m4 tuts pcol p1

Pharmacology

Study of uses and efforts of drugs

AUTONOMIC NERVOUS SYSTEM

Nervous System	Preganglionic NT (Receptor)	Postganglionic NT (Receptor)	Response
Parasympathetic	Longer Acetylcholine (Nn ACh receptor)	Acetylcholine (Cholinoceptor)	M-AChR: SM, heart, glands DUMBBELLSS Learning & Cognition Nm-AChR: Skeletal muscles (neuromuscular junction) - DEPOLARIZATION Increased muscle contraction
Sympathetic	Shorter Acetylcholine (Nn ACh receptor)	Norepinephrine (Adrenoceptor)	a, B Reverse of DUMBBELLS

Parasympathetic (Cholinergic)

Neurotransmitters:

• Preganglionic NT: Acetylcholine

• Postganglionic NT: Acetylcholine

• Receptor: Cholinoceptor

Muscarinic Receptor Subtypes

Subtype	Location/Effect
M1 - Gq	Mind, gastric mucosa
M2 - Gi	Heart – ↓ heart rate
M3 - Gq	Most dominant and most common - smooth muscle
M4 - Gi	CNS modulation
M5 - Gq	CNS modulation

Parasympathetic Peripheral Effects

M1, M2, M3

• Diarrhea: ↑ peristalsis

• Urination: contraction of detrusor muscle (relax or dilate of sphincter)

• Miosis (pupil constriction)

• Bradycardia: ↓ heart rate, inotropy, dromotropy

• Bronchoconstriction

• Emesis, erection

• Lacrimation

• Salivation

• ↑ Secretion

Parasympathetic in the Brain

Brain: M1, M4, M5 – modulation of neurotransmission

Nn-ACh receptor

• Modulation of dopamine release in the brain

• ANS ganglia

• Inhibited by ganglionic blockers

Nm-ACh receptor

Muscular depolarization (contraction)

Direct-acting Cholinergic Agonists

• Muscarinic receptor agonists:

  • Bethanechol

  • Pilocarpine

  • Muscarine

    • Analog: Cevimeline

  • BET MUSCle PIoLO

• Nicotinic receptor agonists:

  • Nicotine ⭐

  • Lobeline

  • Cytisine

    • Analog: Varenicline ⭐

• Muscarinic & Nicotinic receptors: Nonselective

  • Carbachol

  • Acetylcholine

  • Methacholine

  • Arecholine

Muscarinic receptor agonists

• Bethanechol

• Pilocarpine

• Muscarine

  • Analog: Cevimeline

Nicotinic receptor agonists

• Nicotine

• Lobeline

• Cytisine

  • Analog: Varenicline

Muscarinic & Nicotinic receptors

• Carbachol

• Acetylcholine

• Methacholine

• Arecholine

Drugs for Sjogren Syndrome

For saliivary gland destruction (dry eyes, dry mouth):

1. Pilocarpine

2. Cevimeline

Treatment of atonic bladder

For acontractile bladder - like postpartum & postoperative urinary retention

• Bethanechol - Bladder emptier (BE)

  • It helps to cause urination and emptying of the bladder

Metacholine

Diagnosis of asthma

Smoking deterrents

Quit smoking aid

• Alkaloid: Nicotine (FULL AGONIST) ⭐

• Non-nicotine: Varenicline (PARTIAL AGONIST) ⭐

Others:

1. Antidepressant: Bupropion ⭐

2. Ganglionic blocker: Mecamylamine (under study)

Indirect-Acting Cholinergic Agonists

• Also known as an anticholinesterase or cholinesterase inhibitor

• Enhances cholinergic activity by blocking the acetylcholinesterase (AChE) enzyme, which normally breaks down the neurotransmitter acetylcholine (ACh) to Choline + Acetate

• Inhibition of AChE = ↑ ACh

• Spectrum: Both nicotinic and muscarinic receptors

Reversible AChE inhibitors

Carbamates:

1. Neostigmine - 4° POLAR

2. Pyridostigmine - 4° POLAR

3. Physostigmine - 3° NONPOLAR (Periphery and Centrally)

Reversible AChE inhibitors

Quaternary ammonium compounds: POLAR

1. Ambenonium

2. Demecarium

3. Edrophonium

Centrally-acting Reversible AChE inhibitors

LIPOPHILIC - for Alzheimer's Disease

• Donepezil

• Galantamine

• Rivastigmine

Irreversible AChE inhibitors (Organophosphates)

LIPOPHILIC - central and peripheral effects

• Malathion

• Parathion

• Echothiophate

• Isoflurophate

Myasthenia gravis

long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness.

