PHARMACOLOGY A

INTRO TO AUTONOMICS & PARASYMPATHETIC DRUGS

DR. ROMMEL Z. DUEÑAS, MD | MD2024
I. ANATOMY II. NEUROTRANSMITTER CHEMISTRY
A. ACH SYNTHESIS & CHOLINERGIC TRANSMISSION
- Choline is brough to the
presynaptic nerve
terminal via Choline
Transporter (CHT), w/c is
Na+-dependent
o Hemicholiniums –
inhibits CHT
1) Synthesis
o In the cytoplasm,
o Somatic – consciously controlled; may sometimes be partly AChE is
conscious, e.g., respiration, posture reproduced when
o Autonomics – activities not under direct conscious control, Choline merges w/
e.g., cardiac output, blood flow to various organs, digestion Acetyl group from
Acetyl CoA via the
enzyme Choline
Acetyltransferase
(ChAT)
2) Storage
o AChE is stored in the vesicle via Vesicle-associated
Transporter (VAT)
▪ Vesamicol – inhibits VAT
o Most of the vesicular-AChE is bound to negatively-charged
SCHEMATIC DIAGREM OF THE ANS vesicular proteoglycans
3) Release
o When an action potential reaches the terminal, it triggers
Ca2+ influx
o This Ca2+ interacts w/ the VAMP Synaptotagmin on the
vesicle membrane → triggers the fusion of vesicle
membrane and terminal and the opening of the pore into
the synapse membrane → exocytotic expulsion of AChE
and cotransmitters into the synaptic cleft
▪ Botulinum toxin – inhibits this process by removal of
two amino acids from the fusion proteins (VAMPs and
SNAPs)
4) Receptor Attachment
o Once AChE is released, it binds to and activates the
cholinergic receptor (cholinoceptor); very rapid process
o At fast cholinergic synapses, AChE is hydrolyzed ≤1ms by
Acetylcholinesterase
o AChE is hardly to bind again to another receptor
5) Degradation
o All AChE molecules released diffuses within the range of an
AChE-ase molecule
o Hence, this is degraded into Choline + Acetate, terminating
Q: Where are the NTAs released? the action of the transmitter
Releases Acetylcholine Releases Norepinephrine 6) Uptake
o Rate-limiting step ★
All preganglionic efferent Most postganglionic
o Choline re-enters the neuron via Na+ symport through
autonomic & somatic motor sympathetic
active transport
All parasympathetic
B. ADRENERGIC TRANSMISSION
Some postganglionic (special - Almost the same as
sweat glands innervated by Cholinergic except for
the SNS) some portions
Note: - Tyrosine is transported
- AChE block @ the ganglia is non-selective – this will block both into the presynaptic
PNS and SNS. nerve cell via a Na+-
- Drugs that target AChE will stimulate both sympathetic and dependent carrier
parasympathetic ganglia 1) Synthesis
o The precursor
Remember!!! ★ (nilagyan ko ng star kasi importante yan. promisze)
molecule Tyrosine
- All Peripheral nerves are cholinergic EXCEPT sympathetic is converted to
postganglionic Dopa via Tyrosine
- Acetylcholine binds to Muscarinic and Nicotinic receptors Hydroxylase; Rate-
- Nicotinic receptors are located in the ganglion and NMJ
limiting step ★
▪ Metyrosine – tyrosine analog; inhibits this step

