C.

PARASYMPATHETIC DRUGS
1. Biosynthesis
2. Receptors, location, response
3. Parasympathomimetics / cholinergic agonist
4. Parasympatholytics / cholinergic antagonist

1. BIOSYNTHESIS OF Ach:
Location: in all preganglionic fiber (symp at para) ; parasym postgang
fiber ; somatic nerves, CNS (brain)
Steps:
o Active uptake of choline into the presynapse
** Rate-limiting step (slowest)**
Can be inh. By hemicholiniums
o Formation of Ach (single step metab.)
Choline + acetyl CoA ---Choline acyl transferase---> Ach
o Vesicular uptake of Ach (at the presynapse) - Ach mole. Are
concentrated within vesicles (each vesicle can contain 10k-50k mole. In
one vesicle)
Can be inh. By Vesamicol
o Quantal release of Ach into the cleft (quantal - millions of Ach being
released at any given time)
Can be inh. By Botulinum toxin / botox

FATE OF Ach AT THE CLEFT

o Can bind to postsynap receptors
o (most impt fate) metabolism by Acetylcholinesterase (AchE) --->
highly efficient (that's why you need quantal release of Ach)
Ach ---AchE---> choline + acetate

CHOLINESTERASES:
a. Acetylcholinesterase - true cholinesterase = RBC
cholinesterase ; Very specific for Ach
b. Butyrylcholinesterase - Pseudo cholinesterase = PLASMA
cholinesterase ; not specific - can act on any ester except Ach

2. Receptors, Location, Response

Receptors Location Response
1. Muscarinic
i. M1 Nerves that supply Gastric acid secretion
gastric glands
(branches of vagus
nerve CN10)
ii. M2 Bradycard., (-)
Nerves that supply the dromotropism
heart (branches of (slow rate of conduction
vagus nerve) across AV node [vagotonic
iii. M3 (Gq response]
linked) Smooth muscles
 • Eyes (circular m.
Of pupils) Pupilloconstriction (miosis)
• Eyes (ciliary
muscles) Contraction =
accommodation (ability to
recognize objects that are
near your face)
• Bronchial s.m.
Bronchospasm /
• GIT (walls) bronchoconstriction
Contraction (thus lead to
• GIT (sphincters) peristalsis)
Relaxation = opening (thus
• Urinary bladder lead to peristalsis)
(detrussor muscle) Contraction (thus lead to
• Urinary bladder urination)
(sphincter and Relaxation = opening (thus
trigone) lead to urination)
**diuresis - inc urine volume
2. Nicotinic (N) not pass out urine**
i. Nn (neural)
Exocrine glands Secretion
• Lacrimal Lacrimation
• Salivary Salivation
• Bronchial Inc. bronchial gland
• GIT secretion
• Eccrine sweat Inc. GIT secretion
gland Sweating
Ganglia, CNS (both Stimulation (may it be
found in Symp Sym/Para)
ii. Nm &Parasymp)
(muscular - not
autonomic,
somatic ito)
NM endplate Skeletal m. contraction

3. PARASYMPATHOMIMETICS = CHOLINERGIC AGONIST

a. Direct-acting Cholinergic agonists - stimulate Directly
cholinergic receptors
i. Choline ester
• Acetylcholine (M, N)
• Betacholine / Urecholine
• Methacoline (M, N)
• Carbachol (N, M)

ii. Cholinergic alkaloids

• Pilocarpine (M)
• Muscarine (M)
• Nicotine (N)
 • Lobeline (N)

b. Indirect-acting cholinomimetic - do not stim. Receptors BUT can

inc. conc. Of Ach in the cleft
MOA: inh. AchEsterase [anti-cholinesterases]
i. Short-acting anti-cholinesterase - duration of action (axn)
does not exceed 30mins (15-20 mins on ave)
• Inhibition: reversible
• e.g. Edrophonium (tensilon (R))
ii. Intermediate-to-long-acting (2 hrs up to less than 24 hrs)
• Inhibition: reversible
• e.g. Neostigmine, Physostigmine, pyridostigmine,
ambenonium, demecarium
iii. Very long-acting agents - duration is days to weeks
• Inhibition: depends on duration of exposure
1st 24-48 hrs ---> potentially reversible
> 24-48 hrs -----> definitely Irreversible (due to "aging" of
PO4 bond which is a covalent bond - like forming a new
mole.)
• e.g Ecothiophate
Malathion, Parathion
Isofluorophate
Sarin, Tabun, Soman (nerve gases for chemical warfare)
iv. Miscellaneous agents - useful for AD (alzheimer's dementia)
• Rivastigmine, Tacrine, Donepezil

