibit heart effects (Gi): smooth muscles including vascular muscles, CNS, and
Negative chronotropic and the heart
dromotropic ▪ Nicotinic receptors located in Neuromuscular junction
Note!! NO negative inotropic effect
in ventricles
(NMJ), adrenal medulla, and sympathetic ganglia are still
M3 The rest of the Stimulatory in nature (Gq): available for acetylcholine binding
organs (“r3st”) Generally smooth muscle ▪ Effect is biphasic (initial rise and gradual sustained fall in
contraction blood pressure) (2020A)
Mnemonic:
• M1: secrete H+ (proton), which has a positive 1 charge; improve Acetylcholine bind to Nicotinic receptors on sympathetic
cognition (“Top 1”) ganglia and adrenal medulla

• M2: heart ❤️, 2+ 2 =

• M3: the r3st of the organs Norepinephrine and epinephrine release

Cardiovascular System Initial rise in BP

• Activity is also influenced by vagus nerve
→ Recall: Vagal effects are cholinergic effects Gradual and sustained fall in BP (since response should still
• Primary effects/Cardiac effects (mediated by M2 receptors) be cholinergic
→ Negative chronotropic: Decrease in heart rate (bradycardia)
→ Negative dromotropic: Decrease in the rate of conduction in
SA and AV nodes GIT
→ Negative inotropic: Decrease in the force of contraction of • GI smooth muscle effects, hollow organs (mediated by M3
the atria receptors)
▪ Note: NOT found in ventricle → Stimulation of GI smooth muscle
→ All primary effects lead to: Decrease in cardiac output → ↑ Tone and motility
▪ BP = CO x TPR → Sphincters are relaxed to allow movement of contents
▪ CO = SV x HR → Larger doses cause spasm, colicky pain
→ Mechanisms of action: • Salivary glands effect (mediated by M3 receptors)
▪ Reduction in L-type Ca2+ channel activity → Increased secretory activity
PHARMACOLOGY 4 of 15
 1.12 Cholinergic Drugs
• Gastric glands effect (mediated by M1 receptors) CNS
→ Increase H+ secretion from parietal cells and thus increasing • Note! Quaternary choline esters do not cross BBB
acidity in the stomach • Only tertiary amines or unionized agonists exert effect since they
→ Mechanism of action: are the ones that can penetrate BBB
▪ Utilizes stimulatory GPCR pathway via PLC • Effects on CNS (mediated by M1 receptors)
▪ Increase DAG and IP3 → Improved cognition
▪ Increase Ca2+ which aids in smooth muscle contraction of ▪ Used in management of dementia and Alzheimer’s Disease
parietal cells to secrete H+ → Increased locomotor activity
▪ Recall: Acetylcholine is a stimulatory neurotransmitter in
Urinary Tract the CNS
• Detrusor muscle effects (mediated by M3 receptors) → Tremors
→ Contraction of detrusor muscle of the bladder → Hypothermia
→ Increase in voiding pressure and ureteral peristalsis • Taclifenasine
→ M2 and M3 receptors are found in urinary bladder → M1 selective agonist
• Trigone and external sphincter muscles (mediated by M3 → Possible use in treating dementia without concomitantly
receptors) stimulating presynaptic M2 receptors and thus reduce side
→ Relaxation of muscles → lead to increased voiding effects
→ In very high dose, patients may also complain of diarrhea
▪ Recall: Stimulation of M3 results to increased GI peristalsis Table 2. Effects of direct acting cholinergic stimulants.
• Bethanechol Organ Response
→ Shows selectivity for GIT & bladder stimulation vs CVS activity Eye
Sphincter muscle of iris Contraction (miosis)
→ Useful in post-operative abdominal manipulation if there is
Ciliary Muscle Contraction for near vision
atony of bladder or paralytic ileus (10-25mg orally, 3-4x daily) Heart
→ Indicated for difficulty in urination (5mg subQ, repeated every SA node ↓ rate (negative chronotropy)
30 minutes if necessary Atria ↓ contractile strength (negative inotropy). ↓
→ Most widely used choline ester drug in refractory period
AV node ↓ conduction velocity (negative
dromotropy). ↑ refractory period
Respiratory System Ventricles Small ↓ in contractile strength
• Contraction of bronchial smooth muscles and increase in Blood vessels
tracheobronchial secretions (mediated by M3 receptors) Arteries, veins Dilation (via EDRF). Constriction (high-
→ Bronchial smooth muscle is sensitive of sympathetic nervous dose direct effect)
system effect Lung
Bronchial muscle Contraction (bronchoconstriction)
→ But is only subserved by parasympathetic constriction Bronchial glands Stimulation
(physiologically) Gastrointestinal tract
▪ NTK: Sympathetic action of bronchial smooth muscles is Motility Increased
vasodilation, which only occurs when given adrenergic Sphincters Relaxation
agonists eg. salbutamol Secretion Stimulation
• This combination of effects can occasionally cause symptoms Urinary bladder
(bronchoconstriction), especially in individuals with asthma Detrusor Contraction
Trigone and sphincter Relaxation
Glands
Eyes Swear, salivary, lacrimal, Secretion
• Smooth muscles of the eye (mediated by M3 receptors) nasopharyngeal
→ Contraction of the of the pupilloconstrictor muscle or iris
sphincter, leading to miosis III. OVERALL THERAPEUTIC USES OF DIRECT ACTING
→ Contraction of the ciliary muscle, leading to cyclospasm CHOLINERGIC DRUGS
▪ Recall: Cyclospasm involves contraction of ciliary muscles
to accommodate focus for near vision A. CLINICAL/THERAPEUTIC INDICATIONS
→ Contraction of the abovementioned smooth muscles exert Ophthalmological
tension on trabecular meshwork of the eye, leading to opening
of its pores and outflow of aqueous humor • Glaucoma
▪ These agents are therefore useful in lowering intraocular → Acute Angle Closure Glaucoma
pressure and treating glaucoma ▪ Treated with cholinomimetics or by surgery (iridectomy).
