Jarvin Enosh Tan, RPh January 16, 2021

• Neurotransmitters • ANS
o Simple Amines
▪ Acetylcholine
▪ Histamine
▪ Catecholamines: Dopamine,
Norepinephrine, Epinephrine
▪ Indole amines: 5-
hydroxytryptamine/Serotonin
o Amino Acids
▪ Gamma-aminobutyric acid/GABA
▪ Glutamate
▪ Glycine
▪ D-serine • Cholinergic neurotransmission
▪ Aspartate o Step 1: Synthesis
▪ Etc. ▪ Acetyl-CoA (mitochondria) +
o Peptides Choline (via choline transporter)
▪ Endogenous opioid peptides: via choline acetyltransferase
Endorphins, Dynorphins, ▪ Blocked by hemacholiniums (Not
Enkephalins clinically significant)
▪ Tachykinins: Neurotensin, o Step 2: Storage
Substance P, etc. ▪ Vesicle-associated transporter
▪ Hormones: ACTH, TRH, etc. (VAT): cytoplasm to vesicle
▪ Others: Neuropeptide Y, ▪ With vesicle-associated membrane
Cholecystokinin protein (VAMP)
o Lipids ▪ Blocked by vesamicol (Still not
▪ Anandamide clinically significant)
▪ 2-Aarachidonoylglycerol/2-AG o Step 3: Release
• Nervous System: Review ▪ Action potential → Ca2+ influx →
o Central Nervous System (CNS): brain interacts with VAMP
and spinal cord ▪ Fusion to terminal membrane
o Peripheral Nervous System ▪ Opening of pore to synapse
▪ Afferent ▪ *Blocked by botulinum toxin
▪ Efferent ▪ Binds to acetylcholine receptor
• Somatomotor (AChR) / cholinoceptor
• Autonomic (ANS) – o Step 4: Termination
Sympathetic and ▪ Acetylcholinesterase
Parasympathetic ▪ ACh → Choline + acetate
▪ Short t1/2
Jarvin Enosh Tan, RPh January 16, 2021

• Receptors (ANS) • Cholinergic drugs/Cholinomimetics

o MOA
▪ Direct acting: receptor agonism
▪ Indirect acting:
acetylcholinesterase inhibition
▪ Direct-acting Cholinergics MOA:
Direct Binding to
• Muscarinic receptors in:
o Effector cells: alter organ
function
o Nerve terminals: inhibit
neurotransmitter release
• Nicotinic receptors
o ion channel opens →
depolarization → muscle
contracts
o Effects
▪ Muscarinic effects (also side
Receptors (CNS)
effects)
• Eye: Miosis, accommodation
• CV
o Bradycardia, decreased
contractility &
conduction
o (inhibition of NE release)
o Vasodilation – NO
• ANS Drugs o Reflex tachycardia
o Cholinergics (Muscarinic and Nicotinic) o *Nicotine: same effect at
▪ Direct-acting (Choline esters, S, PS ganglia
alkaloids, and synthetic) • Respiratory:
▪ Indirect-acting: bronchoconstriction
Acetylcholinesterase Inhibitors • GI: peristalsis, secretions
(ANS and CNS) (saliva, gastric)
▪ Partial agonist • Genitourinary: bladder
o Anticholinergics (Antimuscarinics) muscle relaxation
o Neuromuscular Blockers • Other glands: sweat, tears,
▪ Depolarizing (NM agonist) nasopharyngeal
▪ Nondepolarizing (NM antagonist) • CNS: Cognition, etc.
o Adrenergics/Sympathomimetics • Mnemonic:
▪ Mixed: Vasopressors and D.U.M.B.B.E.L.S.S.: Diarrhea,
Inotropics Urination, Miosis,
▪ α, β, D receptor agonists Bradycardia,
o Antiadrenergics/Adrenergic Bronchoconstriction, Emesis,
Antagonists Lacrimation, Salivation,
▪ α, β antagonists Sweating
▪ Mixed
Jarvin Enosh Tan, RPh January 16, 2021

