PharmDrug List Complete SGU-UST

Class of Drugs: Direct-Acting Cholinergic Agonists
Drug Name Receptor Chemical Structure Mechanism of Action Effects Indications/Use Pharmacokinetics Adverse Effects
Muscarinic: Binds to M receptor,
induces parasympathethic activity;
Muscarinic: parasympathetic, symp
Blocked by ATROPINE
Ester of choline sweat glands
M1,3,5 - Gq (PLC, IP3, DAG, Ca2+) Therapeutically no use due to
Acetylcholine (Ach) M/N M2,4 - Gi (K+ channels, ↓ cAMP) multiplicity of actions & rapid
(charged Quaternary Nicotinic: stimulate all autonomic Cholinergic hyperactivity:
Nicotinic: effects seen once inactivation
Ammonium, so insoluble) ganglia; secrete EPI from adrenal "DUMBELLS"
muscarinic receptor blocked by medulla; stim voluntary muscle Sweating, salivation, flushing, low BP,
atropine
nausea, abdominal pain, diarrhea,
N - cation channels
bronchospasm, urination
GI: post-op distention, atony &
retention, adynamic ileus,
Not hydrolyzed by AChE (use
Bethanechol M only Ester of choline Parasympathetic megacolon, reflux
other esterases
Atonic bladder
Xerostomia (dry mouth)
Glaucoma (decrease intraocular External only: high potency & long
Carbachol M/N Ester of choline Parasympathetic Miosis (pupillary constriction)
pressure) duration
Diagnose bronchial hyperreactivity &
Methacholine M/N Ester of choline Hydrolyzed by AChE slowly
asthma
Sweat, salivary, lacrimal, & bronchial Acute-closed angle Glaucoma (2nd
Natural Alkaloid CNS disturbances
Pilocarpine (M) Partial gland secretions to timolol for open-angle)
(Tertiary Amine) Sweating, salivation
Contract iris Xerostomia/Sjogren's Syndrome
Muscarine M Natural Alkaloid
Low dose: ganglion stim by CVS: sympathomemitic due to

Ganglion blockade, nausea, vomiting,
depolarization (both symp and catecholamine from adrenergic nerves
diarrhea, urination
Natural Alkaloid parasymp) & adrenal medulla
Nicotine Nn > Nm Smoking cessation Acute Poisoning: above + abd. pain,
(Tertiary amine) GI & Urninary: parasympathomimetic
cold sweat, confusion, weakness, low
High doses: ganglionic & Initial stim of salivary & bronchial
BP, weak pulse,
neuromuschular blockade secretions
Areocoline Natural Alkaloid

Lobeline Natural Alkaloid
Tetramethylammonium (TMA) +
Nn > Nm Synthetic Experimental only
Dimethylphenyl Piperazium (DMPP)
Varenicline Nn (partial) Ganglion stimulant Smoking cessation therapy Oral
Class of Drugs: Indirect Cholinergic Agonists (anti-cholinesterases)
Drug Name Receptor Chemical Structure Mechanism of Action Effects Indications Pharmacokinetics Adverse Effects
Inhibit AChE & ButyrlcholineEst → ↑
Ach Diagnosis of myasthenia gravis (v.s.
Simple alcohol with Lambert Eaton Syndrome Hydrolyzed by receptor, Short
Edrophonium
quaternary ammonium Binds reversibly to active site duration of effect (not for
(a.k.a. Tensilon, Enlon)
group Reverse neuromuscular bock from treatment)
Enzyme inhibitor doesn't involve non-polarizing muscular blockers
covalent bond, short-lived
Stimulates GI, bladder

Carbamate esters of CNS: EEG activation → alerHng Salivation
Antidote for tubocurarine, other
alcohol response; convulsions → Flushing
competitive NMJ blockers
coma → respiratory arrest Low BP
Neostigmine quaternary ammonium (no Hydrolyzed by receptor Nausea
Treat myasthenia gravis
CNS) Eye, Respiratory, GI & Urinary: Abd pain
parasympathetic Diarrhea
More effect on NMJ than
AChE Bronchospasm
physostigmine (Also direct nicotinic
Inhibit AChE & ButyrlcholineE → CVS: neg chronotropic, dromotropic, effect at NMJ)
↑ Ach inotropic → ↓ cardiac output;
hypotension
Binds covalently to active site Convulsions
NMJ: increased contraction in weak Bradycardia
Carbamate esters of
Binding to target lasts longer muscles Accumulation of Ach → paralysis of
alcohol
Intestinal, bladder atony skeletal muscle
Physostigmine Hydrolyzed by receptor
Treat anticholinergic drug overdose
Tertiary amine (can enter
Contraindicated in pts w/TCA
CNS)
overdose (aggrevates depression of
cardiac conduction)
Carbamate esters of
alcohol (Most common AChE for)
Pyridostigmine CNS Toxicity
Myasthenia gravis
quaternary ammonium
Glaucoma
Organophosphate All organophosphates are Organophosphate
(Chronic open-angle,
Echothiophate distributed to all parts of body, overdose/exposure is treated with
subacute/chronic angle-closure after
(but not liposuluble) including CNS Atropine and Pralidoxime
iridetomy or if surgery is not chosen)
Activated in body by conversion

Inhibits AChE & Butyrlcholinesterase
to oxygen analogs;
Malathion rapidly metabolized
Organophosphate Binds to & hydrolysed by enzyme
Malathion & Parathion Insecticide to inactive products in birds & CNS Toxicity
(Thiophosphate) → acHve site phosphorylated
AChE (covalent bond extremely stable)
humans, but not insects;
Palathion not detoxed in
vertebrates
Phosphorylated enzyme may undergo
ageing (bond strengthens)
Tabun
Sarin Organophosphate Extremely potent CNS toxin Terrorism CNS Toxicity
Soman
Tacrine
Donepezil
Alzheimer's disease
Rivastigmine
Galantamine
Pralidoxime is an AChE reactivator,

AChE ONLY OUTSIDE THE CNS, can split the
Pralidoxime Early organophosphate poisoning
regenerator enzyme-phosphate bond if ageing has
not occurred
Class of Drugs: (Cholinergic) Muscarinic Antagonists
Eye: Mydriasis, unresponsiveness to

light, cycloplegia
Mydriasis & cycloplegia
GI: antispasmodic (decr. gastric
(phenylephrine preferred for
motility); HCl not affected
pupillary dilation if cycloplegia
(ciliary paralysis) not required) May raise intraocular pressure in
Urinary: decr hypermotility of bladder;
Antispamodic in GI & bladder close angle glaucoma
enuresis (alpha-adrenergic preferred)
Antidote for (in)direct ACh agonists
Binds competitively to muscarinic
Belladonna alkaloid Antisecretory in respiratory Readily absorbed, partially Cutaneous vasodilation in upper
receptors CVS: high dose → blockade of atrial M2,
Atropine Reverse sinus bradycardia metabolized by liver; eliminated body
tachycardia;
Tertiary amine in urine; half life 4 hrs
Central and peripheral low dose → iniHal BRADYCARDIA (due
Given with neostigmine to counter High body temp (no sweat)
to blockage of presynaptic M2 on vagal
unwanted muscarinic effects (NMJ
postganglionic fibers that normally
blockade) of neostigmine Dry mouth, blurred vision, sandy
inhibit ACh in the sinus node)
eyes, tachycardia, constipation,
Blocks vasodilation of skeletal muscle
AChE inhibitor/organophosphate urinary retention
and coronary vascular bed
poisoning
Bradycardia (low dose), Tachycardia
Secretions: inhibition of salivary, sweat,
+ CNS effects (higher doses)
M lacrimal glands
Tertiary only:
CNS: confusion, hallucinations,
delirium → depression, circulatory &
Belladonna alkaloid Anti-motion sickness (can be respiratory collapse → death
Mydriasis & cycloplegia in diagnostic
Tertiary amine transdermal) (Drug of choice)
Scopolamine procedures & tx of iridocyclitis
Greater effects on CNS and Unusual: blocks short-term memory Contraindicated in pts with:
Prevents motion sickness
longer Sedation, excitement at higher doses Peptic ulcers
Old age
Quaternary ammonium Asthma/COPD pts unable to take Close angle glaucoma
Ipratropium
(No CNS) adrenergic agonists Prostatic hypertrophy (risk of
Quaternary ammonium decreased detrussor contraction
Tiotropium Bronchodilation COPD only
(No CNS) → urinary retenHon)
Homatropine
Mydriasis with cycloplegia (preferred
Cyclopentolate Tertiary amine Ophthalmology
due to short duration)
Tropicamide
Benztropine Parkinsonism & extrapyrimidal
Tertiary amine
Trihexyphenidyl effects of anti-psychotic drugs
Inhibit GI motility (oral) Prevent
Quaternary ammonium
Glycopyrrolate bradycardia during surgery
(No CNS)
(parental)
Tolterodine Tertiary amine Overactive bladder
Class of Drugs: (Cholinergic) Nicotinic (Nn) Antagonists, a.k.a. GANGLION BLOCKERS
Tetraethylammonium (TEA) Quaternary ammonium First ganglion blocker, little use Very short duration
Blocks action of ACh at nicotinic
receptors of both parasymp & symp
Hexamethonium (C6) Quaternary ammonium Hypertension Longer duration
autonomic gangia
Vaso-/venodilation, hypotension,
Severe/essential and
via 1. Prolonged depolarization (after tachycardia, mydriasis, reduced
Mecamylamine Nn Only ganglion blocker in US
initial stimulation) or, 2. Antagonism
uncomplicated/malignant
GI/urinary motility, xerostomia,
hypertension
of nicotinic receptors anhydrosis
The only other ganglion Some also block the ion channel
Trimethaphan gated by the Nn
blocker in clinical use
Class of Drugs: (Cholinergic) Nicotinic (Nm) Antagonists, a.k.a. NMJ BLOCKERS

Autonomic effects: Some agents are

moderate blockers of muscarinic
Nondeploarizing antagonist
Small, rapidly contracting muscles (face receptors
(competitive) blocker
& eye) paralyzed first, followed by Anaesthesia adjuvant during surgery IV (poor oral absorption, poor May cause histamine release
Tubocurarine Prototype, from curare Binds Nm, prevents Ach binding →
fingers, limbs, neck & trunk, to relax skeletal muscle membrane/BBB permeability)
prevents depolarization of cell
intercostals, then diaphragm Overcome by increased [Ach] in
membrane, contraction inhibited
synaptic cleft w/AChE inhibitors, e.g.
neostigmine/edrophonium
Nm IV by continuous infusion; Malignant hyperthermia: AD disoder

of skeletal muscle: stimulus-elicited
Depolarizing agnositic blocker Poorly metabolized at synapse, excessive release of Ca2+ from SR.
Respiratory muscles paralyzed last
Binds Nm, acts like Ach → end plate Endotracheal intubation rapidly hydrolyzd by plasma Main cause of anesthesia related
Succinylcholine Ganglion block at HIGH doses
depolarization Electroconvulsive therapy cholinesterase death (mostly when combined with
Weak Histamine release
→ generalized disorganized halogenated anesthetic).
contraction of motor units → flaccid Rapid onset (1-1.5 min), brief Tx: Dantrolene (blocks Ca2+ release
paralysis duration (5-10min) from SR → decr heat producHon)
Decamethonium (C10 analog of C6)
Blocks choline transporter →

ACh
Hemicholinium-3 prevents choline uptake, and hence, Only for research
transporter
ACh synthesis
Blocks ACh-H+ antiporter used to
Ach-H+
Vesamicol transport ACh into vesicles Only for research
antiporter
→ prevents Ach storage
Diseases with ↑ muscle tone

Degrades synaptobrevin → prevents
Protein by anaerobic (Torticollis, achalasia, straismus,
Synapto- synaptic vesicle fusion w/axon
Botulinum Toxin bacillus Clostridium blepharospasm, etc) IM
brevin terminal membrane → inhibits ACh
botulinum Facial wrinkles
release
Headache & pain syndromes
Class of Drugs: Direct-Acting Adrenergic Agonists
Drug Name Receptors Chemical Structure Mechanism of Action Effects Indications Pharmacokinetics Adverse Effects Contraindications
CVS: positive inotropic (contractility), chronotropic
(HR), dromotropic (conduction): beta1
↑ CO → ↑ O2 demands of heart
Blood pressure: low doses, beta → ↑ systolic due to
Interactionwith both alpha an
↑ contracHle force (beta1) ↓ diastolic pressure due
beta receptors
to vasodilation (beta2) → liQle change in mean BP (so Rapid onset, admin IV in
Low doses: beta (β) effects
no baroreceptor reflex) emergencies; can also admin
High doses: alpha (α) effects
high doses, alpha → ↑ BP due to ↑ ventricular subcut., endotracheal tube, CNS: anxiety, fear, tension,
Anaphylactic shock Enhanced CV actions with
Made from tyrosine in contraction (beta1), ↑ HR (beta1), vasoconstricHon inhalation, or topically to eye; headache, tremor
All β - Gs Asthmatic attack Hyperthyroidism (increased
the adrenal medulla (alpha1) → ↑ BP may ↓ HR (baroreceptor reflex) Oral admin ineffective Cerebral hemorrhage
Epinephrine α+β Polar, does not enter
α1 - Gq
Respiratory: bronchodilation (beta2)
Local anaesthetic: increased
Cardiac arrhythmias (esp.
receptors) & Cocaine
α2 - Gi duration of anesthesia by (inhibited reuptake)
CNS Metabolic: hyperglyecemia (liver glycogenolysis, Metabolized by COMT & MAO -if takng digitalis)
producing vasoconstriction
glucagon release) (beta2), insulin inhibition (alpha2); metabolites excreted in urine: Pulmonary edema
Gs = adenyl cyclase, ↑cAMP,
lipolysis (beta3) → ↑ oxygen consumpHon metaephrine & vanillyl-
voltage gated Ca2+-channels
GI: smooth muscle relaxation (alph2 & beta 2), mandelic acid (VMA)
relaxes detrusor muscle (beta2), contracts trigone &
Gi = K+ channels, ↓ cAMP
sphincters (alpha 1)
CVS: vasoconstriction (alpha1), ↑ peripheral

resistance, ↑ in both systolic & diastolic BP → Tx for shock (↑ vascular
baroreceptor reflex → ↓ HR; Note: reflex resistance → ↑ BP), but With atropine, causes
Norepinephrine α + β1 Mostly α at therapeutic doses
compesation does not affect postive inotropic dopamine is better to maintain
Same as Epi Shut down of kidneys
tachycardia
effects (CO is unchanged or decreased) renal perfusion
Renal: vasoconstriction of kidneys (alpha1)
Renal vasodilation (D1), ↑ GFR
Dopamine D+α+β D1 - Gs Positive inotropic effects on myocardium (beta1) Shock (drug of choice) Ineffective orally Nausea, HTN, arrhythmias
Release of NE from nerve terminals
Vasodilation of selective In-hospital, shorterm
Feneldopam D1 vascular beds D1,5 = Gs management of severe HTN
Given by continuous IV only
Class of Drugs: β Adrenergic Agonists

Pulmonary: bronchodilation (β2 action)
CVS: may increase systolic BP slightly, but greatly
Absorbed sublingually,
decreases mean arterial & diastolic pressure Rarely used as bronchodilator
Isoproterenol β Stim. heart in emerg situations
parenterally, or inhaled Same as Epi
Not a substrate for MAO
GI inhibited, less hyperglycemia than Epi (Insulin not
blocked), lipolysis
Racemic mixture of (+)

and (-) isomers; Stimulates β1 and/or β2
(-) is α1-agonist and
↑ CO, little change in HR, and does not sig raise O2 Same as Epi Increases AV conduction →
weak β1 agonist; Generally: stimulates heart (rate
Dobutamine β1 (+) is α1-antagonist and and force) (for arrhythmias),
demands of myocardium (Advantage over other Management of heart failure use with caution in atrial
sympathethic drugs) Tolerance with long term fibrillation
potent β1 agonist; vasodilation, and
use
(the α1 properties bronchodilation
cancel out)
Bronchodilator (fast acting) Status asthmaticus Oral, inhalation, or SC
Terbutaline β2 Contains resorcinol ring
Reduce uterine contractions Premature labor Not a substrate for COMT
Albuterol (Salbutamol) β2 Bronchodilator (fast acting) Asthma Oral, inhalation, or SC
Long hydrocarbon chain Not for prompt relief of
Salmeterol β2 (liposoluble)
Bronchodilator (prolonged duration - 12hrs)
bronchospasm attacks
Formoterol β2 Bronchodilator (prolonged duration - 12hrs)
Class of Drugs: α Adrenergic Agonists
Nasal decongestant
No direct effect on heart Mydriatic (pupillary dilator) Combined with H1-histamine
Not a catechol Hypertensive headaches
Phenylephrine α1 derivative
Peripheral vasoconstriction Vasoconstriction (raises both BP) induces reflex without cycloplegia as oral nasal decongestant
Cardiac irregularities
brachycardia Supraventricular tachycardia Not a substrate for COMT
Hypotension, shock
Transient vasconstriction
(HTN) leading to prolonged Not to be taken with
Activation of α2 in the CV Centrally acting anti-hypertensive hypotensive response Yohimbine (α2 antagonist)
Clonidine α2 (partial) control centers in the CNS Suppresses sympathetic outflow from brain
Htn
(seen only when admin IV) (Antihypertensive effects will
Sedation, mental lassitude, be reversed)
impaired concentration
Taken up by noradrenergic
neurons & metabolized to α- Reduces sympathetic outflow Sedation, mental lassitude,
Methyldopa α2 methylnorepinephrine → Decreases BP
Hyperension during pregnancy
impaired concentration
activiation of α2
Vasoconstriction of ciliary body Reduces aqueous humor production & ↑uveoscleral
Bromidine α2 blood vessels outflow → Lowers intraocular pressure
Glaucoma
Class of Drugs: Indirect-Acting Adrenergic Agonists

1. Displaces/releases
↑ alertness, ↓ fatigue, appetite suppression,
endogenous catecholamines Narcolepsy Fatigue & depression
insomnia
Ampetamine Misc from storage vesicles Depression following central
↑ BP by α action on vasculature + β-stimulatory
2. Weak inhibitor of MAO Appetite suppression stimulation
central effects on heart
3. Blocks catecholamine release
Structural analouge of
Methylphenidate Same as above ADHD in children
amphetamine
Persons taking MAO
Product of tyrosine Found in fermented foods
Storage Displaces/releases stored inhibitors (antidepressants)
Tyramine metabolism (cheese & Chianti wine)
vesicle norepinephrine (can precipitate serious
Not clinically useful Normally oxidized by MAO
vasopressor episodes)
Class of Drugs: Mixed-Acting Adrenergic Agonists

Plant alkaloid
↑ systolic & diastolic BP Excellent absorption orally
Not a catecholamine → Chronic asthma prophylaxis
Bronchodilation (weaker than Epi) Penetrates CNS Life threatening CV
Ephedrine poor substrate form Nasal decongestant
α+β+ Mild stimulation of CNS (↑ alertness, ↓ fatigue) Long duration reactions
COMT & MAO → long Induces release of NE and Performance improving
Storage Improves athletic performance Eliminated unchanged in urine
duration activates adrenergic receptors
vessicle
One of 4 ephedrine Combined with H1-histamine
Pseudoephedrine Nasal decongestant
enantiomers as oral nasal decongestant
Activate α1 in venous
Oxymetazoline &
Xylomethazoline
α1/2 capacitance vessels, decreasing Topical nasal decongestant
volume of nasal mucosa
Class of Drugs: Adrenergic Antagonists (α-Adrenergic Blockers)
General Mechanism of Action: Bind to adrenoreceptors but don't trigger receptor-mediated intracellular efects
General Effect: Affects BP; α1 blockade → ↓ peripheral vascular resistance (vasodilaHon) → reflex tachycardia
Epinephrine reversal: ALL α1-adrenergic blockers reverse the α-agonist effects of EPI:
α1 vasoconstriction of EPI is blockd, but β2 vasodilation is NOT blockd;
Thus, systemic BP decreases in repsonse to EPI given in the presence of phenoxybenzamine (α-blockers)
Note: α1 blockers are NOT drugs of choice for HTN;
"First dose" effect (exaggerated hypotension → syncope) may be minimized by admin 1/3 or 1/4 of normal dose
Pts with ↓ coronary perfusion
Pheochromocytoma (Prior to (induces tachycardia)
α1 Alkylates → irreversibly blocks α CVS: prevents vasoconstriction of peripheral blood
surgical removal of tumor to Postural hyotension β blockers should not be given
H1, M, haloalkylamine protect from catecholamine spill nasal stiffness before establishing α
Phenoxybenzamine Also blocks H1, M, Serotonin-R, vessels → reflex tachycardia
Serotonin-R, NE- (nitrogen mustard) NE-reuptake α2 blockage in the heart can ↑ CO
→ HTN, sweaHng) nausea, vomiting blockade, since unoppposed β
reuptake Chronic mgt of inoperable inhibit ejaculation blockade could cause BP
pheochromocytoma elevation dut to ↑
vasoconstriction
Diag of pheochromacytoma
(phentolamine blocking test),
control HTN from same, preop
Postural hyotension
α Reversibly blocks α1 and α2 Hypertensive crisis due to
Reflex cardiac stimulation Patients with ↓ coronary
Phentolamine serotonin Also blocks serotonin stimulant drug overdose or
and tachycardia perfusion
M, H1, H2 Agonist of M, H1, H2 symp anti-hypertensive
Arrhythmias, anginal pain
withdrawl
Prevent dermal necrosis after
NE extravasation
CVS: lowers arterial BP (no reflex tachycardia) 1st dose must be small (1/3 or
Hypertension Dizziness, lack of energy,
Relaxes both arterial and venous Suppresses symp from CNS 1/4 of maintanence dose) due
Prazosin α1 smooth muscle ↓ LDL/TAG, ↑ HDL
Benign Prostatic Hyperplasia
to rapid
nasal congestion,
(BPH) headache, drowsiness,
Improves urinary blod flow hypotension/syncope
orthostatic hypotension
Terazosin Prazosin analogs with HTN Sodium and fluid retention
Doxazosin
α1 longer half life BPH (Sx relief)
Tamsulosin
α1A Relaxes genitourinary smooth muscle
BPH (Sx relief)
(genitourinary) Little effect on BP
Can reverse antihypertensive

Blocks α2, acts as indirect Not to be taken with
Yohimbine α2 adrenergic agonist
↑ NE release ↑ BP Erectile dysfunction
Clonidine
effects of α2 agonist of
Clonidine (dangerous)
Class of Drugs: Adrenergic Antagonists (α1 and β-Adrenergic Blockers, Partial agonists)
HTN of pheochromacytoma & Orthostatic hypotension, For HTN with bradycardia, use
Labetalol Competitive antagonist Decrease HTN hypertensive emergencies dizziness pure α blocker to maintain β2
α1 + β Stimulant drug overdose Hepatic injury vasodilation
HTN
Carvedilol
Congestive heart failure
Smaller reductions in resting HR HTN with diminished cardiac
β-antagonist with "ISA" (insrinsic sympathomimetic Clinical significance of ISA
Pindolol β (partial) & BP
activity)
reserve or propensity to
uncertain
Less metabolic effects bradycardia (esp. in diabetics)
Class of Drugs: Adrenergic Antagonists (β-Adrenergic Blockers)
General effects: slow HR & ↓ myocardial contracClity → ↓ CO
Decrease intraocular pressure (Tx for glaucoma)
Note: non-selecHve β blockers ↓ glycogenolysis & glucagon secreHon
Lowers BP in HTN by ↓ CO
Inhibits cardiac β1 and CNS
Propanolol Also decreases stage fright & test anxiety
sympathetics
↑ glucagon release (hypoglycemia)
Bronchconstriction
Up-regulation of β-
HTN
receptors
Glaucoma
(arrhythmias/severe HTN if
Migraine
β Hyperthyroidism
withdrawn quickly) Asthmatics
non-selective Masks hypoglycemic Variant (prinzmetal) angina
Angina Pectoris
Timolol Ocular anti-hypertensive (for open angle glaucoma) tachycardia (a warning
Post-MI
sign)
Performance anxiety
Sedation, sleep
disturbances, depression
Nadolol Long term management of angina Long duration of action
Hypertensive pts with impaired

