M3 SELECTIVE Pilocarpine, Cevimeline MOA Only M3 Use/s Acute angle closure glaucoma, Sjögren

syndrome, Sicca syndrome SE Miosis, Blurring of vision (due to cyclospasm), Pilocarpine -

Hypertension For others, again think DUMB BELLS Hypertension is an interesting exception to the
rule for promuscarinics; it may be seen after a brief period of hypotension due to the activation of
sympathetic postganglionic M1 receptors in pilocarpine Dr. Rodriguez Table guide: just want to
emphasize that among the muscarinic agonist, Pilocarpine has a Selective action to M3. Most are
Non-selective and have “CHOL” in their name; which reminds you of AcetylCHOLine. Sometimes in
the boards they give the less common drugs we encounter, so it’s best to tackle some based on their
etymology. At this point, it is wise to recall the locations of M1 to M5. Can you try to practice recall
without looking back at the tables? Dr. Rodriguez TOXICITY WITH MUSCARINIC AGONISTS • This is
seen in overdosage of muscarinic agonists and certain types of mushrooms (genus: Inocybe) o CNS
stimulation o EYE: miosis, spasm of accommodation o LUNGS: bronchoconstriction o GIT/GUT:
excessive gastrointestinal and genitourinary smooth muscle activity o Increased secretory activity
(sweat glands, airway, gastrointestinal tract, lacrimal glands) o Vasodilation • Treatment: Atropine
(Cholinergic antagonist) * Note that the symptoms of muscarinic poisoning are essentially the same
with organophosphate poisoning minus symptoms of nicotinic excess. DIRECT ACTING (NICOTINIC)
NICOTINIC NEURAL AND NICOTINIC MUSCULAR AGONIST Nicotine, Varenicline, Lobeline MOA
Activates: Nn and Nm Nicotine: Full agonist Varenicline: Partial agonist Use/s Smoking cessation SE
Generalized ganglionic stimulation (hypertension, tachycardia, nausea, vomiting, diarrhea) NICOTINIC
MUSCULAR AGONIST Succinylcholine MOA Activates: Nicotinic (more selective to Nm) Use/s
Depolarizing NMJ blocker, Muscle relaxation SE Initial muscle spasms and postoperative pain,
prolonged action in persons with abnormal butylcholinesterase Table guide: In these two tables,
appreciate that all the drugs for smoking cessation will both stimulate Nn and Nm and notice that
they also rhyme. Recall where are Nn receptors found? How about Nm receptors? Great!, now that
you know that Nm receptors are found at the NMJ, this should somehow help you recall that
Succinylcholine is a neuromuscular blocker. But why is it called a blocker if it’s called an AGONIST?
Pause and answer. As agonist, it should stimulate the Nm receptor. Pero dahil ayaw niya umalis sa
pagkakabind sa Nm receptor, continuous muscle depolarization will result to paralysis. Kasi ghorl
sobrang napagod yung muscle sa too much stimulation. Remember muscles need to relax in order
have another contraction. Hence in a way, nagiging “blocker” yung end effect niya dahil na-paralyze
yung muscle. Dr. Rodriguez NICOTINIC TOXICITY • Largely due to the nonspecific ganglionic
stimulation (affecting sympathetic, parasympathetic and neuromuscular junctions) • Blockade of
neuromuscular end plate depolarization o Leading to fasciculations and paralysis o CNS toxicity:
stimulation (convulsions) followed by CNS depression • Treatment: symptom directed (atropine for
muscarinic excess, diazepam & anticonvulsants for CNS stimulation, mechanical ventilation if with
neuromuscular blockade) Notice that Nicotinic toxicity is like a mixture of Sympathetic reactions and
Parasympathetic reactions. Why? Clue, it lies in the location of the nicotinic receptors. Ans. Because
remember nicotinic neural receptors are found in the ganglion either in sympathetic and
parasympathetic nervous system. So meaning if nastimulate yung Nn both systems are stimulated.
Try to look at the SE of Nicotine above. ‘di ba? Hypertension and tachycardia is sympathetic, nausea
vomiting and diarrhea are parasympathetic. Dr. Rodriguez INDIRECT ACTING CHOLINERGIC AGONISTS
• Bind to acetylcholinesterase (AChE) and undergo prompt hydrolysis o Prevents the binding and
hydrolysis of endogenous acetylcholine → amplify acetylcholine effects Acetylcholinesterase
inhibitors: indirect acting cholinomimetics act by raising Ach concentrations in the synaptic cleft by
inhibiting the action of the enzyme that metabolizes Ach. Dr. Uy Indirect acting cholinomimetics will
be divided into 4: Alcohol, Carbamates, Organophosphates and some drugs for Alzheimer’s . To
generalize, this section will have the same MOA and SE MOA: Inhibits acetylcholinesterase. SE:
Encompassed by DUMB BELLS, but will just note some must knows. We will not repeat each per
section to simplify. Dr. Rodriguez ALCOHOL: EDROPHONIUM Use/s Diagnosis of MG (Tensilon test)
Depolarizing NMJ blocker, Muscle relaxation Differentiation of cholinergic crisis and myasthenic crisis.