▪ Nicotinic effects (also side effects) ▪ Synthetic

• Neuromuscular junction – • Cevimeline
depolarizing block • Aceclidine
o Fasciculations • Partial agonist: Varenicline
o Muscle weakness • ***in practice,
o Paralysis cholinergic/anticholinergic =
• CNS muscarinic/antimuscarinic
o CNS depression o Direct-acting Cholinergics: Indications
o Lethargy ▪ Open-angle glaucoma (Pilocarpine:
o Seizures alternative)
o Coma ▪ Xerostomia (Sjogren’s syndrome)
o Cognition • Cevimeline
o Euphoria o Longer t1/2 = TID dosing
o Less flushing, more GI
side effects
• Pilocarpine: Shorter t1/2 = QID
dosing
• Bethanechol: radiation-
induced
▪ Urinary retention and
postoperative ileus (GI paralysis)
• Bethanechol: bladder, bowel
▪ Miosis during surgery: Carbachol
▪ Bronchoprovocation testing:
Methacholine (alternative:
Mannitol)
• Indirect-acting cholinergics
o Classification
o Direct-acting Cholinergics ▪ Simple alcohols with quaternary
▪ Choline esters: ACh, ammonium: Edrophonium
MethacholineI, Carbachol, (historical; phased out)
Bethanechol ▪ Carbamates (carbamic acid esters
• All quaternary: lipid-insoluble, of alcohols with 3o/4o NH3/NH4+
can’t cross BBB group)
• Varying acetylcholinesterase • Pyridostigmine
susceptibility • Neostigmine
• Poor absorption • Physostigmine*
• ACh: rapid (IV bolus: 5-20s *Not FDA registered
effect) ▪ Central Acetylcholinesterase
• β-methyl group: less nicotinic Inhibitors
potency • Donepezil
▪ Alkaloids • Rivastigmine
• Nicotine • Galantamine
• Pilocarpine • Phased out: Tacrine
• Muscarine, Lobelline,
Arecoline*
*causes oral cancer
Jarvin Enosh Tan, RPh January 16, 2021

▪ Organophosphates (also block o Lewy body dementia &

butylcholinesterase and Parkinson’s disease
neuropathy target esterase) dementia
• Echothiophate – some clinical • Frontotemporal dementia
use (FTD)
• Malathion, parathion o Heterogenous
(prodrug insecticides) • Vascular (multi-infarct)
• G series nerve agents (tabun, dementia (VaD) (11.7% of PH
sarin, soman, cyclosarin) cases)
o Indirect-acting cholinergics: MOA o Vascular accidents
▪ Inhibition of cholinesterase • Limbic-predominant age-
▪ After some time: aging related TDP-43
• Enzyme inactivation encephalopathy (LATE)
irreversible • Behavioral and Psychological
• Antidote: Atropine (blocks Symptoms of Dementia
muscarinic AChR only), • Aggression and agitation
Pralidoxime* (reactivates o Physically aggressive
enzymes; give with Atropine) agitation – pushing, kicking,
biting, spitting
*Not FDA registered o Physically nonaggressive
o Acetylcholinesterase inhibitors: 3 behavior – pacing,
indications wandering, inappropriate
voiding, undressing
▪ Myasthenia gravis (carbamates) – o Verbally aggressive
Particularly Pyridostigmine behavior – screaming,
• Autoimmune disease: yelling, cursing
antibodies vs AChR o Verbally nonaggressive
• Fatigue, muscle weakness, behavior – requesting
difficulty with muscle attention, repetitively
contraction calling out
• *Myasthenia Gravis • Apathy (72%)
Samahang Pilipino • Delusions (70%)
▪ Dementia (central AChEIs) • Aggression/Agitation (60%)
▪ Reversal of nicotinic • Anxiety (48%)
neuromuscular blockade (NM) • Psychomotor disturbance (46%)
(carbamates) • Irritability/lability (42%)
o Dementia • Sleep/wake disturbance (42%)
▪ Causes of dementia • Depression/dysphoria (38%)
• Alzheimer’s disease (AD) • Disinhibition (36%)
(85.5% of PH cases) • Sundowning (18%)
o Probable or possible • Hallucinations (15%)
o Preclinical (only for • Hypersexuality (3%)
research, using • Euphoria (2%)
biomarkers) • Obsessive-compulsive (2%)
• Dementia with Lewy Bodies • Medications for dementia
(DLB) • Central AChEIs
o Parkinson’s Sx • NMDAR antagonist
Jarvin Enosh Tan, RPh
• Ginkgo biloba Egb 761???
• BPSD: antidepressants, mood
stabilizers, antipsychotics*****,
Propranolol
• Central AChEIs: Donepezil,
Rivastigmine, Galantamine
• Indications
o Alzheimer’s disease
o Dementia with Lewy
bodies: Donepezil,
Rivastigmine
• MOA
• Onset
o 6 weeks to symptom
improvement
o Months for stabilization of
degenerative course
(Does not change course of
degeneration or improve
mortality)
• Administration (counsel both
service user and carer)
o Donepezil – once daily at
bedtime; orodispersable
tablet
o Rivastigmine, Galantamine
– twice daily with food
▪ Reduced GI SEs
▪ Delay absorption,
reduce Cmax, increase
AUC
• Contraindications –
hypersensitivity
• Restarting dose: caution with
Rivastigmine (if stopped >3 d)
o Vomiting with esophageal
rupture
• Common side effects
o GI: N/V/D, appetite loss,
increased gastric acid
secretion, dyspepsia (take
with food)
January 16, 2021
o Etc: Weight loss, headache,
dizziness, fatigue,
depression, asthenia
o Insomnia (if so, take
Donepezil in morning)
• Rare side effects
o Seizures
o Syncope
• Interactions: AVOID
ANTICHOLINERGICS
• Memantine
• Indications – adjunct to
Alzheimer’s disease [OD (ER) or
BID (IR)]
• MOA
o Low-affinity uncompetitive
NMDAR antagonist
o Memory problems (short-
term)
o Free radicals (long-term)
• Onset
o No expected symptom
improvement
o Months for stabilization of
degenerative course
• Side effects
o Dizziness, headache
o Hallucinations, insomnia
o Constipation
o Rare seizures
• Drug Interactions
o Drugs that raise urine pH
can reduce elimination,
increase plasma levels
o Clearance down by 80% at
urine pH 8
o CAIs, NaHCO3
• Ginkgo biloba Egb 761
• Flavonoids, bioflavonoids
• Proanthocyanidins
• Trilactonic diterpenes
(ginkgolide A, B, C)
• 240 mg
• Publication bias, low quality
studies, inconsistent findings
• Financially toxic
Jarvin Enosh Tan, RPh January 16, 2021