▪ eg. Pilocarpine: a tertiary amine; can cross conjunctival ▪ Initial therapy: a combination of other drugs with direct
membrane muscarinic agonist
▪ Cholinomimetic drugs used:
Exocrine Glands − Pilocarpine: miotic agent; can cross the conjunctival
membrane; facilitates the outflow of aqueous humor
• Effects on secretory portion of secretory glands (mediated by M3 from the anterior chamber into the canal of Schlemm
receptors) − Carbachol: may also activate nicotinic receptors (risk for
→ Occur only on glands containing M3 receptors muscular side effects)
→ Stimulate secretory portion contraction and increase secretion → Open Angle Glaucoma
of secretory products ▪ Treated with pharmacologic treatment and laser
→ Increased salivation and diaphoresis techniques
• Pilocarpine
NTK: Other drugs used for Open Angle Glaucoma
→ Causes marked diaphoresis (increased sweating:2-3L of
• Diuretics
sweat may be secreted) • Alpha-2 agonist eg. Apraclonidine
→ Markedly increases salivation • B-blockers eg. Timolol
▪ Used as a sialogogue, when membranes become dry • Prostaglandin analogues eg. Latanoprost
following radiation treatment
PHARMACOLOGY 5 of 15
 1.12 Cholinergic Drugs
→ Accommodative esotropia in strabismus • GIT Obstruction
▪ Due to hypermetropic accommodative error in young → Increase in smooth muscle contraction following the
children obstruction may rupture and perforate the intestines, since the
▪ Treated with cholinomimetric agonists contents have nowhere to go but to accumulate at the
→ Iritis or keratitis obstruction
▪ To break adhesions
▪ Pilocarpine which is normally used for treatment is C. ADVERSE EFFECTS
alternated with mydriatic agents
• Flushing
→ Due to vasodilation (M3)
GI Disorders • Sweating
• Conditions wherein there is a decrease in GIT smooth muscle → Increased exocrine gland stimulation (M3)
tone: • Belching
→ Postoperative abdominal distention → Increased parietal cell stimulation, leading to increased acidity
→ Gastric atony of stomach (M1)
→ Congenital megacolon • Salivation
→ Adynamic Ileus secondary to toxic states (eg. atropine toxicity) → Increased exocrine gland stimulation (M3)
→ Drug used: • Abdominal cramps
▪ Bethanechol – oral; smooth muscle stimulant → Increased tone and motility (M3)
− For acute cases, 2.5mg/dose • Tightness of the urinary bladder
− For chronic cases, 10-50mg, 2-4 times a day → Intense contraction of detrusor muscle (M3)
− Indicated for bladder atony in the postpartum or • Difficulty in visual accommodation
postoperative period • Bronchospasm (M3)
• Hypotension (M2: cardiac, M3: vasodilation)
CNS • Bradycardia (M2)
• Dementia
→ Drugs used: D. TOXICOLOGY
▪ Taclifenasine: M1 selective agonist without concurrent • Poisoning is characterized chiefly by exaggeration of their
stimulation of M2 (less side effects) primary parasympathetic effects
▪ Xanomeline: investigative drug; M1 agonist → Drug used as antidote (inhibit excess parasympathetic effect):
▪ Atropine sulfate:
Xerostomia − 0.5-1mg, SubQ or IV
• Dryness of mucous membrane, including the mouth − Competitive muscarinic blocker that blocks muscarinic
• Sjӧgren’s Syndrome: an autoimmune disorder wherein the receptors by competitive antagonis
salivary and lacrimal glands are compromised in which their − No intrinsic activity on its own
secretions are decreased; primarily found in women − Given until the signs and symptoms of atropization
• Usually occur after head and neck radiation treatment o Recall: “Alice in Wonderland” effects
→ Drug used: ▪ Epinephrine:
▪ Sialagogues: activates M3 receptors and enhances − 0.3-1mg, SubQ or IM
salivation and sweating − Sympathetic agonist
− Pilocarpine: 5-10mg, 3 times a day, orally ▪ Mechanical ventilation
− Bethanechol: given as an alternative; less diaphoresis
side effect Mushroom Poisoning (Mycetism)
− Cevimeline: more selective M3 receptor agonist as • Toxicity and treatment strategies depend on species ingested
compared to Pilocarpine; longer duration of action and
• Inocybe sp. and Clitocybe sp.
fewer side effects
→ Contain high concentrations of muscarine
→ Symptoms of intoxication: within 30-60mins of ingestion
B. MAJOR CONTRAINDICATIONS → Treatment:
• Asthma ▪ Atropine sulfate: 1-2mg IM, every 30mins
→ Smooth muscle contraction of bronchi leads to • Amanita muscaria
bronchoconstriction then bronchospasm → Less concentrations of muscarine
• Hyperthyroidism → Contains muscimol, ibotenic acid, and other isoxazole
→ Increased levels of thyroid hormones derivatives with neurologic and hallucinogenic properties
→ Tissues become very sensitive to circulating catecholamines → Symptoms:
→ May lead to atrial fibrillation and tachycardia due to nicotinic ▪ Irritability and restlessness
receptor stimulation and subsequent adrenal medulla ▪ Ataxia
stimulation ▪ Hallucinations and delirium
• Coronary insufficiency ▪ Drowsiness and sedation
→ Compromised heart may lead to hypotension due to less blood → Treatment:
flow ▪ Mainly supportive
▪ Recall: M3 action causes vasodilation ▪ Antidote: Benzodiazepines when excitation predominates
→ Slowing of cardiac tissues due to hyperpolarization − NTK: Benzodiazepines cause hyperpolarization and
▪ Recall: M2 action causes bradycardia and negative relaxation
dromotropic effect on the heart • Psilocybe sp. and Panaeolus sp.
• Acid Peptic Disease → Contains psitocybin and related derivatives of tryptamine
→ Increase in gastric acid secretion due to stimulation of M1 → Cause short-lasting hallucinations
receptors in gastric parietal cells
→ May worsen duodenal ulcer
PHARMACOLOGY 6 of 15
 1.12 Cholinergic Drugs
• Gyromitra sp. Carbamates (Reversible/Non-covalent Inhibitors)
→ Acetaldehyde methformyl-hydrazone is coverted to reactive • Carbamic acid esters of alcohols
hydrazines which causes GI disorders and delayed • Contains quaternary or tertiary ammonium groups
hepatotoxicity → Tertiary amines are lipid-soluble
→ Treatment: Benzodiazepines when excitation predominates → Quaternary amines are charged, and lipid-insoluble; for
• Amanita phalloides, Lepiota sp., Galerina sp. glaucoma and for delaying progression of mild-moderate
→ Amatoxins: principal toxins Alzheimer’s disease by improving the cognitive function
→ Account for 90% of fatal cases • Tertiary Amines:
→ Mechanism of Action: → Physostigmine:
▪ Inhibition of RNA Polymerase II → block mRNA synthesis ▪ Naturally occurring tertiary amine
→ Cell death ▪ Has greater lipid solubility
→ Treatment: • Quaternary Amines:
▪ Largely supportive → Pyridostigmine:
▪ Antidotes: ▪ Synthetic quaternary ammonium agents
− Penicillin ▪ For chronic management of myasthenia gravis
− Thioctic Acid
Mnemonic: Myasthenia Gravis
− Silibinin • Edrophonium: Diagnosis
• PyRIDostigmine: Get RID of MG; Chronic management
IV. INDIRECT ACTING CHOLINERGIC DRUG
→ Neostigmine:
A. TWO TYPES OF CHOLINESTERASE ▪ Synthetic quaternary ammonium agent
• Members of the group have the same pharmacodynamic ▪ For stimulation of bladder and GI system
properties but have different pharmacokinetic properties ▪ Treatment for tubocurarine poisoning
• Acetylcholinesterase Inhibitors → Rivastigmine
→ Inhibits AChE from degrading/hydrolyzing Ach ▪ Treatment of senile dementia of the Alzheimer type along