Edrophonium

Diagnosis of Myasthenia gravis (Tensilon test)

Treatment of Myasthenia gravis

Extreme fatigue in muscles so choose quaternary amines

1. Pyridostigmine (first line; (+) corticosteroids if poor response)

2. Neostigmine

Methacholine

Diagnosis of bronchial hyperreactivity

Alzheimer’s disease

↓ Low ACh = suffering from retrograde amnesia (past events)

First-line drugs: Centrally Acting Reversible AChE blockers

• Rivastigmine

• Donepezil

• Galantamine

• Tacrine* (obsolete - toxic in liver, inferior effect)

Physostigmine

DOC for atropine poisoning

• Atropine is a tertiary amine = antidote should be tertiary amine

Treatment of pesticide poisoning

Pesticide poisoning (i.e., organophosphates)

1. Atropine (MOA: Cholinoceptor blocker)

2. Pralidoxime (MOA: regenerates AChE)

---

• Organophosphate poisoning (cholinergic crisis)

• Mechanism:

  • Organophosphates bind to acetylcholinesterase (AChE)

  • Inhibition can be irreversible after a process called aging

• Aging:

  • Time-dependent process where the organophosphate-AChE complex becomes permanently bound = irreversible

  • Makes reactivation of the enzyme impossible

• Treatment:

  • Pralidoxime (2-PAM)

    • Reactivates AChE only if given before aging occurs

  • Atropine

    • Competitive antagonist at muscarinic receptors (Cholinoceptor blocker)

    • Relieves muscarinic symptoms such as salivation, bronchorrhea, and bradycardia

Open-angle glaucoma

• Most common type

• Decreased aqueous humor reabsorption

• Painless visual loss

Angle-closure glaucoma

• Blockade of the canal of Schlemm (normally held open by trabecular meshwork)

• Can be acute (painful) or chronic (genetic)

Chemical warfare agents

Sarin, Soman, Tabun

True

Condition / Use	Drug / Notes
Diagnosis of Myasthenia gravis	Edrophonium
Treatment of Myasthenia gravis	1. Pyridostigmine (first line; (+) corticosteroids if poor response) 2. Neostigmine
Diagnosis of bronchial hyper-reactivity	Methacholine
Alzheimer’s disease	First-line drugs: Reversible AChE blockers
DOC for atropine poisoning	Physostigmine
Treatment of pesticide poisoning	(i.e., organophosphates)
	1. Atropine (MOA: muscarinic receptor blocker)
	2. Pralidoxime (MOA: regenerates AChE)
Chemical warfare agents	Sarin, Soman, Tabun

Open-angle glaucoma

• Most common type

• Decreased aqueous humor reabsorption

• Painless visual loss

Angle-closure glaucoma

• Blockade of the canal of Schlemm (held open by trabecular meshwork)

• Acute (painful) or chronic (genetic)

True

Glaucoma treatment goal

• Primary goal: Decrease intraocular pressure (IOP)

• Methods to achieve:

  • ↓ Aqueous humor production

  • ↑ Aqueous humor outflow

• Drugs: PBAC

  • P - prostaglandins analogues

  • B - beta blockers

  • A - alpha 2 agonists

  • C - carbonic anhydrase inhibitors

Decrease aqueous humor production

• Beta Blockers:

  • Timolol

  • Betaxolol

• Carbonic anhydrase inhibitors

  • Acetazolamide

  • Dorzolamide

Increase aqueous humor outflow

• PGF2α analogs:

  • Latanoprost

  • Bimatoprost

• Miotics: e.g., Pilocarpine

• Non-selective alpha agonist: Dipivefrin → Epinephrine

Decrease production & increase outflow aqueous humor

Alpha-2 agonists:

• Brimonidine

• Apraclonidine

Synthesis of Acetylcholine

• Choline Uptake - rate limiting step

  • Blocked by: Hemicholinium

• ACh Synthesis (Choline + Acetyl CoA)

  • Enzyme: Choline Acetyltransferase (ChAT)

  • Product: Acetylcholine (ACh)

• Vesicular Storage

  • Blocked by: Vesamicol

• Release via Exocytosis

  • Inhibited by: Botulinum Toxin

  • Stimulated by: α-latrotoxin (black widow spider)

  • Facilitated by: High Ca²⁺ influx

• Neurotransmitter Binding → Response

  • Occurs at muscarinic or nicotinic receptors

  • Inhibited by: Anti-cholinergics (atropine)

• Enzymatic Metabolism

  • Enzyme: Acetylcholinesterase (AChE)

  • Products: Choline + Acetate

  • AChE Blockers (↑ ACh)

    • Neostigmine, Physostigmine (reversible), Organophosphates (irreversible)

  • Cholinoceptor Blockers: Anti-cholinergics

    • Atropine (muscarinic)

    • Tubocurarine (nicotinic)

• Choline Recycling

  • Choline is reabsorbed for reuse in ACh synthesis

True

Column A	Column B
1. Blocks the uptake of choline	A. Hemicholinium
2. Blocks the release of ACh	C. Botulinum toxin
3. Stimulates the release of ACh	D. Latrotoxin
4. Blocks the receptor of ACh	E. Atropine (anticholinergics)
5. Blocks the storage of ACh	B. Vesamicol

Choline Acetyltransferase (ChAT)

Enzyme responsible in synthesis of ACh:

Acetylcholinesterase (AChE) / Cholinesterase

Enzyme hydrolyzing ACh

Parasympathetic (Cholinergic) Blockers

• Block cholinergic receptor = Parasympatholytic effect = Anti-DUMBBELLS

• A/E: mydriasis - blurred vision, ↓ secretion - dry mouth & eyes

Nonselective Parasympathetic (Cholinergic) Blockers

• Atropine ⭐

• Homatropine ⭐

• Benztropine ⭐

• Trospium

• Ipratropium ⭐

• Tiotropium ⭐

• Scopolamine

• Dicyclomine

• Cyclopentolate

• Oxybutynin

• Flavoxate

• Propantheline

Selective Parasympathetic (Cholinergic) Blockers

M3-Selective (for management of OA bladder) ⭐

• Darifenacin

• Solifenacin

• Tolterodine

• Fesoterodine

M1-Selective ⭐ (management of ulcer disease)

• Pirenzepine

• Telenzepine

Natural alkaloids

Drug	Use / Notes
Atropine	Antidote for cholinesterase (AChE) inhibitor
	a. Physostigmine toxicity (reversible)
(+) Pralidoxime	b. Organophosphate poisoning (irreversible)
Scopolamine	Aka Hyoscine
	Treatment of motion sickness (via transdermal patch & postoperative nausea & vomiting)

Atropine

Antidote for cholinesterase (AChE) inhibitor

a. Physostigmine toxicity (reversible)

b. Organophosphate poisoning (irreversible) (+) pralidoxime

Scopolamine

Aka Hyoscine

• Treatment of motion sickness (via transdermal patch & postoperative nausea & vomiting)

Anti-Parkinson drug

1. Pseudoparkinsonism - by using haloperidol

2. EPS

3. ↑ Acetylcholine = lead to tremors

• Tx: anticholinergics (3 BiBe)

  • Benztropine - Treatment of extrapyramidal symptoms (e.g., acute dystonia and Parkinson-like symptoms) ⭐

  • Biperiden

  • Trihexyphenidyl

Mydriatic, cycloplegic drugs

• Atropine

• Homatropine

• Tropicamide

• Cyclopentolate

COPD and asthma

Tx: Inhibit M3 = bronchodilation

• Ipratropium and Tiotropium

Treatment of overactive bladder

Tx for Urinary frequency, urgency, and incontinence

• Inhibits M3 (detrusor muscle ) = ↓ contraction (urinary retention)