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 o Dopa → Dopamine via Dopamine Decarboxylase
2) Storage
o Dopamine is transported into the vesicle via Vesicular
Monoamine Transporter (VMAT)
▪ Reserpine – inhibits VMAT; depletes transmitter stores
o In the vesicle, Dopamine → Norepinephrine via Dopamine
β-hydroxylase
o Note:
▪ In the Adrenal Medulla and in certain parts of the Brain:
some Norepinephrine → Epinephrine via
Phenylethanolamine-N-methyltransferase
▪ In Dopaminergic neurons: Dopamine is the final
product
3) Release
o Action potential triggers Ca2+ influx
o Fusion of vesicles w/ surface membrane releases
Norepinephrine, cotransmitters, and Dopamine β-
hydroxylase
▪ Bretylium, Guanethidine – inhibits release of NE
▪ Sympathomimetics, e.g., Tyramine, Amphetamines,
Ephedrine
• Can release NE by a calcium-independent process
• Avidly taken up by NET into the cell, and then by
VMAT into the vesicles, displacing NE,
subsequently expelling them into the synaptic
space by reverse transport via NET
4) Termination of NE action
o NE is NOT DEGRADED
o Termination NE occurs by several mechanisms:
▪ Diffusion away from the synaptic cleft
▪ Uptake/Reuptake 1 – NE is transported back into the
presynaptic cell via Norepinephrine Transporter (NET)
• Cocaine, Tricyclic Antidepressants – inhibits NET,
resulting in increase of transmitter activity in the - Muscle type: Nm (N1) | Neuronal type: Nn (N2)
synaptic cleft - Always remember that the Nicotinic receptors are Ligand-gated
ion channels
1. True or False. Acetylcholine is released in all parasympathetic nerves. ____ - When 2 AChE molecules bind to the alpha subunit, a
2. Rate-limiting step in norepinephrine synthesis conformational change in the latter takes place → opening of K+
a. Tyrosine → Dopa c. Dopamine → Norepinephrine and Na+ channels → influx of cations → depolarization
b. Dopa → Dopamine d. NET reuptake of NE
3. Inhibits your answer in number 2.
a. Metyrosine c. Cocaine
b. Bretylium d. Tyramine

C. RECEPTORS
- Para sa madaling malito (like me): almost all adrenergic =
sympathetic; almost all cholinergic = parasympathetic

- Some organs may be innervated by either parasympathetic and

sympathetic, or both (e.g., heart)
o Heart is predominantly cholinergic
▪ Removing adrenergic influence: nothing will happen
▪ Removing cholinergic influence: it will beat faster
o Arterioles and Veins are predominantly adrenergic

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 ▪ Removing adrenergic influence: dilatation Intestine ↑ tone and motility
- Adrenergic and Cholinergic can also produce opposite and
similar effects Bladder Sphincter RELAXation
o GIT can increase motility and defecation (Para) and reduce Detrusor CONTRACTion
peristalsis (Sympa)
o Bladder can cause urination (Para) or retention (Sympa)
o Heart can decrease contractility and heart rate (Para) and
increase them (Sympa)
- Organs innervated by only one division of the ANS:
o Sympathetic only: Sweat Glands, Resistance arteries, most
blood vessels
o Parasympathetic only: Bronchial smooth muscles
▪ No fibers for Norepinephrine
▪ However, adrenergic receptors are present, which will Review previous tables re: Cholinergic receptors (lagyan
respond to β2 Agonists (e.g., Salbutamol for asthma) ng check ang box pag nabatak mo na)
i. SITES OF DRUG ACTION

SITE OF DRUG ACTION IN CHOLINERGIC TRANSMISSION

Synthesis Storage Reuptake Release Receptor Degradation
4. The ff. are predominantly cholinergic EXCEPT:
Hemicholiniums Vesamicol Hemicholiniums Botulinum toxin α-bungarotoxin Rivastigmine
a. Ciliary Muscles c. Sweat glands at the feet
b. GIT d. Heart Triethylcholine Reserpine Triethylcholine Mg2+ Trimethaphan Edrophonium
5. All of the ff. are adrenergic effects EXCEPT:
a. Increased heart rate c. Increased cardiac force of contraction Beta- Atropine Pyridostigmine
b. Increased urination d. Decreased peristalsis Bungarotoxin
6. Ligand-gated ion channel Amphetamine Tubocurarine Parathione
a. α1 c. M2
Aminoglycoside Direct acting Donepezil
b. β3 d. Nm Cholinergic
receptor
III. PARASYMPATHETIC NERVOUS SYSTEM Non depolarizing Other
A. CHOLINERGIC PHARMACOLOGY drugs cholinesterase
(Atracurium, inhibitors
7. Fill in the blanks (recall):
Mivacurium)
- _______ enters the Cholinergic
neuron via CHT, receptor
which is the rate- blockers
(Scopolamine,
limiting step of Ipratropium,
cholinergic Hexamethonium)
transmission IV. CHOLINOMIMETIC DRUGS
- Acetylation of o Parasympathomimetic
choline and acetyl ▪ Mimics the effect of parasympathetic nervous system
CoA via _____________________________ into Acetylcholine o Parasympatholytics
- AChE is packed into the synaptic vesicles at high concentration ▪ Oppose the effect of PNS
via the carrier-mediated transporter, _____ (acronym lang)
- AChE is released via ___2+-mediated exocytosis, where 100 – 500
vesicles are released at the NMJ, enough to excite the post-
synaptic cell
Organs Primarily Affected by Parasympathetic
NS
Organ Effects
Eye Contraction of Iris sphincter
(Miosis)
Contraction of ciliary muscle A. DIRECT ACTING DRUGS
(near vision) - Bind to and activate muscarinic or nicotinic receptors ★
Secretion - Divided on the basis of chemical structure into choline esters
Salivary Secretion and alkaloids
Glands - Many of these drugs affect both muscarinic and nicotinic; a few
Heart ↓ heart rate are highly selective for either muscarinic or nicotinic
↓ conduction velocity - None of the clinically useful drugs is selective for receptor
↓ contraction subtypes in either class
Lungs Bronchial CONSTRICTion i. Choline Esters
Pancreas ↑ insulin secretion - Includes: Acetylcholine, Methacholine, Carbachol, Bethanechol
- Properties:

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 o Choline esterified with an acidic substance – acetic or Blood Arteries - Dilation (via EDRF)
carbamic acid Vessels - Constriction (high dose direct effect)
Veins
o Presence of the β-methyl group (Methacholine, Note: Not innervated by the
Bethanechol) parasympathetic NS but has an indirect
▪ Reduces the potency at the nicotinic receptors but it effect
allows said drugs to have an oral activity and prevents - Stimulate glands
hydrolysis in the GIT GIT - Smooth muscle contraction (increase
o Relatively insoluble in lipids, because they contain a intestinal motility)
quaternary ammonium group - Relax Sphincters
o Readily hydrolyzed and poorly absorbed in the GIT, - Contraction of detrusor muscles
therefore not given orally (EXCEPT Methacholine, Genito-Urinary Tract (promotes urination)
Bethanechol) (GUT) - Relax trigone and sphincter muscles
o Poorly distributed in the CNS (because they are hydrophilic) - Promote micturition
Drugs Susceptibility to Target e.g., Bethanechol for Spastic Bladders
AChEase Brain - Contains both muscarinic and
Acetylcholine Highly susceptible Both nicotinic receptors, but
Cholinoceptors CNS M>N
Bethanechol Muscarinic Spinal - Contains both muscarinic and
Non-susceptible Cord nicotinic receptors, but N > M
Carbachol N>M
Low dose - Mild, alerting effects
Methacholine Less susceptible Muscarinic Larger - Tremors, emesis, stimulation of
dose respiratory center
ii. Alkaloids High dose - Convulsion, Coma (toxicity levels)
- Includes: Tertiary amines (Pilocarpine, Nicotine, Lobeline)
Autonomic - Simultaneous discharge of
- Properties:
PNS (Ganglia) parasympathetic and sympathetic
o Usually of plant origin
system because both receptors there
o Well-absorbed from most sites of administration
would be nicotinic
o Nicotine – absorbed through skin (i.e., nicotine path to help
CVS - Nicotine effects are chiefly
in smoking withdrawal)
sympathomimetic (Hypertension)
o Muscarine – a quaternary amine, is less completely
GIT/GUT - Nicotine effects are chiefly
absorbed from the GIT (similar to choline esters), but when
parasympathetic (nausea, vomiting,
ingested, it is quite poisonous; can enter CNS
diarrhea, voiding of urine) e.g., some
o Chiefly excreted in the kidneys, enhanced with acidification
people can’t move their bowels w/o
of the urine
smoking
- Clinical uses: Pilocarpine – eye drop | Nicotine – cigarettes (one
with the most medical use)
DIRECT ACTING CHOLINOCEPTOR AGENTS - NICOTINIC
Drugs Target
(GANGLION STIMULANTS)
Pilocarpine Chiefly Muscarinic Drugs NICOTINE: tertiary amine; tobacco
Muscarine LOBELINE: tertiary amine; lobelia
DIMETHYLPHENYLPIPERAZINIUM (DMPP):
Lobeline
synthetic compound
Nicotine Chiefly Nicotinic
Dynamics Most nicotinic receptor agonists affect both
iii. Effects of Direct Acting Cholinoceptor on Organ System ganglionic and motor endplate receptors but
- Contraction of Iris Sphincter (Miosis) show selectivity
- Pupillary Constriction Kinetics Cause complex peripheral responses associated
Ocular - Ciliary muscle contraction for near with generalized stimulation of autonomic ganglia
vision/accommodation Tachycardia
- Facilitates outflow of aqueous humor; Increase in BP
treat Glaucoma → use PILOCARPINE Variable effects on GI motility and secretions
Increase bronchial, salivary, sweat secretions
- Stimulate sweat, lacrimal, Clinical use Nicotine is a ganglion stimulant Not used clinically
Miscellaneous nasopharyngeal glands but as experimental tools (non-selective)
Secretory Glands - During toxicity, there is increase in Note:
secretions - Most nicotinic receptor agonists affect both ganglionic and
- Bronchoconstriction motor endplate receptors but show selectivity
Respiratory - Contraction of glandular secretion o It does not mean that if a substance is a ganglionic
- Contraindicated in asthmatics stimulant, it won’t act on the organ itself
SA Node - Decrease in rate (Negative Nicotine Toxicities
Chronotropy) Acute
Cardiac - CNS stimulation-seizures, coma, respiratory arrest
Atria - Decrease in contractile strength - Motor end plate depolarization, depolarization blockade,
(Negative Inotropy) respiratory paralysis
- Hypertension and arrythmias
AV Node - Decrease in conduction velocity
- Treatment: Symptomatic; Atropine, Diazepam, mechanical
(Negative Dromotropy) ventilation
- Increase in refractory period Chronic
- Slower heart rate - Increased risk for cardiovascular disease such as hypertension,
Ventricle - Small decrease in contractile strength coronary artery disease, and heart attacks, ulcers
- Treatment: Behavioral modifications, Varenicline, Bupropion