▪ Increases levels of Ach with donepezil, tacrine, and galantamine
▪ Increases duration of action of ACh → Distigmine
→ Galantamine
→ Tacrine (not used anymore due to hepatotoxicity)
Acetylcholinesterase (AChE)
→ Donepezil
• True choline esterase → Propoxur (Baygon): Insecticide and pesticide
• Specific type of choline esterase → Demecarium
• Membrane-bound → Ambemonium
• Specifically, for acetylcholine (Ach)
• Responsible for rapid Ach hydrolysis at cholinergic synapse
Remember: Centrally-Acting Acetylcholinesterase Inhibitors
→ Actions of acetylcholine are terminated when
• Tacrine (not used anymore due to hepatotoxicity)
acetylcholinesterase is hydrolyzed • Rivastigmine
→ Rate of hydrolysis dictates the duration of action • Donepezil
• Also found in erythrocyte membrane • Galantamine
These are indicated for Alzheimer’s DIsease
Butyrylcholinesterase (BuChE) • PyRIDostigmine: Get RID of MG; Chronic management
• Also known as pseudocholinesterase or plasma cholinesterase
Organophosphates (Irreversible/Covalent Inhibitors)
• Found in plasma and in liver tissue, skin, brain tissue, and GI
smooth muscle • Organic derivatives of phosphoric acid
• Non-specific type of choline esterase • Represents more water-soluble type
• Non-selective; Can degrade other esters like succinylcholine • The bond between the phosphate group and another atom is
• Not important in the physiologic termination of synaptic Ach hydrolyzed when organophosphates bind with the enzyme
action • Eg. -phates, -thion
→ Since inhibition of butyrylcholinesterase does not have a large → Echothiophate
effect in the action of indirect-acting cholinomimetic drugs → Isofluorophate
→ Malathion
B. CHEMISTRY (CHEMICAL GROUPS) → Parathion
• Commonly used as farm pesticides
Simple alcohols (Reversible/Non-covalent Inhibitors)
• Contains quaternary ammonium group NOTES (included in the lecture):
• Edrophonium PAN = Pyridostigmine, Ambenomium, Neostigmine; for the
→ Synthetic quaternary ammonium agent management of myasthenia gravis
→ Not used for treatment
→ Used for diagnosis of Myasthenia Gravis (MG)
▪ Diagnosis of MG C. PHARMACOKINETICS
− (+) MG: muscle strength improves
− Other causes: muscle strength did not improve Reversible or Non-covalent Inhibitors
→ Used for assessment of adequacy and treatment with anti- • Shorter/fast duration of action: 30mins to 6 or 8 hours
cholinesterases for Myasthenia Gravis → Binding to acetylcholinesterase (AChE) is not that strong
▪ Assessment of MG treatment → Only held by hydrogen bonds; short-lived
− Undertreatment: muscle strength improves (myasthenia • May be liberated from its binding site in the AChE which makes
gravis or myasthenic crisis) the enzyme amenable in degrading another Ach
− Overtreatment: muscle weakness persists or worsens • Example: Simple alcohols and Carbamates
(cholinergic crisis)
PHARMACOLOGY 7 of 15
 1.12 Cholinergic Drugs
1. Simple Alcohols • High lipid solubility → easily absorbed
• Edrophonium: MG diagnosis → Highly toxic to humans since it is well-absorbed from the skin,
→ Volume of distribution is limited lung, gut, conjunctivae (and can easily penetrate the CNS)
→ Fast onset which can lead to organophosphate poisoning
▪ Drug is readily absorbed → Exception: Echothiophate: highly polar; more stable than
→ Short duration of action (5-15mins) other organophosphates
▪ Hard to use for maintenance of Alzheimer’s disease • Hydrolyzed by plasma and liver esterases
→ Rapid renal elimination • Excreted in the urine
▪ Only attached to the anionic site and histidine residues • Highly effective as insecticides
▪ No covalent bonds, thus; can be easily hydrolyzed and
eliminated
NOTES (from the book)
2. Tacrine and Donepezil Treatment for Organophosphate Poisoning:
- Maintain respiration and decontaminate (to prevent further absorption)
• Management of mild to modest form of Alzheimer’s disease - Administer pralidoxime within minutes of exposure
• Higher affinities for AChE - Administer atropine parenterally (to inhibit muscarinic effects)
• More hydrophobic which readily crosses the blood-brain barrier
(centrally-acting)
• Longer duration of action Table 5. Organophosphates
Drugs Clinical Uses Pharmacokinetics
• Tacrine is no longer used due to its hepatotoxicity effect
Used a mitotic agent
• Donepezil is used more often for the treatment of cognitive for the highly resistant
Highly polar, stable in
dysfunction on Alzheimer’s since it is a more selective AChE Echothiophate aqueous solution, does not
cases of glaucoma;
inhibitor readily penetrate the skin
Not a first line drug
Highly lipid soluble, well-
3. Carbamates absorbed across all
Isofluorophate
• Increase in acetylcholinesterase inhibiting potency vs simple membranes, can penetrate
the skin
alcohols
Thiophosphate prodrugs;
• Longer duration of action (2-8 hours) vs simple alcohols Converted to phosphate
→ Duration of effect is determined primarily by the stability of the derivatives;
inhibitor-enzyme complex Quite lipid-soluble; rapidly
• Relatively stable in aqueous solutions and poorly absorbed absorbed and must be
▪ SHOULD therefore be given orally and at larger doses Used as insecticides
activated by conversion
Parathion and into oxygen analogs;
• Rivastigmine:
Malathion Parathion: not detoxified
→ High lipid solubility effectively (dangerous to
→ Readily cross BBB (centrally-acting) humans);
→ Long duration of action Malathion: rapidly
metabolized to inactive
Table 3. Difference between Physostigmine and Neostigmine products (safe to humans)
Physostigmine Neostigmine
Tertiary amine Quaternary amine Nerve gases
Used in Chemical
Lipid soluble Poorly lipid soluble (Tabun, Sarin,
Warfare (extremely
Can cross Blood-brain barrier Cannot penetrate CNS Soman, and
potent)
VX)
Indirectly acting Direct action on the Nicotinic (Nm)
receptor at the Neuromuscular
junction (NMJ)
Used in atropine or anti-muscarinic Used as anti-curare drugs since it Table 5. Cholinesterase Inhibitors
poisoning involving CNS effects acts directly on the Nm receptors, Cholinesterase Drug Uses Length
(eg. psychosis and agitation) since thus; promoting skeletal muscle Inhibitors of Action
it can cross the blood-brain barrier contraction Alcohol Edrophonium Myasthenia 5-15
Given at the end of the surgery to gravis, Ileus, minutes
counteract the effects of Arrythmias
neuromuscular blockers Carbamates and Neostigmine Myasthenia 0.5-2
related agents gravis, Ileus hours
Pyridostigmine Myasthenia 3-6 hours
Irreversible or Covalent Inhibitors gravis
Physostigmine Glaucoma 0.5-2
• Irreversibly inactivate AChE via covalent bonding hours
→ May not be released from its binding site → ACh will not be Ambenomium Myasthenia 4-8 hours
degraded gravis
→ To increase free acetylcholinesterases (unbound to covalent Demecarium Glaucoma 4-6 hours
inhibitors): Organophosphates Echothiophate Glaucoma 100 hours
▪ Provide regenerator compounds such as pralidoxime and
diacetylmonoxime (only effective during early exposure to
covalent inhibitors) → remove binding D. MECHANISM OF ACTION OF AChE INHIBITORS
▪ Synthesis of new AChE
• Increase the concentration of endogenous ACh at cholinoceptors
• Example: Organophosphates by inhibiting AChE