• Dementia: All adjunctive ▪ Amifampridine (3,4-

• Multicomponent interventions diaminopyridine) and
• Music (decreases BPSD, Dalfampridine (4-aminopyridine)
agitation, dep./anx.) • MOA: K+ channel blockade →
• Encourage exercise (better prolonged
ADLs) depolarization/delay
• Tailored occupational therapy repolarization → Increased
• Redirect, refocus; increase social ACh release
activities, eliminate sources of • ADR:
conflict, frustration o Common (3,4-DAP):
• ABCs (antecedent, behavior, Perioral, extremity
consequence) paresthesias; headache,
• Carer support (forgotten service nausea, abdominal pain,
user) diarrhea, elevated LFTs
• Indirect-acting cholinergics o Serious: seizure activity,
o Indirect-acting cholinergics: QT prolongation
Neuromuscular blockade reversal o In terms of CNS
• Neuromuscular blockers penetration,
o Depolarizing: NM agonists Amifampridine <
o Non-depolarizing: NM Dalfampridine
blockers o Amifampridine preferred
▪ Acetylcholinesterase • Anticholinergics (Antimuscarinics)
inhibitor → increased o Intro
ACh → compete with ▪ Muscarinic antagonists -
non-depolarizing anticholinergic/parasympatholytic
neuromuscular ▪ Prototype: Atropine (Atropa:
blockers at NM Fates)
receptors (reversal) • Or Hyoscyamine
▪ Neostigmine • Atropa belladonna (deadly
▪ Edrophonium nightshade)
(historical) • Datura stramonium (jimson-
o Increased ACh binds to weed/sacred Datura thorn
muscarinic receptors also, apple)
so need • 3o amine alkaloid esters of
atropine/glycopyrrolate to tropic acid
prevent GI/heart side ▪ Other plant alkaloids
effects • Scopolamine/hyoscine
o +
K channel blockers (for Lambert-Eaton (Hyoscyamus niger / henbane)
myasthenic syndrome) • l-(-) isomers of scopolamine &
▪ LEMS: NMJ dysfunction, muscle atropine more potent than d-
weakness (+)
• Antibodies blocking voltage- • Homatropine
gated Ca2+ channels o Pharmacokinetics
• Decreased ACh release ▪ 30 – good oral absorption, wide
distribution (up to CNS)
▪ 4o – poor oral absorption, poor BBB
penetration
Jarvin Enosh Tan, RPh January 16, 2021