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 B. INDIRECTLY ACTING DRUGS - Pentavalent phosphorus compounds, contains a labile group
- Inhibits acetylcholinesterase → increased AChE in the synaptic (fluoride) or an organic group
clefts and neuroeffector junctions → stimulates cholinoceptors - Can cause a severe type of peripheral nerve demyelination
to evoke increased responses ★ - Typically, lipid soluble, EXCEPT Echothiopate - Use in
Structure Drugs Duration of action glaucoma, more stable in aqueous medium, with 100 hours
duration of action
Simple Alcohol w/ Edrophonium Short acting (2-
Effects
a Quaternary 10mins.)
- “Nerve gas” causing seizures, frothing at the mouth due to
group
excessive salivation, possible wheezing due to
Carbamic Acid Carbamates e.g., Medium acting
bronchoconstriction, promotes micturition
Esters of alcohols Neostigmine (30mins – 6 hrs.)
Antidote:
w/ quaternary or - Forms
- ATROPINE
tertiary covalent
o Therapy often includes treatment with Pralidoxime
ammonium bonds w/
(cleaves the phosphorus enzyme bond; most effective
groups AChE, thus
before aging, because once aging occurred →
more
irreversible)
resistant to
iv. EFFECTS OF PERIPHERALLY ACTING CHOLINESTERASE
hydrolysis
INHIBITORS ON ORGAN SYSTEM
Organic Organophosphates Irreversible
Ocular - Decrease intraocular pressure in
derivatives of e.g., anticholinesterase
Glaucoma
Phosphoric Acid Echothiophates
- Muscarinic stimulants and
i. Edrophonium
cholinesterase inhibitors reduce IOP by
Structure:
contraction of the ciliary body, w/c
- Simple alcohol with a quaternary ammonium group
facilitates outflow of aqueous humor
Kinetics:
Respiratory - Bronchoconstriction
- Bind reversibly to the anionic site of the enzyme
- Very weak ionic bond is formed, action is brief
Cardiac - Decrease heart rate
- Very short acting; effect lasts for ten minutes
- Decrease impulse conduction
Clinical use:
- Decrease force of contraction →
- Used mainly for diagnosing myasthenia gravis (MG); treatment
reduction of cardiac output
for acute MG
Blood vessels - Minimal effects
- To diagnose: Give edrophonium – patient with MG will then
be able to raise arms for >2 minutes and ptosis disappears GIT/GUT - Increased secretions and peristaltic
- Use for Ileum (feel ko dapat ileus ‘to ) and Arrythmias movement
ii. Carbamates - Clinical conditions that involve
Structure: depression of smooth muscle activity
- Carbamic acid esters of alcohol bearing tertiary w/o obstruction, e.g., Post-operative
(NEOSTIGMINE, PYRIDOSTIGMINE) or quaternary ammonium Ileus, Neurogenic bladder
groups (PHYSOSTIGMINE)
Kinetics: Drug Action Main site Notes
- Possess strongly basic groups which bind to the anionic site of duration of action
the enzyme Edrophonium Short NMJ IV; for diagnosis of
- Undergo a two-step hydrolysis that allows for the formation of MG
a carbamylated covalent bond Neostigmine NMJ IV: reverse NM block
- Hydrolyzed by acetylcholinesterase but at a very slow rate Oral: tx of MG
- Slow recovery of the carbamylated enzyme Medium
Physostigmine Post- Eyedrops for
- Action of drug is 4-6 hours
ganglionic glaucoma
Clinical use:
Pyridostigmine NMJ Oral: tx of MG
- Used for symptomatic treatment of myasthenia gravis
Dyflosmine Post- Toxic
- IV forms reverse neuromuscular block
ganglionic organophosphate
Neostigmine Pyridostigmine Physostigmine
glaucoma
Duration 0.5-4 hours 4-6 hours 0.5-2 hours Used topically
of Action Long
Echothiopate Post- Glaucoma
Structure Synthetic quaternary Naturally
ganglionic
ammonium occurring
Parathion, - Insecticide
tertiary amine
Melathion
Solubility Lower lipid solubility Greater lipid
(OrgPO4)
solubility
Clinical Myasthenia gravis, Ileus Glaucoma
TOXICITIES OF PERIPHERALLY ACTING
Use
CHOLINESTERASE INHIBITORS
iii. Organophosphate
D Diarrhea
Structure
- Organic derivatives of phosphoric acid U Urination
- Irreversible anti cholinesterase M Miosis (pupil constriction)
Kinetics B Bronchoconstrictions
- Form a phosphorylated covalent bond, the “aging” of which E Excitation (still with some CNS effects)
strengthens the phosphorus-enzyme bond. L Lacrimation
- It deactivates acetylcholinesterase for the life of that enzyme. S Salivation
- Inactive phosphorylated enzyme is very stable S Sweating