• Quaternary ammonium anti-AChE have additional direct
1. Organophosphates cholinergic action on the NMJ
• Irreversible inactivation of AChE
• Less stable than carbamates
Active Sites of AChE
• Anionic Site (glutamate residue):
→ Binds basic (choline) moiety of Ach

PHARMACOLOGY 8 of 15
 1.12 Cholinergic Drugs
• Esteratic site (histidine and serine residues):
→ Most important active site, especially at serine residue
→ Main site where AChE inhibitors bind (especially
organophosphates)
1. Edrophonium
• Reversibly bind electrostatically and by hydrogen bonds to the
anionic site of the enzyme only
• Does not involve a covalent bond; short-acting
• Onset: 1-5 min; Brief duration: 2-15 mins
2.Carbamate Esters
• Bind to both the anionic site and esteratic site
• All possess basic groups that bind the anionic site
• Carbamyl groups are transferred to the serine hydroxyl group of
the esteratic site, forming the carbamylated enzyme which is
slowly hydrolyzed
• Duration of action: 30 mins- 6 hours
3. Organophosphates
• Interacts only with the serine hydroxyl group of the esteratic site
resulting in a phosphorylated enzyme
→ Exception: Echothiophate: also binds to anionic site
• Covalent phosphorus enzyme bond is extremely stable and
undergoes hydrolysis in water at very slow rate (hundreds of
hours)
• After initial binding-hydrolysis step, phosphorylated enzyme
complex may undergo aging (breaking of one of the oxygen-
phosphorus bonds of the inhibitor → further strengthens the
phosphorus-enzyme bond)
E. CHOLINESTERASE REACTIVATORS
• Composed of substituted oximes capable of regenerating active
enzyme from organophosphorus-cholinesterase complex
• Treatment for organophosphorus poisoning.
• Given only in patients who have been subjected to overdose of
organophosphates
• Strong nucleophiles does not enter the CNS
• Note! Must be given before the process of aging
→ Only effective during early poisoning!
• Mechanism of Action: breaks the phosphorus-enzyme bond
forming a phosphooxime bond
1. Pralidoxime
• Used for organophosphate poisoning only
• Note! Not effective in antagonizing toxicity of carbamylated
inhibitors
• Most extensively studied in humans of these agents but is only
available for clinical use in the USA
• Most effective in regenerating the cholinesterase associated with
skeletal muscle neuromuscular junctions (NMJ)
• Administered via intravenous infusion, 1-2 g given over 15-30
minutes
• Contains quaternary ammonium (positively charged) → Cannot
cross BBB (limited effectiveness on central effects)
• MOA: The oxime group (=NOH) in pralidoxime has a very high
affinity for the phosphorous atom of organophosphates and can
cause the bond between the organophosphate agent and the
cholinesterase to hydrolyze if the complex has not “aged” or
stabilized due to the spontaneous loss of an alkyl group from the
organophosphate compound
• Pralidoxime's effect on non-aged organophosphate-enzyme
complexes causes a reactivation of cholinesterase activity.
2. Obidoxime
• For nerve poisoning
• Quaternary choline ester: Do not cross BBB → Limited
effectiveness on central effects.
PHARMACOLOGY
3. Diacetylmonoxime
• Crosses BBB in experimental animals
• Can regenerate some CNS cholinesterases
F. IMPORTANT PHARMACOLOGIC EFFECTS
• Very similar to the effects of direct-acting agents but most
important site of actions are the: CNS, eyes, GIT, urinary tract,
and the NMJ
Eyes
• Contraction of the pupilloconstrictor muscle (miosis) and ciliary
muscle (block accommodation reflex) to facilitate the outflow of
aqueous humor → Decreases an elevated intra-ocular pressure
(IOP) in glaucoma
• Drugs:
→ Physostigmine: used with Pilocarpine (direct acting)
→ Demecarium
→ Echothiopate:
▪ Seldom used
▪ Not a first line drug due to its vasodilation and vasospasm
effects which may increase IOP → worsen glaucoma
▪ Only used for more resistant cases of glaucoma
NTK:
However, there are better drugs now that are being used for glaucoma,
such as:
• Prostaglandin F2α analogs (Bimatoprost and Latanoprost): first line
Other drugs used for glaucoma:
• Direct and indirect acting cholinomimetics
• Beta blockers eg. Timolol
• Alpha-agonists eg. Brimonidine, Apraclonidine
Gastrointestinal and Urinary Tract
• Increase motor and secretory activity of the gut
• Increase GIT motility and tone
→ Assumes the effect of acetylcholine: Contraction of walls and
relaxation of sphincters → increase in voiding (defecation)
• Increase detrusor muscle contraction and relaxation of trigone
and sphincter → increase in voiding (urination)
• Drugs:
→ Neostigmine:
▪ Indirect acting/cholinesterase inhibitor
▪ Stimulates the GIT & bladder in cases of postoperative
intestinal & bladder atony
▪ NOT used in peritonitis or in obstruction of the intestine or
bladder (otherwise, may cause rupture of GIT or GUT)
Neuromuscular Junction
• Mechanism: Inactivation of acetylcholinesterase increase
acetylcholine which eventually binds to nicotinic receptors
• At therapeutic concentrations:
→ Actions of released ACh are moderately prolonged and
intensified → ↑Strength of contraction
• At higher concentrations:
→ Fasciculations, unsynchronized contractions, and twitching
may occur followed by flaccid paralysis due to ACh
accumulation (desensitization block)
• Reverse the antagonism caused by competitive neuromuscular
blockers (NTK: eg. Pancuronium, Rocuronium, Atracurium, and
Mivacurium)
• Enhance NM blockade caused by non-competitive
neuromuscular blockers eg. succinylcholine (SCh)
▪ SCh contains 2 molecules of ACh so the effects are the
same as Ach
▪ It is a depolarizing neuromuscular blocker and it acts at the
NMJ and causes depolarization followed by paralysis
• Edrophonium: Used to differentiate myasthenic vs. cholinergic
crisis
9 of 15
 1.12 Cholinergic Drugs
Myasthenia Gravis: Cardiovascular System
• Chronic autoimmune disorder in which antibodies destroy nicotinic • In the heart, the effects on the parasympathetic limb
receptors at the motor end-plate, resulting to skeletal muscle predominate. Thus, cholinesterase inhibitors mimic the effects of
weakness vagal nerve activation on the heart:
• Autoimmune disease producing antibodies against α1 subunits of the
nicotinic receptor-channel complex on NMJ
→ Negative chronotropic, dromotropic, and inotropic effects
• Antibodies reduce nicotinic receptor function by: → Decrease in CO
→ Cross-linking receptors: stimulates their internalization and • Moderate doses:
degradation → ↓BP as a result of modest bradycardia,
→ Lysing of their postsynaptic membrane → ↓ Cardiac output
→ Binding to the nicotinic receptor and inhibiting function → ↑Vascular resistance
• There is still normal Ach release and normal nerve impulse, but the • Toxic doses:
effects are reduced due to reduction of receptors (less sensitivity)
• Frequent findings are ptosis, diplopia, difficulty in speaking and → Marked bradycardia occurs
swallowing, and extremity weakness. → Cardiac output decreases significantly
• First to disappear are muscles involved in fine motor movements. → Hypotension
Last to disappear are those involved in respiration including the • Similar effects with ACh
diaphragm → Negative inotropic, especially in the atrial muscles
▪ Note: Not ventricular!