o Elimination ▪ Scopolamine (patch; behind the

▪ Atropine: 2 phases ears) and antihistamines – motion
▪ Rapid phase t1/2 = 2 h, slow phase = sickness
13 h • Scopolamine also used
▪ 50% excreted unchanged preoperative for nausea
▪ Effects decline across body rapidly ▪ Homatropine, Cyclopentolate,
except eyes (persist 72 hours) Tropicamide – ophthalmologic
o Selective Anticholinergic Drugs disorders (eye drops)
▪ 3o • Strabismus (cycloplegic
• Atropine penalization)
• Biperiden, Benztropine, • Amblyopia (lazy eye)
Trihexyphenidyl, Procyclidine • Corneal abrasions
• Cyclopentolate • Ophthalmologic examinations
• Darifenacin, Solifenacin ▪ Chronic obstructive pulmonary
• Dicyclomine/Dicycloverine disease (COPD)
• Homatropine • Ipratropium (short-acting) –
• Oxybutynin blocks M1, M2, M3
• Scopolamine o Preferred agent
• Hyoscine N-butylbromide (duration of action, low
• Tolterodine side effects, QoL)
• Tropicamide • Tiotropium (long-acting) –
▪ 4o blocks M1 and M3
• Aclidinium, Umeclidinium o Role in severe asthma
• Ipratropium, Tiotropium • Umeclidinium (long-acting) –
• Otilonium M3-selective
• Trospium • Aclidinium (long-acting) – M3-
• Glycopyrronium/ selective, twice daily
Glycopyrrolate • Glycopyrronium
o MOA: reversible inverse agonism (most; (Glycopyrrolate)
atropine, pirenzepine, trihexyphenidyl, ▪ GI
ipratropium, glycopyrrolate) or • Atropine + Diphenoxylate –
antagonism diarrhea (atropine
o Effects: opposite of DUMBBELS and CNS discourages abuse)
ACh effects (+cycloplegia) • Otilonium,
▪ Low dose: bradycardia → blockade Dicyclomine/Dicycloverine,
of presynaptic AChR (provides Atropine, Hyoscine N-
feedback inhibition) butylbromideOTC(tab only) –
o Indications irritable bowel syndrome
▪ Biperiden, Benztropine, ▪ Bladder – urinary incontinence
Trihexyphenidyl, Procyclidine – (M3-preferring)
Parkinson’s & extrapyramidal • Oxybutynin
symptoms • SOlifenacin, DArifenacin
• Tolterodine (M2, M3)
• Fesoterodine
Jarvin Enosh Tan, RPh January 16, 2021

• Propiverine ▪ Not desensitized

▪ Cardiovascular: Atropine o ADR: nausea, insomnia, abnormal
• Atrioventricular (AV) block dreams
(post-MI, or in Chagas) • Adrenergic Neurotransmission
▪ Others o Tyrosine –(tyrosine transporter into
presynaptic neuron)---(Tyrosine
• Glycopyrronium/
Hydroxylase)→DOPA –(DOPA
Glycopyrrolate –
decarboxylase)→ Dopamine –
hyperhidrosis, sialorrhea (Dopamine beta-hydroxylase)→
o Contraindications Norepinephrine –(Vesicular
▪ Uncontrolled tachyarrhythmias Monoamine Transporter 2/VMAT-
▪ Myasthenia gravis 2)→vesicles
▪ Gastric retention o Tyrosine –(L-amino acid
▪ Narrow angle-closure glaucoma decarboxylase)→ Tyramine
o Beer’s criteria: avoid in elderly as much o Metabolized by Monoamine Oxidase
as possible and Catechol-o-methyltransferase
• Ganglionic blockers o Inhibitors of Tyrosine Hydroxylase (rate-
o Historical limiting step)
▪ Hexamethonium: 1st drug for ▪ Metyrosine (not clinically
hypertension (ion channel blocker) significant)
o Rarely used (competitive nicotinic o Inhibitors of VMAT2:
ganglionic blockers) ▪ Reserpine: outdated agent for
▪ Trimethaphan – hypertensive hypertension
emergencies due to dissecting ▪ Tetrabenazine and
aortic aneurysm, pulmonary Deutetrabenazine
edema • Tardive dyskinesia
▪ Mecamylamine – moderately • Huntington’s chorea
severe to severe HTN o Dextroamphetamine
• Direct-acting cholinergics: nicotinic ▪ 1st line for ADHD
o Nicotine Replacement Therapy ▪ Narcolepsy
▪ α4β2 nAChR → DA in?
• Reward
• Desensitization after 1 stick
• Resensitization (craving,
withdrawal) during gap
between sticks
• Chronic use → chronic
desensitization →
upregulation → ↑craving
▪ α7 nAChR → Glu → DA
• Mental alertness, pro-
cognitive
o ADR: GI, headache
• Partial agonist
o Varenicline: α4β2 nAChR partial agonist
▪ Stabilizes channel in less
frequently open state
Jarvin Enosh Tan, RPh January 16, 2021