Clinical Uses of cholinergic agonists:

o Dx and Mx of Myasthenia Gravis
o Mx of neuromuscular blocker toxicity -useful to counteract effect
of curare derivatives (atracurium etc.) which leads to respiratory paralysis
• Edrophonium - more commonly used in clinics
o Mx of glaucoma
• Drugs: ecothiopate, carbachol
o Mx of non-obstructive ileus
• Pilocarpine (direct acting cholinergic alkaloid) comb. With
physostigmine(indirect acting), bethanechol
o Mx of atropine poisoning
NOW: Neostigmine (quat. ammonium Peripheral agents), pilocarpine,
o Mx of urinary retention in BPH
• Bethanechol = urecholine
o Smoking cessation
o Nicotine, lobeline
o Mx of AD
• Rivastigmine, Tacrine, Donepezil

• Cholinergic SE and toxicities: [DUMBBELS]

• Diarrhea
• Urination
• Miosis
• Bradycard
 • Bronchospasm
• Emesis
• Lacrimation
• Salivation & Sweating
• Mx of Toxicities:
• Primary Tx (DOC) for toxicities with ALL cholinergic agonist -
Initial Tx is Atropine (base treatment)

4. PARASYMPATHOLYTICS = CHOLINERGIC ANTAGONIST

a. Anti-muscarinic = anticholinergic (si antimuscarinic siya ang
nirerefer na anticholinergic)
= atropine-like effects or SE
• Prototype: anti-muscarinic all throughout = Atropine
• Effects due to M1 block- dec. in GIT secretion
• M2 block - tachycard. And (+) dromotropism --->
Vagolytic effect (inh. Effects of vagus)
• M3 block: s.m ---> relax
• Eyes - mydriasis, Cycloplegia / loss of near vision (Blind
as a bat)
• Cycloplegia - relaxation / paralysis of ciliary
m. ---> ciliary musc. move towards each other
---> can close canal of schlemm ---> absolute CI:
narrow-angled glaucoma
Ciliary muscles contract - move away from each
other - open canal of schlemm
Ciliary muscles relax - move towards each other -
close canal of schlemm
• Glaucoma - problem is inc. in IOP due to inc.
in aqueous Humor volume
• may be overproduction (normal
drainage) - angle is open or open/wide-angle
glaucoma
• problem in drainage (normal
production) - narrow-angle glaucoma
• Complication if given cycloplegic --->
angle will close ---> acute angle closure
glaucoma (can cause blindness in 24-48
hrs --> retina will be impinged --->
madami b.v and optic nerve is there)
• Bronchi - bronchodilation
• GIT - constipation & ileus
• Urinary bladder - urinary retention
• Exocrine glands - dec. secretion (lacrimal, saliva,
etc.) / drying effect (Dry as a bone)
• Anhydrosis - absence of sweating (eccrine -
thermoregulator)
• Complication: hyperthermia / atropine
fever (potentially fatal in children) - hot as a
hare / hot as hell
 • Flushing / cutaneous vasodilation (so
that heat will be released) - red as a beet
• CNS effects (atropine can cross BBB)
• CNS agitation, confusion, seizure, acute
psychotic reaction - mad as a hatter

**IMPORTANT!!!! REMEMBER THIS!!!! atropine effects: ALICE IN

WONDERLAND – BLIND AS A BAT, DRY AS A BONE, HOT AS HELL, RED AS
BEET, MAD AS HATTER**

• Clinical Uses of Atropine

• Topical: mydriatic-cyclopegic
• Systemic (IV): Mx of symptomatic bradycard. Or heart
block
• Mx of anti-Ach overdose (organoPO4 poisoning)
• Given with diphenoxylate (opioid anti-diarrheal - can cross
BBB ---> minimal euphoria) to minimize risk of addiction
with diphenoxylate(opioid ito, nakaka-adik di ba?
• e.g. 10 tablets ---> they will experience the
alice in wonderland due to atropine toxicity so
they will stop :) ahahahaha. Yes!