Atenolol
pulmonary function
β1 Decreases HTN
Diabetic hypertensives receiving
Avoid in asthmatics since
cardioselective Increases exercise tolerance in angina selectivity is modest at best
Metoprolol insulin or oral hypoglycemic
Ultra-short acting agents Rapidly broken down by
Esmolol Ester bond
Anti-emetic esterases in RBCs
Class of Drugs: Indirect Adrenergic Antagonists (act presynaptically)

Competitive inhibitor of tyrosine
Given with phenoxy-benzamine
α-methyltyrosine Tyrosine hydroxlase
Inhibits NE synthesis (anti-α) to manage malignant
(Metyrosine) hydroxylase Intereferes with DA synthesis
pheo-chromocytoma and preop
→ ↓ NE & Epi secretion
Irreversibly damages VMAT
→ vesicles lose ability to
Slow, gradual decrease in BP and
Reserpine VMAT concentrate & store NE & DA Depletes NE stores
HR
Long duration of action
→ NE broken down by MAO in
cytoplasm & depleted
Displaces NE from vesicles Parasympathetics NOT altered
Transported into symp Orthostatic hypotension
Disrupts process by which action Depletes NE stores (distinguishes drug from
Guanethidine Unknown athetic nerve by NET Male sexual dysfunction
potentials trigger release of Prevents NE release ganglion blockers)
Polar (no CNS) Supersensitivity to NE
stored NE from terminals 1970s
Blocks monoamine reuptake
DAT → monoamines accum in
synaptic space Increased/prolonged monoamine signaling
Cocaine SERT + NET Especially dopamine in the (limbic) pleasure centers
Local anesthetic
Na+-channel Blocks voltage gated sodium
channels
TCAs Inhibit reuptake transporters
NET Increased NE signaling
(imipramine & → NE & serotonin accumulate in Depression
SERT Antidepression
amitriptyline) synaptic cleft
MAOIs Prevents deaminiations of
Increased NE signaling Depression Foods with tyramine →
(phenelzine, moclobemid, MOA catecholamines → acccum in
Antidepression Parkinson's disease hypertensive crisis
selegiline) presynaptic vesicles
Inhibitors of Cell Wall Synthesis
Class: Penicillin (Cell wall inhibitor)
Drug Description Mechanism of Action Indications Drug of Choice Pharmacokinetics Bacterial Resistance Mechanism Combo therapy Adverse Effects
Gram +/- cocci,
Gram + bacilli, IV only (acid unstable) General for all:
Treponema Pallidum
Penicillin G (benzylpenicillin) "Natural" penicillin spirochetes Penicillin + Aminoglycoside =
(syphilis) Hypersensitivity: penicilloic acid =
Binds to penicillin binding Non-β-lactamase producing t1/2 = 0.5-1 hr synergistic (dosage can be
major antegenic determinant; cross
protein (PBPs) which anaerobes reduced);
reaction between β-lactam drugs;
"Natural", higher MBC (higher dose transpeptidate peptidoglycan General mechanism: rash, anaphylaxis
Penicillin V chains Oral (acid stable) Penicillins facilitate
requires)
movement of amino-
Methicillin (monitors MRSA) Nafcillin excreted 1. inactviation by β-lactamase ; Diarrhea
Inhibits cell wall synthesis β-lactamase-producing glycosides through cell wall;
Nafcillin "Antistaphyloccal penicillins" mainly via biliary Intersititial nephritis (esp. methicillin)
Staph Staph infections Never place in same IV fluid
Oxacillin β-lactamase resistant route (use for renal 2. modification of target PBPs; Neurotoxicity (epileptic pts)
Cell lysis (by autolysins) (very narrow) → forms inacHve complex
Dicloxacillin disorders) Hematologic toxicities
-cidal
3. impaired penetration of drug to Neutropenia (nafcillin)
"Extended Spectrum Penicillin" Ampicillin: Listeria Amoxicillin: target PBPs; With β-lactamase inhibitor Maculopapular rash (ampicillin,
Ampicillin Gram +ve cell wall easier to
More effective against Gram-ve Respiratory tract infections monocytogenes absorption NOT (e.g. clavulanic acid, amoxicillin)
Amoxicillin cross, only some gram -ve
bacilli (Gram +ve bacillus) impaired by food 4. efflux pumps sulbactam) Hepatitis (oxacillin)
have the required porins
Pseudomembranous colitis (ampicillin)
Carbenicillin Pseudomonas (no MRSA uses #2 GI upsets (large doses)
(with sulbactam)
Ticarcillin "Antipseudomonal" penicillin Gram-ve bacilli porins for other β-lactamase inhibitor Secondary infections
IV/IM only
Piperacillin (most potent) penicillins)
Benz: Syphilis, rheumatic IM sustained rls Probenecid inhibits renal secretion
Penicillin G procaine Repository Penicillins
procaine = local anesthetic fever prophylaxis, strep. pro t1/2 = 12-24 hrs
Penicillin G benzathine Prolongs life of penicillin G
pharyngitis ben t1/2 = 3-4 wks
General PK: absorption impaired by food (except: amoxicillin, ampicillin, dicloxacillin)

Admin: (ticarcillin, carbenicillin, piperacillin, ampicillin) + sulbactam; piperacillin + tazobactam = IV or IM
Poor penetration into CNS unless inflamed (can be given for meningitis)
Penicillin V, amoxicillin + clavulanic acid, carbenicillin (indanyl ester) = ORAL
Insufficient in eye & prostate; excreted in breast milk, kidneys (except Nafcillin → bile)
Class: Cephalosporin (Cell wall inhibitor)

Gram+ve cocci
1st Generation
Cefazolin P. mirabilis B. Fragilis resistant
Penicillin G substitutes Surgical prophylaxis
Cephalexin E. Coli Same as penicillins
resistant to staph penicillase General PK for all:
K. pneunomiae
Poor oral absorption;
cross placenta;
Cross-sensitivity with penicillin
H. Influenza, allergic reactions
Cefalor Sinus, Ear, Resp. RENAL elimination
2nd Generation Enterobacter aerogenes, pain at infection site (IM)
Cefoxitin Infections except 2
Neisseria spp. thrombohlebitis (IV)
Same as penicillins
-mandole (2), -perazone (3),
-tetan (2) contain methyl-thiotetrazole
Cefoperazone -triaxone & -taxime: Same as penicillins
group → hypoprothroboinemia (Tx
Cefotaxime Meningitis
w/Vit K), disulfram-like reaction (avoid
Ceftazidine 3rd Generation Gram-ve Cocci -tazidine, -perazone:
alcohol)
Ceftriaxone P. aeruginosa
Cefixime Gonorrhea
Gram-ve organisms
4th Generation
Cefepime Enterobacter, Haemophilus,
Wide spectrum
Neiserria
Treating STDs (DOC):

Generation based on:
General Description: Gonorrhea - Ceftriaxone (Cefixime)
1. order of introduction into clinical use,
β-lactam deriviatives of 7-amino cephalosporic acid; (too much Fluoroquinolone resistance)
2. bacterial susceptibility,
NOT active against enterococci & Lisateria monocytogenes Syphillis - Penicillin G Benzathine
3. resistance to β-lactamases
Chlamydia - Doxycycline (Alt: azithromycin)
Class: Carbapenems (Cell wall inhibitor)
Forms nephrotoxic metabolite
IV MUST give with cilastatin to protect
penicillinase-producing Enterobacter &
Well distributed in CSF
Imipenem β-lactam antibiotics; Gram +/- extended-spectrum β- imipenem + cilastatin
(when inflamed); Seizures
β-lactamases resistant (most) anaerobes lactamases producing
Renal excretion
P. aeruginosa gram-ve
Allergy cross reactive w/penicillin
Meropenem Not broken down Allergy cross reactive w/penicillin
Class: Monobactams (Cell wall inhibitor)

β-lactam ring not fused to another GI upset, vertigo, headache
IV or IM
Aztreonam ring Aerobic gram-ve rods ONLY Little cross-reactivity with other β-
Urinary excretion
Resistant to β-lactamases lactams
Class: β-Lactamase Inhibitors

Clavulanic acid
Contain β-lactam ring, but
Sulbactam Only in fixed combinations with
do not have antibacterial with penicillins
Tazobactam specific penicillins
activity
Class: Misc
Slow (60-90min) IV for

MRSA, MRSE, enterococci systemic infection Fever, chills, phlebitis at infusion site
Gram+ve, esp Staph Given orally only for C. Vancomycin + gentamycin = Flushing & shock (rapid IV)
Plasmid-mediated changes in drug
difficile alternative regimen for: Dose-related hearing loss (drug
Inhibits cell wall synthesis & permeability
Use restricted to Tx of MRSA Penetrates CSF if -meningitis caused by accum)
Vancomycin Bacterial glycoprotein peptidoglycan
serious infections from MRSE inflamed penicillin-resistant Nephrotoxicity (if combined with
polymerization Modification of the D-Ala-D-Ala
β-lactam-resistant, 90-100% excreted by pneumococcus other drug causing same effects)
binding site to D-Ala-D-lactate
Gram+ve organisms or glomerular filtration -enterococcal endocarditis 'Red-neck' syndrome (infusion-related
strongly allergic pts (reduce dose for flushing)
kidney disease)
Constipation
Nausea
Binds to cell emebrane via Headache
Gram+ve orgs (MRSA,
Ca2+-dependent insertion of 90-95% protein-bound Insomnia
enterococci, vancomycin-
Daptomycin -cidal (concentration-dependent) lipid tail → depolarizaHon of NOT orally absorbed
resistant enterococci &
membrane with K+ efflux → Renally excreted Elevated creatine
VRSA)
cell death phosphokinases →
Do not use with Statins (due to
creatinine kinase accumulation)
Interferes with late-stage cell Gram + orgs (MRSA,
Bacitracin Peptide antibiotic Topical use ONLY Nephrotoxicity (thus topical)
wall synthesis enterococci, VRSA, VRE)
Inhibits very early stage cell
wall synthesis Gram +/-ve
Fosfomycin Oral, IV
(cytoplasmic enzyme Uncomplicated lower UTIs
enolpyruvate transferase)
Inhibitors of Protein Synthesis
Class: Tetracycline (Broad Spectrum)
Community acq. Chlamydia ALL contraindicated in
Doxy- preferred for
pneumonia (macrolide Mycoplasma 1. impaired influx or ↑ efflux via Immunocompromised (since
Broad spectrum parenteral
Doxycycline altern.) Spirochetes (Lyme) pump tetracyclines are -static);
-static Binds reversibly to 30S Anaerobic orgs 2. production of protiens that
Malaria prophylaxis
Gram +/- organisms (incl. Inhibits tRNA binding Excreted in bile
Amebiasis (Clostridium) interfere with ribosome binding Teratogen: discoloration & hypoplasia
anaerobes)
Gram-ve rods (e.g. 3. enzymatic inactivation of teeth/bone (upto age 8), Fetal
Enters via passive diffusion Reaches CNS
Minocycline Cholera) hepatotoxicity;
and energy-dependent Excreted in urine
Gram+ve bacilli
transport at inner membrane Complicated skin, soft (anthrax) Little resistance
Class: Glycylcycline tissue, intra-abdominal IV only Decreases OC effectiveness
Tigecycline Rocky Mountain (except efflux pumps of Proteus &
Chem. modified tetracycline infections Biliary/fecal excretion Decreases warfarin clearance
Spotted Fever Pseudomonas)
MRSA, VRE
General PK: oral absorption ↓ by divalent caHons, including dairy (Mg2+, Ca2+) General Adverse Effects: GI effects;
concentrates in liver, kidney, spleen, skin; Photosensitization (more likely to sunburn);
Teratogenic: crosses placenta & excreted in breast milk (FDA category D, i.e. ony give to Dizziness, vertigo (esp. doxycycine & minocycline)
pregnant women in life-saving measures) Pseudotumor cerebri (fatal HTN in the brain)
Class: Aminoglycosides
Amikacin E. coli, Enterobacter, E. Coli, Enterobacter, Ototoxicity

Passive diffusion across Parental ONLY except
-cidal Klebsiella, Proteus, Klebsiella, Proteus,
Gram-ve membrane, then noemycin (topical 1. Plasmid-assoc. enzymes that
Providencia, Pseudomonas, Providencia, With penicillin or vancomycin
Gentamicin actively transported (O2- only d/t toxicity) modify & inactivate Nephrotoxicity
Once-daily dosing - serious Serratia, Pseudomonas (if to ↑ membrane permeability
dependent) across
toxicities (use safer drugs) H. Influenza, Moraxella penicillin intolerant),
cytoplasmic membrane Poor distribution (not 2. Impaired entry of drug into cell
Tobramycin catarrhalis, Shigella Serratia Nephrotoxicity
Time & Concentration dependent Binds to 30S prior to CSF, eye) (anaerobes lack O2 dependent
ribosome formation → High in renal cortex & transporter)
Streptomcin Post-antibiotic effect TB, plague, tularemia Plague, TB
initiation complex blocked → inner ear (nephro-
misreading of mRNA → /ototoxicity) 3. Receptor 30S ribosomal subunit
Neomycin From streptomyces (mycin) or Ototoxicity, nephrotoxicity
polysomes break up into deletion or altered
micromonospora (micin)
nonfunctional monosomes Glomerular excretion
Netilmicin
General Indications: Empirical Tx of suspected aerobic Gram-ve Other General Adverse Effects: Neuromuscular paralysis
Note: Anaerobes lack O2-dependent transport & unaffected by Aminoglycosides Teratogen: Contraindicated in pregnancy (neurologic damange) - FDA Category D
Class: Macrolides
Campyobacter, ↓ absorption with
Emperical for
Chlamydia, food;
Erythromycin community acquired
Mycoplasma, Biliary excretion
pneumonia
Legionella CYP450 inhibition GI irritation
Above + H. Influenza 1. Reduced membrane permeability rashes
↑ absorption with or active efflux eosinophilia
Macrocyclic lactone structure Binds irreversibly to 50S Greater activity for food Cholestatic jaundice (esp.
-static M. avium (MAC)
Clarithromycin ribosomal subunit → Chlamydia Liver metabolism + 2. Production of esterase erythromycin)
Gram +/- H. Pylori
translocation inhibited Legionella urinary excretion (enterobactericeae) that hydrolyze Ototoxicity
Alt. for penicillin allergy
Moraxella CYP450 inhibition drugs CYP450 inhibition
Binding site close to that of Ureaplasma
clindamycin & ↓ with food 3. Modification of ribosomal
chloramphenicol Same as erthyromycin + Urethritis (Chlamydia Greater tissue binding site (mutation or
Azithromycin
better for H. Influenza & Trachmatis) penetration methylation of 50S)
Moraxella Long t1/2 (2-4 days)
Less effective against Can prolong QT interval
Strep/Staph Stable to food
Telithromycin Ketolide Contraindication: Myasthenia gravis;
CYP450 inhibition
Hepatotoxicity
Class: Chloramphenicol
Very potent and toxic Gram +/-, anaerobes, GI

Toxicity limits use to life- H.Influenza, N. Bone marrow toxicity (aplastic
threatening situations with no Binds reversibly to 50S meningitidis, bacteroides Oral or IV Factor coding for Acetyl CoA anemia)
alternatives ribosomal subunit NOT effective against P. Well distributed transferase
Chloramphenicol Inhibit protein synthesis in aeruginosa or Chlamydiae (enters CSF) inactivates drug by altering Teratogen: Gray baby syndrome
Broad spectrum mitochondrial ribosomes → (penicillin also ineffective, Breast milk secretion membrane permeability (cyanosis)
bone marrow toxicity use aminoglycosides or 3rd-
-static (/-static) cefalosporin) Inhibits CYP450
Class: Clindamycin
Oral GI
Skin & soft tissue infections
Gram-ve aerobes and enterococci Well distributed (NO + primaquine = AlDS-related Skin rashes
Same as erythromycin: caused by Staph, Strep;
are resistant CSF) PCP Neutropenia
Topical for eye infections Anaerobes
Clindamycin Binds irreversibly to 50S Prophylaxis of endocarditis (Bacteroides fragilis)
Pseudomembranous colitios (C.
C. difficile (Gram+ve anaerobe) is Inhibits translocation Extensively + pyrimethamine = AIDS- difficile)
in valvular disease patients
resistant metabolized, excreted related toxoplasmosis
(penicillin allergic)
in bile or urine Imapired liver function
Class: Streptogramins (Quinupristin/Dalfopristin)

Mix of 2 streptogramins
VRE infections Venous irritation,
Reserved for Tx of VRE Binds to separate sites on IV (w/5% dextrose);
Quinupristin/Dalfopristin Gram+ve cocci arthralgia & myalgia,
Long post-antibiotic effect Penetrates Enzymatic processes With each other
(30/70)
Narrow spectrum 50S NOT for Enterococcus
macrophages & PMNs
hyperbilirubinemia;
faecalis CYP 3A4 inhibition
-cidal
Class: Linezolid (techinically, Oxazolidinone)

Community acquired
pneumonia (CAP);
Oral (100% BA) & IV;
Oxazolidnone drug Skin infections; Decreased binding to target site GI, headaches, rash;
1 of 2 metabolies is
Linezolid
Narrow spectrum Binds to 23S of 50S VRE;
antimicrobial;
Hematologic (reversible, mild)
-static (-cidal against Strep & C. Inhibits formation of 70S Mainly against multidrug NO cross-resistance with other Optic/peripheral neuropathy + lactic
Renal & non-renal
perfringens) resistant Gram+ve classes acidosis (with prolonged use)
elimination
organisms (staph, strep,
entero, coryne, listeria)
Miscellaneous Drugs (Metronidazole, Polymyxins)

Drug Description Mechanism of Action Indications Drug of Choice Pharmacokinetics Adverse Effects Combo therapy Contraindications
Reductive bioactivation of Metallic taste
Bacteroides, Clostridium, Pseudomembranous
nitro group by ferrodoxin Oral, IV, Topical GI irritation (nausea, vomiting)
Imidazole deriviative Anaerobic + mixed intra- colitis (C. difficile) If Metro fails, use
Metronidazole → cytotoxic products → Wide distribution Dark urine coloration Avoid alcohol (disulfuram-like)
Activity against protazoa & bacteria abdominal infections, Brain Vaginitis (trichomonas Vancomycin
interferes with nucleic acid Hepatic metabolism Leukopenia, dizziness, ataxia
abscess, H. Pylori & bacterial vaginosis)
synthesis Opportunisit fungal infections
Neurotoxicity (paresthesis,
Distort membrane lipid Only for topical therapy of
Polypeptides dizziness, ataxia)
structure → ↑ permeability resistant Gram-ve
Polymixins -cidal Acute renal tubular necrosis
to polar structures → infections (Pseudomonas,
Gram-ve (hematuria, proteinuria, nitrogen
changes in cell metabolism enterobacter)
retention)
Nucleic Acid Synthesis & Intermediary Metabolism Interference
Class: Fluoroquinolones
1st generation
Uncomplicated UTIs
Nalidixic Acid (quinolone) Narrow spectrum
Gram-ve only
Moderate Gram-ve
Oral; cipro & levo can
Enter bacterium via porins Chromosomal mutations →
Travellers diarrhea, be IV;
2nd generation Interferes with ↓ target sensitivity
Ciprofloxacin Anthrax (Tx & prophylaxis), Synergistic with β-lactams Inhibits theophylline metabolism
Expanded Gram-ve, some Gram+ve topoisomerase II
P. aeruginosa (CF, UTIs) Fe, Zn, Ca (divalent
Cross-resistance to other FQs
(DNA gyrase) & IV cations) interfere with
Prostatitis (E.coli)
absorption;
Inhibits DNA replication STDs (not syphilis) Respiratoy FQs for Gonocci: mutations in Topo 2
3rd genreration topo 2 - Gram-ve; Skin infections LRTI
Levofloxacin (3rd and 4th - some gram+ve, incl. topo 4 - Gram+ve Elimination via tubular Can prolong QT interval;
Acute sinusitis M. tuberculosis, S. aureus, & S.
Strep pneumoniae) secretion (blocked by Raises serum warfarin, caffeine, &
Chronic bronchitis pneumoniae: efflux pumps
probenicid) cyclosporin
-cidal Nosocomial pneumonia
4th generation
Moxifloxacin Not P. aeruginosa
Extended Gram+ve, anaerobes
General Adverse Effects: GI (nausea, vomiting); CNS (headach, dizziness); rash; photosensitivity; Teratogen: Connective tissue problems → tendon rupture (avoid in pregnancy, nursing moms, kids ≤ 18yrs)
Class: Sulfonamides (Anti-metabolites)

Sulfisoxasole (short acting) Simple UTI Crystalluria (nephrotoxicity);

Inhibit bacterial folic acid
Analogs of p-aminobenzoic acid hematopoietic disturbances (esp. with
synthesis; Oral/Topical; Plasmid transfer/random
(PABA) G6P-DH deficiency);
Sulfamethoxazole (med) Competitive inhibitors (& Well distributed (incl. mutations:
GI distrubances;
substrate) of CSF); -altered DHP synthase (target); With Trimethoprim (DHF
-static drug potentiation (e.g., warfarin)
Acetylated in liver -↓ membrane permeability; reductase), synergistic
Sulfadoxine (long acting) dihyropteroate
→ precipitaHon at pH -↑ PABA synthesis;
Active against Gram +/-, Chlamydia, synthase → inhibiHon of Teratogen: under 2 mos old,
≤ 7 → kidney damage -↓ drug accumulaHon
& nocardia Kernicterus (competes with bilirubin
Triple sulfa bacterial folate production Simple UTI for albumin binding)
Infection Sulfonamide ROA

Ocular Infections Sulfacetamide Topical
Mafenide,
Burn Infections Topical
Silver Sulfadiazine
Ulcerative Colitis
Sulfasalazine Oral
Rheumatoid arthritis
Sulfadiazine + pyrimethamine +
Toxoplasmosis Oral
folinic acid
Class: Trimethoprim
Inhibits bacterial Penetrates CSF;