CNS o Central
▪ MethylphenidateS2,
Amphetamines
▪ PhentermineS2
o Others
• Vasopressors
o Indication: when >30 mmHg ↓BP or
>60 mmHg ↓mean arterial pressure
▪ Hypoperfusion → organ damage
▪ Correct hypovolemia first
o Principles
• Sympathomimetic Drugs ▪ 1 drug, many receptors
o Vasopressors ▪ Dose-response curve – dose-
▪ Epinephrine dependent activation of receptors
▪ Norepinephrine ▪ Direct vs reflex actions
▪ Dopamine o Epinephrine
o Inotropes ▪ Kinetics
▪ Dobutamine
• Absorption: poor PO BA
▪ IsoproterenolI
o α1 agonist (COMT)
▪ PhenylephrineOTC (eye drops: PNF) • IV (central venous catheter
▪ PhenylpropanolamineOTC preferred)
▪ Pseudoephedrine • Nasal, inhalational,
▪ Methoxamine intraocular (indication-
▪ Propylhexedrine specific)
▪ Midodrine ▪ MOA: agonist, α1 = α2 = β1 > β2
o α2 agonist • ↑↑CO (+inotropic,
▪ Clonidine +chronotropic)
▪ Brimonidine
• ↑SVR (decreased at low
▪ Apraclonidine
doses because of β2 agonism)
▪ Methyldopa
▪ Guanfacine, Guanabenz ▪ Indications
▪ Dexmedetomidine • 1st line: anaphylactic shock
▪ Tizanidine • Cardiopulmonary
o α1-α2 agonist resuscitation (cardiac arrest)
▪ TetrahydrozolineOTC, • Hypotension during coronary
OxymetazolineOTC, Xylometazoline artery bypass grafting (CABG)
o β2 agonist • Severe, refractory asthma
▪ Terbutaline, Isoxsuprine
• (+)local anesthetics →
(tocolytics)
vasoconstriction
▪ Salbutamol / Albuterol (SABA)
o Norepinephrine (IV)
▪ LABAs
• Salmeterol, Formoterol and ▪ Aka levarterenol
Arformoterol ▪ MOA: α1 = α2 > β1
• Vilanterol • ↑↑SVR
• Indacaterol and Olodaterol • ↑CO (+inotropic, mild
o Mixed – EphedrineS2 +chronotropic) reflex
bradycardia (net effect: - / ↓)
Jarvin Enosh Tan, RPh January 16, 2021

▪ Indications o IsoproterenolI
• 1st line: septic shock ▪ IV; Inotrope, NOT vasopressor
• Cardiopulmonary ▪ MOA: β1 = β2
resuscitation (cardiac arrest) • ↑CO +inotropy,
• Cardiogenic, hypovolemic chronotropy
shock • ↓SVR
o Dopamine ▪ Indication
▪ IV; Different drug at different • Bradyarrythmia
doses • Hypotension due to
▪ MOA: D1 = D2 >> β1 >> α1 bradycardia
• Low dose (0.5-2 mcg/kg/min) o Vasopressors and Inotropics:
– renal vasodilation Complications
(+cerebral, coronary) ▪ Hypoperfusion (excessive
o Urine output, natriuresis vasoconstriction): extremities,
• Moderate dose (5-10 kidneys, etc
mcg/kg/min) – ↑CO, ↑SVR ▪ Dysrhythmias (β1 receptor
o Variable effects: stimulation)
vasodilation vs ↑CO via ▪ Myocardial ischemia
↑stroke volume ▪ ↑ myocardial O2 consumption
• High dose (>10-20 (coronary vasodilation insufficient)
mcg/kg/min) – ↑↑SVR ▪ Peripheral extravasation
▪ Indication • Excessive vasoconstriction →
• Heart failure skin necrosis
• Cardiopulmonary • Give via central catheter
resuscitation (cardiac arrest) • Give Phentolamine to
• Cardiogenic shock counteract infiltration
▪ AVOID in septic shock ▪ Hyperglycemia (inhibition of
o Dobutamine insulin secretion) – NE/E>DA
▪ IV; Inotrope, NOT vasopressor • α1 agonist
▪ MOA: β1 > β2 o Nasal decongestants
>>>>>>>>>>>>>>>>>>>>>>>>>>α1 ▪ Phenylephrine (vasopressor)
• Hypotension
• ↑CO → +inotropy,
• Reserved; when NE
chronotropy
contraindicated due to
• ↓SVR arrythmias or failed other
▪ Indication therapies
• Preferred: Cardiogenic shock • Nasal congestion
• Acute, decompensated heart • Eye drops are PNF
failure (vasoconstrictor,
• AVOID: sepsis (hypotension decongestant, mydriatic)
risk) ▪ PhenylpropanolamineOTC
• Nasal congestion
• Toxicity: hemorrhagic stroke
(phenylpropanolamine
Jarvin Enosh Tan, RPh January 16, 2021