• Other anti-muscarinics
1. CNS-acting:
a. Scopolamine
• Sedative (dreamless sleep)
• Use: anti-motion sickness
• Historical use: obstetric anesthetic - "twilight
sleep" Scopolamine(sedative) + morphine(analgesic)
b. Biperiden (akineton(R))
Benztropine (cogentin (R))
Trihexyphenidyl (artane (R))
• Use: adjuncts in tx of parkinsonism
Mx of some Sx of EPS(extrapyramidal Sx)
assoc. With anti-psychotic tx

2. Eyes - mydriatics-cycloplegic
a. Atropine - topical (effect lasts for 72 hrs)
b. Homatropine
c. Tropicamide
d. Cyclopentolate
• Mydriatics: indicated to allow full exam of retina (if
pupils are constricted, it will be hard to examine
retina)
• Cycloplegics - to relax ciliary m. In the mx of eye
pain due to ciliary spasms (infections/inflammation)
• CI: in Px with narrow-angled glaucoma as
mentioned a while ago

3. Bronchi - bronchodilators
 a. Ipratropium Br - usually comb. With salbutamol
(albuterol in US) Combivent (R)
b. Oxytropium
c. Tiotropium
• Choice bronchodilator in COPD
• Alternative adjunct bronchodilator in BA

4. GIT and urinary bladder

a. M1-selective blockers - useful for hyperacidity
(adjuncts)
• Pirenzepine, Telenzepine
b. M3-blockers - useful for GIT and urinary bladder
conditions
Hypermotility disorders ---> abdominal cramps
Urinary incontinence, abdominal colic
• Hyoscine-N-butyl bromide
• Dicycloverin
• Glycopyrrolate, clidinium, dicyclomine
• Methscopolamine

b. Anti-nicotinic - may specific group names

i. Neuromuscular blockers
Target receptor: Nm (kaya these drugs act on somatic NS)
a. Depolarizing ('stimulate') irreversible noncompetitive
Nm blocker
e.g. Succinyl choline MOA: irreversibly STIMULATE Nm
receptor but it is IRREVERSIBLE
2 phases of effects
• Phase 1: continuous and tetanic skeletal m.
Contraction[cycle ito na may contraction-relaxation]
w/o relaxation (sa succinyl choline, puro contraction
lang) so yung muscle contraction dito ay INEFFECTIVE
---> muscle fatigue and loss of Ca ions
• Phase 2: skeletal muscle paralysis (flaccid
paralysis) kasi wala na Ca2+ to stimulate Contraction
b. Non-depolarizing reversible competitive Nm blocker
MOA: directly INHIBIT Nm receptor ---> skeletal muscle
paralysis agad
e.g. Curare derivatives (from natural product L-tubocurarine)
2 classes:
• Isoquinoline structure (-curium)
Atracurium, mivacurium
• Steroidal nucleus (-curonium)
Pancuronium, vecuronium

Clinical Uses:
Skeletal muscle relaxants during surgery (muscles should
be retracted in abdominal surgery)
 Side Effects / toxicities:
Shared toxicity: diaphragmatic muscle paralysis
** in case of prolonged paralysis - antidote: edrophonium or
neostigmine
• Succinyl choline SE: muscle pain
• myositis or rhabdomyolysis (break down of muscles)
---> HYPERKALEMIA (kasi cells burst/breakdown so
lalabas K) ---> heart may stop
---> myoglobinemia
(myoglobin is toxic to
renal tubules) = acute
tubular necrosis (ARF)
• lactic acidosis due to severe muscle contraction
• Malignant hyperthermia = Neuroleptic (anti-
psychotics)
• Tubocurarine SE: anaphylactoid rxn (due to direct
histamine releasing effect of tubocurarine on mast cells)

ii. Ganglionic blockers

Target receptor: Nn in the ganglia
Non-specific (block both Sym and Parasym ganglia)
No longer used clinically due to non-spec. effects
Historical use: Hexamethonium, Mecamylamine, Trimethaphan
camsylate
• Alternatives in HTNsive emergency cases
Effects: (mixed)
• Mydriasis, tachycard, constipation, urinary
retention (all are parasym block)
• Vasodilation (sym block) anhydrosis (both para and
sym block)

** all tissues are dominantly innervated by the

parasympathetic EXCEPT blood vessels & sweat
glands**