Edrophonium:
→ Inhibits acetylcholinesterase → increase Ach levels at the NMJ → ↓Rate of spontaneous depolarization of SA node: bradycardia
→ Diagnosis of Myasthenia Gravis vs Myasthenic Crisis vs → Vasodilation of vessels
Cholinergic Crisis → Total result: Decreased cardiac output
▪ Myasthenia gravis: Edrophonium improves muscle strength
− Treatment: Give Pyridostigmine G. ADVERSE EFFECTS
▪ Myasthenic Crisis vs Cholinergic Crisis
Myasthenic Crisis Cholinergic Crisis • Mimic effects that would occur during exaggerated
 Due to severe  Due to excessive drug therapy parasympathetic activity
myasthenia  An acute exacerbation of • Similar effects with acetylcholine
 An exacerbation of muscle weakness caused by • Primary effects:
myasthenic symptoms overmedication of cholinergic → GI distress (nausea, vomiting, diarrhea, abdominal cramps)
cause by under anticholinesterase drugs
→ Increased salivation and sweating, hyperhidrosis (abnormal
medication of • Edrophonium: no increased sweating)
anticholinesterases improvement or worsening
• Edrophonium: result to of condition (due to excessive
→ Bradycardia
improvement of muscle supply of Ach) → Bronchospasm or bronchoconstriction
movement → Initial: muscle contraction → Difficulty in visual accommodation (due to cyclospasm)
• Treatment: Give higher (bombard muscle with Ach) → Flushing (generalized vasodilation due to activation of M3
dose of anti-AChE → Eventually, muscle stops receptors in vascular endothelium)
responding (desensitization)
→ ALL muscles are contracted
→ Lead to: flaccid paralysis
• Cholinergic crisis or Organophosphate poisoning seen as:
• Treatment: Reduce dose of
anti-AChE
(MNEMONIC: DUMBELS)
→ Diarrhea
→ Urinary Frequency
• Some quaternary carbamate cholinesterase inhibitors (e.g. → Miosis, Muscle weakness at toxic dose
neostigmine) have an additional direct nicotinic agonist effect at → Bronchospasm, Bradycardia
the neuromuscular junction → Emesis, Excitation (CNS)
→ This may contribute to the effectiveness of these agents as → Lacrimation
therapy for myasthenia → Salivation, Sweating, Seizures

Central Nervous System V. OVERALL THERAPEUTIC USES OF INDIRECT ACTING

• Lipid soluble anti-AChEs (can traverse the BBB)
→ Low concentration: initial excitation
→ High concentration: generalized convulsions followed by
coma and respiratory failure Glaucoma
→ eg. Physostigmine • Disease characterized by increased intraocular pressure (IOP)
▪ Tertiary amine (unionized) and can pass through BBB
▪ Recall: Used for atropine toxicity involving CNS effects
(psychosis and irritability)
▪ Note! It is not the drug of choice for atropine toxicity and it
must be used with caution due to its potential for coma and
• Types of Glaucoma
respiratory depression
→ These central actions are antagonized by atropine
(antimuscarinic, tertiary amine, can also traverse CNS)
• Drugs for management of mild to moderate Alzheimer’s Disease:
→ Tacrine:
▪ Previously used drug for Alzheimer’s disease;
− No longer used because it is hepatotoxic
→ Donepezil, Rivastigmine, Galantamine
▪ More selective AChE inhibitors in treatment of cognitive
dysfunction in Alzheimer’s patient
▪ Less toxic than Tacrine
▪ Longer acting anticholinesterases
PHARMACOLOGY
CHOLINERGIC DRUGS
A. OPHTHALMOLOGIC
→ NTK: Normal IOP: approx. 10-15 mmHg above atmospheric
pressure
→ Causing contraction of the ciliary body → outflow of aqueous
humor → reduction of IOP
→ Acute Angle Closure
▪ Peripheral iris blocks drainage of aqueous humor in the
anterior chamber through the trabecular meshwork →
Accumulation of aqueous humor → IOP increase
▪ Initial therapy often consists of a combination of a direct
muscarinic agonist and a cholinesterase inhibitor
− eg. Pilocarpine + Physostigmine
▪ Medical emergency requires stabilization of intraocular
pressure
− Treated with cholinomimetics followed by surgery (laser
iridectomy)
10 of 15
 1.12 Cholinergic Drugs
▪ Treatment:
− Pilocarpine (directly-acting, muscarinic agonist)
− Carbachol (directly-acting, mixed cholinergic agonist)
− Physostigmine (indirect, reversible, carbamate)
− Demecarium (indirect, reversible, carbamate)
− Echothiopate (indirect, rarely used, irreversible,
organophosphate)
→ Open Angle Glaucoma
▪ Amenable to pharmacologic treatment & laser techniques
▪ Chronic condition in which there is gradual blockage of
aqueous outflow despite seemingly open space or angle
between cornea and the iris (chamber angle) → ↑IOP
▪ May be due to eye aging
− Clogged drainage system of eye, or
− Overproduction of aqueous fluid
▪ Treatment: Goal is to provide alignment to trabecular
meshwork
− Cholinomimetics (direct or indirect)
− Beta blockers (ex. timolol)
− Alpha agonists (ex. Brimonidine)
− Prostaglandin F2 analogs (latanoprost, bimatoprost)
Accommodative Esotropia in Young Children
• Strabismus caused by hypermetropic accommodative error
• Treatment:
→ Cholinomimetic agonists
• Dosage is similar or higher than that used for glaucoma
B. NEUROMUSCULAR
Myasthenia Gravis
• After management, first to recover are the large muscles and the
last are those for fine movements.
• Patients with myasthenia are exquisitely sensitive to the action of
curariform drugs and other drugs that interfere with
neuromuscular transmission (eg. aminoglycoside antibiotics)
• Diagnostic purposes (Drug of Choice: Edrophonium)
→ Cholinergic stimulants that can be used to diagnose
Myasthenia gravis from other disorders
→ In assessment of Myasthenic vs Cholinergic crisis
→ Assess adequacy of treatment
→ Note: Edrophonium is not use for treatment since it is short
acting (fast onset, but short acting)
• Treatment of Myasthenia Gravis
→ Drugs
▪ Pyridostigmine
▪ Neostigmine
▪ Ambemonium
→ Note: Atropine can be used to control excessive muscarinic
stimulation by AChE inhibitors.