formerly abused for weight • Open-angle glaucoma

loss) alternative (Lower IOP)
▪ Propylhexedrine • Cause allergic conjunctivitis,
o MidodrineI (prodrug → hyperemia, ocular pruritus
desglymidodrine) – Tmax = 1h o Allergic conjunctivitis
▪ Orthostatic hypotension (may onset can be delayed up
cause HTN when Px is supine) to 18 months
o α1 agonist toxicity ▪ Clonidine (binds to I1 receptors)
▪ Hypertension • 2nd line: Hypertension
▪ Tachycardia or reflex bradycardia • 2nd line: ADHD, Tourette’s,
▪ Agitation smoking cessation
▪ Diaphoresis (sweat) • Other indications
▪ Mydriasis ▪ ADRs
• α2 agonist • Dry mouth, sedation,
o Imidazolines: MOA: α2 agonist, but orthostatic hypotension
where? • Rebound hypertension on
▪ Receptors withdrawal → reinstitute drug
• α2A + non-selective beta-blocker
o CNS – postsynaptic • +withdrawal symptoms:
regulation of inattention, headache, apprehension,
hyperactivity, impulsivity tremors, abdominal pain,
o Spinal cord: analgesia sweating, tachycardia.
o ANS – presynaptic brakes o Guanfacine, Guanabenz
on NE release ▪ Alternative: HTN
• α2B ▪ Guanfacine: alternative for ADHD
o CNS – sedation
and Tourette’s
o ANS – vasoconstriction
o Dexmedetomidine
(blood vessels)
▪ Sedation in ICU mechanically-
• α2C
o CNS – sedation, ventilated Px before anesthesia
hypotension; spinal cord: (decreased need for opioids)
analgesia ▪ ADR: hypo/hypertension,
o ANS – presynaptic brakes bradycardia, nausea, atrial
on adrenaline release fibrillation
(adrenal gland) o Tizanidine – skeletal muscle relaxant
▪ MOA o Methyldopa
• Initial: postsynaptic α2 ▪ “False neurotransmitter” –(DOPA
receptor agonism → decarboxylase)→ α-
vasoconstriction methyldopamine –(dopamine β-
• Then: CNS Imidazoline 1 (I1) hydroxylase) → α-
receptors → downstream
methylnorepinephrine
catecholamine release →
▪ HTN (esp in pregnant women)
presynaptic α2 receptors → ?
• Though mild effect and slow
• CNS postsynaptic α2C
agonism? onset of action (3-6h), still
▪ Apraclonidine (no CNS useful
penetration) and Brimonidine
Jarvin Enosh Tan, RPh January 16, 2021

▪ ADR • Mixed
• Sedation, dry mouth, mild o Pseudoephedrine – nasal congestion in
orthostatic hypotension, nasal U.S.; controlled
congestion o EphedrineS2 – found in ma huang
• (+)-Coombs test; rarely ▪ Less potent vs epinephrine; used in
associated with hemolytic post-anesthesia hypotension
anemia • Central
• Mixed α1-α2 agonist o MethylphenidateS2
o OxymetazolineOTC, TetrahydrozolineOTC, ▪ Allosteric blockade of
Naphazoline norepinephrine transporters and
▪ Red eye dopamine transporters (NET, DAT)
▪ Oxymetazoline (nasal spray OTC): ▪ Bioequivalent formulations are
nasal congestion (α2A-selective) NOT clinically equivalent
• ADR: rhinitis medicamentosa o Amphetamines
▪ MOA
• Do NOT use >3 days
• Therapeutic doses: Blocks
• β2 Agonists
NET, DAT competitively as
o Short-acting (SABA)
pseudosubstrate
▪ Albuterol/Salbutamol &
Levalbuterol • Misuse doses:
▪ Procaterol??? o Transported into
▪ For asthma rescue presynaptic terminal,
o Long-acting (LABA) competitively blocks
▪ Salmeterol, Formoterol and VMAT2
Arformoterol for asthma o Amphetamine hitchhikes
▪ Vilanterol (in combo) on VMAT2, displaces DA
▪ Indacaterol and Olodaterol for in vesicles
COPD o Presynaptic cytoplasm
flooded with DA
• β3 Agonist, D1 agonist
o DAT changes direction,
o Mirabegron – β3 agonist for urinary
spills DA into synapse
retention
▪ Indications (Methylphenidate and
o Fenoldopam
Amphetamines)
▪ MOA: peripheral D1-selective
agonist → peripheral arterial • 1st line, ADHD
vasodilation • Narcolepsy (excessive
▪ t1/2 = 10 min (admin.: continuous IV daytime sedation)
infusion) ▪ ADRs (Methylphenidate and
▪ Indications Amphetamines)
• Postoperative hypertension • GI: Anorexia, nausea,
• Hypertensive emergencies abdominal pain, weight loss
▪ ADRs • CNS: Insomnia, headache, tic
• Headache worsening, nervousness,
irritability, overstimulation,
• Reflex tachycardia
tremor, dizziness, manic
• Flushing
switch
• Increased IOP
Jarvin Enosh Tan, RPh January 16, 2021