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 Note (prev. table): V. PARASYMPATHOLYTIC/ANTI-CHOLINERGIC DRUGS
- Seen in all forms of cholinergic excess
v. CENTRAL ACTING DRUGS
- Includes (RGD): Rivastigmine, Galantamine, Donepezil
- Kinetics:
o Orally active, lipid soluble enough to enter the BBB
o Half-lives: 1.5 – 70 hrs.
o Common side effects: promote GI motility → nausea,
vomiting
- Clinical use: Symptomatic treatment of Alzheimer’s Disease (type
of dementia)

Clinical Pharmacology of CHOLINOMIMETICS

Glaucoma and Strabismus Pilocarpine

Ileus, Megacolon Bethanechol, Neostigmine Remember: Cholinergic receptors when blocked opposes the
effect of your parasympathetic nervous system
Neurogenic bladder Neostigmine A. CHOLINORECEPTOR BLOCKERS
GERD Bethanechol i. Anti-Muscarinic Agents

Sjogren syndrome Pilocarpine Drugs Natural alkaloids: Atropine, Scopolamine

Myasthenia gravis Tertiary ammonium: Pirenzepine, Tropicamide,

Edrophonium Dicyclomine, Benztropine
Supraventricular arrythmia

Reverse surgically induced Neostigmine or Edrophonium Quaternary ammonium: Propanthelin, Ipratropium,

NM block Glycopyrrolate

Alzheimer’s disease (RGD) Rivastigmine, Selectivity M1- selective

Atropine/TCA overdose
Galantamine, Donepezil (Pirenzepine, Telenzepine, Dicyclomine,
Trihexyphenidyl)
Pyridostigmine
(Author’s note: as per prev. tables +
M2-selective
Katzung, this drug may also be used to
treat MG) (Gallamine, Methoctramine, AF-DX116 )