Excreted unchanged
Structure like folic acid, dihydrofolate Effects of folic acid deficiency (e.g.
UTIs, bacterial in kidney; Altered dihyrofolate reductase
Trimethoprim 20-50x more potent than reductase Vaginitis With sulfonamide megaloblastic anemia, leukopenia,
prostatis,vaginitis High conc. in (target)
sulfamethoxazole etc.)
Inhibits folate & nucleic acid prostatic, vaginal
synthesis fluids
Class: Cotrimoxazole
Synergistic inhibition of UTIs, RTIs, ear & sinus (H. Influenza, M. catarrhalis);
Combination of trimethoprim +
dihyropteroate Ampicillin or chloramphenicol-resistant salmonella;
Penetrates CSF;
Dermatologic (common, mild rash);
cholera, typhoid fever, shigellosis (backup), MRSA, GI disturbances;
Cotrimoxazole sulfamethoxazole synthase & L. monocytogenes
Generally oral, can be Same as individual drugs It is a combo
hematologic;
-cidal dihydrofolate IV
Aeromonas hydrophilia; Higher incidence with AIDS
reductase PCP, nocardiosis, toxoplasmosis
Anti-Mycobacteria Drugs
Drugs for Tuberculosis
Drug Description Mechanism of Action Anti-bact. Spectrum Indications Resistance Pharmacokinetics Combo therapy Adverse Effects
Oral absorption imparied by food
Peripheral neuritis (hands/feet
Mutations → of KatG, (carbs) & aluminum containing
parasthesias) → Tx: Vit. B6
Pro-drug (activated by Only affects mycobacteria acyl carrier proteins, antiacids
Analog of pyridoxine (Vit B6) supplement;
catalase-peroxidase KatG) overexpression of Diffuses throughout body &
Most potent anti-TB drug Hepatitis + idiosyncratic
Targets enoyl acyl carrier Bacilli in stationary phase Latent TB: use alone inhA caseous material
Isoniazid (INH) Part of COMBO therapy hepatotoxicity;
protein reductase (AcpM) & = -static Active TB: use combo
Given alone only for latent CYP450 inhibitor
β-ketoacyl-ACP synthase Bacilli rapidly dividing No cross resistance N-acetylation & hydrolysis →
infection Initial 3 drug regimen (INH, Mental abnormailities, convulsions if
(KasA) = -cidal between any other inactive
rifampin, & pyrazinamide) prone to seizures, optic neuritis;
anti-TB drugs 'fast acetylator' t1/2 = 60-90min;
If organisms susceptible & Hypersensitivity (rashes, fever)
'slow acetylator' t1/2 = 3-4hrs
HIV -ve pt = pyrazinamide can
TB, Latent TB if INH be discontinued after 2 mos
Point mutations in Oral absorption
intolerant/resistant, & 2 drug regimen cont for 4
-cidal for intra/extracellular rpoB (gene for RNA Well dist (incl CSF) Avoid in HIV +ve due to CYP450
Leprosy, Meningitis mos
mycobacteria (TB, kansasii ) pol β subunit → ↓ Enterohepatic cycling induction →
Rifampin* prophylaxis from
affinity of target for Strong inducer of CYP450 → ↓ t1/2 of ARTs
meningococci or H. Alternative regimens:
Blocks transcription by Other Gram +/- orgs drug); shorter t1/2 (antiretroviral therapies)
Rifamycin drug Influenzae , MRSA INH + Rifampin (9mos)
binding to β subunit of ↓ permeability Biliary excretion (feces) or urinary INH + ethambutol (18 mos)
(w/vancomycin)
From soil mold Streptomyces bacterial RNA Intermittent (2 or 3 x/wk)
high dose 4 drug regimen) Similar to rifampin +
Preferred for HIV
Rifabutin* polymerase → inhibits Uveitis, skin hyper-pigmentation,
-cidal Less CYP450 activation
RNA synth neutropenia
Long t1/2 (weekly dosing)

Intensive phase (1st 2 mos) = 2x/wk
Rifapentine* Not to be used alone
Subsequent phase = weekly for 4
mos
Dose-dependent visual disturbances

(↓ Visual acuity, red-green color
Inhibits arabinosyl
Specific for Occurs fast if used Well absorbed, distrb (incl. CSF) blindness, optic neuritis, retinal
transferases (synthesis Resistance > 4%: incl.
Ethambutol -static M. tuberculosis alone (mutations in Large fraction eliminated damage), reversible;
ethambutol or streptomycin
of mycobacterial cell wall M. kansasii emb gene) unchanged in urine Headach, confusion,
Rifampin + pyrazinamide +
components) ↓ urate excreCon → hyperuricemia,
ethambutol or streptomycin
peripheral neuritis, gout exacerbated
(6 mos)
Nongouty polyathralgia (40%)

Unknown Lack of Well absorbed, distrb (incl. CSF) Multi-resistant strains: 3+
TERATOGENIC
Pyrazinamide -cidal Enzymaticaly hydrolyzed to pyrazinamidase, Drug & metabolite excreted in known susceptible drugs (18
Myalgia, GI, porphyria, hepatotoxicity
active pyrazinoic acid ↑ efflux urine + mos, + 12 mos after
(rare)
cultures are neg)
Combine for Tx of life-
Ototoxic
threatening TB disease
Streptomycin Used for drug resistant strains Nephrotoxic
(meningitis, miliary,
Vertigo, hearing loss
organ TB)
ALT: Amikacin Used for streptomycin- or multi-drug resistant strains. Always use in combo
ALT: Ciprofloxacin Active against first-line drug-resistant strains. Always use in combo
ALT: Ethioamide Congener of INH (no cross resistance). Severe GI irritation, adverse neurologic effects.
Drugs for Leprosy (Hansen's Disease)

Drug Description Mechanism of Action Anti-bact. Spectrum Indications Resistance Pharmacokinetics Combo therapy Adverse Effects
-static Inhibits WHO recommends: Hemolysis (esp. G6PDH deficiency); GI
Well absorbed, high levels in skin
Related to sulfonamides Also pneumonia (PCP) in Leprosy Pauci-bacillary (PB): 1-5 skin irritation;
Dapsone dihydropterate Undergoes hepatic acetylation,
HIV+ve pts lesions: 2 drugs - erythema nodosum leprosum (Tx
synthetase → no folate elimination in urine
Acedapsone = repository form Rifampin + Dapsone (6mos) w/corticosteroids or thalidomide)
Redox properties may generate cytoxic
Oral absorption Multi-bacillary: > 5 skin
Clofazimine
-cidal Binds to DNA, inhibiting Some activity against MAC Leprosy Accum in tissues lesions: 3 drugs -
oxygen radicals
Phenazine dye replication Red-brown discoloration of skin
No CSF Rifampin + Dapsone Eosinophilic enteritis
+ Clofazimine (12 mos)
Rifampin SEE ABOVE
Diuretics
Drug Name Drug Class/Receptor Effects MOA Indications Effect on Urine Composition Pharmokinetics Adverse Effects
Hydrochlorothiazide ↓ peripheral vacsular Blocks Na+/Cl- cotransporter in distal HTN Hypokalemia
↑ Na+, K+, Cl- Oral
Chlorthalidone (od) Thiazides resistance convoluted tubule Heart Failure Hyponatremia
↑Mg2+ t1/2 = 40 hrs (1-3wks for stable
Metolazone (potent) NCCT ↓ BP, even after volume "ceiling" dieuretic - saturates at low hypercalcuria
↓Ca2+ effects)
Hyperuricemia
Indapamide (long efx) recovery dose Diabetes Insipidus Volume Depletion
Acute pulmonary edema Otototoxicity
Bumetanide
Heart failure Hyperuricemia
Furosemide (most Loop (High Ceiling) Produces a lot of urine Blocks Na+/Cl-/K+ cotransporter in Hypercalcemia Oral Acute Hypovolemia
common) ↑Ca2+, Na+, K+, Mg2+
Torsemide
NKCC2 Most effective dieuretic ascending loop of Henle Hyperkalemia t1/2 = 2-4 hrs K+ depletion
Ethacrynic Acid is a non-sulfa Hypomagnesemia
Ethacrynic Acid
drug used for sulfa allergies Allergic rxns (sulfonamides)
GI upset + peptic ulcers

Antagonizes aldosterone at Endocrine effects (gynecomastia,
Hepatic cirrhosis Oral + stongly protein-bound
Potassium Sparing cytoplasmic receptors (prevents irregular menstrual cycles -
Spironolactone 2° Hyperaldosteronism Active spironolactone metabolite =
receptor complex translocation) spirinolactone resembles sex
Eplerenone Aldosterone-R Heart failure (prevents ↑Na+ canrenone
steroids)
remodeling) Induces CYP450
Acts at collecting duct ↓K+ Hyperkalemia, nausea, lethargy,
mental confusion
Potassium Sparing Blocks Na+ transport channels (↓ Same as spirinolactone + Leg

Triamterene 1° hyperaldosteronism
Na+/K+ exchange) cramps, ↑ BUN, uric acid & K+
Amiloride EnaC Acts at collecting duct
Heart Failure
retention
Metabolic Acidosis
Glaucoma (lowers elevated Oral K+ depletion
Acetazolamide
Carbonic Anhydrase Acts mainly in the PT
Prevents formation of H+ needed for
intraocular pressure) ↑ Na+, K+, HCO3- Increases urine pH (alters solubility Renal stones
inhibitor Na+ reabsorption in proximal tubule
Mountain sickness (prophylaxis) of other drugs) Do not use w/Hepatic cirrhosis (↓
NH4+ excretion)
↑ intracranial pressure, Extracellular H2O expansion
Does not affect Na+ Filtered into glomerulus, draws H2O Acute renal failure (shock) Dehydration
Mannitol Osmotic N/A IV only
excretion into tubular fluid Drug toxicity Hypo- or hypernatremia
Trauma (maintain urine) Osmotic diarrhea if oral
Renders CT H2O Sydrome of Inappropriate ADH
Inhibits effects of ADH ↑ plasma Na+ IV only Nephrogenic diabetes Insipidus
Conivaptan ADH Antagonists impermeable → dilutes
↓ aquaporins in collecting duct
secretion (SIADH)
↓ H2O reabsorpHon t1/2 = 5-10 hrs Renal Failure
urine Elevated ADH
Contraindications for Anti-Hypertensives Positive Criteria for Drug Selection

Disease Contraindicated Reason
1. Diuretics: old age, black, CHF, chronic renal failure (loop diuretics)
COPD, Asthma β-blockers, ACE-Is Bronchospasm, cough (use AT1-R Blocker)
Clonidine, β-blockers,
Bradycardia Aggrevation, risk of Adams-Stokes syndrome 2. β-blockers: young, white, post-MI, migraines, atrial fibrillation, paroxysmal supraventricular tachycardia
Verapamil, Diltiazem
Thiazides, unselective β-
Diabetes Mellitus Reduces glucose tolerance, blunt Sx of hyppoglycemia 3. Long-acting Ca2+ blockers: old age, black, migraine
blockers
Gout Thiazides Reduced excretion of uric acid 4. ACE Inhibitors: young, white, type I diabetes w/nephropathy, impotence
Hyralazine, Prazosin, 5. AT1 blockers (ARBs): same as ACE inhibitors. Used when ACE inhibitors contraindicated due to cough or
Coronary artery disease Can provoke angina (reflex tachycardia)
Minoxidil hypersensitivity
Peripheral artery disease β-blockers Aggrevation, manifestation 6. α-blockrs: prostatism, diabetes mellitus, dyslipidemia
Ca2+ blockers, high dose-
CHF Negative inotropic
β-blockers
Amiloride, Triamterene,
Renal Failure Spironolactone, ACE Hyperkalemia
Inhibitors
Anti-Hypertensives (Part 1)
Drug Drug Class/Receptor Description MOA Indications Drug of Choice Pharmacokinetics Adverse Effects Contraindications
Hypokalemia & Hyperuricemia
Lowers BP by ↑ Na+, H2O excretion → Counteract Na+ & H2O retention
Blacks & elderly (ACE-Is are less (70%), hyerglycemia (10%),
Thiazide Thiazide Lowers BP 10-15 mmHg ↓ in extracellular volume → ↓ caused by other anti-HTN drugs Oral Diabetics
effective) hypomagnesemia,
cardiac output & renal blood flow → useful in combo therapy
hyperlipidemia
↓ renal vascular resistance & Pts with poor renal function or
Loop Diuretics Loop diuretic
↑ renal blood flow unresponsive to other diuretics
Potassium-sparing
K+ Sparing Diuretics ↑ K+ loss in urine
diuretics
First line if other diseases are Bradycardia, CNS effects,
Non-selective β1 + β2 ↓ cardiac output Oral (extensive 1st pass Asthmatics (broncho-
Propanolol present (e.g., supraventricular hypotension, ↓ libido → impotence
receptors ↓ sympatheHcs from CNS More effective in young white metabolism) constriction via β2)
β-blockers tachyarrhythmias, previous Mis, Lipid disturbance (↓HDL, ↑TAG)
inhibit release of renin (β1) → pts
Metoprolol Selective β1 receptors angina pectoris, chronic HF, Oral Abrupt withdrawal → angina, MI in Use cautiously in
↓ angiotensisn II & aldosterone
Atenolol (most widely used) migraine) Oral pts w/heart disease asthmatics
Reflex tachycardia
↓ peripheral vascular resistance & ↓
Competitively block α1- 1st dose syncope
arterial BP by relaxation of arterial + Mild-moderate HTN & in combo
Prazosin receptors Concomitant use of β blocker used
venous smooth muscle w/propanolol or a diuretic
α-antagonists to blunt short term reflex
Minimal change in cardiac output,
Na+ retention (when admin tachycardia
renal blood flow & GFR → no long
Doxazosin without diuretic) Doxazosin: Same as above
term bradycardia
Terazosin + ↑ rate of CHF
IV labetalol = rapid reduction in BP
Advantage: no reflex ↑ in
Labetalol Mixed α + β antagonist Long-term Tx of HTN → useful in hypertensive Oral, Parenteral Pheochromacytoma
HR or CO (β1 also blocked)
emergencies
Does NOT reflexively increase CO, rate, HTN - most effective in young Dry cough (30%), rash, fever,
Captopril or contractility white patients Standard tx 24 hrs post-MI altered taste, hypotension,
↓ Na+ & H2O retention (via ↓ With diuretic = same efficacy in hyperkalemia Pregnancy (2nd, 3rd
↓ BP by ↓ peripheral
ACE Inhibitors aldosterone) whites & blacks Angioedema (rare, deadly) → admin trimesters) → risk of
vascular resistance
Slows diabetic nephropathy, Oral pro-drug of (IV) enalaprilat 1st with physician fetal HTN + renal
Enalapril
↑ Bradykinin levels (potent neuropathy, & ↓ albuminuria (intrahepatic conversion) Reversible renal failure (if bilateral failure
Lisinopril vasodilator) Chronic HF renal artery stenosis)
Blacks, elderly (renin
↓ BP by arteriolar & venous dilaCon levels in these people
Same as ACEIs
Blocks aldosterone secretion → ↓ Na+ are much lower than
Valsartan Angiotensin I Receptor Altern. to ACE inhibitors
& H2O retention HTN in diabetics Similar to ACE inhibitors whites)
Losartan Blockers Blocks AT1 receptors Hypertensive diabetics
DOES NOT ↑ BRADYKININ
(↓nephrotoxicity)
(no dry, irritating cough)
Inhibits enzyme activity of renin → ↓ Hyperkalemia, renal impairment

Aliskiren Renin inhibitor Very new HTN
angiotensin I, II, & aldosterone Potential teratogenic
Diphenylalkyamines High doses of short acting Ca2+
Angina
(least selective) channel blockers ↑ risk of MI
Verapamil Supraventric. tachyarrhythmias CHF
Cardiac + vascular sm. Bind to L-type Ca2+ channels in heart Constipation (10%)
Used when 1st line agents for Migraine
Muscle effects & muscle of peripheral vasculature & Reflex tachycardia
HTN ineffective or
heart ↓ → Ca2+ entry → Muscle
Benzothiazepine contraindicated
relaxation, -ve inotropism, arteriolar Oral
Cardiac + vascular sm. Pts w/angina, diabetes, asthma, Good side-effect profile
Diltiazem 2+ dilation
Ca - channel muscle (less -ve inotropic peripheral vascular dx Short t1/2 (3-8 hrs) Reflex tachycardia
blockers than Verapamil) Amlodipine & other 2nd gen
Effective in Black & White pts have long t1/2
Dihydropyridines
Nifedipine
1st generation = Nifedipine Intrinisc natriuretic effect → no Dizziness, headache, fatigue, ankle
(also Amlodipine, Greater affinity for vascular sm. NOT for cardiac
2nd generation = others need for diuretic edema
Felodipine, Isradipine, muscle arrhythmias
(little interaction with Reflex tachycardia
Nicardipine, Nisoldipine)
digoxin & warfarin)
Anti-Hypertensives (Part 2)
Drug Drug Class/Receptor Description MOA Indications Drug of Choice Pharmacokinetics Adverse Effects Contraindications
α2-agonist
Reduces sympathetic outflow by 2nd-line when HTN does not
Clonidine Does NOT ↓ renal blood Sedation
Centralling Acting acting on pre-synaptic autorecpetors respond to Tx with 2+ drugs Oral, well absorbed
flow or GFR Dry nasal mucosa
Sympathoplegic Admin w/diuretic (can cause Na+,
Rebound HTN after abrupt
α2-agonist Converted to ↓ sympatheHc ou^low from CNS → ↓ H2O retention)
Pregnancy-induced HTN withdrawal
Methyldopa methyldopamine & peripheral resistance, ↓ BP (note: Pregnancy-induced HTN
Renal insufficiency
methylnorepinephrine cardiac output NOT ↓)
Never 1st line Headache, tachycardia, nausea,
Direct-acting smooth Always admin w/β-blocker (prevents
Hydralazine Pregnancy-induced HTN sweating, flushing
muscle relaxant reflex tachycardia)
Dilates arterioles, not veins Arrhythmia, angina
Always has reflex
Vasodilators
tachycardia + ↑ plasma
K+ channels Opening of K+ channels in sm. muscle Severe, malignant HTN Reflex tachycardia & fluid retention
[renin] → Na+ & H2O
membranes (must use w/loop diuretic & β-
Minoxidil (Rogaine) retention Oral
Male pattern baldness (causes blocler) →
Side effects blocked if given
hypertrichosis) Volume overload/edema → CHF
with diuretic
Blocks initial transient depressor (ETA)
Endothelins →
Non-selective Endothelin & prolonged pressor (ETB) responses
Bosetan vasoconstriction in vascular Pulmonary HTN
receptor blocker to IV endothelin → Endothelin syntesis
beds → Pulmonary HTN
inhibited
Hypertensive Emergencies
General management: Etiology:
Crisis: DBP > 150 mmHg (if healthy) (with SPB > 210) Essential HTN
Admit to ICU, administer IV drugs, Arterial line to measure BP
DBP > 120 mmHg (with complications) → organ damage, vascular Renal parenchymal disease
Progressively reduce BP using short-acting titratable IV drug
injury Renovascular disease
a) Lower BP no more than 25% (within mins-1hr); GOAL: DBP = 100-110mmHg
Emergency: Severe HTN, with organ damage Pregnancy (pre-eclampsia)
b) If stable, further reduce to 160/100 mmHg in 2-6hrs & to normal over next 8-24 hrs
Urgency: Severe HTN without organ damage Endocrine (Pheochromocytoma, Cushing's, renin-producing tumors)
Note: Abrupt decreases in BP as can lead to MI, stroke, or visual changes
Drugs (cocaine, sympathomimetics, amphetamines, MAO-inhibitors, tyramine)
Drugs Description Effects Pharmacokinetics Adverse Effects Contraindications
Drug withdrawl (clonidine, nifedipine)
Hypotension (overdose), abd
CNS disorder (injury, stroke, tumor)
cramping, nausea, vomiting
Prompt vasodilation & IV only Autonomic hyperreactivity
Nitroprusside metabolite →
Sodium Nitroprusside Drug of choice! venodilation → t1/2 = 1-2 min → requires conHnuous
cyanide toxicity (rare) → Tx:
reflex tachycardia infusion
Sodium thiosulfate infusion →
thiocyanate → eliminated
Asthma, COPD,
Combined α + β blocker, IV bolus or infusion
Labetalol 2nd or 3rd degree AV block or
NO reflex tachycardia t1/2 = 3-6hr
bradycardia
Peripheral dopamine-1
Maintains or ↑ renal
receptor agonist t1/2 = 30mins
Fenoldopam perfusion as it lowers BP Glaucoma
Good for ppl w/renal IV infusion
(i.e., kidney not affected)
insufficiency
Vascular smooth muscle t1/2 = 30mins
Nicardipine Ca2+ channel blocker
relaxation IV infusion
Drug of choice for pts
w/cardiac ischemia,
Nitroglycerin Vasodilation
angina, or post cardiac
bypass procedure
Drug of choice for pts
Phentolamine w/catecholamine-related
emergencies
Used for aortic dissection
Esmolol
or post-op HTN
Treat pregnancy-induced
Hydralazine
eclampsia
Congestive Heart Failure Drugs (Part 1)
Drug Drug Class Description MOA Indications Pharmacokinetics Adverse Effects Contraindications
Single therapy in pts w/mild
Oral (food may ↓ absorpHon) Persistent dry cough
↓ vascular resistance & ↓ BP → exertional dyspnea (no sign of
Captopril Pro-drugs (except: Captopril) Renal insufficiency
↑ CO (↓ a_erload) volume overload)
Enalapril ACE Inhibitor Dilates arterioles and veins t1/2 = 2-12 hrs Hyperkalemia
↓ salt & H2O retention (↓ preload) Asymptomatic, recent MI (most
Lisinopril Newer (ramipril, fosinopril) = Angioedema
↓ long-term remodeling benefit if low EF) Pregnancy
once/day-dosing Teratogenic
All stages of LVF
Losartan (prototype) Do NOT affect bradykinin If intolerant to ACEIs (severe Oral & once/day dosing Same as above, but NO cough
AT-II Antagonist Block AT-I receptor
Valsartan levels (thus, no cough) cough or angioedema) Losartan → acHve metabolites Teratogenic
↓ HR & inhibits renin release
Negative inotropic Heart disease (except those at Start at low doses → gradually
Carvedilol (non-select) Prevents deleterious effects of NE on
β-blocker (thus can initially risk w/no symptoms or in acute titrate to effective doses (to avoid
Metoprolol (β1-select) cardiac muscle fibers →
exacerbatw symptoms) HF) sudden effects on heart)
↓ remodeling, hypertrophy
Loop Diuretics Most commonly used in HF
Relieve pulm congestion & peripheral
↓ congesHve symptoms & Hypertensive heart disease (with
edema
Diuretic intravascular volume congestive symptoms)
Thiazide Diuretics ↓ symptoms of volume overload (e.g.
overload Ineffective with chronic kidney
orthopnea)
↓ Plasma volume → disease
Prevent: Na+ retention, ↓ VR (preload) →
↓ cardiac workload & 02 demand Advanced heart disease GI (gastritis, peptic ulcer)
hypertrophy, K+ loss
↓ A_erload (Pts have elevated aldosterone CNS effects (lethargy, confusion) K+ supplements (Spironolactone
Aldosterone-R
Spironolactone levels, excess angiotensin Endocrine (gynecomastia, ↓ libido, promotes K+ retention, inhibits
antagonist Combined with ACEIs, ↓
Ald-R antagonists block intracellular stimulation, reduced hepatic menstrual irregularities) Digoxin)
morbidity & mortality of
receptors clearance) Hyperkalemia
severe HF (↑ survival)
Co-admin w/diuretics
Hydralazine (congestive Sx) In CHF, If intolerant of ACEIs or β-
↑ venodilaHon → ↓ preload
Dilates arterioles blockers, can use a combo of
Direct vasodilator ↑ arterial dilaHon → ↓ systemic
Co-admin w/diuretics Hydralazine & Isosorbide
arteriolar resistance & ↓ a_erload
Isosorbide dinitrate (congestive Sx) dinitrate (↓ mortality)
Dilates veins, venules
Inhibits active transport of Na+ Very low theraputic window Treatment:

#1 factor for adverse effects is
Widely distributed (incl. CNS) 1) Withdraw drug
(Na+/K+ ATPase) → Hypokalemia (also, drug accum/OD,
t1/2 = 36-40 hrs Diastolic or R-sided HF 2) Monitor drug/K+
↓ [Na+] gradient → hypomagnesemia or hypercalcemia,
Uncontrolled HTN 3) Adjust electrolyte
Positively inotropic ↓ ability for Ca2+ to move out of cell Accumulates in muscile (large Vd, hyperthyreosis, abnormal renal
Bradyarrhythmias 4) For ventricular
Negatively chronotropic (via Na+/Ca2+ exchanger) → need loading dose) function, respiratory disease, acid- tachyarrythmias:
↑ cytoplasmic [Ca2+] Heart failure with atrial Non-responders or intolerance
Digoxin and K+ compete for binding base imbalance, >65 yrs, low body lidocaine, magnesium,
Inotropic agent ↑ contracHlity (atria & ventricles) fibrillation
Digoxin (digitalis) Inhibits Na+/K+ ATPase sites on the ATPase. Low K+ = weight, fever) ↑ K+
(Cardiac Glycoside) Quinidine, verapamil, &
↓ sympatheHcs and RAAS → digoxin toxicity. Digoxin OD Atrial arrhythmias (of slow AV 5) Pacemaker
CHF grade NYHA 3 or 4 Amiodarone displace digoxin from
From digitalis (foxglove) ↓ peripheral resistance; presents with with hyperkalemia, conduction (↑ PR))
(fat) tissue protein-binding sites & Severe intoxication:
plant Enhanced vagal tone → ↓ myocardial but potassium OD presents with GI-Anorexia, nausea, vomiting
compete for renal excretion; -Hyperkalemia
O2 demand decreased Digoxin activity. CNS-headache, confusion, blurred
Digoxin can ↑ by 70-100% -Bradyarrhythmias
↓ conducHon velocity @ AV node Digoxin facilitates Ca2+ overloading vision, altered color perception, -Use digitalis antibodies
Baroreceptor sensitization (and Mg2+ loss) halos on dark objects
(Digibind)
+ve inotropic effects, vasodilation

↑ cAMP (via Gs) → PKA acHvity
Ca2+ channels phosphorylated
Dobutamine β-agonist
↑ Ca2+ entry into myocardium
↑ contracHon
Inotropic Agent Little or no effect on HR
↑ cAMP & ↑[Ca2+] → cardiac
Amrinone Phosphodiesterase (PDE) 3 contractility & arterial & venous
Milrinone Inhibitors dilation
Potentiates effects of dobutamine
Congestive Heart Failure Drugs (Part 2)
Low doses - act on dopamine
receptors
D1 = dilates renal blood vessels,
D2 modulates transmitter release
Dopamine Intermediate - act on β1 receptors (↑ Intermediate dose for acute HF Used as titrate IV infusion
Inotropic Agent force & rate of contraction, ↑ renin
release) High -
act on α1 receptors (incr. force of
contraction)
↑cAMP → Acute cardiac dysfunction
Glucagon
↑myocardial contractility (from β-blocker overdose)
Steps in Treatment of Chronic HF CLASS

ACC/AHA Stage Step Intervention 1 → NA
A,B 1 Control HTN, hyperlipidemia, diabetes, obesity 1a - slow 0 (slow 3)
C 2 ↓ workload of heart (limit acHvity, temp bed rest) 1b - fast 3
3 Restrict Na+ intake, admin diuretics (to ↓ volume overload) 1c - slow 0
4 Restrict water (rarely required)
C,D 5 Give ACE Inhibitors or ATII Blockers 2 → B-blocker
6 Admin Digoxin if systolic dysf(x) or atrial fibrillation present 2 - slow 4
7 Admin β-blockers to pts w/stable class II-IV HF 3 → K-inhibitor
8 Admin Spironolactone 3 - slow 3
9 Admin vasodilators
Cardiac resynchronization if wide QRS interval is present in
4 → Ca-blocker
10 4 - slow 4 (slow 0)
D normal sinus rhythm
11 Cardiac transplant
Anti-Arrhythmics (Part 1)
Drug Classification Mechanism of Action Effect/MOA Class I Fast Na+ channel blockers: General MOA
Slow Phase 0 depolarization in ventricles, also Slow Phase 3 → ↓ in excitability & conducHon velocity
Slow/prolong action potential rate of rise and repolarization → Use/state-dependence = binds more to open/inactivated (not resting)
IA Na+ channel blocker
↑ effecHve ventrcular refractory period Na+ channels → ↑ effect in tissues depolarizing faster →
Intermediate speed of association/dissociation w/activated/inactivated Na+ channels Blocks cells discharging at abnormally high frequency
Shortens Phase 3 repolarization in ventricles
IB Na+ channel Blocker ↓ duraCon of acCon potenCal by shortening repolarization (due to effect on Na+ channels) Rapid 1a - slow 0 (slow 3)
association/dissociation with Na+ channels 1b - fast 3
Significantly slows Phase 0 depolarization in ventricles 1c - slow 0
Markedly depresses rate of rise of action potential 2 - slow 4
IC Na+ channel Blocker 3 - slow 3
No effect on duration of ventricular refractory period
Binds/dissociates slowly to Na+ channels 4 - slow 4 (slow 0)
Slows Phase 4 depolarization in SA & AV nodes →
depresses automaticity, prolonging ventricular conduction→ ↓ HR & contracHlity
II β Blocker
General Indication: Tachyarrhythmia (from ↑ sympathetics), atrial flutter & fibrillaion, & AV-nodal re-
entrant tachycardia
Slows Phase 3 repolarization in ventricles
Block K+ channels → slower outward K+ during repolarizaHon
III K+ channel Blocker Prolongs action potential w/o altering Phase 0 or resting membrane potential
Prolong effective refractory period → longer for cells to generate acHon potenHal
All can induce arrhythmias
Slows Phase 4 + 0 of action potential in SA & AV nodes
↓ inward Ca2+ current → ↓ rate of Phase 4 spontaneous depolarizaHon
IV Ca2+ channel Blocker
Slow conduction in tissues dependent on Ca2+ current (i.e., most heart tissue)
Major effects on vascular smooth muscle & heart
Anti-Arrhythmic Drugs (Part 2)
Prevents Na+ influx (binds to open &
Arrhythmias (torsades de pointes)
inactivated channels)
Also class III activity (Blocks SA + AV block (asystole)
Slows Phase 0
K+ channels) → can Nausea, vomiting, diarrhea (30-50%)
Quinidine Slows Phase 4 Rapid oral absorption
precipitate arrhythmias Rarely used d/t adverse effects Toxic doses - ventircular tachycardia (worsened by hyperkalemia)
(prototype) Slows Phase 3 (Inhibits K+ channels, Active metabolites → CYP450
(Ca2+ antagonists preferred Cinchonism (blurred vision, tinnitus, headache, psychosis), dut to:
like Class 3)
due to toxicity) Mixed α-adrenergic block & atropine-like action (hypotensive)
Can ↑ [digoxin] by ↓ renal clearance → toxicity
Prolongs action potential
High incidence with chronic use
Oral
Atrial/ventricular arrhythmias Reversible lupus-like syndrome (25-
Blocks activated Na+ channels t1/2 = 2-3 hrs
Derivative of local 30%), arthritis, rash
Blocks K+ channels Some is acetylated → N-
anesthetic procaine 2nd/3rd choice (after lidocaine or Toxic doses = asystole, ventricular
Procainamide Class IA amiodarone) for sustained
acetylprocainamide (NAPA),
arrhythmias
Antimuscarinic prolongs duration of action
Similar to Quinidine ventricular arrhythmias assoc CNS (depression, hallucination,
α-sympatholytic activity potential (i.e., Class III)
with acute MI psychosis)
NAPA eliminated via kidneys
Hypotension
Cardiac failure without pre-existing
conditions
Stronger negative inotrope Blocks Na+ cannels ~50% excreted unchanged by kidney Severe atropine-like systemic effects
Disopyramide than quinidine and Causes peripheral vasoconstriction Ventricular arrhytmias ONLY ~30% converted in liver to mono-N- (dry-mouth, uriniary retention,
procainamide Blocks K+ channels dealkylated metabolite blurred vision, constipation)
NO α-blocking (thus, no side effects
assoc. w/α-receptor)
Local anesthetic
Drug of choice for termination of
Rapidly assoc/dissoc, "use- Wide therapeutic ratio
ventricular tachycardia &
dependent" IV only (↑ 1st pass metabolism) No effect on LV funtion (inotropy)
Lidocaine prevention of ventricular
Rapidly assoc & dissoc from Na+ Metabolized by liver Arrhythmias (<10%)
fibrillation after cardioversion
LITTLE EFFECT on K+ channels Toxic doses = convulsions, coma
Class IB with acute ischemia
channels Shortens Phase 3 repolarization
Chronic treatment of ventricular
Nausea, tremor, blurred vision, rash
Mexiletine ↓ duraCon of a(x) potenCal arrhytmias assoc with previous
Orally active derivatives of fever, agranulocytosis
MI Oral
lidocaine
Above, plus
Tocainide Ventricular tachyarrhythmias
Pulmonary toxicity
Suppresses Phase 0 upstroke in Aggrevates CHF (-ve inotropic
Slowly dissociates from
Purkinje & myocardial fibers (Life-threatening) Refractory Dizziness, blurred vision, headache,
resting Na+ channels Post-MI with premature
ventricular arrhythmias Oral nausea
Flecainide Class IC Marked slowing of conduction Prevention of paroxysmal t1/2 = 16-20hrs
contractions
Prominent effects, even at (negative inotrope → 2x mortality)
↓ automaHcity by ↑ threshold supraventricular tachycardia Arrhythmias & ventricular
normal heart rates
potential (doesn't change Phase 4) tachycardia
Slows conduction in all cardiac tissues

Propafenone Similar to Flecainide Supraventricular tachycardia
→ broad spectrum anH-arrhythmic
Drug Therapy of Atrial Fibrillation General Applications

1. Slow ventricular rate (negative dromotropic agents) 1A Atrial fibrilations, flutter; supraventricular & ventricular tachyarrhythmias
digoxin (misc) 1B Ventricular tachyarrhythmias only (not atrial)
verapamil, diltiazem (4) 1C Life threatening supraventricular & ventricular tachyarrhythmias
β-blockers (2) 2 Atrial fibrilations, flutter; AV nodal re-entrant tachycardia
2. Induction / maintenance of sinus rhythm. 3 Atrial fibrilations, flutter; supraventricular & ventricular tachyarrhythmias
Blockade of fast action potentials 4 Supraventricular tachycardia
Class 1a eg, quinidine
Class 1c eg, flecainide, propafenone
Class 3 eg, amiodarone, dofetilide
Studies show rate control has better benefit-to-risk outcome than rhythm control
Anti-Arrhythmic Drugs (Part 3)
↓ incidence of sudden
Hypotension, aggravates CHF,
arrhythmic death after MI;
asystolia
Propanolol Supraventricular tachycardia; CHF
Can cause asthma or diabetes in
Class II Exercise or stress-induced
predisposed persons
ventricular arrhythmias
Most widely used β-blocker
Metoprolol for arrhythmias
↓ risk of bronchospasm
Short-acting Acute arrhythmias during surgery Admin IV
Esmolol
β1-selective or in emergency t1/2 = 9 mins
Complex class I, II, & III effects (i.e.

Structurally related to Assoc with long term use in 50%;
blocks Na+, Ca2+, & K+)
thyroxine (contains iodine) Low doses = maintains normal Interstitial pulmonary fibrosis, GI
Dominant = prolongs (Phase 3) AP &
sinus rhythm in pts with atrial Oral intolerance, tremor, ataxia, Digoxin
refractory (blocks K+)
Most commonly used anti- fibrillation t1/2 = weeks (extensively distributes dizziness, hyper/hypothyroidism, Theophylline
Amiodarone Blocks mostly inactivated Na+
arrhythmic in adipose tissue), loading dose req. liver toxicity, photosensitivity, Warfarin
channels (Re: Class I, blocks activated
Prevention of recurrent Full clinical effects take ~6 weeks neuropathy, muscle weakness Quinidine
Na+ channels)
Anti-anginal & anti- ventricular tachycardia Blue skin discoloration (iodine
Weak Ca2+ blocker
arrhythmic activity accumulation)
Weak non-competitive β-blocker
Class III Long term (↓ sudden death following MI)
Inhibits rapid outward K+ current
Suppress ectopic beats Lowest rate of acute or long term
(delayed rectifier)
Potent non-selective β- ↓ 02 demand effects
Sotalol
blocker Life threatening ventricular arrythmia Torsades de pointes (prolongs QT
Prolongs repolarization
Maintenance of sinus rhythm in pts with atrial fibrillation interval), 3-4%
Lengthens refractory period
Supraventricular arrhythmia in kids
1st line for persistent atrial
fibrillation + HF, or t1/2 = 10hr USE RESTRICTED TO IN-PTS (risk of
Dofetilide
Coronary artery disease + Urinary excretion (~80% unchanged) proarrhythmia)
impaired LV function
Block voltage-gated Ca2+ channels
Phenylalkylamine
→ ↓ inward current (slow 4)
Selective for heart tissue Atrial arrhythmia;
Binds to open, depolarized channels, Oral
Verapamil Dihydropyridines are Supraventricular tachycardia;
prevents repolarization until drug Extensively metabolized by liver Negative inotropes
Class IV selective for vascular
dissociates
↓ ventricular rate in atrial
↓ BP (peripheral vasodilaHon)
Depressed cardiac function
smooth muscle fibrillation & flutter;
Use/state-dependent
HTN, angina
Benzothiazepine Slows conduction & prolongs effective
Diltiazem Oral
Also potent vasodilator refractory period
In HF = +ve inotrope (↑ [Ca2+])

Shortens refractory period
Arrhythmias = ↑ parasymp tone
in atrial & ventricular
(inhibits Ca2+ currents in AV node,
myocardial cells
activates ACh-mediated K+ currents in Toxic doses = ectopic ventricular
Prolongs refractory period Control ventricular response in
Digoxin atrium); hyperpolarization, shortening beats → ventricular tachycardia &
& diminishes conduction atrial fibrillation & flutter
of atrial APs; ↑'s in AV nodal fibrillation
speed in AV node (note
refractoriness (slow AV conduction)
different effects of
→ ↓ fracHon of atrial impulses
blocking ATPase)
conducted through node
Miscellaneous
High dose = ↓ conducHon speed &
Naturally occurring
prolongs refractory period
nucleoside (P1 receptor Low toxicity: Flushing, chest pain,
↓ automaHcity in AV node Drug of choice for acute IV admin
Adenosine agonist) hypotension
Enhanced K+ conductance supraventricular tachycardia Super short t1/2 = 15sec
Majority of effects in AV Bronchoconstriction (upto 30 mins)
↓ cAMP-mediated Ca2+ influx →
node
hyperpolarization in AV node
Torsades de pointes (prolonged QT)
Functional Ca2+
Magnesium Digitalis-induced arrhythmia
angtagonist
Prophylaxis of arrhythmias in acute MI
Atropine Increase HR Decrease vagal tone Bradyarrhythmias
Angina Pectoris Drugs
↓ coronary vasoconstricHon →
↑ myocardium perfusion 1 min to onset Headache (30-60%)
↑ 1st pass effect →
Nitroglycerin Ongoing attack
Nitroglycerin relaxes sm. muscle by admin sublingually, transdermally, High doses = postural hypo-tension,
Simple nitric + nitrous conversion to nitrite ions → NO → NO buccal, IV flushing, tachycardia
esters of glycerol activates guanylate cyclase & ↑ cGMP
Isosorbide dintrate Organic Nitrates → dephosphorylaHon of myosin light Ongoing attack Similar to above (longer action) Note: tolerance develops rapidly
Rapid reduction in chain → vascular sm. muscle relaxaHon (vessels desensitize to
myocradial 02 demand & >1 hr for onset Sildenafil (viagra)
vasodilation), overcome by daily
(NO → guanyl relief of ymptoms Active ant-anginal metabolites due to synergistic effects
Isosorbide mononitrate Dilates large veins → ↓ preload & ↓ Prophylaxis "nitrate-free interval" (10-12hr)
t1/2 = 2-8 mins (metabolites have
cyclase) work of heart
longer t1/2 & sig. activity
Indicated for all
anginas All anginas, ICU & emergency; IV
Caution with borderline systolic t1/2 = <3 mins
Direct NO donor → very effecHve Severe nausea, vomiting, headache
Sodium Nitroprusside BP, MI (with no HF), Protect from light (converted to
immediate vasodilator High doses = cyanide poisoning
hepatic/renal insufficiency; cyanide → toxicity)
Discontinue use after few hrs (+ thiosulphate = thiocyanate)
Propanolol = not
Block β1 receptors Asthma, Diabetes, COPD,
cardioselective Prophylaxis in MI patients
Propanolol (Prototype) ↓ force and rate of contracHons Severe Bradycardia,
β-blocker (prolong surivival) NEVER discontinue abruptly
Metoprolol ↓ O2 demand Peripheral vascular disease
(Antagonist) Metoprolol & atenolol = Comibine with nitrates → ↑ (rebound HTN or angina)
Atenolol ↓ frequency and severity of angina Variant/Prinzemetal angina (use
selective at therapeutic exercise tolerance & duration
attacks Ca2+ blockers or nitrates)
doses
Hypoxia induced ↑ [Ca2+] in ischemic Flushing
Nifedipine tissue; Headache
Minimal effect on cardiac L-type Ca2+ channel = dominant in
Nicardipine Oral (sustained release) Hypotension
conduction cardiac & smooth muscle Prophylaxis
Felopdipine Peripheral (ankle) edema
Entry of Ca2+ blocked → ↓ smooth Constipation
muscle tone & vascular resistance
Amlodipine Ca2+ channel Does not affect HR or CO → ↑ arterial vasodilaHon & ↓ BP
Blockers Slows AV conduction directly →
Pre-existing depressed cardiac
↓ HR, contracHlity, BP & 02 need
Varapamil Constipation function or AV conduction
Greater inotropic effets than
abnormalities
Class IV antiarrhythmic nifedipine (weaker vasodilator) Extensively metabolized in liver
Similar effects to verapamil (slow AV Use w/caution in pts taking digoxin
Variant/Prinzemetal Angina
Diltiazem conduction) → ↓ HR (lesser extent Same, but lower incidence (↑ digoxin levels)
(relief of coronary spasm)
than verapamil) & ↓ BP
Blocks Na+ current that supports Ca2+
QT interval prolongation
entry via Na/Ca exchanger
Na+ channel Nausea
Ranolazine Blocks Ca2+ entry ↓ contracHlity Prophylaxis Metabolized by CYP3A4
Blockers Constipation
↓ 02 demand
Dizziness
May modify fatty acid oxidation
Treatment of Angina with Concomintant Diseases General Effects of Drugs in Angina Pectoris
β-blockers or Ca2+ channel Nitrates + β-blocker or
Comorbidity Drugs Commonly Used in Treating Anginas Nitrates
Ca2+ channel blocker
blockers
None Nitrate β-blockers Ca2+ channel Blockers Heart Rate (HR) Reflex increase Decrease Decrease
Recent MI Nitrate β-blockers Arterial Pressure Decrease Decrease Decrease
Asthma, COPD Nitrate Ca2+ channel Blockers End-diastolic volume Decrease Increase None or decrease
HTN Nitrate β-blockers Ca2+ channel Blockers Contractility Reflex increase Decrease None
Diabetes Nitrate Ca2+ channel Blockers
Chronic Renal Dx Nitrate β-blockers Ca2+ channel Blockers Stable Angina Use one of first 3 classes; if inadequate, add another class
Unstable Angina Use nitroglycerine + β-blocker
Variant Angina Respongds to nitroglycerine + equally to all Ca2+ channels
Steroids
β2-agonist Anti-IgE antibody (e.g.
Anti-Inflammatory Agents Lipoxygenase inhibitor
Asthma Drug Groups Bronchodilators Muscarinic antagonists
(Most important in asthma)
Omalizumab) Leukotriene antagonists
Leukotriene receptor blockers
PDE inhibitors Release Inhibitors (e.g.
Cromolyn Na, mast cell)
Bronchial Asthma Drugs

Albuterol (Prototype)
Inhalation via pressurized aerosol Higher doses → β1 effects (tachycardia,
Terbutaline Short-acting
Acute exacerbations or rarely nebulizers arrhytmias, tremors) COPD patients with cardiac
Pirbuterol < 6 hrs Relaxes brochial smooth muscle by:
Inhalation ↓ systemic side effects disease may develop
Metaproterenol activating Gs → acHvate adenylyl cyclase →
Salmeterol (Prototype) β2-agonists ↑ cAMP →→ Prophylaxis for attacks
Tolerance = loss of response with excess arrhythmias
Long-acting (12hrs) use
Formeterol Bronchodilation COPD
Bradycardia or heart block IV, Oral, Intranasal,
Isoprotenerol Non-Specific agonist ↑ β1 effects
via β2 with asthma Subcutaneous, or IM
Inhibits PDE3 (PhosphoDiEsterase = enzyme CNS (tremors, insomnia, convulsions)
degrades cAMP to AMP) → Oral & IV Cardiac stimulation (arrhythmias) Erythromycin, Coffee, Tea,
Theophylline (Prototype) Bronchodilator Nocturnal asthma (slow
↑ cAMP →→ Low theraputic index; plasma ↑ GI moHlity Smoking induce CYP450 →
Aminophylline Methylxanthines Not a safe drug release preparation)
Bronchodilation levels must be monitored (Use β-blockers/Adenosine agnoists to ↓ theophylline acHon
PDE inhibitor Also blocks adenosine receptors counter theophylline toxicity)
Derivative of theophylline; Intermittent claudication
Pentoxifylline Inhibits PDE4
Bronchodilator from ↓ blood viscosity
Admin via pressurized aerosol Minor anti-musarinic effects with excessive
Ipratropium bromide (Prototype) Muscarinic Short-acting Competitively block muscarinic-R → prevent Pediatric asthma
(inhalation) dosage
antagonists vagal mediated constriction COPD (alt. to β-agonist)
Tiotropium Long-acting No CNS or CVS effects (safe)
Inhibits release of mediators (LT, Used for prophylaxis
Oral, aerosol, drops
histamine) from mast cells Oral preps for preventing
Cromolyn (Prototype) Mediator inhibitors Mast cell stabilizers No bronchodilator effect food allergy & hay fever;
Aerosol admin for prophylaxis Cough & irritation of respiratory tract may
Nedocromil (Mast stabilizer) occur with aerosol
Effects seen on acute (block the initiation Drops for conjunctival &
Ineffective in acute cases
& delayed) as well as late responses nasopharyngeal allergies
Beclomethasone (Prototype)
Inhibits phospholipase A2 → 1st line inhalational drugs
Dexamethasone Surface/ICS - Inhalational ↓ synthesis of arachodonic acid & for moderate to severe
Fluticasone
Corticosteroids expression of cyclooxygenase asthma (even in peds) Step up, step down ICS therapy:
Budesonide
Also for pts not responding to National Heart, Lung, & Blood Oropharyngeal candidiasis
Flunisolide phospholipase A2
↑ β-adrenoreceptors sensitivity in the β2-agonists aerosol Institute recommends dosing be Initial mild growth retardation in children
Mometasone
respiratory tract stepped up (start slowly & ↑ Slight adrenal supression
Life-saving steroids in status
Active metabolite of gradually; keep up high dose for 3-Major systemic toxicities with daily oral use
Prednisolone asthmaticus;
prednisone Bind intracellular receptors & activate 6mos) → asthma controlled → ↓ (Cushing-like syndromes)
I.V. Corticosteroid Prevents remodeling of
glucocorticoid response elements (GREs) in dosage
phospholipase A2 bronchial tree in chronic
the nucleus → synthesis of inflammaHon &
Hydrocortisone asthma & enhances β2
allergy inhibiting substances
receptors
Antigen, exercise, & Very safe; Rarely, may produce Churg-
Zafirlukast (Prototype) aspirin induced asthma Strauss syndrome (inflammation of
Blocks LTD4 & LTC4 receptors
Montelukast Not for acute asthma vasculature in kidney, lung, & GI) & allergic
Not as effective as steroid
granulomatous angiitis
AntiLeukotriene & β2-agonists in severe (Aspirin bronchospasm is Oral
asthma 5-Lipoxygenase inhibitor due to diversion to LOX
Zileuton (Prototype) Blocks conversion of arachodonic acid to pathway from COX Elevation of liver enzymes
leukotrienes blockade)
Monoclonal Antibodies Binds to IgE on sensitized mast cells &