→ Tolerance may develop to long-term use of the AChE
inhibitors.
Competitive Neuromuscular Blocker-Induced
Neuromuscular Paralysis
• Curare or curare-like over dosage
→ Recall: Anticholinesterase inhibitors may antagonize or
reverse the antagonistic action of competitive NMJ blockers
(eg. curare, -curonium, -curium)
NTK:
• Curare or curare-like drugs, such as Atracurium and Pancuronium,
are classified as competitive neuromuscular blockers.
• They competitively inhibit nicotinic receptors, resulting in loss of
depolarization, and consequent muscle relaxation
• They are therefore used as muscle relaxants
• Do not have intrinsic activity
PHARMACOLOGY
• Adjunct to surgical anesthesia (given after surgery to reverse
pharmacologic paralysis)
→ Quaternary ammonium anticholinesterases (anti-curare
drugs) are given to counteract NMJ blockers and bring up
again contractions by increasing ACh
• Anti-curare-like drugs
→ Direct action: Stimulation of nicotinic receptor at NMJ
(compete with NMJ blocker) → shorten paralysis or relaxation
→ Indirect action: Spares Ach from being degraded
▪ Combined with Atropine to inhibit muscarinic receptor
activation
− Note: Since nicotinic receptors are blocked, and Ach is
not degraded, more ACh will bind to the muscarinic
receptors. This might result to pronounced muscarinic
effects. Thus, atropine is given to antagonize this.
→ Examples:
▪ Neostigmine
▪ Edrophonium
C. GASTROINTESTINAL AND URINARY SYSTEM
Postoperative ileus and congenital megacolon
• This condition induces reflux esophagitis
• Cholinomimetic drugs are sometimes used to increase the tone
of the lower esophageal sphincter in patients with Reflux
Esophagitis
→ Recall: Cholinergic effect is rest and digest. Lower esophageal
sphincter is closed during digestion in stomach
• Treatment:
→ Neostigmine
Urinary Retention & Bladder Atony
• Post operatively or postpartum neurogenic bladder
→ Recall: Acetylcholine induces urinary bladder contraction and
urinary sphincter relaxation, leading to increased voiding
(urination)
• Treatment:
→ Neostigmine (0.5-1mg subQ or 15mg orally): most widely
used cholinesterase inhibitor
Recall: Drugs used to induce GI motility and GUT voiding
• Neostigmine: Acetylcholinesterase inhibitor (carbamate, reversible)
• Bethanechol: Cholinomimetic / Muscarinic agonist
NOTE: Cholinomimetic drugs are not to be given to patients with
mechanical obstruction or peritonitis as it may lead to perforation
and further spread of infection
D. ANTI-MUSCARINIC DRUG INTOXICATION
• Results from exposure to:
→ Atropine (muscarinic antagonist)
▪ Children: lethal effects
▪ Adults: Prolonged severe behavioral disturbances and
arrhythmias
→ Phenothiazines, H1R blockers (anti-allergy pills), and TCAs
(Tricyclic antidepressants): Have both central and peripheral
anticholinergic activity
• Muscarinic receptor blockade produced by all these agents is
competitive in nature and can be overcome by increasing the
amount of endogenous acetylcholine at the neuroeffector
junctions.
• Treatment:
→ Physostigmine IV or IM (2mg)
▪ Given only if deemed necessary because it may precipitate
seizures
▪ Useful in reversing central and peripheral anticholinergic
syndrome
▪ Used only in patients with dangerous elevation of body
temperature or very rapid supraventricular tachycardia
11 of 15
 1.12 Cholinergic Drugs
E. CENTRAL NERVOUS SYSTEM (CNS) a. Gastric secretion
• Alzheimer’s Disease (mild to moderate) b. Neuromuscular end plate
→ Treatment: c. Salivary glands
▪ No evidence of retardation of disease process d. Sweat glands
▪ Result in slight improvement of cognitive function e. Ureteral tone

Table 6. Centrally-acting acetylcholinesterase inhibitors 7. Parathion has which one of the following characteristics?
Drug Property DOA Administration a. It is inactivated by conversion to paraoxon
Rivastigmine CNS selective 8 hr Given 2x daily b. It is less toxic to humans than malathion
Donepezil CNS selective 24 hr Given once daily c. It is more persistent in the environment than DDT
Galantamine Non-selective 8 hr Given 2x daily d. It is poorly absorbed through skin and lungs
cholinesterase e. If treated early, its toxicity may be partly reversed by
inhibitor pralidoxime
Tacrine Non-selective 6 hr Given 2-3x daily;
cholinesterase No longer used due to 8. Charice Zyrus has been treated for myasthenia gravis for
inhibitor; hepatotoxicity
Hepatotoxic several years. She reports to the emergency department
complaining of recent onset of weakness of her hands, diplopia,
and difficulty swallowing. She may be suffering from a change in
VI. REFERENCES response to her myasthenia therapy, that is, a cholinergic or a
2020 Trans myasthenic crisis. Which of the following is the best drug for
Recording distinguishing between myasthenic crisis (insufficient therapy)
PPT and cholinergic crisis (excessive therapy)?
Katzung a. Atropine
b. Edrophonium
VII. QUIZ c. Physostigmine
2020A d. Pralidoxime
e. Pyridostigmine
1.Which of these is not used for management of myasthenia 9. Xian Gaza, a crop duster pilot, has been accidentally exposed
gravis? to a high concentration of a highly toxic agricultural
a. Pyridostigmine organophosphate insecticide. If untreated, the cause of death
b. Ambenomium from such exposure would probably be
c. Physostigmine a. Cardiac arrhythmia
d. Neostigmine b. Gastrointestinal bleeding
e. All of the above c. Heart failure
2.Which of these is the correct pair (cholinesterase inhibitor: d. Hypotension
use) e. Respiratory failure
a. Echothiphate: Ileus
b. Physostigmine: Myasthenia Gravis 10. Jake Pempengco has just been diagnosed with dysautonomia
c. Demecarium : Ileus (chronic idiopathic autonomic insufficiency). You are considering
d. Edrophonium : Arrhythmia different therapies for his disease. Pyridostigmine and
3. It is a type of AchE inhibitor that binds to the serine residue neostigmine may cause which one of the following?
at the esteratic site. a. Bronchodilation
a. Organophosphates b. Cycloplegia
b. Carbamate Esters c. Diarrhea
c. Edrophonium d. Irreversible inhibition of acetylcholinesterase
4. Which of these is the right effect of direct acting e. Reduced gastric acid secretion
cholinergic stimulants on a specific organ?
a. Brochodilation of the brochial muscle in the lungs 11. Parasympathetic nerve stimulation and a slow infusion of
b. Constriction of the sphincters of the GIT bethanechol will each:
c. Small increase in the contractile strength of the a. Cause ganglion cell depolarization
ventricles of the heart b. Cause skeletal muscle end plate depolarization
d. dilation via EDRF of the arteries c. Cause vasodilation
d. Increase bladder tone
5. Which of these is a natural cholinomimetic alkaloid that e. Increase heart rate
increases salivation while chewing?