7. True or False. Many cholinomimetic drugs exhibit high selectivity, affecting
only either muscarinic or nicotinic. _________
8. Used to diagnose and treat acute myasthenia gravis:
a. Pilocarpine c. Pyridostigmine
b. Edrophonium d. Physostigmine
9. Mechanism of action of indirectly acting cholinomimetic drugs:
a. Binds to and activates M1 and M2 receptors
b. Binds to either Nm or Nn receptors
c. Inhibits acetylcholinesterase
d. Inhibits Ca2+ influx, preventing AChE exocytosis from the
vesicles
Cholinomimetic drugs in a nutshell:
M3-selective
(4-DAMP, Darifenacin, Solifenacin, Oxybutynin,
Tolterodine)
• Tertiary amine antimuscarinics are often utilized in eye and CNS
indication
• Because of similarities in the chemical structures, many
antihistamines, antidepressants, and antipsychotics have a lot of
antimuscarinic effects
• Quaternary amines because of reduced lipid solubility, they have
less ability to penetrate and affect the CNS

ANTI MUSCARINIC AGENTS - NATURAL ALKALOIDS

ATROPINE SCOPOLAMINE

SOURCE Derived from Atropa l (-) isomer derived from

belladonna (deadly Hyoscyamus niger
nightshade) and Datura (henbane)
stramonium
(jimsonweed)

*Atropa belladonna was

used to dilate women’s
pupil

DYNAMICS Non selective for

muscarinic receptors

KINETICS biphasic elimination;

EFFECTS Half-life:

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 rapid phase = 2 hours ATROPINE TOXICITIES
slow phase = about 13
hours B “Blind as a bat” – cycloplegia (near vision is affected)

About 60% of atropine is D “Dry as a bone” – decreased sweating

excreted unchanged in
the urine; H “Hot as hell” – thermoregulation
effect declines rapidly in
all organs EXCEPT those R “Red as a beet” – thermoregulation (blood vessels of the skin
in the eyes (iris and dilate and radiate heat due to inability to sweat)
ciliary
muscle) which lasts for at M “Mad as a hatter” – hallucinations
least 72 hours.

EFFECTS Low doses – minimal

effects EFFECTS OF DIRECT ACTING CHOLINOCEPTOR ON ORGAN
SYSTEM
Central vagal stimulant The l(-) forms of both
effect (bradycardia) agents are 100 times OCULAR - Mydriasis (sympathetic dilator
supplanted more potent than their activity)
by tachycardia d(+) forms. - Cyclopegia (loss of ability to
(compensatory) accommodate, cannot focus for
near vision)
Tissues most sensitive to - Reduction of lacrimal secretion,
atropine effects: salivary, “sandy eyes”
bronchial, and sweat
glands CVS - Increase heart rate (Blockade of
vagal slowing)
Intermediate sensitivity: Have good skin - Blocks vasodilation (can cause
smooth muscles and absorption; marketed cutaneous vasodilatation in toxic
cardiac as a transdermal patch. doses, esp. @ upper part of the
tissue body)
- Net CVS effects: tachycardia
Least sensitive: gastric (manifests with moderate to high
parietal cells therapeutic doses of atropine due
to the vagal nerve blockade), little
Therapeutic dose: effect on BP
sedation , drowsiness and
amnesia RESPIRATORY - Bronchodilation (Ipatropium
bromide in asthma)
Significant High Doses: excitement , - Decrease in secretions
concentrations are Hallucinogenic, agitation,
reached in the CNS 30 coma GASTROINTESTINAL - Dry mouth (prominent effect of
mins to 1 hour after TRACT antimuscarinic agents because of
administration. the sensitivity of the salivary gland)
- Basal gastric secretion blocked
Well-absorbed from the gut and across the - Decrease in gastric motility (i.e.,
conjunctival membrane; widely distributed after Loperamide)
absorption
• Gastric emptying time and
intestinal transit time are
prolonged
ANTI MUSCARINIC AGENTS
GENITOURINARY - Relaxation of ureteral smooth
BENZTROPINE IPATROPIUM TRACT muscle bladder wall
- Voiding is slowed
KINETICS Well-absorbed from the Poorly absorbed in the - Promotes urinary retention
gut and widely gut;
distributed after not taken up in the CNS SWEAT GLANDS - Thermoregulatory
absorption - Sweating suppressed (by opposing
the stimulatory effects on the
Reduced lipid solubility eccrine sweat glands which
and contains the muscarinic receptors)
Therefore, less ability to
penetrate and affect the
CNS