Prophylaxis for asthma Parenteral
Omalizumab prevents activation by triggers
(anti-IgE antibody) attacks (Expensive)
Prevents release of LTs & other mediators
Broncho-constrictive
Severity of COPD FEV1 % Predicted Treatment Classification Spirometry/peak flow Long-term control Quick relief of symptoms
episodes
SABA (short acting
Mild ≥ 80 Mild intermittent < 2 / week Near normal No daily medication Short acting β2-agonist
bronchodilator)
Moderate 50-79 ≥1 dilator + ICS Mild persistent > 2 / week Near normal Low dose ICS Short acting β2-agonist
≥1 dilator + ICS + AB Low to medium dose ICS
Severe 30-49 Moderate persistent Daily 60%-80% of normal Short acting β2-agonist
(antibiotic) and a long acting β2 agonist
< 30 or chronic ≥1 dilator + ICS + AB +
Very Severe Severe persistent Continual Less than 60% of normal High dose ICS & a long acting β2 agonist Short acting β2-agonist
respiratory failure assisted ventilation
Receptor Tissue Effect
Smooth muscle cells Broncho-/GI tract constriction
H1 Nerve endings Stimulates sensory nerve endings, esp. pain/itching H1 → Gq → PLC → IP3/DAG
Both have constituitive
Endothelium Formation of NO ↑ capillary permeability
→ Edema → Utricaria
activity
Vascular smooth muscle Vasodilation via cAMP H2 → Gs → Adenylyl cyclase → cAMP
Gastric mucosa Gastric acid secretion
H2
Cardiac muscle ↑ contractility, ↑ rate
Some Immune cells
Histamine Antagonists (Autacoids)

Drug Drug Class Description MOA Indications Pharmacokinetics/Drug Interactions Adverse Effects
Opposite effect of
Epinephrine Physiological antagonist Acts at separate receptor
histamine
Cromolyn Reduces immunologic mast
Mast stabilizer
Nedocromil cell degranulation
Chlorpheniramine
Diphenhydramine (Benadryl)
Sedative effects
Dimenhydrinate H1 Receptor (penetration of BBB)
Sedation
Doxylamine Antagonists Actually inverse agonists Dry mouth (due to anti-cholinergic
& are more likely to block
Hydroxyzine (First generation) (decrease constituitive effects)
autonomic receptors
Meclizine activity) Allergic rhinitis & urticaria (Drug of
Promethazine choice)
1st gen also block Motion sickness & nausea
Less sedating because less cholinergic, α-adrenergic, Somnifacient (Tx of insomnia, less Ventricular arrhythmias in patients
liposoluble serotonin, & local common with 2nd generation) taking terfenadine or astemizole with
Fexofenadine
Loratadine (Claritin)
H1 Receptor Substrates of P- anesthetic receptors (i.e., CYP3A4 inhibitors/Grapefruit juice
Dry mouth (due to anti-cholinergic
Antagonists glycoprotein transporter Na+ channels) (terfenadine & astemizole block cardiac
Cetirizine (Reactine) effects)
(Second generation) (i.e. MDR-1), so they are K+ channels responsible for
Acrivastine
actively pumped out of the repolarization → arrhythmia)
brain (drugs withdrawn in US)
Very safe drugs (AE <3%)

Cimetidine inhibits cytochrome P450
Cimetidine Peptic ulcer (promotes healing of gastric
Competitively blocks H2 → slows metabolism of some drugs;
Ranitidine (Zantac) H2 Receptor Inhibitors of gastric acid
receptors → ↓ secreHon of
and duodenal ulcers)
also binds androgen rceptors & has
Famotidine (Pepcid) Antagonists secretion Acute stress ulcers
gastric acid antiandrogenic effects →
Nizatidine (Axid) GERD (prevents & treat heart burn)
gynecomastia + ↓ sperm count,
galactorrhea in women
Serotonin Receptor Agonists & Antagonists (Autocoids)
Drug Drug Class Description MOA Indications Pharmacokinetics/Adverse Effects
Sumatriptan (Prototype)
5-HT1D/1B Receptor suffix - tryptan
Drug of choice for acute severe migraine
Agonist attacks
ligand-gated ion channel receptor

5-HT3 → ONLY monoamine with
Promote & organizes
Metoclopramide Lazy gut & anti-emetic
peristalsis of the gut
5-HT1 - 5-HT7 → G-linked

5-HT4 Receptor Agonist Prokinetic agent
Cisapride Serious cardiac effects (no longer used)
Allergic/Vasomotor rhinitis
Cold urticaria, dermatographism
Cyproheptadine 5-HT2 Receptor Also blocks H1 Treatment of smooth muscle effects of
Antagonist carcinoid tumor
Serotonin syndrome
Ondansetron 5-HT3 Receptor Most powerful anti-emetic

Severe nausea & vomiting with cancer
Antagonist therapy
Ergotamine Migraine (highly specific, but Triptans
Produced by Claviceps
Dihydroergotamine Affect α-adrenoreceptor, 5- preferred)
purpurea, a fungus that
Bromocriptine HT receptors, & CNS
infects grain Hyperprolactinemia (pituitary tumor)
Cabergoline Ergot Alkaloids (5-HT dopamine receptors
receptor antagonists) (very non-selective Post-partum hemorrahage (oxytocin 1st
Oxytocin
agonists/partial line)
Methylergonovine Admin IM for post-partum bleeding
antagonists) Ergonovine IV used to provoke/ diagnose
Ergonovine
variant angina
Eicosonoids & Eicosanoid Antagonists (Autacoids)

Drug Drug Class Description MOA Indications
Act in autocrine & Ripens cervix at term prior to induction
Dinoprostone (PGE2) PGE2 paracrine fashion of labor with oxytocin
Bind to G protein-coupled Induces abortion
Carboprost tromethamine 15-methyl-PGF2α receptors on cell surface Induces abortion
Induces abortion when combined with
Couple to: antiprogestin mifepristone or
Misoprostol Derivative of PGE1 -activation of adenylyl methotrexate
cyclas (Gs) Prevents peptic ulcers in patients taking
Eicosanoids -inhibition of adenyly high-dose NSAIDs for arthritis
cyclase (Gi)
Maintains patency of ductus arteriosus
Alprostadil (PGE1) PGE1 -activation of PLC (Gq)
Impotence
Contractile effects on Severe pulmonary HTN
Constitutive on most cells, makes PGs
Prostacyclin PGI2 smooth muscle by Ca2+ Prevent platelet aggregation in dialysis COX-1
for homeostasis
Relaxing effects by cAMP machines
Latanoprost, Bimatoprost, Glaucoma (Latanoprost is GOLD COX-2 On inflammatory cells, make
PGF2α derivative
Travoprost, Unoprostone standard) inflammatory PGs
Zileuton LOX inhibitor Inhibits 5-Lipoxygenase LOX . LTs associated with asthma,
Zafirlukast Inhibits binding of LTD4 to Asthma anaphylactic shock and cardiovascular
Montelukast receptor disease
Inhibit production of
arachidonic acid by LTC4 and LTD4 are potent
Corticosteroids
Eicosanoid phospholipase A2 bronchoconstrictors, secreted in
Antagonists Also inhibits COX2 asthma and anaphylaxis
production
Fever
NSAIDs (e.g., Ibuprofren, Anti-pyretic, analgesic, anti-
Inhibits COX Pain
aspirin) inflammatory
Inflammation
Gastrointestinal Drugs (Antacids)
↓ bioavailability of
Aluminum hydroxide Reaction with HCl froms Pts unable to tolerate
Weak bases react with HCl tetracyclines, digoxin, & Constipation
Al(OH)3 aluminum chloride primary therapies
in the stomach --> antimuscarinics
Gastric Acid ↑ intra-gastric pH Diarrhea
Symptomatic relief of
Magnesium hydroxide
Neutralizing Drugs dyspepsia with GERD,
(Milk of Magnesia) (Pepsin is inactivated at To avoid AE, admin
gastritis, peptic ulcers
(Antacids) pH > 4) Al(OH)3 + Mg(OH)2
Same as above
Calcium carbonate Non-absorbable Nephrolithiasis
Also admin as adjuvant in
(Tums) Dense fecal matter
osteroporosis
Inhibits CYP450
Single dose ↓ basal --> slows metabolism
Oral
gastric acid by 80-90% Cimetidine only: of warfarin,
Cimetidine (Tagmet) Peptic ulcers, (prevents Urinary excretion (70%
Antiandrogen: diazepam, phenytoin,
recurrence) unchanged)
Produces anti-androgenic gynecomastia, quinidine,
prototype Short t1/2, ↑ with renal
or prolactin-stimulating galactorrhea, ↓ sperm carbamazapine,
Only partially inhibits acid failure
effects count (acts as non- theophylline,
induced by Ach or
steroidal anti-androgen) imipramine
Bethanechol
Competitively blocks H2
H2 Receptor Acute stress ulcers (major
Headache, dizzines,
Longer acting (5-10x more receptors --> ↓ secreJon of diarrhea, muscular pain
Ranitidine (Zantac) Blockers potent than Cimetidine) gastric acid trauma in ICU)
CNS: confusion,
Long acting (20-50x more Pre-operative: prevents
halluciniations (in elderly
Famotidine (Pepcid) potent than Cimetidine, 3- aspiration pneumonia
or after IV admin)
20x more than Ranitidine)
GERD (works 50% of time,
↓ ketonconazole (anJ-
use PPIs instead) Oral fungal) absorption
No 1st pass metabolism
Nizatidine (Axid)
(bioavailability ~100%)
Renal excretion
Coating removed in alkaline Inhibits metabolism of

Pro-drug (weak base), acid-
duodenum --> absorbed & DoC for GERD & bleeding warfarin, phenytoin,
resistant enteric coated,
transported to parietal cell ulcers (from diazepam, & cyclosporine
protected from gastric
canaliculus --> converted to aspirin/NSAID use) Long-term use --> Vit B12
H+/K+-ATPase acid degradation
active form Erosive esophagitis Pro-drug, activated in deficiency
Omeprazole (prototype) inhibitors Inhibits gastric acid (H+)
Active duodenal ulcer duodenum C. difficile colitis, diarrhea
Esomeprazole (Proton-pump Reacts with cysteine residue Long-term Zollinger- Once daily dosing with H2 Use Calcium citrate as
secretion by >90%
on H+/K+-ATPase, forming Ellison Syndrome tx antagonist = effective alternative to Calcium
inhibitors) irreversible covalent bond --> (gastrin-producing tumor) carbonate
Support platelet
acid suppression in 1-2 hrs Hemorrhagic ulcer Pancreatitis,
aggregation, maintain clot
(~18hrs for pump to be Eridcation of H.Pylori hepatotoxicity, interstitial
integrity
resynthesized) nephritis
Inhibits pepsin and increases

Bismuth salts Pepsin inhibitor mucus secretion
Gastrointestinal Drugs (Antacids)
Binds to proteins, forming

complex gels with epithelial
cells --> physical barrier
Complex of Prevents ulcer recurrence Require acidic pH for H2 antagonist or
Sucralfate against HCl --> prevents
Al(OH)3 + sulfated sucrose (long-term) activiation Antacid
degradation of mucous
Stimulates prostaglandin
release
Inhibits pepsin
Cytoprotective ↑ secreJon of mucous
Pepsin inhibitor
Bismuth subsalicylate (Mucosal protective) Interacts with glycoprotein in
Some microbial action
agents necrotic mucousal tissue to
coat & protect ulcer
Inhibits secretion of HCl
Normally made in gastric
Prostaglandins (PGE2) Stimulates secretion of
mucosa
mucous & bicarbonate
Prevention of NSAIDs- Produces uterine

induced ulcers (elderly or contractions
Misoprostol Analog of PGE1 Pregnancy
patients with ulcer history Dose-related diarrhea &
are at risk) nausea
Parietal cells have M3;

Poor BBB penetration
Pirenzepine Anti-cholinergic ↓ acid 40-50% Likely suppresses acid via M1 Refractory peptic ulcer Dry mouth, blurred vision,
(less CNS toxicity)
in inramural ganglia urinary retention,
(muscarinic arrhythmia, and
antagonists) Binds mAChR in parietal cells -- IBS: Irritable Bowel
Dicyclomine Constipation at ↑ dose
> blocks acid secretion Syndrome
Treatment for H. Pylori Infection

Regimen Duration Eradication Rate
PPI + Clarithromycin + Amoxicillin OR
10-14 days 70-85%
PPI + Clarithromycin + metronidazole
Bismuth subsalicylate + metronidazole + Tetracycline +
10-14 days 75-90%
Ranitidine or PPI
Gastrointestinal Drugs (Prokinetic Drugs)

Blocks dopamine and some
D2 antagonist serotonin -->
Diabetic gastroparesis Inhibits DA (which is a May exacerbate
Metoclopramide Anti-emetic (due to D2
(Reglan)
5-HT3 antagonist/ blockage in CTZ in CNS)
Anti-emetic prolactin-inhibiting symptoms in
5-HT4 agonist GERD hormone) --> galactorrhea Parkinson's disease
Prokinetic activity via
5-HT4 agonist activity
Prokinetic Drug
Release Ach in myenteric Long QT syndrome
plexus Diabetic gastroparesis --> predisposition to
Cisapride (Propulsid) 5-HT4 agonist ↑ gastric emptying Constipation arrhythmias with
↑ muscle tone in esophageal GERD erthromycin, ketoconazole
sphincter Diarrhea
Gastrointestinal Drugs (Laxatives)
Risk of losing effect of
Evacuation of bowels in
Used in combo with a other drugs (less time in
8-10 hrs Opioid-induced
Senna Gut Stimulant docusate (makes stools
↑ H20 & electrolyte secretion constipation
Oral intestines)
softer, easier to pass) Electrolyte imbalances
into bowel
(chronic)
Antacids/PPI -->
premature
Abdominal cramps
Potent stimulator of the Acts directly on nerve fibers in Suppository dissolution of enteric
Bisacodyl Atonic colon with
colon the colon mucosa Enteric-coated tablet (oral) coating in stomach --
prolonged use
Gut Irritants and > gastric irritation,
Stimulants pain
Broken down in small
intestine to ricinoleic acid Stimulates uterine
Castor Oil Gut irritant Pregnancy
(irritates gut) --> increases contractions
peristalsis
Form gels in large intestine -->

Methylcelulose Hydrophilic substances
H20 retention, intestinal Intestinal obstruction in
Psyllium seeds Bulking Agents from indigestible parts of
distention --> bed-bound patients
Bran fruits/vegetables
↑ perastalsis
Magnesium citrate
Mg sulfate Suppository
Non absorbable salts
Mg phosphate Enteric-coated tablet (oral)
Mg hydroxide Hold water in the intestine by
Saline & Osmotic osmosis and distend the
Degraded by colonic
Laxatives Semi-synthetic bowel, causing stimulation
Lactulose bacteria to form lactic,
disaccharide sugars and defecation
formic, and acetic acid
Colonic lavage
PEG (polyethylene glycol)
Endoscopy/Radiologic
Docusate sodium Surface active agents
Docusate calcium Stool Softener emulsified with stools to
Docusate potassium make stool softer
Mineral oils Aid in easy passage of
Glycerine
Lubricant Laxatives stools
Suppositories
Gastrointestinal Drugs (IBS/IDS)

Drug Drug Class Description Indications Drug Drug Class Description Indications
Sulfasalazine Loperamide
Anti-diarrheals
Sulfapyridine + 5-ASA Anti-inflammatory IBD (UC) Diphenoxylate IBS-D (diarrhea)
Opoid analogs
(Olsalazine) Drugs for Codine
Fibre, PEG, sorbitol, Drugs for Irritable
Infliximab Inflammatory Anti-TNF antibody IBD, Rheumatoid arthritis
lactulose
Osmotic agents IBS-C (constipation)
Bowel Syndrome
Methotrexate Bowel Disease Anti-folate
Hyocyamine Antispasmodics
6-Mercaptopurine Anti-metabolite IBD (Crohn's) Cramps, Diarrhea
Dicyclomine (Anticholinergic)
Predniso(lo)ne Steroid (↓ immune)
Gastrointestinal Drugs (Antiemetics)
Scopolamine
Muscarinic
antagonist
Dimenhydramine Motion sickness
Dimenhydrinate
Meclizine H1 antagonist
Cyclizine
Low to moderate Hypotension, restless-ness
Prochlorperazine Phenothiazine emetogenic chemo- (dose limiting)
Droperidol Butyrophenones theraputic agents; Extrapyramidal sx,
Haloperidol D2 blocker Reserved for refractory Sedation; Droperidol may
cases prolong QT
Periphery: block visceral vagal
Ondansetron 5-HT3 Receptor Block receptors in the afferent fibers
Prior to chemotherapy
IV, Oral Prolong QT interval
Granisetron Blockers periphery and brain Brain: chemoreceptor trigger Long duration of action (Dolasetron)
zone
Antidopaminergic:
Substituted High doses for sedation, diarrhea,
Metoclopramide
benzamide emetogenic cisplatin extrapyramidal (dose
limiting)
Lorazepam May be due to sedative, Anticipatory (nervous)
Alprazolam
Benzodiazepines Low potency
anxiolytic, amnesic effects vomiting
Insomnia,
Dexamethasone Used in combo with other Unknown (maybe due to PG Mild to moderate
Methlyprednisolone
Corticosteroids drugs blockade) chemotherapy emesis
hyperglycemia,
diabetes mellitus
Dysphoria, sedation,
Dronabinol Marijuana derivatives Mild to moderate
Nabilone
Cannabinoids Not first line chemotherapy emesis
hallucinations, vertigo,
disorientation
Given orally with
Blocks NeuroKinin-1/ Constipation
Aprepitant NK1 antagonist New
Substance P in brain
dexamethasone
Fatigue
Can induce CYP3A4
Metabolized by CYP3A4
Gastrointestinal Drugs (Emetics)

Apomorphine Stimulates CTZ
Syrup ipecac
Emetic Gastric mucosal irritant
Accidental poisonings
Gastrointestinal Drugs (Antidiarrheals)

Activates presynaptic opioid
Atropine with Addictive Young children: Toxic
Diphenoxylate Opioid-like actions on gut receptors in enteric nervous DoC for traveller's
Diphenoxylate to Drowsiness, abdominal megacolon, severe
Loperamide No analgesia system to inhibit Ach and ↓ diarrhea
discourage abuse cramps, dizziness colitis
peristalsis
Antidiarrheal Diarrheas associated with
Octreotide Somatostatin derivative carcinoid tumors and
VIPomas
Bismuth subsalicylate Coats intestinal epithelium
Cytoprotective
(Pepto Bismol) and decreases GI irritation
Contraceptives
Drug Drug Class Description MOA Pharmacokinetics Adverse Effects Contraindications Drug interactions
Absolute Contraindications:
Nausea, bloating, breakthrough
Fixed doses of estrogen -History of thromboembolic
Monophasic oral bleeding (improve by 3rd cycle)
& progestin in each 1. 21 hormonally active disease, stroke (or current
contraceptive Rifampin induces CYP450 -->
active pill pills + 7 placebo pills cerebral vascular disease),
-Headache (mild, transient) ↑ metabolism of estrogen
(most common) coronary artery disease,
-Migraine associated w/CVA
breast CA, estrogen-
Suppress LH & FSH -Depression Carbamazepine, oxcarbazepine,
2. Extended cycle dependent neoplasm, hepatic
release --> prevents phenytoin, phenobarbital,
formulations: ↑ to 84 tumors
ovulation -Insulin resistance (due to primidone, topiramate, vigabatrin
hormone-containing pills -Undiagnosed abnormal
progestins in older OCs) (anti-epileptics), & St. John's Wort
Combined oral + 7-day placebo phase -- uterine bleeding, pregnancy
Progestin thickens -Hirsutism, oily skin, acne also induce CYP450 --> ↑
> four menstrual -Heavy smokers (≥15/day) +
Biphasic oral contraceptive contraceptives cervical mucous -->
cycles/year
(androgenic progestins)
older than 35 yrs
metabolism of OCs
Contain varying prevents sperm -Melasma (estrogen -->
(estrogen + progestin) proportions of -Active liver disease
penetration; melanocyte production) Broad-spectrum antibiotics --> ↓
hormones during the pill impairs implantation by 3. Continuous -Amenorrhea intestinal flora (which hydrolyze
cycle combination regimens: Relative Contraindications:
inducing changes in -Dyslipidemia conjugated extrogen in bile) -->
Mimics hormonal 21 hormone-containing -Smoking (<15/day), any age
endometrium interrupt enterohepatic circulation
changes of menstrual pills + 4-7 very low-dose -History of migraine headache
-CVD: thromboembolism, of estrogen -->
cycle & tries to limit the estrogen & progestin disorder
thrombophlebitis, HTN, MI, ↓ estrogen levels -->
amount of progestin pills (NO menstrual -HTN
Triphasic oral contraceptive cerebral & coronary ↓ contracepJve efficacy
cycle) -Uterine fibroid
thrombosis (common in
-Breast-feeding
smokers & >35yrs old)
-Diabetes
Slightly less effective Blocks ovulation in only

than combo OC 60-70% of cycles
No risk of thromboembolic
Benefits: Thickens cervical
Norethindrone (NE) events
Norgestrel (NGrel)
Progestin-only pills No thromboembolism mucous --> ↓ sperm
Unscheduled bleeding,
↓ dysmenorrhea penetration;
spotting common
↓ menstrual blood loss endometrial changes
↓ PMS symptoms impair implantation
Transdermal Patch The Patch Estrogen + progestin Transdermal

Contains ethinyl
Tranvaginal Ring (etoNGrel) Contraceptive Ring estradiol +
etonorgestrel
Menstrual irregularities
Contains depot Weight gain
Depo-Provera® Progestin Injection medroxyprogesterone Admin IM every 3 mos Significant loss of bone
acetate (DMPA) mineral density, irreversible
with long-term use (> 2 yrs)
Placed under skin of