a. Muscarine 12. Actions and clinical uses of muscarinic cholinoceptor agonists
b. Oxotremorine include which one of the following?
c. Arecoline a. Bronchodilation (asthma)
d. DMPP b. Improved aqueous humor drainage (glaucoma)
c. Decreased gastrointestinal motility (diarrhea)
Answers: C, D, A, D, C
d. Decreased neuromuscular transmission and
relaxation of skeletal muscle (during surgical
6. Ate Shawy, a 30-year-old woman, undergoes abdominal
anesthesia)
surgery. In spite of minimal tissue damage, complete ileus
e. Increased sweating (fever)
(absence of bowel motility) follows, and she complains of severe
bloating. She also finds it difficult to urinate. Mild cholinomimetic
13. Which of the following is a direct-acting cholinomimetic that is
stimulation with bethanechol or neostigmine is often effective in
lipid-soluble and is used to facilitate smoking cessation?
relieving these complications of surgery. Neostigmine and
a. Acetylcholine
bethanechol in moderate doses have significantly different effects
b. Bethanechol
on which one of the following?
c. Neostigmine
PHARMACOLOGY 12 of 15
 1.12 Cholinergic Drugs
d. Physostigmine
e. Varenicline 13. Varenicline is a lipid-soluble partial agonist at nicotinic
receptors and is used to reduce craving for tobacco in smokers.
14. Bim By, a 3-year-old child, is admitted after taking a drug from The answer is E.
her mommy’s medicine cabinet. The signs suggest that the drug
is an indirect-acting cholinomimetic with little or no CNS effect and 14. Neostigmine is the prototypical indirect-acting cholinomimetic;
a duration of action of about 2–4 h. Which of the following is the it is a quaternary (charged) substance with poor lipid solubility; its
most likely cause of these effects? duration of action is about 2–4 h. Physostigmine is similar but has
a. Acetylcholine good lipid solubility and significant CNS effects. The answer is C.
b. Bethanechol
c. Neostigmine 15. Cholinomimetics cause smooth muscle contraction mainly
d. Physostigmine through the release of intracellular calcium. This release is
e. Pilocarpine triggered by an increase in IP3 acting on receptors in the
endoplasmic reticulum. The answer is D.
15. Which of the following is the primary second-messenger
process in the contraction of the ciliary muscle when focusing on
near objects? 2020B
a. cAMP (cyclic adenosine monophosphate)
1. Which direct-acting cholinomimetic agents are polar
b. DAG (diacylglycerol)
compounds and will have poor absorption and distribution
c. Depolarizing influx of sodium ions via a channel
in the CNS?
d. IP3 (inositol 1,4,5-trisphosphate)
a. ACh
e. NO (nitric oxide)
b. Pilocarpine
c. Lobeline
Answers and Rationale (numbers 6 to 15)
d. Both A & B
6. Because neostigmine acts on the enzyme cholinesterase,
2. The following cholinergic agonists, the drug with the
which is present at all cholinergic synapses, this drug increases
most nicotinic activity is:
acetylcholine effects at nicotinic junctions as well as muscarinic
a. metacholine
ones. Bethanechol, on the other hand, is a direct-acting agent that
b. pilocarpine
is selective for muscarinic receptors and has no effect on nicotinic
c. carbachol
junctions such as the skeletal muscle end plate. The answer is B.
d. bethanechol
3. The action of a cholinergic agonist on the heart is
7. The “-thion” organophosphates (those containing the PÓS
primarily brought about by: a. increasing calcium
bond) are activated, not inactivated, by conversion to “-oxon”
channel activity
(PÓO) derivatives. They are less stable than halogenated
a. Increasing the calcium channel activity
hydrocarbon insecticides of the DDT type; therefore, they are less
b. Inhibiting potassium channels
persistent in the environment. Parathion is more toxic than
c. Activating phospholipase
malathion. It is very lipid-soluble and rapidly absorbed through the
d. Inhibiting adenyl cyclase
lungs and skin. Pralidoxime has very high affinity for the
4. Dr. Glenn free samples of physostigmine eyedrops to
phosphorus atom and is a chemical antagonist of
Ronnie, his glaucoma patient. What is an expected effect
organophosphates. The answer is E.
of physostigminie on Ronnie’s eye?
a. Increase aqueous humor production
8. Any of the cholinesterase inhibitors (choices B, C, or E) would
b. Increase aqueous humor drainage
effectively correct myasthenic crisis. However, because
c. mydriasis
cholinergic crisis (if that is what is causing the symptoms) would
d. cycloplegia
be worsened by a cholinomimetic, we choose the shortest-acting
5. What is the cholinesterase inhibitor used in the
cholinesterase inhibitor, edrophonium. The answer is B.
diagnosis of Myasthenia gravis?
a. Ambenomium
9. Respiratory failure, from neuromuscular paralysis or CNS
b. Physostigmine
depression, is the most important cause of acute deaths in
c. Pyridostigmine
cholinesterase inhibitor toxicity. The answer is E.
d. Edrophonium
10. Cholinesterase inhibition is typically associated with
increased (never decreased) bowel activity. (Fortunately, many
Answers: A, C, D, B, D
patients become tolerant to this effect.) The answer is C.
VIII. FREEDOM CORNER
11. Choice (E) is not correct because the vagus slows the heart.
Parasympathetic nerve stimulation does not cause vasodilation
(most vessels do not receive parasympathetic innervation), so
choice (C) is incorrect. Ganglion cells and the end plate contain
nicotinic receptors, which are not affected by bethanechol, a
direct-acting muscarinic agonist. The answer is D.

12. Muscarinic agonists cause accommodation and cyclospasm,

the opposite of paralysis of accommodation (cycloplegia). In
open-angle glaucoma, this results in increased outflow of
aqueous and decreased intraocular pressure. These agents may
cause bronchospasm but have no effect on neuromuscular
transmission. They may cause diarrhea and are not used in its
treatment. Muscarinic agonists may also cause sweating, but
drug-induced sweating is of no value in the treatment of fever.
The answer is B.
PHARMACOLOGY 13 of 15
 1.12 Cholinergic Drugs

IX. APPENDIX
Table A1. Subtypes and characteristics of cholinoceptors. (From 2020A trans)
Receptor Other names Location Structural Features Postreceptor Mechanism
type
M1 Nerves 7 transmembrane IP3, DAG cascade
segments; Gq/11 protein
linked
M2 Cardiac M2 Heart, nerves, smooth 7 transmembrane Inhibition of cAMP production, activation of K+
muscle segments; Gi/10 protein channels
linked
M3 Glands, smooth muscle, 7 transmembrane IP3, DAG cascade
endothelium segments; Gq/11 protein
linked
M4 CNS 7 transmembrane Inhibition of cAMP production
segments; Gi/10 protein
linked
M5 CNS 7 transmembrane IP3, DAG cascade
segments; Gq/11 protein
linked
NM Muscle type, Skeletal muscle Pentamer (α2βδγ)1 Na+, K+ depolarizing ion channel
end plate neuromuscular junction
receptor
NN Neuronal type, Postganglionic cell body, α & β subunits only as Na+, K+ depolarizing ion channel
ganglion dendrites α2β2 or α3β3
receptor
.