Clinical Use Parkinson's Disease Asthma, COPD

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 ▪ Administration: repeated administration may be
EFFECTS OF DIRECT ACTING CHOLINOCEPTOR ON ORGAN
required because effects of cholinesterase inhibition
SYSTEM
may last for days
Clinical Pharmacology of Cholinoceptor Blocker
CNS ATROPINE SCOPOLAMINE
Disease Drug Structure
Peptic dse., Propantheline, Quaternary amines
Low doses – minimal More CNS effects
hypermotility Glycopyrrolate
effects (drowsiness,
amnesia); at toxic doses, Dicyclomine Tertiary amines
cause excitement, Peptic dse. Pirenzepine Tertiary amines
agitation, Asthma Tiotropium Quaternary amines
hallucinations, coma Mydriatic, Tropicamide Tertiary amines
Cycloplegic
Central vagal stimulant Tremor of Parkinson’s Parkinson’s dse. Benztropine Tertiary amines
effect disease is
(bradycardia) reduced (patch) ii. Anti-Nicotinic Agents
supplanted by - May either be Neuromuscular blockers or Ganglion blockers
tachycardia 1) Ganglion Blockers
(compensatory) - Includes:
o Trimetaphan – only one w/ use; anti-hypertension,
Used in motion sickness fast acting, short half-life, can block ganglia (duh),
(as used by anesthesiologists
patch in USA) o Mecamyline
o Hexamethonium
Hexamethonium Quaternary
Clinical Pharmacology of CHOLINORECEPTOR BLOCKERS
Tetraethyl ammonium
Parkinson’s Disease Atropine
Mecamylamine Tertiary
Motion sickness/vestibular Scopolamine
dysfunction Non depolarizing competitive antagonists
Mydriatic, Cycloplegic
Note:
Atropine/Scopolamine
Pre-anesthetics - They can be overcome by increasing
AChE/Nicotine/other agonists
Asthma/COPD Ipratropium, Tiotropium,
Effects of Ganglionic Blocking Agent on Organ
Aclidinium
System
Peptic Disease
Ocular - Cycloplegia, loss of
Myocardial Infarction (MI) accommodation
- Moderate dilation of pupil
Neck pressure induced
syncope (seen in hyperactive CVS - Decrease in vascular tone due to
carotid sinus) Atropine loss of sympathetic tone
- Hypotension, orthostatic
Chagas Disease, Idiopathic
hypotension
Cardiomyopathy
- Decrease cardiac contractility
- Moderate tachycardia (due to loss
Traveler’s Diarrhea
of parasympathetic tone)
Overactive Bladder (OAB), Oxybutynin, Trospium, Sweat - Sweating impaired
Incontinence Darifenacin, Solifenacin, Glands
Tolterodine, and Fesoterodine GIT - Secretion decreased
Note: - Decreased motility/constipation
- Tiotropium and Aclidinium has longer lasting effects and can GUT - Hesitancy in urination
be given once daily because of the M1 dissociation that is - Urinary retention
slow - Impaired sexual function
- In MI, Atropine is given IV Note:
o Also other antimuscarinic drugs that can be used to blunt - Quaternary ammonium agents (e.g., Trimethaphan)
the vaso-vagal induced pain or even the pacemaker o DO NOT cross the blood brain barrier
impairment and depression of the cardiac output in M1 o Used to lower BP during surgery
- In Chagas Dse., the use of Atropine can prevent the effects of - Secondary ammonium compound (e.g.,
autoantibodies, w/c attack the M2 receptors Mecamylamine)
- In Traveler’s Diarrhea, the antimuscarinics are often combined o Enters the CNS
with opioid-based drugs, such as the combination of Atropine o Sedation, tremor, choreiform movements
and Diphenoxylate

o Atropinization
▪ For nerve gases poisoning
▪ Large doses of Atropine
▪ Dose: 1 – 2 mg every 5 – 15 mins.
▪ Endpoint: dry mouth, reversal of miosis