Drugs / Suffix
1. -fenacin
2. -terodine
3. -butynin
4. Trospium
5. Propantheline

Antispasmodic agent

To relieve GIT spasm caused by IBS

• Dicyclomine (dicycloverine)

• Propantheline

Sympathetic (Adrenergic)

Neurotransmitters

• Preganglionic NT: Acetylcholine

• Postganglionic NT: Norepinephrine

• Receptor: Adrenoceptor (a, B)

• Opposite of DUMBBELLS

Sympathetic (Adrenergic) Receptors

Receptor	Response
Alpha 1	Vasoconstriction Mydriasis Contraction of bladder neck (closed sphincter) = urinary retention
Alpha 2	Central: ↓ NE release = vasodilation Peripheral: vasoconstriction NET effect: Vasodilation Ex. Clonidine - transient increase in BP ↓ intraocular pressure
Beta 1 ❤	↑ Heart rate/chronotropy, ↑ contractility/inotropy, ↑ dromotropy
Beta 2 Baga Bahay bata Bladder	Relaxation of Lungs: bronchodilation Bladder detrusor: Urinary retention Uterus: Tocolysis (pampakapit)
Beta 3	↑ Lipolysis Relaxation of Bladder (detrusor muscle)

Sympathetic (Adrenergic) Receptors

• Alpha 1

  • Vasoconstriction

  • Mydriasis

  • Contraction of bladder neck (closed sphincter) → urinary retention

• Alpha 2

  • Central: ↓ NE release → vasodilation

  • Peripheral: vasoconstriction

  • NET effect: Vasodilation

  • Example: Clonidine → transient increase in BP

  • ↓ Intraocular pressure

• Beta 1 ❤

  • ↑ Heart rate / chronotropy

  • ↑ Contractility / inotropy

  • ↑ Dromotropy

• Beta 2

  • Lungs: bronchodilation

  • Bladder detrusor: relaxation → urinary retention

  • Uterus: tocolysis (pampakapit)

• Beta 3

  • ↑ Lipolysis

  • Relaxation of bladder (detrusor muscle)

True

Sympathetic agonists:

• Direct Acting

  • Alpha 1 agonist

  • Alpha 2 agonist

  • Beta agonists

  • Catecholamines

  • Dopamine agonists

  • Mixed acting

• Indirect acting

  • Displacers

  • Reuptake inhibitors

Natural (endogenous) catecholamines

Catecholamine	Use / DOC
Epinephrine	Adrenaline DOC for anaphylactic shock
Norepinephrine	Noradrenaline DOC for septic shock
Dopamine	Adv: Versatile Shock + hypotension Shock with renal shutdown Hypovolemic shock (fluid)

Epinephrine

Adrenaline

• DOC for anaphylaxis/anaphylactic shock

Norepinephrine

Noradrenaline

• DOC for septic shock

Dopamine

Adv: Versatile

• Shock + hypotension

• Shock with renal shutdown

• Hypovolemic shock (fluid)

Synthetic (exogenous) catecholamines

Drug	Use
Isoproterenol (Isoprenaline)	Inhalation: Acute asthma IV: refractory bradycardia and AV block
Dobutamine	Shock without hypotension Treatment of cardiogenic shock

Isoproterenol

Isoprenaline

• Inhalation: Acute asthma

• IV: refractory bradycardia and AV block

Dobutamine

• Tx of shock without hypotension

• Treatment of cardiogenic shock

Atropine

Symptomatic bradycardia DOC

Phenylephrine

4 uses

• Nasal decongestant

• IV: Tx of orthostatic hypotension

• Injection: Priapism (prolonged & painful erection)

• Topical: Mydriatic agent (retina exam)

Dexmedetomidine

Used to reduce opioid requirement in pain control (ICU) - potency enhancer

• Analgesic and sedative effect

Clonidine

Used to facilitate abstinence from opioid

INDIRECT-ACTING ADRENOCEPTOR AGONIST

• Displacers

  • Amphetamines

  • Methylphenidate

  • Modafinil

• Reuptake inhibitors

  • Cocaine

  • TCAs, SNRIs

Displacers (stimulants)