Table A2. Some cholinomimetics: spectrum of action and pharmacokinetics. B: Both; M: Muscarinic; N: Nicotinic. (From 2020A trans)
Drug Spectrum Pharmacokinetic Features
of Action
Direct Acting
Acetylcholine B Rapidly hydrolyzed by cholinesterase (ChE); duration of action 5–30 s; poor lipid solubility
Bethanechol M Resistant to ChE; orally active, poor lipid solubility; duration of action 30 min to 2 h
Carbachol B Like bethanechol
Pilocarpine M Not an ester, good lipid solubility; duration of action 30 min to 2 h
Nicotine N Like pilocarpine; duration of action 1–6 h; high lipid solubility
Varenicline N Partial agonist at N receptors, high lipid solubility; duration 12–24 h
Indirect Acting
Edrophonium B Alcohol, quaternary amine, poor lipid solubility, not orally active; duration of action 5–15 min
Neostigmine B Carbamate, quaternary amine, poor lipid solubility, orally active; duration of action 30 min to 2 h or
more
Physostigmine B Carbamate, tertiary amine, good lipid solubility, orally active; duration of action 30 min to 2 h
Pyridostigmine B Carbamate, like neostigmine, but longer duration of action (4–8 h)
Echothiophate B Organophosphate, moderate lipid solubility; duration of action 2–7 days
Parathion B Organophosphate, high lipid solubility; duration of action 7–30 days

Table A3.  Effects of cholinomimetics on major organ system. Refer to Table A5 of Trans 1.13 for the specific receptor of each organ. (2020A)
Organ Response
CNS Complex stimulatory effects. Nicotine: elevation of mood, alerting, addiction; physostigmine:
convulsions; excessive concentrations may cause coma
Eye Sphincter Muscle of Iris Contraction (miosis)
Ciliary Muscle Contraction (accommodation for near vision), cyclospasm
Heart Sinoatrial Node Decrease in rate (negative chronotropy)
Atria Decrease in contractile force (negative inotropy); decrease in refractory period
Atrioventricular Node Decrease in conduction velocity (negative dromotropy), increase in refractory period
Ventricles Small decrease in contractile force
Blood Vessels Dilation via release of EDRF from endothelium
Bronchi Contraction (bronchoconstriction)
GIT Motility Motility Sphincters
Increase in smooth muscle contraction, peristalsis
Sphincters Decrease in tone, relaxation. (Exception: gastroesophageal sphincter contracts)
Urinary Detrusor Increase in contraction
Bladder Trigone and Sphincter Relaxation; voiding
Skeletal Muscle Activation of neuromuscular end plates, contraction
Glands (Exocrine) Increased secretion (thermoregulatory sweating, lacrimation, salivation, bronchial secretion,
gastrointestinal glands)

PHARMACOLOGY 14 of 15
 1.12 Cholinergic Drugs
Table A4. Drug Summary Table: Cholinoceptor-Activating & Cholinesterase Inhibiting Drugs (From 2020A trans)
Subclass MOA
Direct-acting, muscarinic agonists
Bethanechol BethanecholActivates Bladder and bowel
muscarinic (M) receptors; atony, for example,
increases IP3 and DAG after surgery or spinal
cord injury
Pilocarpine Same as bethanechol; may
also activate EPSP via M
receptors in ganglia
Muscarine Same as Bethanechol
Direct-acting, nicotinic agonists
Nicotine Activates all nicotinic (N)
receptors • opens Na+-K+
channels in ganglia and
neuromuscular end plates
Varenicline A partial agonist at N
receptors
Succinylcholine N-receptor agonist,
moderately selective for
neuromuscular end plate
(NM receptors)
Indirect-acting, alcohol
Edrophonium Inhibitor of cholinesterase;
amplifier of endogenously
released ACh
Indirect-acting, carbamates
Neostigmine Like edrophonium plus
small direct nicotinic
agonist action
Pyridostigmine Like edrophonium
Physostigmine Like edrophonium
Indirect-acting, organophosphates
Parathion Like edrophonium
Malathion Like edrophonium
Sarin, tabun, etc. Like Parathion
Indirect-acting, for Alzheimer’s disease
Rivastigmine, Cholinesterase inhibition
galantamine, donepezil; plus variable other poorly
tacrine is obsolete understood effects
PHARMACOLOGY
Clinical and Other Pharmacokinetics
Application
Oral, IM activity; Poor
lipid solubility: does
not enter CNS;
Duration: 0.3–2 h
Sjögren’s syndrome Oral, IM activity; Good
(increases salivation); lipid solubility, topical
was used in glaucoma activity in eye
(causes miosis,
cyclospasm)
Alkaloid found in Low lipid solubility but
mushrooms readily absorbed from
gut
Smoking cessation High lipid solubility,
(also used as absorbed by all routes;
insecticide) For smoking
cessation, usually
used as gum or
transdermal patch;
Duration: 4–6 h
Smoking cessation High lipid solubility,
oral activity; Duration:
~12 h
Muscle relaxation Highly polar, used IV;
Duration: 5–10 min
Reversal of NM block Highly polar; used IV;
by nondepolarizing Duration: 5–10 min
drugs • diagnosis of
myasthenia gravis
Reversal of NM block, Moderately polar but
treatment of orally active; Duration:
myasthenia 2–4 h
Treatment of Moderately polar but
myasthenia orally active; Duration:
4–8 h
Reversal of severe Lipid soluble; can be
atropine poisoning used topically in the
(IV); occasionally used eye; Duration: 2–4 h
in acute glaucoma
(topical)
Insecticide only Highly lipid-soluble
Duration: days to
weeks
Insecticide and Highly lipid-soluble but
scabicide (topical) metabolized to inactive
Duration: days products in mammals
and birds
Nerve gases; terrorist Like parathion but
threat more rapid action
Alzheimer’s disease Lipid soluble, enter
CNS • Half-lives: 1.5–
70h
Toxicities, Interactions
All parasympathomimetic
effects: cyclospasm,
diarrhea, urinary urgency,
plus vasodilation, reflex
tachycardia, and sweating
Similar to bethanechol but
may cause
vasoconstriction via
ganglionic effect
Mushroom poisoning of
fast-onset type
Generalized ganglionic
stimulation: hypertension,
tachycardia, nausea,
vomiting, diarrhea
Major overdose:
convulsions, paralysis,
coma
Hypertension, sweating,
sensory disturbance,
diarrhea, polyuria,
menstrual disturbance
Initial muscle spasms and
postoperative pain;
Prolonged action in
persons with abnormal
butyrylcholinesterase
Increased parasympathetic
effects, especially nausea,
vomiting, diarrhea, urinary
urgency
Like edrophonium but
longer duration
Like edrophonium but
longer duration
Like edrophonium but
longer duration plus CNS
effects: seizures
Highly dangerous
insecticide • causes all
parasympathetic effects
plus muscle paralysis and
coma
Much safer insecticide than
parathion
Rapidly lethal
Nausea, vomiting
15 of 15