4-cm implant with
Implanon® (etoNGrel) Progestin Implants etonorgestrel
upper arm Menstrual irregularities
Effective for 3 years
Levonorgestrel-releasing
system
Mirena® (LGN) Intrauterine System Polyethylene body with
Effective for 5 years
a LGN resevoir
Contraceptives
Estrogen Progestins Note: 1-6 are androgenic
1. Ethinyl estradiol 1. Norgestrel (NGrel) 1/2: Oldest NGrel & LNG have highest androgenic activity
2. Mestranol (a prodrug 2. Levonorgestrel (LNG) NE & NEA > NGmate & DG > DS (ANTI-androgenic)
of ethinyl estradiol) 3. Norethindrone (NE)
4. Norethindrone acetate Most widely used combined OCs are "low dose", (≤35 µg of ethinyl estradiol)
3/4: 2nd Gen
(NEA) Low dose = ↓ adverse effects & risk, BUT ↑ contraceptive failure if doses are missed
5. Norgestimate (NGmate) 5/6: 3rd Gen
6. Desogestrel (DG) Overall Benefits of Combined OCs:
7. Drospirenone (DS) ↓ risk of endometrial+ovarian cancer; improved menstrual regulaJon; relief of benign breast disease;
7: Newest
↓ ovarian cysts; ↓ symptomaJc PID; improved acne control (using DS)
Non-Hormonal Contraceptive Methods Emergency Post-Coital Contraception

Barrier Contraceptives Method Description Pharmacokinetics
-Condoms Yuzpe regimen Two tablets within 72 hours of intercourse,
Preven®
-Diaphrams ethinyl estradiol + Two tablets 12 hours later
(Hormonal)
-Cervical caps levonorgestrol (LGN)
-Spermicides One tablet within 72 hours of intercourse,
Plan B® Regimen of choice
One more 12 hours later
(Hormonal) Levonorgestrel (LNG)
Intrauterine Device (IUD) ↓ nausea & vomiƟng (no estrogen) --> ↓ risk of failure
Sterilization Copper IUD Non-hormonal Inserted within 5 days of intercourse
Effectiveness of Different Methods of Contraception

Method of contraception Theoretical Effectiveness Actual Effectiveness
Combined OCP 99.9 97
Progestin only pill 99.5 97
Depo-Provera 99.7 99.7
Implanon (most effective) 99.95 99.95
Mirena 99.9 99.8

Condoms 98 88
Diaphragm 94 82
Cervical cap 94 82
Spermicides 97 79
Copper IUD 99 97
Male Sterilization (most
99.9 99.9
effective non-hormonal)
Female Sterilization (most
99.8 99.6
effective non-hormonal)
Uterine Drugs - Oxytocics (Uterine Stimulants)
Class Drug Description MOA Indications Pharmacokinetics Adverse Effects Contraindications
Fetal distress, placental abruption,
Peptide hormone, Acts via Gq --> phospholipase C Induction of labor (DoC) uterine rupture Predispositions to
secreted by posterior --> IP3/DAG --> voltage-gated Ca2+ Augment dysfunctional labor uterine rupture
pituitary channels Postpartum hemorrhage [High] Activate vasopression
(DoC) IV infusion receptors --> excessive fluid Fetal distress
Oxytocin Elicits milk ejection in ↑ local prostaglandin synthesis Oxytocin challenge test IM retention --> hyponatremia, heart Prematurity
lactating women, --> uterine contractions (abnormal response = fetal Nasal spray failure, seizures, death Abnormal fetal
induces uterine (↑ oxytocin receptors in uterine hypoxia --> immediate C- presentation
contractions & smooth muscle in 2nd half of section) Bolus injection --> hypotension Cephalopelvic
maintains labor pregnancy) Abortion (thus admin diluted, at controlled disproportion
Oxytocics (Uterine Stimulants)
rate)
Ergot alkaloids HTN

Partial agonist: Very small doses: evoke rhythmic Headache Angina pectoris
α-adrenergic & contraction & relaxation of uterus Seizures MI
Ergonovine & Post-partum hemorrhage
some serotonin IM Nausea, Vomiting, Chest pains, Pregnancy
Methylergonovine (2nd line)
[Higher] induce powerful, Dyspnea, Leg cramps History of CVA, TIA,
Uterine sensitivity ↑↑ prolonged contracture Ergot poisoning of nursing infant or HTN
during pregnancy (ergotism) --> gangrene
2nd trimester abortion

Evacuate uterine contents of
Vaginal insert
missed abortion
Dinoprostone PGE2 Vaginal suppository
Manage hydatidiform mole
Cervical gel
Ripen cervix for induction of
labor
2nd trimester abortion

Carboprost Post-partum hemorrhage
PGF2α IM
tromethamine due to uterine atony (3rd
line)
Cervical ripening
PGE1 analogue
Labor induction
Note: not FDA
Postpartum hemorrhage
Misoprostol approved for obstetric
Currently only approved to
indications (under
↓ risk of NSAID-induced
clincial trials)
gastric ulcers
Uterine Drugs - Tocolytics (Uterine Relaxants)
Class Drug Description MOA Indications Pharmacokinetics Adverse Effects Contraindications
Palpitations
Tremor
Activation of β2-receptors (Gs) on
Nausea
myometrium --> adenylyl cyclase --
Vomiting
> Tertbutaline (not
Nervousness
↑cAMP --> PKA --> phosphorylate FDA approved,
Shortness of breath
Most commonly used smooth muscle myosin light chain used <33 weeks)
β2-agonists Hyperglycemia
tocolytic agent kinase (SmMLCK) --> admin orally,
HypOkalemia
↓ affinity of SmMLCK for the Ca2+- subcutaneously, or
Tocolytics (Uterine Relaxants)
HypOtension
calmodulin complex --> myosin not IV injection
Pulmonary edema, cardiac
phosphorylated --> relaxation of
insufficiency, arrhythmias,
myometrial sm.muscle
myocardial ischemia, maternal
Prolong intrauterine life
death
(prevent labor) to benefit
fetus or allow additional
↓ Ca2+ uptake by compeJng for its time for drugs treatment,
Mg toxicity is deadly
binding sites e.g. corticosteroids (for fetal Lost patellar reflex (8-10 mM)
Activates adenylyl cyclase lung surfactant) Repiratory depression & paralysis,
Magnesium sulfate --> stimulates Ca2+ uptake by SR
(10-12mM)
--> Inhibits cellular action Temporary uterine relaxation Respiratory & cardiac arrest (>12-
potentials --> Uncouples excitation- (e.g. for intrauterine fetal
15 mM)
contraction in myomterial cells resuscitation)
Premature closure of fetal ductus

NSAID (most popular Oral ateriosus (patency required during
Indomethacin
drug) Rectal procedure to repair Transposition
of the Great Vessels)
Blocks Ca2+ entry into myometrial

Nifedipine Oral
cells
Atosiban Not available in US Competitive oxytocin antagonist

Drugs to Reduce Clotting
Drug Drug Class Description MOA Indications Pharmacokinetics Adverse Effects
Irreversibly acetylates COX --> Prophylaxis for transient cerebral
Cyclooxygenase inhibitors Inhibits TXA2 synthesis --> ischemia
Aspirin (Recall: TXA2 causes platelets to prolong bleeding time ↓ recurrent MI
degranulate & aggregate) (Other NSAISs are reversible) ↓ mortality post-MI
Risk of bleeding 5-7 days after
Irreversibly inhibits P2Y12 (1 of 2 ADP Placement of coronary stent cessation
Clopidogrel (preferred) ADP Receptor Blockers
receptor subtypes on platelets) Prevent cerebro-, cardio- and Inhibit CYP450
Ticlopidine
Platelet Prodrugs (slow action)
--> Aggregation reduced peripheral vascular disease Thrombocytopenic purpura
Ticlopidine only: neutropenia
aggregation Prevent postoperative (valve
Inhibits phosphdiesterase &/or blocks
inhibitors uptake of adenosine (which acts at A2
replacement) thromboembolism Little effect alone
Dipyridamole Phosphodiesterase inhibitors receptors to activate adenylyl cyclase)
(with warfarin) Given with warfarin or
Coronary vasodilator Prevent cerbrovascular disease (with aspirin
--> ↑ cAMP
aspirin)
Cilostazol
1° hemostasis Inhibits phosphdiesterase Intermittant claudication
Monoclonal antibody (irreversible) against
Abciximab Block Platelet GPIIb/IIIA
GPIIb/IIIa
(IIb/IIIA complex = receptor for Parentally No GP2b/3a = Glanzmann's
Cyclic peptide reversible antagonist of
Eptifibatide fibrinogen, vitronectin, fibronectin, & Acute coronary syndrome
GPIIb/IIIa Ab t1/2 = 18-24 hrs thrombasthenia
vWF; activation is final common
Non-peptide (tyrosine analog) reversible
Tirofiban pathway for platelet aggregation)
antagonist of the GPIIb/IIIa
Bleeding
Hypersensitivity
Heparin-induced Thrombocytopenia
(HIT)
Naturally occuring anticoagulant UFH: Binds to anti-thrombin III (an α- -Type I (mild, common,
Heparin complexed with histamine in mast globulin) --> increases antithrombin first 5 days)
cells activity 1000x --> inhibits thrombin -Type II (1-4%, UFH for 7+ days)
Low-molecular weight IgG recognizes complexes of
(F2) not already bound to fibin (by
(LMWH) UFH = Mixture of straight-chain Thromboembolic condition heparin + (soluble) Platelet
Enoxaparin Anticoagulants anionic glycosaminoglycans (GAGs) forming a ternary complex), factor IXa, IV
Factor 4 --> IgG binds to FcR
Subcutaneous
Dalteparin and Xa (ternary complex not required) Can be used in pregnancy on plateltes --> platelets
Tinzaparin LMWH have higher therapeutic index degranulate and aggregate
& 2° hemostasis than UFH (thus not necessary to LMWH inhibits factor Xa, but have less --> more PF4 released --> -->
Unfractionated heparin (UFH) monitor LMWH blood levels with aPTT effect on thrombin than UFH (cannot form THROMBOCYTOPENIA
assay) ternary complex) & THROMBOSIS
Discontinue heparin, (admin
protamine sulfate if bleeding)
Switch to Direct Thrombin
Inhibitor or fondaparinux
Selective Factor Xa inhibitor Binds to antithrombin 3, allowing it to Tx and prevent
Fondaparinux Once-daily subcutaneous NO antidote to overdose
Synthetic pentasaccharide bind & inactivate factor Xa. deep vein thrombosis
Independent of antithrombin III, thus can
Lepirudin
Direct Thrombin Recombinant form of hirudin (a reach and inactivate free and fibrin-
bound thrombin in developing clots Thrombosis related to HIT
Parental
NO ANTIDOTE EXISTS
thrombin inhibitor from leeches) Excreted renally
Inhibitors Monitored by aPTT (measures intrinsic &
common pathways)
Bivalirudin Anticoagulants Synthetic derivative of hirudin Inhibits thrombin and platelet activation Percutaneous coronary angioplasty
IV
2° hemostasis Small molecule thrombin inhibitor HIT Monitor with aPTT
Argatroban
(others are peptides) Coronary angioplasty
Drugs to Reduce Clotting
Inhibit vitamin K epoxide Narrow theraputic index

Coumarin "Oral anti-coagulants" reductase --> prevents activation of Hemorrhage
Cutaneous necrosis with ↓ acJvity of
Warfarin clotting factors 2, 7, 9, 10 (no γ-carboxy-
Anticoagulants Must be monitored every 2-4 weeks glutamyl residues to bind Ca2+) Hypercoaguable states
Oral protein C during 1st weeks of therapy
Prolongs PT by ↓ funcJonal factor VII Effects take 8-12 hrs
Dicoumarol via prothrombin time (PT)
Crosses placenta --> hemorrhagic
--> tests extrinsic & common pathways (clotting factor with shortest t 1/2)
2° hemostasis Anti-coagulant effects can be overcome disorder in fetus, birth defects
with Vit. K (takes 24 hrs) Contraindicated in pregnancy
Plasminogen Protein (not enzyme) made by β-

Combines with plasminogen, catalyzing Acute MI, acute pulmonary
Streptokinase conversion to plasmin and degredation of embolism, arterial thrombosis,
activators hemolytic streptococci
fibrinogen, and factors 5 & 7 occluded shunts
(Thrombolytics)
Human enzyme mady by kidneys, Hemorrhage
Urokinase 3° hemostasis found in urine
Directly converts plasminogen to plasmin Pulmonary embolism
Contraindication in patients with:
Acute MI, massive pulmonary healing wounds,
Alteplase Recombinant t-Pa t1/2 = 3-6 mins
Tissue plasminogen Tissue plasminogen activator
embolism, acute ischemic stroke pregnancy,
history of CVA,
activator analogs (t-Pa) (human serine protease) activates t1/2 = 14-18 mins
metastatic cancer
Recombinant t-Pa
Reteplase plasminogen bound to fibrin ("fibrin Acute MI Given as double bolus,
Less fibrin selective
selective") 30 mins apart
3° hemostasis
Mutant t-Pa t1/2 = 20-24 mins
Tenectaplase
More fibrin selective Single IV bolus
Purified human plasminogen and
Anistreplase Mixed bacterial streptokinase
(acetylated to protect active site)
Drugs that ↓ Warfarin metabolism (↓ P450), potenJaJng Drugs that ↑ Warfarin metabolism (↑ P450), Venous thrombosis Venous thrombosis
Arterial thrombosis
anticoagulation ↓ anJcoagulaJon, ↑ thrombus Prevention Treatment
Cimetidine Phenylbutazone Barbituates Primary prevention UFH, LMWH for 5-7 days Platelet inhibitors: aspirin +
Chloramphenicol Sulfinpyrazole Carbamazepine SC admin of UFH, LMWH, or with Warfarin clopidogrel or ticlopidine
Disulfuram Trimethoprim + Phenytoin fondaparinux
Fluconazole Sulfamethoxazole Rifampin Warfarin continued for 3- (TIA, Strokes, Unstable angina, acute
Metronidazole 6 months MI)
Drugs to Treat Bleeding

Adjunct in hemophilia Intravascular thrombosis

Bleeding from fibrinolytic tx HTN, myopathy, abdominal
Aminocaproic Acid Plasminogen Competitively inhibits plaminogen
Synthetic inhibitor of fibrinolysis Rebleeding from intracranial discomfort, diarrhea, nasal stuffiness
(EACA) Activation Inhibitor activation (opposite of t-Pa drugs)
aneurysms Do not use in DIC or upper GU
Postsurgical GI bleeding bleeding
Chemical antagonist of heparin Cationic protein interacts with anioinc Coagulation if no heparin
Heparin toxicity (mostly UFH)
Protamine Sulfate High in arginine (very positively heparin to form complex with no Hypersensitivity, dyspnea, flushing,
(inactive against fondaparinux)
charged) anticoagulant activity bradycardia, hypotension
Use fresh-frozen plasma infusion for Stops bleeding due to oral
Vitamin K Antidote immediate hemostasis
Carboxylates clotting factors
anticoagulants (Warfarin)
Response takes 24 hrs
Deficiencies (< 5-10% of normal) in

Mostly ↓ F8 (classic hemophilia/A) &
Plasma Fractions plasma coagulation factors can cause
↓ F9 (X-mas disease or hemophilia B)
bleeding
Anemia Agents
Black stools (may obscure GI blood
Oral
Ferrous sulfate loss)
Discontinue 3-6 mos
Ferrous gluconate Oral Iron Therapy Iron deficiency anemia Nausea, Episgastric discomfort,
(after correction of cause
Ferrous fumarate Abdominal cramps, Constipation,
of iron loss)
Diarrhea
High-molecular-weight iron dextran:

hypersensitivity
(use a small test dose first)
Headache, fever, nausea, vomiting

Iron Preparations
Iron deficiency + inability to tolerate Arthalgias
Iron Dextran
or absorb oral iron Flushing, Pruritis
Sodium ferric gluconate IV
Parental Iron Therapy
complex Deep IM (Dextran only)
Extensive chronic anemia that cannot Acute Iron toxicity (kids who ingest
Iron sucrose
be maintained with oral iron alone iron tablets) --> necrotizing
gastroenteritis with vomiting,
abdominal pain, bloody diarrhea;
(possible shock, metabolic acidosis,
coma, death
--> Tx: Deferoxamine (iron chelator)
Chronic Iron Toxicity due to excess

iron deposition in heart, liver,
Deferoxamine Note: Use phlebotomy for chronic iron pancreas, etc.
Deferasirox
Iron Chelator overload without anemia
Binds absorbed iron, promoting excretion
i.e.: hemochromatosis
numerous blood transfusions
(e.g. β-thalassemia)
Parental Injections
5-30 μg in daily diet
Cyanocobalamin Converted to methylcobalamin & Required for DNA synthesis reactions and Malabsorption of Vit B12 -->
Hydroxocobalamin
Vitamin B12 deoxyadenosylcobalamin methylmalonyl-CoA processing deficiency --> Megaloblastic anemia
1-5 μg absorbed
3-5 mg in storage
2 μg daily requirement
Folic acid Folic Acid Required for DNA synthesis reactions Folate or B12 deficiency anemia 1-6 month body stores
Hypertension & thrombotic
Anemia with renal failure
complications (especially if with
Long acting version of erythropoietin EPO stimulates erythroid proliferation and (Chronic anemias)
chronic renal failure or cancer whose
Receptors are member of the differentiation Primary bone marrow disorders
Darbepoetin 3x longer t1/2 than EPO serum Hb is ↑ >12g/dL with an EPO
JAK/STAT superfamily Also induces release of reticulocytes from Cancer chemotherapy
agent)
(Banned by Olympics) the bone marrow HIV treatment, Bone marrow
Faster tumor growth in patients with
transplant
advanced head, neck cancer
Hematopoietic Growth G: Bone pain
Myeloid Growth Factors Stimulate proliferation & differentiation Accelerate recovery of neutrophils
Filgrastim (G-CSF) Factors GM: Fever, arthralgia & capillary
Receptors are member of the of neutrophils (G-CSF) & other myeloid after cancer chemotherapy
Sargramostin (GM-CSF) damage (+ edema)
JAK/STAT superfamily progenitor cells (GM-CSF) 1° & 2° neutropenia
Allergy (rare)
History of thrombocytopenia with
Stimulates growth of megakaryocytic
Interleukin-11 Megakayocyte Growth Factor cancer chemotherapy (↓ need for
progenitors & ↑ peripheral platelets
platelet transfusions)
Relieve painful clinical course of sickle- Sickle cell anemia Bone marrow suppression
Hydroxyurea ↑ HbF dilutes HbS (takes several months)
cell disease CML, Polycythemia vera Cutaneous vasculitis
Anti-Hyperlipidemic Drugs
Atorvastatin ** Analogs of 3-OH-3- DoC for LDL reduction

Effects liver due to
Fluvastatin methylglutarate (HMG) Competitively inhibit HMG-CoA ↓ CV mortality Elevated aminotransferases
Lovastatin (prodrug)
HMG-CoA reductase (rate limiting/first
extensive first-pass
Myopathy & rhabdomyolysis
extraction
Pravastatin Reductase Pleotrophic/unexpected effects: committed step in cholesterol Note: Patients homozygous --> myoglobinuria --> renal injury
Rosuvastatin *** Inhibitors ↑ endothelial funcJonal synthesis) --> for familial (monitor serum creatinine kinase)
Used alone, or in
Simvastatin (prodrug) ↓ platelet aggregaJon depletes intracellular cholesterol --> hypercholesterolemia lack
combo with bile-acid
↓ InflammaJon upregulation of LDL receptors --> functional LDL receptors & Contraindicated in pregnancy
(Statins) resins, niacin, or
*** most potent ↓ plasma C-reacJve protein ↑ clearance of LDL from blood thus benefit less of from (category X) and for lactating women
ezetimibe
** 2nd ↓ LDL (20-55%) statins
Intense cutaneous flush (when dose

is started or ↑); Tx: admin aspirin
Inhibits adenylyl cyclase (via Gi) -->
(PGE-mediated)
↓ cAMP --> ↓ PKA -->
Favorably affects all parameters inhibit hormone sensitive lipase -->
Pruritis, rashes, dry skin, &
↓ plasma facy acids to liver -->
acanthosis nigricans
Most effective to ↑ HDL, and the ↓ hepaJc TAG synthesis -->
Nicotinic Acid Niacin only agent that may ↓ Lp(a) ↓ VLDL producƟon & release
Hepatotoxicity (↑ serum
transaminases)
↑ HDL (30-40%) ↑ LPL acJvity --> ↓ circulaJng LDL
↓ TAG (35-45%) ↓ HDL catabolism rate --> ↑ HDL
Insulin resistance --> severe
↓ fibrinogen, ↑ t-PA --> reverses
hyperglycemia
endothelial dysfunction
↑ uric acid (precipitate gout)
Only modest ↓ of LDL Activate peroxisome proliferator-

Fibrates Mild GI disturbances
activated receptor-α (PPAR-α) Hypertriglyceridemias Myositis (muscle inflammation),
Gemfibrozil With combined hyperlipidemia: (nuclear transciption factor) --> Patients with renal insuffiency at risk
Fenofibrate (Fribric acid ↓ TAG --> ↑ LDL ↑ muscle LPL, ↓ apoC3, ↑ apoA1 Dysbetalipoproteinemia Rhabdomyolysis
(may be artifact of formula) --> ↓ TAG, ↑ HDL
derivatives) Lithiasis (gallstones)
↓ TAG (20-50%) (PPAR-α are in liver & brown fat)
Mild GI (bloating, nausea, cramping,
Binds anionic bile acids in intestine,
constipation)
prevents reabsorption --> resin-bile
Useful in hyperlipidemias with Colesevelam has fewer GI AE
acid complex is excreted in feces -->
↑ LDL ONLY
↓ bile acid -->
Contraindicated in HyperTAG:
Cholestyramine H20 insoluble, large molecular ↑ hepatocytes producJon of bile acids
Bile Acid-Binding Used with statins or niacin to Completely excreted in --> May ↑ TAGs/VLDL
Colestipol weight (neither absorbed nor from cholesterol -->
Resins ↓ LDL feces
Colesevelam metabolized) ↓ intracellular cholesterol -->
Cholestyramine & colestipol ↓
↑ LDL receptors in liver -->
DoC for pregnant women absorption of some drugs &
↓ plasma LDLs
(Colesevelam) & children liposoluble vitamins (A,D,E,K)
(Less bile-specific, will bind
Modest ↑ in HDL
"anything")
Anti-Hyperlipidemic Drugs
Inhibits absorption of cholesterol Inhibits intestinal trasport protein,
& phytosterols (and ↑ NPC1L1, which takes up cholesterol Reversible impaired hepatic function
Cholesterol cholesterol synthesis) from the lumen --> Use with statin to (especially when admin with a
Ezetimibe Absorption ↓ cholesterol absorJon by 54% prevent ↑ cholesterol statin)
Compliments statins (which ↓ cholesterols in chylomicrons
Inhibitors synthesis
inhibit cholesterol synthesis & ↑ (↓ cholesterol delivered to liver by
Myositis
cholesterol absorption) chylomicron remnants) →
↓ LDL (10-20%, main effect) ↑ LDL receptors --> ↓ plasma LDLs
Ethyl esters of
Adjunct to diet to ↓ TAG in
Eicosapentanoic acid (EPA) & EPA & DHA ↓ TAG synthesis & ↑ facy
Lovaza ω-3 Fatty Acids docoahexanoic acid (DHA) acid oxidation in the liver
adult with very high
(>500mg/dL) TAG
"Fish oils"
Drug Combinations Drug Effect on LDL Effect on HDL Effect on TAG