Drug	Use / Notes
Amphetamine	Treatment of ADHD, narcolepsy & obesity
Methylphenidate	Treatment of ADHD
Modafinil	DOC for narcolepsy

MOA: NE & DA displacers

• Displace norepinephrine (NE) from storage vesicles

• Result: Reverse transport of NE into the synapse through the norepinephrine transporter (NET) into the synaptic cleft, even without an action potential

• ↑ NE & DA in synaptic cleft

• ↑ Sympathetic stimulation (CNS stimulation, increased HR, alertness)

Amphetamine

Treatment of ADHD, narcolepsy & obesity ( ↑ DA, ↑ NE)

Methylphenidate

Treatment of ADHD

Modafinil

DOC for narcolepsy

Non-stimulants for ADHD

• Atomoxetine ⭐

• Clonidine

• Guanabenz

Short-acting beta2 agonists (SABAs)

Examples:

• Albuterol (Salbutamol)

• Levalbuterol

• Fenoterol

• Terbutaline

Uses:

1. Acute asthma (reliever)

2. Treatment of Hyperkalemia

Side effect:

• Hypokalemia

Long-acting beta2 agonists (LABAs)

Examples:

• Salmeterol

• Formoterol

Uses:

1. Chronic asthma (controller) + Inhaled Corticosteroids

2. Nocturnal asthma

Mirabegron

Beta-3 agonist for overactive bladder (promote urinary retention)

Fenoldopam

Dopamine-1 agonist for hypertensive crisis (outcome is vasodilation)

Vasopressors

(Vaso = vessel, Pressor = compress) = CONSTRICTORS

Used in shock, orthostatic hypotension

• Epinephrine

• Norepinephrine

• Phenylephrine

• Vasopressin

Inotropes

Used in acute HF (cannot be used in chronic) - stimulate contractility of 💖

• Dobutamine (Vasodilator)

• Milrinone

Vasopressor + inotrope

Dopamine (dose dependent)

• mcg/mg/min

  • 1 to 3 low dose = stimulate D receptor = VASODILATION

  • 4 to 10 intermediate dose = Stimulate B-receptor = INOTROPIC

  • Grater than 10 high dose = Activate a-1 receptor = VASOCONSTRICTION (vaspressor)

SYMPATHETIC NT SYNTHESIS & DEGRADATION

• Synthesis of Norepinephrine

  • Tyrosine enters the neuron

  • Tyrosine → DOPA via Tyrosine Hydroxylase

    • Inhibited by: Metyrosine → ↓ DOPA production → ↓ NE

  • DOPA → Dopamine via DOPA Decarboxylase

  • Dopamine enters vesicle

  • Dopamine → Norepinephrine (NE) via Dopamine β-Hydroxylase

• Storage

  • NE is stored in vesicles inside the neuron until release

    • Inhibited by: Reserpine → blocks VMAT → prevents dopamine from entering vesicle → ↓ NE formation

• Release

  • Action potential arrives → causes calcium influx

  • Calcium triggers exocytosis → NE is released into the synaptic cleft

    • Inhibited by: Guanethidine, Bretylium, Guanabenz → block NE release from neuron

• Receptor Binding and Response

  • NE binds to adrenergic receptors (α and β)

  • Leads to sympathetic effects (opposite of DUMBBELS):

    • ↑ heart rate

    • Bronchodilation

    • Vasoconstriction

    • Mydriasis, etc.

  • Inhibited by sympatholytic agents

• Termination of Action

  • Reuptake into the presynaptic neuron (main mechanism)

    • Inhibited by: Cocaine, TCAs, SNRIs (e.g., Venlafaxine, Duloxetine) → block NET → ↑ NE in synapse

  • NE is either recycled into vesicles or degraded

• Metabolism

  • Monoamine Oxidase (MAO) → degrades NE inside the neuron

    • Inhibited by: MAO inhibitors (e.g., Selegiline, Phenelzine, Tranylcypromine) → ↑ NE levels

  • Catechol-O-Methyl Transferase (COMT) → degrades NE in the synapse/periphery

    • Inhibited by: COMT inhibitors (e.g., Entacapone, Tolcapone) → ↑ NE levels

True

Column A	Column B
1. Blocks the storage of dopamine	B. Reserpine
2. Blocks the release of NE	C. Bretylium, Guanethidine, Guanadrel
3. Stimulates the release of NE	F. Amphetamine
4. Blocks tyrosine hydroxylase	A. Metyrosine
5. Blocks NET transporter	D. TCAs and SNRIs (including cocaine)
6. Blocks the metabolism of NE	E. MAO inhibitors

B. Dobutamine

Which of the following is not a vasopressor?