▪ Boxed warnings (Methylphenidate o β-blockers

and Amphetamines): ▪ Intrinsic sympathomimetic activity
• Dependence and addiction (ISA)
risk ▪ Membrane stabilizing action (MSA)
• Sudden death and serious ▪ Cardioselective
cardiovascular events ▪ Mixed
o Atomoxetine ▪ No improvement in outcomes in
▪ MOA: Blocks NET, Increases NE and HTN – Atenolol
DA(how?) in prefrontal cortex, but • α1 blockers
not nucleus accumbens o Prazosin, Doxazosin, Terazosin;
▪ No abuse potential Uroselective: Alfuzosin, Tamsulosin
▪ ADHD (2nd line) o MOA: α1 antagonists; tamsulosin: α1a-
o PhentermineS2 selective
▪ MOA: same with amphetamines o Indications: Benign Prostatic
(NET, DAT, VMAT2 block) → pro- Hyperplasia (BPH), urolithiasis (stone
opiomelanocortin (POMC) neurons passage – Tamsulosin)
→ α-melanocyte stimulating o ADRs
hormone (MSH) → Binds ▪ Hypotension (1st dose
melanocortin 4 receptors (MC4R) phenomenon) – exaggerated
→ Appetite suppression response
▪ Chronic weight management in ▪ Solution: take at bedtime
obesity (+Topiramate) ▪ Tamsulosin
▪ Monotherapy: tolerance, weight • Ejaculatory dysfunction
loss reverses, abuse potential, BP (decreased volume)
and cardiovascular risks • Intraoperative floppy iris
▪ Synergism with topiramate at syndrome (flaccid iris,
lower dose prolapsed, miosis)
o Reserpine – VMAT2 inhibitor ▪ Others
o Tetrabenazine and Deutetrabenazine • Headache, dizziness, nasal
▪ Purpose of deuterium: prolong congestion
half-life, as body doesn’t recognize o Prazosin for PTSD nightmares?
deuterium ▪ MOA: α1 antagonist, penetrates
▪ Huntington’s chorea BBB (most lipophilic among α1
▪ ADR: sedation, akathisia, blockers)
Parkinson’s • Fear response, REM sleep
• Others ▪ Indications: Posttraumatic Stress
o Tyramine Disorder (PTSD) nightmares
• Adrenergic antagonists ▪ Issues
o α1 blocker • Dosing – supramaximal???
▪ Prazosin, Doxazosin, Terazosin (due to tolerance)
▪ Alfuzosin, Tamsulosin • Extinguishing nightmares =
o α2 blockers blocking trauma healing
▪ Yohimbine, Tolazoline, process?
Rauwolscine • PH: only Doxazosin available
o α1-α2 blockers (penetrates less)
▪ Irreversible: Phenoxybenzamine
▪ Reversible: PhentolamineI
Jarvin Enosh Tan, RPh January 16, 2021

• α2 blocker ▪ Distribution and clearance

o Yohimbine • Rapid, moderate distribution
▪ NOT recommended for erectile (Vd)
dysfunction (superseded) • Propranolol and Penbutolol:
▪ 3rd line: orthostatic hypotension lipophilic, cross BBB
o Rauwolscine / isoyohimbine • Propranolol and Metoprolol:
• α1, α2 blocker extensive liver metabolism
o Irreversible: Phenoxybenzamine • Esmolol: t1/2 = 10 min
▪ Added MOAs: norepinephrine
reuptake inhibition, antagonism at
H1, AChR, and 5-HT receptors
(HAM blockade)
▪ Duration: 14-48 hours
▪ Preferred agent for preoperative
preparation for
pheochromocytoma (10-14 days
before)
▪ Slow onset, long-lasting, enters
CNS
o Reversible: PhentolamineI (rapid onset,
short t1/2)
▪ Added MOAs: mild 5-HT receptor
antagonist, agonist at H1, H2, and
M1 receptors
▪ Hypertensive crisis in
pheochromocytoma or due to o Effect
MAOI + tyramine ▪ β1
▪ Extravasation in vasopressor Tx • (-)ino and chronotropy (CO?)
o Another competitive antagonist: • Suppression of renin release
tolazoline (t1/2 = 313 h) ▪ β2
• β-blockers • Vasoconstriction (SVR?) →
o Heterogenous as a class long-term decrease (+inhibit
o Intrinsic sympathomimetic activity (ISA) renin release)
– partial agonists • Bronchoconstriction
o Membrane stabilizing action (MSA) –
o Other Mechanisms
local anesthetic
▪ Potent 5-HT1A antagonists
o Cardioselective
o Mixed (especially Pindolol)
▪ Carvedilol ▪ Block release of endogenous
▪ Labetalol melatonin
▪ Nebivolol
o Pharmacokinetics
▪ Absorption: Most have good oral
BA (except?)
▪ Propranolol – variable, depends on
1st pass and absorption improved
with protein-rich diet
Jarvin Enosh Tan, RPh January 16, 2021