Reversal of neuro-muscular blockade. CARBAMATES (-STIGMINES) Neostigmine, Pyridostigmines,
Ambenonium, Use/s Treatment of MG Neostigmine: Bladder and bowel atony Reversal of
nondepolarizing neuromuscular blockage (by curiums and curoniums) Physostigmine, Demecarium,
Echothiophate Use/s Reversal of Atropine Poisoning Acute glaucoma SE Physostigmine: CNS effects
SEIZURES ORGANOPHOSPHATES Parathion, Malathion Use/s Insecticide Scabicide (Malathion) SE
Dangerous cholinergic crisis Tabun, Sarin, Soman Use/s War nerve gases SE Rapidly lethal DRUGS FOR
ALZHEIMERS Rivastigmine, Donepezil, Galantamine, Tacrine Use/s Alzheimer’s Disease Rivastigmine
(as transdermal patch) Donepezil + Memantine: Alzheimer’s Dementia SE Nausea and vomiting
Section guide All inhibits acetylcholinesterase kaya sila tinawag na indirect agonist Take note which is
used for diagnosis versus treatment of MG. Don’t think much of the SE for each, since they are
cholinomimetic, think anything DUMBBELLS! Then add the additional notes if there are any. The uses
are very distinct. Improve recall with repetition. Dr. Rodriguez MYASTHENIA GRAVIS • An
autoimmune destruction of nicotinic ACh receptors, characterized by: o Fluctuating muscle o
Weakness o Ocular symptoms o Bulbar symptoms o Proximal muscle weakness • May be worsened
by the ff drugs: o Nondepolarizing neuromuscular blockers (because the mechanism of the disease
and its MOA are similar) o Aminoglycoside antibiotics (because these drugs interfere with
neuromuscular transmission) Differentiating MYASTHENIC CRISIS VS CHOLINERGIC CRISIS •
Myasthenic Crisis: acute worsening of symptoms due to infection, stress or UNDERmedication o
Edrophonium IMPROVES muscle strength • Cholinergic Crisis: excessive activation of cholinoceptors
(skeletal muscle weakness and parasympathetic signs) due to OVERmedication o Edrophonium
WEAKENS muscle strength ORGANOPHOSPHATE POISONING • Accidental exposure to toxic amounts
of pesticides • Clinical manifestation: DUMBBELLS Treatment of Organophosphate Poisoning •
Atropine: addresses only MUSCARINIC symptoms o Notorious for causing hyperthermia in
susceptible patients (because Atropine suppresses thermoregulatory sweating) • Pralidoxime:
addresses BOTH Nicotinic and Muscarinic symptoms o Must be administered before 6-8 hours of
organophosphate bond with cholinesterase occurs (before the bond has AGED or turned covalent,
which is a stronger bond) o has oxime group which has high affinity for phosphorus Atropine MOA
Blocks all Muscarinic receptors. Use/s • 1st choice: Organophosphate poisoning Added in general
anesthesia: for Bradycardia, hypersalivation, decrease airway secretion. SE Antimuscarinic effects
Pralidoxime MOA Binds phosphorus of organophosphate. Breaks organophosphate bond with
cholinesterase. (Regenerates active acetylcholinesterase) Use/s • Antidote for early stage
cholinesterase inhibitor poisoning (organophosphate poisoning and nerve gas poisoning) • Can
relieve skeletal muscle and endplate block SE Muscle weakness Good job! You’re done with
Parasympathomimetics! Okay tara quick synthesis. Parasympathomimetics are divided mainly into
two: Direct acting and indirect acting. Direct acting will act on the receptors mismo; what are these
receptors? ____________ and _____________. Prototype direct acting drug is __________. For for
the muscarinic agonists, carbachol is nonselective, while pilocarpine is selective for _____ muscarinic
receptor. Indirect acting parasympathomimetics will increase the levels of Ach by preventing its
degradation by the enzyme ______________. “-Stigmines” are known examples of this and used
mainly for treatment of ___________. Answers: muscarinic, nicotinic, Ach, M3, AChE, MG Dr.
Rodriguez D. PARASYMPATHOLYTICS Adapted from Katzung and Trevor’s Pharmacology Examination
and Board Review. 12th ed. 2019 Parasympatholytics in other words are known as CHOLINERGIC
ANTAGONIST. Quick recall before going forward, what are the two receptors ulit under cholinergic?