A. Dopamine

B. Dobutamine

C. Isoproterenol

D. Phenylephrine

E. Epinephrine

D. Phenylephrine and Acetylcholine (ACh is not a catecholamine)

Which of the following are not catecholamines?

A. Dopamine and Dobutamine

B. Dobutamine and Isoprenaline

C. Isoproterenol and Adrenaline

D. Phenylephrine and Acetylcholine

E. Epinephrine and Noradrenaline

A. Acetylcholine (-) AChE = ↑ ACh

What neurotransmitter is increased by Rivastigmine in the CNS synapses?

A. Acetylcholine

B. Norepinephrine

C. Epinephrine

D. Dopamine

A. Methyldopa

Anti-HPN for pregnant women

A. Methyldopa

B. Aliskiren

C. Candesartan

D. Captopril

---

Aliskiren, ARBs, ACEi = renal dysgenesis

Sympathetic (Adrenergic) Blockers

Sympathoplegics/Sympatholytics = Inhibit adrenoceptor = ↑ DUMBBELLS (same effects with parasympathetic)

• Non-selective alpha blockers

• Selective alpha-1 blockers

• Selective alpha-1A blockers

• Selective beta blockers

• Non-selective beta blockers

Drugs for pheochromocytoma

Tumor in adrenal medulla = ↑↑EPI/NE = Hypertensive episodes

Treatment: Nonselective a-blockers

• Reversible, competitive: PHENTOLAMINE

• Irreversible, non-competitive: PHENOXYBENZAMINE (preferred)

• A/E: reflex tachycardia (mx: B-blockers)

Nonselective a-blockers

For pheochromocytoma

• Reversible, competitive: PHENTOLAMINE

• Irreversible, non-competitive: PHENOXYBENZAMINE (preferred)

Phentolamine

Reverses the effect of EpiPen® after accidental injection to the finger

First line drugs for LUTS

First line drugs for LUTS (nocturia, urinary frequency, urgency, incomplete micturition) caused by BPH - Benign Prostatic Hyperplasia (FDA-approved)

Tx:

• a1 blockers (-zosins) = vasodilation = increased urinary flow = used for HTN + BPH (mx of LUTS - symptoms of BPH only)

  • Prazosin

  • Terazosin

  • Doxazosin

• a1-a blockers = less amount in BV = lesser vasodilation tx of BPH only

  • Silodosin

  • Tamsulosin

  • Alfuzosin

• Agent of choice for BPH to decrease prostate size

  • Finasteride

a1 blockers (-zosins)

• = vasodilation = increased urinary flow = used for HTN + BPH (mx of LUTS - symptoms of BPH only)

  • Prazosin

  • Terazosin

  • Doxazosin

a1-a blockers

• = less amount in BV = lesser vasodilation tx of BPH only

  • Silodosin

  • Tamsulosin

  • Alfuzosin

Finasteride

Agent of choice for BPH to decrease prostate size

First-dose phenomenon

Adverse effect of alpha blockers

• Mx: start with low dose at bedtime, monitor BP

Prazosin

• Treat HPN (non-first line - inferior)

• Non-FDA (off-label)

  • Raynaud's phenomenon (nifedipine/CCBs - DOC)

  • Reduce nightmares in PTSD (SSRI - DOC)

  • Scorpion envenomation

Nicotinic Receptor Blockers

• Type 1 - Nm: Blocked by:

  • Non-depolarizing Neuromuscular blockers (Paralytic agents)

• Type 2 - Nn: Blocked by:

  • Ganglionic blockers

Nicotinic Receptor Blockers

Ganglionic blockers

Malignant HTN (RARE)

1. Mecamylamine (used as smoking deterrent)

2. Trimethaphan