o Atenolol for hypertension? • 1st line: Chronic stable angina

▪ β1-selective antagonist, no local o Acute myocardial
anesthetic / membrane-stabilizing infarction (after
activity stabilizing)
▪ Most dependent on renal o Coronary artery disease –
elimination (up to 50%) pathologic processes
▪ Vs Placebo affecting coronary
• All-cause mortality, CV arteries
mortality, myocardial o Coronary/ischemic heart
infarction = placebo disease – inadequate
[HEP, MRC Old, Dutch TIA, blood supply due to
TEST] obstruction of epicardial
▪ Vs active drug – all-cause mortality, arteries
CV mortality, stroke o Angina – chest
• Favored HCTZ/Bendrofluazide pain/discomfort due to
[HAPPHY] myocardial ischemia
• Favored HCTZ [MRC Old] (iskhein – keep back
• Favored Captopril [UKDPS] + hemia – blood)
• Favored Losartan [LIFE] o Stable – symptoms only
• Favored Lacidipine [ELSA] on exertion
o Metoprolol tartrate vs succinate for o Infarction – necrosis due
heart failure? to really bad ischemia
▪ Tartrate: Twice daily dosing o β1 receptor blockade →
▪ Succinate (XR): once daily negative
▪ Possible that Tartrate was ino/chronotropy →
underdosed in clinical trials reduced myocardial O2
• Counterargument: heart rate demand
for patients on Carvedilol and o Adipose β-receptor
patients on Metoprolol blockade → Lipolysis
tartrate not significantly inhibited → Less FFAs →
different (COMET) shift to carb. metabolism
▪ To be safe, use succinate for HF (less FFA uptake by heart)
o Indications • Arrythmias (more in
▪ Cardiovascular antiarrythmics)
• 2nd line – Primary o Class II (Class IIa?)
hypertension antiarrhythmics – beta
o Pregnancy: Labetalol blockers
• Stabilized congestive heart ▪ Sinus tachycardia,
failure (after ACEI/ARB) atrial fibrillations
o Bisoprolol o Class III (Class IIIa?) –
o Carvedilol (IR and CR) SotalolI (Ikr blocker)
o Metoprolol succinate XR ▪ Ventricular
tachycardia, atrial
fibrillations
Jarvin Enosh Tan, RPh January 16, 2021

▪ Neurological ▪ Smooth muscle spasm

• Essential tremor (β2)– • Airway resistance (non-
Propranolol selective)
• 1st line – Migraine o Caution for asthma,
prophylaxis: Propranolol, COPD
Metoprolol • Cold extremities
• PRN for stage fright • Peripheral artery disease
▪ Others worsening (claudication)
• Open-angle glaucoma ▪ CNS (not just lipid-soluble drugs)
o Inferior to • Mild sedation, vivid dreams,
prostaglandins, except depression
for $$$$$ ▪ Metabolic
o Timolol, Betaxolol, • Masking hypoglycemia
Carteolol, Levobunolol, • Slight weight gain
Metipranolol • Increase in TGs, decrease in
• Hyperthyroidism HDL (older BBs)
(symptomatic) – Propranolol o Peripheral
• Primary prophylaxis, variceal vasoconstriction →
bleeding (alternative) – insulin resistance
Propranolol, Nadolol o Less with Carvedilol,
o Block mesenteric Nebivolol
arteriole vasodilation (β2) ▪ Others
→ unopposed α- • Fatigue (limits exercise
mediated capacity),
vasoconstriction → • Sexual dysfunction (erectile
↓portal inflow dysfunction)
• Infantile hemangiomas • Hyperkalemia (non-selective)
(entangled BVs under skin) – β2
o Uncomplicated – topical
Timolol, Propranolol
o High-risk – Propranolol
(1st line)
o ADRs
▪ Cardiac
• Bradycardia [(-) inotropy]
• Precipitation/worsening CHF
• ↓CO, ↑SVR
• Less with ISA
• Withdrawal (abrupt
discontinuation) → ischemic
symptoms, MI
Jarvin Enosh Tan, RPh
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