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2) Neuromuscular blockers - Maintained depolarization at
the endplate leads to loss of
excitability
- Fasciculation observed at
prolonged depolarization
- Augmentation/enhancement
through cholinesterase
inhibitors, which further
increase AChE concentration
and subsequent
depolarization
Phase II block: - As the initial endplate
Desensitizing depolarization decreases,
Block the membrane repolarizes
- Channels behave as in a
prolonged closed state
Tubocurarine – prototype of non-depolarizing
- Blockade reversal achieved
Succinylcholine – prototype of depolarizing
through increasing the AChE
Note: Drugs eliminated via Kidney = longer acting;
concentration (repeated
via Liver/spontaneous/cholinesterase = short acting
stimulation or cholinesterase
- Structure: presence of quaternary nitrogens (structural
inhibitors)
resemblance w/ AChE
o Succinylcholine – looks like 2 AChE molecules; only
▪Intended effects: Motor paralysis
depolarizing drug
• Sequence: Eye muscles > small muscles of
- Clinical uses:
the face, limbs > respiratory muscles
o During intubation
▪ Unwanted effects:
▪ Use of NMJ blockers significantly increased the
• Bradycardia (preventable by Atropine)
safety of anesthesia
▪ Prior to surgery, px. is intubated and initially • Hyperkalemia (due to increased
sedated w/ Propofol (?), after which intubation permeability on motor end plates)
and giving of NMJ blocker • Increased intraocular pressure
▪ General anesthetics can cause muscular • Prolonged paralysis
relaxation, however, at a very high dose • Malignant hyperthermia (tx: Dantrolene)
▪ Using NMJ blocking drug, it can lessen the dose B. CHOLINESTERASE REGENERATORS
that is needed for general anesthetic → less - Includes: Pralidoxime (PAM), Diacetylmenoxime (DAM)
anesthetic required for muscle relaxation → - Kinetics:
allows px. to recover quickly and completely o PAM and Obidoxime – used to hydrolyze phosphorylated
o Muscle spasm control for intoxication and infections cholinesterase and therefore cannot be used to regenerate
o Status epilepticus acetylcholinesterase in the CNS
▪ Electrical activity of seizure in the brain goes on, ▪ Most common agent used: PAM (esp. for enzyme
but those in the motor neuron stop regeneration @ NMJ)
- Types: Non-Depolarizing, Depolarizing ▪ Both are quaternary ammonium, thus cannot cross BBB
o Non-depolarizing Agent o DAM – can cross the BBB
▪ MOA: o Regenerate its activity from the enzyme-inhibitor complex
• Competitive antagonist at the nicotinic for as long as they are given before aging has set in (idk if this
applies to PAM and Obidoxime only or all three drugs )
receptor site (compete w/ AChE at the
receptor w/o stimulating the receptor)
10. The only depolarizing neuromuscular blocker
• Can block prejunctional Na+ channels a. Tubocurarine c. Both
• Blockade reversal achieved through b. Succinylcholine d. NOTA
increasing AChE concentration (Tetanic 11. True or False. Quaternary amines can cross the BBB. ________
stimulation) or administration of 12. Used for motion sickness as a patch
cholinesterase inhibitors (e.g., a. Atropine c. Tubocurarine
b. Pralidoxime d. Scopolamine
Pyridostigmine)
• High MW drugs can also block ion pore
Sources:
channel (e.g., Pancuronium)
Doc Duenas’ ppt and lecture
▪ Intended effects: Motor paralysis
Katzung
▪ Unwanted effects:
Pharma Lecture Notes
• Tubocurarine – arterial BP falls due to
ganglion block, histamine released by
mast cells
• Vecuronium – less ganglion block and
histamine release
• Gallamine/Pancuronium – muscarinic
receptor block at the heart → tachycardia
o Depolarizing Agent
▪ MOA: Answer key:
Phase I block: - Muscle is depolarized at first 1. True 2. A 3. A 4. C 5. B 6. D 7. False 8. B 9. C 10. B 11. False 12. D

Depolarization
Block

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