Nicotinic and muscarinic. Therefore, parasympatholytics or cholinergic antagonists may be
expounded further to muscarinic antagonist and nicotinic antagonist. Okie lezzgo, you’re ready for
the next sections. Dr. Rodriguez MUSCARINIC ANTAGONISTS Again for this part, I won’t be repeatedly
mentioning the SE to simplify your thought process and save brain space. Haha. Basta SE ng mga ‘to
ay ANTIMUSCARINIC effects – Alice in Wonderland. o HOT as a hare (hyperthermia) o DRY as a bone
(decreased secretion) o RED as a beet (cutaneous vasodilation) o BLIND as a bat (cycloplegia) o MAD
as a hatter (CNS toxicity) Dr. Rodriguez NON-SELECTIVE BLOCKERS Atropine, Homatropine,
Cyclopentolate, Tropicamide MOA Blocks all Muscarinic receptors. Use/s Mydriatic, Cycloplegic • 1st
choice: Organophosphate poisoning Added in general anesthesia: for Bradycardia, hypersalivation,
decrease airway secretion. SE Antimuscarinic effects If you remember your ophtha rotation, you
might have been requested to dilate your patient prior to an eye surgery. These drugs are being used
for that. Dr. Rodriguez Ipratropium, Tiotropium, Umeclidinium, Glycopyrronium, Aclidinium MOA
Blocks muscarinic receptors in bronchial smooth muscles Use/s Acute Asthma, COPD Tiotropium:
More selective for M3 SE Antimuscarinic effects; dry mouth, blurred vision Scopolamine MOA Blocks
All Muscarinic receptors Use/s Motion Sickness Decrease acid secretion in GIT Nausea and Vomiting
SE Antimuscarinic effects; M3 RECEPTOR BLOCKERS Dicyclomine, Hyoscyamine, Glycopyrrolate Use/s
Diarrhea IBS, decrease acid secretion in GIT SE Tachycardia, confusion, urinary retention, increased
IOP Oxybutynin, Darifenacin, Solifenacin Fesoterodine, Tolterodine, Trospium, Imidafenacin MOA
Modest M3 Selectivity; reduces detrusor muscle tone Use/s Urinary urgency, incontinence SE Excess
parasympatholytic effects M1 SELECTIVE BLOCKER Pirenzepine, Telenzepine Use/s Peptic disease (not
available in USA) SE Excess parasympatholytic effects Pirenzep1ne and Telenzep1ne. Change “i” to 1
to remember the drugs for M1 blocker Dr. Rodriguez Section guide Just in case you’ll forget the drugs
that might come out; take this as a clue that drugs related to Atropine may have TROP in their name.
Take note of the drugs that have selectivity to M1 and M3. This would also help in remembering their
uses. Again for the SE, study smart by knowing the effects of ATROPINE (Alice in Wonderland)
because Atropine would be our prototype cholinergic antagonist (see the toxic effects below) Dr.
Rodriguez ATROPINE TOXICITY • Atropine: prototype nonselective muscarinic blocker, found in
Atropa belladonna plant • Features of Atropine Toxicity: o Atropine fever (hyperthermia) - due to
inhibition of sweating o Atropine flush (cutaneous vasodilation) o Decreased secretions o Tachycardia
o Arrhythmias (intraventricular conduction block) o Constipation o Blurred vision o CNS toxicity •
Atropine Toxicity Mnemonic: o HOT as a hare (hyperthermia) o DRY as a bone (decreased secretion)
o RED as a beet (cutaneous vasodilation) o BLIND as a bat (cycloplegia) o MAD as a hatter (CNS
toxicity) • Treatment: Symptomatic o Temperature control: use of cooling blankets o Seizure control:
Diazepam o To reverse antimuscarinic effect: Physostigmine CONTRAINDICATIONS TO MUSCARINIC
BLOCKERS • Cautious use in infants (since they are sensitive to the hyperthermic effects of atropine)
• Acute angle-closure glaucoma (since mydriasis can block the normal drainage of aqueous humor) •
Benign prostatic hyperplasia (can precipitate further urinary retention already present in this
subgroup because muscarinic antagonists will relax smooth muscle of the ureters and bladder wall)
NICOTINIC ANTAGONISTS Recall again where are the nicotinic receptors found? _____________ In
the ganglion what nicotinic receptor is found? ___________ How about in the NMJ? ___________
Answer: Ganglion and Neuromuscular junction. Nn Nm So since they are found in these area, our
next topic will be about Ganglionic blockers and Neuromuscular blockers. Getchieee?