General Indications: 1) If unable to attain LDL goal with a single drug; Statin ↓ (20-55%) ↑ (5-15%) ↓ (40%) Only Rosu- & Atorva-
2) Combined hypertriglyceridemia & hypercholesterolemia that cannot be controlled
Fibrate ↓ (10-30%) ↑ (10-35%) ↓ (20-50%)
with a single drug;
3) High LDL, low HDL levels Resin ↓ (10-20%) ↑ (3-5%) May ↑
Drug Description Note Ezetimibe ↓ (15-20%) ↑ (1-2%) ↓ (5%)
Use if patient has normal plasma
Vytorin Ezetimibe + Simvastatin Niacin ↓ (10-25%) ↑ (30-40%) ↓ (30-45%)
TAG
Niacin (extended release) Lovaza
Advicor Use if HDL < 40 mg/dL ↑ Long term ↓ (25-40%)
+ lovastatin (ω-3 Fatty Acids)
↑ incidence of severe myopathy
Statin-fibrate & rhabdomyolysis (b/c both drugs
have same AE)
Pregnancy Primary Hyperlipidemias

Statins: X - NEVER use Disease Lipid Profile Etiology
Type I
Gemfibrozil/fenofibrate: C - teratogenic in animals ↑ Chylomicrons ↓ LPL or apoCII
Familial hyperchylomicronemia
Type IIa
Niacin: C - safety unknown ↑ LDL ↓ or nonfuncJonal LDL receptors
Familial hypercholesterolemia
Cholestyramine/colestipol: C - may interfere with Type IIb ↑ LDL
Overproduction of VLDL by liver
nutrient absorption Familial combined hyperlipidemia ↑ VLDL
Type III
Cholesevelam: B - appears to be safe (DoC) ↑ IDL Abnormal apoE
Familial dysbeta-lipoproteinemia
Type IV
Ezetimibe: C - skeletal defects in some animals ↑ VLDL Overproduction and/or impaired catabolism of VLDL
Familial hyper-triglyceridemia
NSAIDs
Actions:
General Adverse Effects:
Anti-pyretic (Block PGE2 synthesis --> prevents setpoint elevation
GI: Ulceration via local irritation of gastric mucosa and inhibition of COX-1 cytoprotective prostaglandins
of the anterior hypothalamic thermoregulatory center);
(Treat with Misoprostol, proton-pump inhibitors, & H2 blockers)
Analgesic (↓ PGE2, which sensiJzes nerve endings to the acJon
chemical mediators released by inflammatory process --> ↓ pain
Renal: ↓ renal blood flow (with compromised renal hemodynamics, kidney makes vasodilating PGE2 &
sensation)
PGI2 to offset vasoconstricting mediators and maintain renal perfusion)
Anti-inflammatory (↓ PGEs --> ↓ inflammaJon)
↓ PGE2 can ↑ Na+ & H20 retenJon, while ↓ PGI2 --> ↑ K+ & acute renal failure;
COX-2 is dominant source of inflammatory prostaglandins
Acute interstitial nephritis (Type 1 hypersensitivity) --> acute renal failure;
Note: NSAIDs are superior to opioids for pain of inflammation;
Analgesic nephropathy (chronic interstitial nephritis caused by prolongd/excessive analgesic use, especially
Headache relief due to inhibiton of cerebral vasculature
NSAID combinations --> renal papillary necrosis --> progressive chronic renal failure
vasodilation by prostaglandins
Drug Interactions:
General Indication: Mild to moderate pain, especially
NSAIDs may ↓ effect of ACE-Inhibitors (blocking vasodilator & natriuretic prostaglandin production)
inflammatory; Rhematoid arthritis; Osteoarthritis; acute gouty
NSAIDs may ↑ frequency or severity of GI ulcers when given with corticosteroids
arthritis; ankylosing spondylitis; dysmenorrhea
Warfarin --> ↑ risk of bleeding with NSAID use
NSAIDs releive symptomatic pain, but do not treat the disease
Decrease risk of colon cancer, prevent Niacin flushing, close
ductus arteriosus
General Mechanism of Action: Cyclooxygenase inhibition Relative Risk of GI AE (ulcers)

COX-1 = constitutive enzyme involved in tissue homeostasis; Non-Selective Lowest Risk
dominant isoform in gastric epithelial cells & major source of -Celecoxib
Inhibitors
cytoproective prostaglandins (protects stomach from erosion) -Diclofenac
COX-2 = inducible by stress, growth factors, cytokines, tumors Low Risk
-Etodolac COX-2 Selective -Ibuprofen (1.0)
(constitutive in kidney & brain), major source of prostanoids in
-Ibuprofen Inhibitors -Aspirin (1.6)
inflammation & cancer and vascular prostacyclins
-Inomethacin -Celecoxib -Diclofenac (1.8)
Note: Aspirin is the ONLY irreversible acetylator of the COX -Ketoprofen -Etoricoxib
-Ketorolac -Meloxicam Medium Risk
enzyme (all others are reversible) -Naproxen (2.2)
-Naproxen
-Piroxicam High Risk
-Tolmetin -Piroxicam (3.8)
-Ketoprofen (4.2)
General Contraindications: Children & young adults (<20

years old) with viral fever --> REYE'S SYNDROME
Use acetominophen or ibuprofen instead
Pregnancy (especially end of term)
NSAIDs (Part II)
Drug Drug Class Description MOA Indications Pharmacokinetics/Dosage Adverse Effects Contraindications
Hypersensitivity (due to diversion of

arachidonate to LOX pathway due to
Niacin-induced flushing Excreted by kidney at low
COX inhibition --> excessive
Mild-moderate pain doses
production of LTs)
(joint, muscle,
dysmenorrhea) Doses >1 g, conjugation Acute gouty attacks
50% ↓ risk of colon CA NOT used for gout: inhibits urate
Irreversibly acetylates Rheumatoid arthritis & enzymes become
excretion at low doses; at high doses,
(inactivates) cylco- other inflammatory saturated, elimination Category C during
Aspirin (prototype) Hydrolyzed to salicylate + competes with uric acid for
oxengenase --> no TXA2 joint conditions at high follows ZERO ORDER trimesters 1 & 2
acetic acid by esterases in reabsorption & thus ↑ uric acid
production in platelets doses KINETICS Catergory D during
tissues & blood excretion, may ↑ risk of renal calculi
Fever trimester 3
Cardioprotective (low Doses LESS than 1 g,
GI: epigastric distress
doses), prevents follow FIRST ORDER
platelet aggregation kinetics
Prolonged bleeding time (A 325 mg
dose = 2x bleeding time for 4-7 days)
Hepatotoxicity with high doses

(occurs after several months of Tx)
Weak, competitive,
reversible COX inhibitor
SALICYLISM = mild CHRONIC
Analgesic & anti-pyretic
salicylate intoxication (headache,
Uncouple oxidative at low doses (325-650
dizziness, TINNITUS, mental
phosphorylation --> mg q4-6h) Converted to Chronic liver disease
confusion, hyperventilation)
↑ CO2 & ↑ respiraJon hydrosoluble conjugates
Anti-inflammatory at (with glycine & Reye's Syndrome
ACUTE salicylate overdose
Salicylate Metabolite of aspirin Higher doses: stimulate higher doses glucuronate) by the liver, (fulminating hepatitis
(especially children) present with
respiratory center --> (3.6-5.4 g/day) excreted renally with cerebral edema) if
mixed respiratory alkalosis &
hyperventilation --> used in children during
metabolic acidosis
alkalosis Low dose (<100 t1/2 = 3.5 hours viral infection
mg/day) for
Due to uncoupling of ox. phos.
Toxic doses: central cardioprotective effects
respiratory paralysis -->
Prolonged: respiratory depression
acidosis
(medulla), ↑CO2, respiratory
acidosis, respiratory failure
DoC for acute gouty

arthritis
Indomethacin
DoC for Closure of
ductus arteriosus
NSAIDs (Part III)
Drug Drug Class Description MOA Indications Pharmacokinetics/Dosage Adverse Effects Contraindications
Sulfonamide --> may cause

Only COX-2 inhibitor in the
hypersensitivity (typically rashes)
USA Selectively block COX-2
enzyme
Renal toxicity similar to non-selective
Analgesic, antipyretic, &
NSAIDs
Celecoxib anti-inflammatory effects Does NOT affect platelet
COX-2 (similar to non-selective aggregation (COX-1
Associated with cardiovascular
Selective NSAIDs) mediated) --> NOT
thrombotic events (inhibition of
Inhibitors cardioprotective
endothelial PGI2, but not platelet
Fewer GI side effects
(Coxibs) TXA2)
Rofecoxib (Vioxx) Withdrawn due to

Valdecoxib thrombotic events
2nd generation COX-2
Available in 60 countries,
Etoricoxib inhibitor with HIGHEST
but not in USA
selectivitiy ratio
Preferentially inhibits COX-2 over COX-1, but not as
Meloxicam
selective as the coxibs
Ineffective in gouty
Tolmetin
arthritis
Mild to moderate pain

when anti-inflammatory
Not a true NSAID effect is NOT necessary
No significant anti- DoC for osteoarthritis

inflammatory or anti- DoC for children with
platelet effects fever & flu-like
MOA is unknown
Does not affect uric acid symptoms HEPATOXICITY with overdose (>6
Acetaminophen DoC forshort term g/day, long term)
Weak COX-1 and COX-2
(Tylenol) Inadequate for treatment of fever & (Antidote: acetylcysteine, a
inhibitor in peripheral
inflammatory conditions minor pain during sulfhydryl donor)
tissues
such as rheumatoid PREGNANCY
arthritis, though may be
used as analgesic adjunct Headache
to anti-inflammatory Myalgia
therapy Postpartum pain
Pts with hemophilia or
peptic ulcer
DMARDs (Part I)
Drug Drug Class Description MOA Indications Pharmacokinetics/Dosage Adverse Effects
Provide symptomatic relief, but little effect on progression of bone & cartilage Control pain while slow-acting DMARDs take effect (6
NSAIDs
destruction weeks-6 months)
Competitive inhibition of aminoimidazole

Nausea
carboxamide ribonucleotide (AICAR) Mucosal ulcers
transformylase (enzyme catalyzes final 2 steps in Given once/week (dose less
Progressive, dose-related hepatotoxicity
than that needed for cancer)
de novo purine biosynthesis for IMP) --> (seen as enzyme elevation)
Antimetabolite Anti-cancer drug, in higher Accumulation & release of adenosine DoC for rheumatoid Cirrhosis
Methotrexate ↓ Methotrexate toxicity by
and antifolate doses arthritis
giving LEUCOVORIN 24 hrs
Adenosine is a potent anti-inflammatory mediator, Hypersensitivity lung reaction
after weekly dose or by daily
acts on A2b receptors --> suppresses NF-κB activation Pseudolymphomatous reaction
use of FOLIC ACID
induced by TNF & other stimuli
Contraindicated in PREGNANCY
Thymidylate snythase pathway may also be affected
Dose-related bone marrow suppression

Metabolite phenylacetic acid mustard crosslinks DNA
Chlorambucil Infertility
--> prevents cell replication
Neoplasia (leukemia)
Alkylating agents Infertility
Cytotoxic Metabolite phosphoramide mustard crosslinks DNA
(Anti-cancer) --> prevents cell replication
Rheumatoid arthitis Bone marrow suppression
Cyclophosphamide Works orally only Hemorrhagic cystitis
Suppresses T & B cell function by 30-40%; T-cell
Lupus erythematosus Bladder carcinoma (likely due to
suppression correlates with clinical response
metabolite acrolein, use Mesna)
Purine antimetabolite Active metabolites are split Xanthine oxidase inhibitors (allopurinol)
Converted to 6-mercaptopurine --> converted to other
by xanthine oxidase (to 6- can precipitate toxicities
Azathioprine metabolites --> inhibit de novo purine synthesis
Imidazolyl derivative of 6- thiouric acid) prior to Bone marrow suppression, GI distrubances,
↓ B & T cell function, ↓ Ig & IL-2 producJon
MP excretion in urine Infections, Malignancies
Quickly converted to active metabolite A77-1726

--> inhibits dihyroorotate dehydrogenase -->
↓ de novo ribonucleotide synthesis --> ↓UMP --> Rheumatoid arthitis
Blocks de novo synthesis, p53 translocates to nucleus --> cells arrested in G1 (Nonresponders to GI disturbances
Leflunomide but not salvage --> slowly phase --> ↓ autoimmune T cells & autoanJbodies methotrexate alone can
dividing cells survive use combo therapy) Elevation of liver enzymes
Antimetabolites Note: activated lymphocytes depend on the de novo
pyrimidine synthesis as the slavage pathway is not
sufficient (need ↑ 8x)
Converted to (MPA) mycophenolic acid (active form) --

> inhibits inosine monophosphate
dehydrogenase (IMPDH) --> ↓ de novo guanosine -
Mycophenolate Mofetil -> only lymphocytes affected
IMPDH exists in two isoforms (Type I & Type II); MPA

preferentially inhibits Type II (found mainly in
lymphocytes)
Often used with other Hemolysis (with G6PD deficiency)
MOA of anti-inflammation is unclear
Drug may take 3-6 months Mild rheumatoid DMARDs, especially
Hydroxychloroquine Anti-malarial to be effective arthritis methotrexate & Corneal deposits (ophthalmologic
Drug's effectiveness may require 3-6 mos to work
sulfasalazine monitoring every 6-12 mos advised)
DMARDs (Part II)
Drug Drug Class Description MOA Indications Pharmacokinetics/Dosage Adverse Effects
Inhibits antigen-triggered signal transduction in T Nephrotoxicity (limiting factor)

lymphocytes --> ↓ lymphokines Tremor
Cyclic polypeptide of 11
HTN
amino acids Forms a complex with cyclophilin (an immunophilin) -- Used for organ
Immunophilin Hyperglycemia, Hyperlipidemia
Cyclosporine
Ligands > complex inhibits calcineurin (phosphatase transplantation Osteoporosis
Produced by the fungus
necessary for activation of a T-cell specific Hirsutism
Beauveria nivea
transcription factor, NFAT) Gum hyperplasia
NFAT induces cytokine genes, including IL-2 Bone marrow toxicity
Nausea
Metabolized to constituents
Both moieties have anti-inflammatory action & inhibit Rheumatoid arthritis Rash
by colonic bacteria
immune reactivity Juvenile arthritis Hepatitis
Sulfapyridine +
Sulfasalazine Ankylosing spondylitis Leukopenia
5-aminosalicylic (5-ASA) 10-20% of sulfasalazine dose
5-ASA is not important in rheumatoid arthritis (unlike Agranulocytosis
remains intact, reabsorbed
ulcerative colitis) (Safe for pregnancy) LUPUS-LIKE SYNDROME
as such
Hemolysis (with G6PD deficiency)
Gold sodium thiomalate Gold salts are taken up by macrophages --> suppress IM Stomatitis, Rash
Not recommended during
Gold Compounds pregnancy
phagocytosis & lysosomal enzyme --> slows Proteinuria
Auranofin progression of bone & articular destruction Oral Leukopenia, Thrombocytopenia (rare)
Fully human IgG1 anti-TNF
Adalimumab
monoclonal antibody
Formation of Human anti-chimeric

Binds soluble TNF-α, preventing interaction with p55 &
Rheumatoid arthritis antibodies (HACA) (Use methotrexate)
p75 (TNFR1 & 2) cell surface receptors -->
Chimeric monoclonal Ankylosing spondylitis Upper respiratory tract infection
Infliximab Down-regulation of macrophage & T-cell function IV infusion
Anti-Cytokines antibody to TNF-α Crohn's Disease Nausea, headache, sinusitis, rash, cough
Psoriatic arthritis ANA & Anti-dsDNA --> mild lupus-like illness
(Anti-TNF-α drugs) (rare)
Recombinant fusion protein Injection site reactions (e.g., erythema,

(2 soluble TNF p75 receptor Subcutaneous (SC) injection local pain, swelling, itching) (20-40%)
Etanercept Binds TNF-α & inhibits lymphotoxin-α
moieties linked to Fc portion Slowly absorbed Anti-etanercept antibodies
of human IgG1 ANA & Anti-dsDNA, but no lupus-like
Recombinant, non-glycosylated version of human

Anakinra Anti-Interleukins IL-1 receptor antagonist
Inhibit phospholipase A2 (which liberates Osteoporosis, weight gain, fluid retention,

arachidonic acid from membrane lipids) Short term use until cataracts
Not usually considered
Glucocorticoids Also selectively inhibit expression of COX-2 effects of DMARDs Poor wound healing, gastric ulcers, GI
DMARDs
become apparent bleeding, hyperglycemia
Prompt, dramatic effects against rheumatoid arthritis HTN, Adrenal suppression, Infections
Combination Therapy (weekly methotrexate given with):

hydroxychloroquine
sulfasalazine
hydroxychloroquine + sulfasalazine
cyclosporine
leflunomide (↑ risk of hepatotoxicity)
gold
Note: The combination of anakinra + TNF inhibitors = ↑ risk of neutropenia & infections --> should not be used routinely
Gout (Acute Attacks)
Two main strategies for treatment of gout:
1. Mgt of acute attacks of gouty arthritis (control pain)
2. Long-term mgt of chronic gout (achieve normal plasma [urate])
Drug Description MOA Indications Pharmacokinetics Adverse Effects Contraindications
NSAIDs (i.e., Indomethacin is DoC Bleeding

indomethacin, etc) Salt & H2O retention Low dose Aspirin (note: high
Aspirin contraindicated First-line drug for acute Renal insufficiency dose ASA can be uricosuric,
Not Aspirin, (competes with uric acid gout COX-2 selective inhibitors blocking uric acid
Salicylates, or for the secretion may cause adverse CV reabsorption)
Tolmetin mechanism in the PCT) effects
Binds to tubulin --> inhibits

polymerization & prevents
microtubule formation --> ↓
granulocytes mobility
Alleviates pain of acute Nausea, vomiting,
--> ↓ migraJon into affected
gout within 12 hours Abdominal pain, PREGNANCY
Replaced by NSAIDs due area
DIARRHEA
Colchicine to diarrhea associated
Must be used within 24-48 Myopathy, neutropenia, Use with caution with
with colchicine therapy Blocks cell division by
hours of onset of the aplastic anemia, alopecia hepatic, renal, or CV disease
disrupting mitotic spindle
attack to be effective (seen with chronic use)
Inhibits synthesis and release
of leukotrienes (involved in
inflammation)
Acute polyarticular gout

(given systemically)
Anti-inflammatory & Depot preparations
Inhibit several steps in
Glucocorticioids immunosuppresive Acute attack in a single injected directly into
inflammatory response
effects joint, unresponsive to site of inflammation
above --> inject directly
into site
Gout (Chronic Gout)
Drug Description MOA Indications Pharmacokinetics Adverse Effects Drug Interaction Contraindications
Incidence of acute gouty

Converted by XO to Anti-cancer drug
arthritis may ↑ during
oxypurinol --> mercaptopurine &
Purine analog early months of therapy
immunosuppressant
NSAID or colchicine is (admin NSAID or
Competitive inhibitor of azathioprine (purine
Facilitates dissolution of coadmin during first 4- colchicine)
analogues) are metabolized
Allopurinol tophi by ↓ [uric acid] in xanthine oxidase 6 months of allopurinol
by xanthine oxidase;
plasma below limits of (last 2 steps of uric acid therapy to ↓ chance of Hypersensitivity reactions
inhibiting xanthine oxidase
solubility synthesis) acute gout attack (skin rashes)
results in toxic levels of the
Rash may progress to
two drugs (dose REDUCTION
↓ uric acid synthesis Steven-Johnson syndrome
required)
(stop drug)
Decrease dose of anionic

Mild GI irritation Gouty patients with
Given with NSAIDs or drugs dependent on
Hypersensitivity nephrolithiasis or
Probenecid Chronic hyperuricemia colchicine to prevent transporter for excretion
Renal stones (prevent with overprodcution of uric
Competes with urate for the acute gouty attack Antagonized by low dose
liberal fluid intake) acid (↑ kidney stones)
transporter that exchanges aspirin
Uricosuric Agent urate (in) for an anion (out)
--> ↑ excreƟon of urate (by GI irritation (more freq)
inhibiting reabsorption) Hypersensitivity (rash +
fever) (less frequent) Inhibits warfarin Patients with underlying
Sulfinpyrazone
↓ hematopoiesis metabolism --> bleeding blood dyscrasias
Renal stones (prevent with
liberal fluid intake)
Initial management of ↑ plasma uric acid in

pediatric patients with leukemia, lymphoma, &
Enhance uric acid
Uricase oxidizes uric acid to solid tumor malignancies receiving anticancer Given with cancer
Rasburicase metabolism allantoin (soluble compound therapies chemotherapy to prevent
Recombinant Asperillus easily excreted by kidneys) Combats tumor cell lysis syndrome (rapid lysis of tumor cell lysis syndrome
uricase (in the US) tumor cells liberate free nucleotides and greatly ↑
plasma urate levels --> renal injury)
Opioids (Part I) - General
Cellular Mechanism of Action:
-Close voltage-gated Ca2+ channels on presynaptic nerve terminals (↓ neurotransmicer release)
Classification of Opioid Analgesics:
-Open K+ channels on postsynaptic neurons (↓ signalling)
-Pure agonists (HIGH affinity for µ receptors, LOWER for δ and κ)
-Can cause release of endogenous opioid peptides, so even a receptor-selective ligand can activate other receptors
-Partial agnoists & mixed agonist-antagonists (agonist at some receptors, antagonist at others;
analgesic CEILING effect; can cause psychotomimetic effects)
Opioid receptors: Neural Mechanisms of Analgesia
-Antagonists (at all receptors)
µ (majority), δ, κ Opioids act at both spinal & supraspinal sites when given systemically;
All are Gi-protein linked Interaction at these sites ↑ their overall analgesic efficacy
µ receptors: responsible Supraspinal analgesia (Activate descending pain-inhibitory circuits)

CNS Effects: for analgesia, euphoria, -Pain inhibitory descending neurons ("D") send processes to the spinal cord & inhibit ascending pain transmission neurons ("P")
-Analgesia (reduce sensory & (especially) emotional components of pain) respiratory depression, -Opioids ("O") inhibit GABAergic inhibitory interneurons ("X") -->
-Euphoria (pleasant floating sensation, lessened anxiety & distress) physiological dependence activated inhibition of pain transmission in the spinal cord
-Sedation & drowsiness (frequent; ambulatory patients at risk for accidents) P - transmits pain (ascending, afferents)
-Respiratory depression (↓ responsiveness of brainstem respiratory centres to CO2) δ + κ receptors contribute D - blocks P (descending, inhibitory)
-Cough suppression (↓ cough reflex, partly by direct effect on medullary cough centre) to anlgesia, especially at X - blocks D, allowing P (inhibitory)
-Miosis (excitatory action on parasympathetic nerves innervating the pupil; pinpoint pupils are spinal level O - blocks X, allowing D to block P
pathognomonic of µ agonist toxicity ; during severe prespiratory depression & asphyxia, miosis i.e. Opioids inhibit the inhibition on ("activates") the inhibition of pain.
may revert to mydriasis)
-Truncal rigidity (from action at supraspinal levels) Spinal/Peripheral Analgesia (Inhibit ascending pain transmission)
-Nausea & vomiting (activate the brainstem chemoreceptor trigger zone) -Opioid receptors on the terminals of sensory (afferent) neurons inhibit glutamate and substance P release
-Receptors on the dorsal horn of the spinal cord are hyperpolarized, preventing pain signalling
General Indications of Opioid analgesics:

Peripheral Effect:
-Analgesia (for constant moderate to severe pain)
-Hypotension (inhibit vasomotor centre in the brainstem causing peripheral vasodilation; also
-Acute Pulmonary Edema via ↓ anxiety (↓ SOB) & ↓ cardiac preload (↓ venous tone) & aierload (↓ peripheral resistance)
inhibit compensatory baroreceptor reflexes & ↑ histamine release)
Adverse Effects: -Cough (dextrometorphan, codeine, levopropoxyphene, noscapine)
-GI tract (constipation)
-Nausea -Diarrhea (loperamide, diphenoxylate)
-Biliary tract (contract biliary smooth muscle, may result in biliary colic)
-Vomiting -Shivering (meperidine, activates α2-adrenoceptors)
-Genitourinary tract (↓ renal plasma flow --> depressed renal function)
-Sedation -Anesthesia:
-Uterus (may prolong labor)
-Itching -Premedicant (before anesthesia & surgery, as sedative, anxiolytic, & analgesic
-Neuroendocrine (stimulate ADH, PRL, & somatotropin release, inhibit LH)
-Constipation* -Intraoperatively (as adjuncts or as primary anesthetic, minimizes cardiovascular depression)
-Pruritis (flushing, warming of skin, sweating, itching; may be due to histamine release)
-Urinary retention -Regional analgesics (in epidural or subarachnoid spaces)
-Hypotension
-Respiratory depression
-Miosis Metabolism of Opioids:
Contraindications & Cautions:
-Converted to polar metabolites (conjugated with glucoronides) --> excreted by kidneys
-Addition of weak partial agonists to a patient taking a pure agonists
When given together, there is risk of ↓ pure opioid analgesia or inducing withdrawal Tolerance (gradual loss of -Codeine, oxycodone, hydrocodone are metabolized by CYP2D6 --> to metabolites of greater potency,
effectiveness with chronic e.g., codeine is converted to morphine
-With head injuries: Respiratory depression --> CO2 retention --> cerebral vasodilation. use) to all except
constipation & miosis Excretion of Opioids:
With ↑ ICP, may lead to lethal alterations in brain function
-Polar metabolites, including glucuronide conjugates, are excreted mainly in the urine
-Pregnancy: Fetus may become physically dependent, show withdrawl symptoms Physiological dependence -Small amounts may be found in urine, unchanged
(withdrawl syndrome -Glucuronide conjugates are also found in bile (small portion)
-With ↓ pulmonary function: acute respiratory failure due to resp depression
-With ↓ renal funcJon: t1/2 may be prolonged when drug is stopped)
Drug Interactions:
-With ↓ hepaJc funcJon: Opioids are metabolized in liver, don't use in prehepaJc coma
-with sedative-hypnotics (↑ CNS depression, especially respiratory depression)
-With endocrine disease: adrenal insufficiency (Addison's) or hypothyroidism (myxedema) may
-with antipsychotics [↑ sedaJon; variable respiratory depression; ↑ CV effects (anJmuscarinic & α-blocking)]
prolong & exaggerate responses to opioids
-with MAO inhibitors (MAOI + meperidine --> life threatening; also MAOI + Tramadol)
Opioids (Part II) - Pure Agonists
Drug Drug Class Description MOA Indications Pharmacokinetics/Dosage Drug Interactions Adverse Effects Contraindications
-Morphine conjugated to morphine-3-glucoronide (M3G) --> neuroexcitatory (not mediated by opioid receptors)
High affinity for µ -10% is metabolized to morphine-6-glucoronide (M6G) --> active metabolite, analgesic potency 4-6x morphine
The standard against which new
Morphine receptors, LOWER affinity -M3G & M6G doesn't readily cross the BBB, likely do not contribute much to CNS effects; effects of metabolites should be
analgeiscs are measured
for δ and κ receptors considered in patients with renal impairment
-Esters (heroin & remifentanil) are rapidly hydrolyzed to monoacetylmorphine & morphine, (then conjugated)
Hydromorphone
Severe pain
Oxymorphone
Rapidly hydrolyzed to 6- Both heroin & 6-MAM are

Morphine & 6-MAM are responsible monoacetylmorphine (6- more liposoluble than Addiction
Heroin
for actions of heroin MAM), which is then morphine --> cross BBB Dependence
hydrolyzed to morphine Excreted in urine
Pupillary constriction
Use with MAO-I -->
Meperidine (t 1/2 = 3 hrs) Affects pituitary
Serotonin Syndrome
µ receptor agonist metabolite normeperidine Large doses at short
(excitatory: delirium,
Activates α2- Anti-shivering DoC (t1/2 = 15-20 hrs) intervals -->
hyperthermia,
Meperidine Blocks serotonin reuptake (SNRI) adrenoreceptorsto block accumulates ↑ [Normeperidine]:
headache, HTN or
shivering Mild-moderate pain tremors, muscle
hypotension, rigidity,
Strong Agonists Significant antimuscarinic effects May ↑ with ↓ renal or twitches, dilated pupils, Tachycardia
convulsions, coma,
hepatic function hyperactive reflexes,
death) MAO inhibitors
convulsions, seizures
↓ Renal/hepatic
µ receptor agonist Fentanyl has very short t 1/2
function
Rapid onset & short duration = 15-30 mins
Fentanyl
Fentanyl is 100x more potent than Anesthetic adjuvants Fentanyl is metabolized by
Sufentanil
morphine CYP3A4 in the liver, has no
Alfentanil
Sufentanil is 1000x more potent Chronic pain active metabolites
Remifentanil
than morphine Transdermal, IV, Oral
Alfentanil rarely used transmucosal
≈ potency to morphine Chronic pain

Less euphoria, longer duration Drug detox Prolonged QT interval
Orally active
Methadone µ receptor agonist Maintanence of chronic Torsades de pointes
No active metabolites
NMDA receptor agonist relapsing heroin Death
SNRI addiction
Related to methadone, but longer
Levomethadyl acetate Drug detoxification Given once every 2-3 days
t1/2
Levorphanol Similar to morphine Dextro-methorphan = OTC antitussive, less constipation
Codeine Low affinity for µ & δ receptors Analgesic effect due to Combined with Aspirin,
Cough (may be via a Combined with aspirin,
Oxycodone Less efficacious than morphine conversion to morphine acetaminophen, or
Codeine receptors) acetaminophen, etc.
Hydrocodone Rarely used alone by CYP2D6 other
Weak µ receptor agonist

Mild to Moderate Dextro isomer is analgesic for mild Mostly metabolized to Elderly
Seizures
to moderate pain norpropxyphene (t1/2 = 30 Often used with
Propoxyphene Agonists Cardiac conduction
Levo isomer is antitussive hrs) --> accumulation may acetaminophen NOT recommended for
abnormalities
Weaker than codeine yield toxicity routine dosing
Controlled substance (misuse)
SNRI (primary) Do not use with other Seizures MAO inhibitors

Tramadol Neuropathic pain
Weak µ receptor agonist serotonergic drugs Serotonin syndrome Seizure disorders
Opioids (Part III)
Drug Drug Class Description MOA Indications Pharmacokinetics/Dosage Drug Interactions Adverse Effects Contraindications
Pentazocine κ AGONIST and a µ

Mixed action antagonist or partial
Psychotomimetic
Butorphanol Originally developed to be less agonist Mild to moderate pain Not recommended for Precipitate withdrawl
Mixed Agonist- effects (κ mediated)
addictive routine use due to ceiling syndrome in opioid
Nalbuphine Antagonists Less respiratory depression (µ
κ AGONIST and a µ
effect dependent patients
antagonist
mediated)
Partial µ agonist and a κ
Buprenorphine Opioid addiction
antagonist
Opioid antidote
Naloxone Acute opioid overdose
Fast acting
Opioid ANTAGONISTS µ, δ, κ receptor antagonist Opioid addiction
Naltrexone Longer duration of action Decreases alcohol
craving
Dextro-metorphan Receptors involved differ
Opioid derivatives used as cough
Codeine from those for other
Levo-propoxyphene
Antitussives suppressant
opioid effects (α2,
Cough MAO-inhibitors
No analgesia at antitussive doses
Noscapine codeine)
Diphenoxylate has CNS
Mainly via µ or δ receptors Diphenoxylate preps
Loperamide effects at high doses,
Diphenoxylate
Antimotility No analgesic effects at usual doses on enteric nerves, DoC Diarrhea have atropine to
and potential for
epithelial cells, & muscle discourage overuse
dependence
Functional effects Associated w/Opioid

Receptors
Receptor Subtype Activity of Some Opioids
Supraspinal analgesia µ, δ, κ Drug µ δ κ
Spinal analgesia µ, δ, κ Agonists
Respiratory depression µ Morphine Agonist Weak agonist Weak agonist
Reduced GI motility µ, κ Fentanyl Agonist
Psychotomimesis κ Meperidine Agonist
Sedation µ, κ Methadone Agonist
Codeine Weak agonist Weak agonist
Mixed agonist-antagonist
Partial agonist or
Pentazocine Agonist
antagonist
Partial agonist or
Butorphanol Agonist
antagonist
Nalbuphine Antagonist Agonist
Buprenorphine Partial agonist Antagonist
Antagonists
Naloxone Antagonist Antagonist Antagonist
Naltrexone Antagonist Antagonist Antagonist
Nalmefone Antagonist Antagonist Antagonist
Pain Management
Nociceptive pain
Acute pain
-noxious stimulus at nociceptors
-result of injury or surgery
-prevents further tissue damage by withdrawal reflex
-usually self-limited, subsides when the injury heals
-somatic (skin, bone, joints, muscle or connective tissue): throbbing, localized
-nociceptive (can be neuropathic)
-visceral (internal organs): referred or localized
-associated with anxiety and sympathetic hyperactivity
-treated aggressively, even before the diagnosis is established, (except in head or abdominal
Inflammatory pain
injury where pain may assist diagnosis)
-protecting injured tissue
-pain hypersensitivity to prevent contact or movement of the injured part
Chronic pain
-pain may persist for months to years
Neuropathic pain
-nociceptive, inflammatory, neuropathic, or functional in origin
-damage to or dysfunction of the PNS or CNS
-not sympathetic hyperactivity, but may be with vegetative signs and depressed mood
-burning, tingling, numbness, shooting, stabbing, or electric-like
-adjuvant analgesics (TCA, anticonvulsants) are often required with opioids for adequate relief
Chronic malignant pain - with a progressive (usually life threatening) disease
Chronic non-malignant pain - not associated with a life-threatening disease, >6 months
Functional pain
beyond the healing period
-abnormal processing or function of the CNS in response to normal stimuli (e.g. fibromyalgia, IBS)
Pain 1-3:
Non-opioid (NSAID) Analgesic Dosing:
-Initial stages of severe pain analgesics given by the clock (fixed intervals), ↑ dose unJl Analgesics NOT for routine dosing:
Pain 4-6: patient feels comfortable -Merperidine: poor oral absorption, t 1/2 = 3 hrs; metabolite, normeperidine: no analgesic
Mild-moderate pain opioids: -Each dose should be given before the prior one has worn off properties, t 1/2 = 6 hrs, significant side effects when accumulated, i.e, tremulousness,
-Codeine
dysphoria, myoclonus, & seizures
-Hydrocodone -Rescue doses: for breakthrough pain; 10-20% of total daily opioid, every 2-6 hours if
-Oxycodone needed; use immediate-release prep of same drug as routine dose, unless it is extended-
-Propoxyphene: usually admin at doses that produce little analgesia; dose escalation leads to
-Meperidine release
accumulation of toxic metabolite Norpropoxyphene --> Elderly + renal dysfunction = greatest
-Propoxyphene -As pain subsides, as-needed schedules may be appropriate
risk
-Tramadol
-Pentazocine, butorphanol, & nalbuphine (mixed opioid agonist-antagonist): NOT for
Pain 7-10:
Analgesic ceiling effect = dose beyond which there is no more analgesic effect; patients already taking a pure agonist opioid:
Moderate-severe pain opioids:
↑ doses = ↑ side effects, but not pain relief (e.g., NSAIDs, acetaminophen) -competition for opioid receptors may cause withdrawal
-Mprphine
Pure opioid agonists have NO analgesic ceiling -Pentazocine & butorphanol also cause psychotomimetic adverse effects in fearful & anxious
-Hydromorphine
-For combo opioid + non-opioid, analgesic ceiling of non-opioid is dose-limiting factor patients
-Oxymorphone
-Mixed agonist-antagonists (pentazocine, butorphanol, nalbuphine, & buprenorphine) -Ceiling effect
-Levorphanol
have a ceiling effect; NOT recommended for severe pain
-Sufentanil
-Methadone
Management of Adverse Effects:
Urticaria, pruritus - due to mast cell destabilization; treat with hydroxyzine or diphenhydramine
Nausea ± vomiting - disappears with tolerance in a few days; treat with hydroxyzine, metoclopramide, or Adjuvant analgesics = drugs useful in the pain management, but not primarily classified as
prochlorperazine analgesics; can be used as monotherapy or with non-opioids & opioids
Sedation - usually disappears with tolerance in a few days; persistent sedation treated with amphetamine,
methylphenidate or modafinil Analgesic Adjunctive Agents:
Respiratory depression - tolerance develops quickly (pain is a potent stimulus to breathe); naloxone may be necessary -Non-opioids
(overdose antidote) -Antidepressants
Constipation - almost universal; affects CNS, spinal cord, & myenteric plexus to reduce opioid gut motor activity; tolerance -Anticonvulsants
develops very slowly, if at all; use stimulant laxative (senna, bisacodyl) or combo stimulants/softeners (senna + docusate); -Corticosteroids - advanced illness, nerve compression, ↑ ICP, bone/visceral pain,
bulk forming agents require ↑ fluid intake, NOT recommended anorexia, nausea, depressed mood (Dexamethasone is DoC for long t1/2 &
*Little to no tolerance to constipation ↓ mineralocorJcoid effect)
-Hydroxyzine - post-op, cancer pain, reduced nausea/vomiting (anti-histaminic)
Routes of Administration -Clonidine - transdermal patch, for sympathetic hyperalgesia
Oral or transdermal: preferred for long-term use, important for providing overnight relief -Lidocaine - patch for postherpetic neuralgia
IV: most rapid onset and easiest titration, but short duration of analgesia; Large, rapid fluctuations in blood levels can lead -Capsaicin - cream for neuropathic & osteoarthritic pain
to toxicity or breakthrough pain -Caffeine - may enhance effect of acetaminophen and NSAIDs
Patient-controlled Anesthesia (PCA): self-administer a preset dose of IV opioid via a pump with a timer; better pain control
and improved patient satisfaction Note: Antidepressants & anticonvulsants are mainstay of treatment for neuropathic pain
IM injections: not recommended due to pain at injection site and fluctuations in absorption and peak [plasma] syndromes
Intraspinal (epidural or intrathecal): used postoperatively
Fentanyl is available for oral mucosa delivery (Lozenges & effervescent tablets for breakthrough pain)
Pain Management - Analgesic Adjunctive Agents

Drug Drug Class Description Indications
Analgesic, antipyretic
Acetaminophen Non-opioid Hepatotoxicity with excess DoC for low back pain, osteoarthritis, fever in young people
analgesic use, overdose
NSAIDs Mild to moderate pain, especially of inflammation in arthritis & gout
Tricyclic Antidepressants Inhibits NE & 5-HT uptake, Neuropathic pain, including diabetic neuropathy, postherpetic pain, polyneuropathy, nerve
Amitriptyline enhancing descending injury, cancer infiltration
Imipramine inhibitory pathways Fibromyalgia pain
Antidepressants
Venlafaxine
SNRIs Neuropathic pain (More effective than SSRIs)
Duloxetine
Carbamazepine DoC for trigeminal neuralgia
Postherpetic neuralgia
Gabapentin
Diabetic neuropathy
Anticonvulsants Postherpetic neuralgia
Pregabalin Diabetic neuropathy
Fibromyalgia
Valproate
Migraine prophylaxis
Topiramate
Pharmacogenomics (Polymorphisms)
Drug Affected Enzyme Polymorphism Effect Adverse effect Comments
Succinylcholine
Butyrylcholinesterase (BChe) ↓ rate of metabolism Prolonged paralysis
(Acetylcholine analogs)
Variations in enzymes of drug metabolism:
Isoniazid Slow acetyl = ↑ drug level Neurotoxicity (see below)

Hydralazine N-acetyltransferase 2 (NAT2) Catalyzes acetylation (phase II)
Fast acetyl = ↓ drug levels Drug-induced lupus
Procainamide
Pharmacokinetics
Codeine, dextromethorphan Poor Metabolizer = Codeine ineffective

(analgesics) ↓ codeine ac(va(on Adverse effects/toxicities Phase I metabolizer
Fluoxetine, imipramine, Varaible number of copie of ↑ ac(vity of others from other drugs
desipramine, amitriptyline gene for CYP 2D6
Opposite effects between
(Antidepressants) (0-12) Ultrarapid Metabolizer = Codeine overdose
opioids and other drugs
Haloperidol (neuroleptic) ↑ morphine effects (Respiratory depression)
Metoprolol (β-blocker) ↓ ac(vity of others Other drugs need ↑ doses
Catalyzes S-methylation of anti-

6-mercaptopurine
Thiopurine S-methyl- *3A in Caucasians = cancer thiopurines
Myelosuppression
transferase (TPMT*3A) ↓ TPMT ac(vity *3C most common in East
Azathioprine Asians
LOX inhibitors are less
If VNTR ≠ 5 --> ↓ LOX VNTR (variable number of
drug targets:
Variations in
Pharmaco-
Zileuton 5-LOX (ALOX5 gene) effective (does not effect

dynamics
inhibition tandem repeats) in promotor

disease process)
Epidermal growth factor ATP-binding site mutation EGFR overexpressed in non-
26% of Japanese have mutation
Gefitinib receptor (EGFR) mutation enhances drug effect (↑ small cell lung cancer, allows
(respond better)
(usually a tyrosine kinase) inhibition of TK) Gefitinib to target it
CYP2C9*1 ↓ metabolism of Accounts for 5-15% of variation
Idiosyn- Multiple
Effects (mixed)
Genes
S-Warfarin (3-5x more potent *2 & *3 have lower activity S-warfarin in warfarin dosage
↑ risk of hemorrhage
than R-Warfarin) VKORC1 (gene for Vitamin K 25-30% of differences in
↑ or ↓ drug effect
epoxide reductase) warfarin metabolism
Primaquine (antimalarials)
cratic
G6PD cSNP AA substitution (A- 90-95% ↓ G6PD func(on Drugs induce oxidative stress-
Sulfonamides, Acetaminophen, 10-20 % of Africans
allele) ↓ glutathione --> ↑ H2O2 -> Hemolytic anemia
Ibuprofen
Anti-Fungals (Part I)
Drug Drug Class Description MOA Indications Pharmacokinetics Adverse Effects Resistance
IV (highly insoluble), ointment
Infusion-related toxicity (universal):
Poor distribution
fever, chills, muscle spasms, vomiting,
Naturally made by Intrathecal therapy for meningeal
DoC for systemic mycoses headache & hypotension
Streptomyces nodosus disease
(Abated by slowing infusion rate or ↓
Widest antifungal spectrum daily dose)
Alters membrane Polyenes bind to ergosterol in Small amounts (metabolites) in
Aspergillus, Preadmin with antihistamines,
Amphotericin B permeability fungal cell membranes to urine; also eminimated in bile Infrequent (↓
Candida albicans, glucocorticoids, antipyretics, or
(Amphotec®, Abelcet®, Polyene form pores --> electrolytes &
Cryptococcus neoformans, meperidine can be helpful
ergosterol in
Ambisome®) Insoluble, prepared in small molecules leak from cell Lipid formulations ↓ membrane)
Histoplasma capsulatum,
deoxycholate colloidal --> death nephrotoxicity (packed in lipid
Coccidioides immitis Renal impairment: renal tubular
suspension vesicles that surround drug to
Mucormycoses acidosis, ↓ GFR, Mg2+, K+,
prevent binding to nephron)
Blastomyces Anemia (damaged tubules, ↓ EPO)
Fungicidal or -static --> equal efficacy to original
Intrathecal admin: seizures & serious
--> safe with reduced
neurological damage
renal/hepatic function
Oral Possibly metabolized by gut flora to 5-FU
Taken by fungal cells via Well distributed (CNS) (anti-cancer)-->
cytosine permease --> Eliminated in urine Bone marrow toxicity (anemia,
Blocks nucleic acid converted intracellularly to 5- Narrow spectrum leukopenia, thrombocytopenia)
synthesis (DNA & RNA) FU then to 5-FdUMP --> Toxic enterocolitis
Used ONLY in combo with
inhibits thymidylate
Pyrimidine amphotericin for meningitis caused by
Flucytosine Mammalian cells cannot synthetase --> synthesis of Crytococcus neoformans & Candida
anti-metabolite uptake drug dTMP (DNA) blocked
AND or with itraconazole for systemic
Fungistatic 5-FUTP also formed --> chromoblastomycosis
protein synthesis (RNA)
inhibited
Inhibits squalene
GI upset,
Does NOT affect CYP450 epoxidase --> inhibits Topical creams
Onychomycosis rash,
Terbinafine Allylamine system --> NO drug
lanosterol (ergosterol) Tinea cruris & tinea corporis
Oral
headache,
interactions Acumulattes in keratinized tissues
synthesis + Toxic squalene taste disturbances
accumulation in fungal cell
Allergy, headaches, confusion, GI
Taken for 2-6 weeks to Energy-dependent cell entry Only use: ↑ absorption with fatty foods irritation, photosensitivity
Disrupt
Griseofulvin allow infected cells to be Disrupts mitotic spindle & Dermatophytosis of skin, hair, nails Accumulates in infected, newly Induces CYP450 enzymes
microtubule replaced inhibits mitosis Replaced by itraconazole, terbinafine synthesized, keratinized tissues --> ↑ metabolism of drugs, (e.g.,
warfarin)
Ointments, creams Can't treat of nails or
Polyene Bitter taste
Nyastatin Similar to Amphotericin B Same as Amphotericin B Only Candidiasis Too toxic for IV hyperkeratinized
macrolide Nausea
Not absorbed tissues
Subcutaneous & Systemic infections Topical Drugs fro superficial mycoses Pneumocystis jirovecii pneumonia
Polyene (Amphotericin B) Polyenes (Nyastatin, Amphotericin B) Fungus that responds to antiprotozoals instead of antifungals
Flucytosine Allylamines (Terbinafine) (does not have ergosterol in membrane)
Azoles (K, F, I, V, P) Azoles (K, M, C) DoC: Co-trimoxazole (Trimethroprim + Sulfamethoxazole)
Echinocandins (capsofungin) Also standard for prophylaxis in all immunocompromised
All are Category C in pregnancy except: AE: rash, neutropenia, hepatitis, fever Moderate-severe
Systemic drug for superficial mycoses Amphoteracin B: B Alt: Pentamidine (2nd line) disease, give
Griseofluvin Clotrimazole: B (if topical, vaginal) Dapsone + Trimethroprim corticosteroids
Allylamines (Terbinafine) Voriconazole: D Atovaquone** (prednisone)
Azoles (K, F, I) Terbinafine: B Clindamycin + primaquine** ** Antimalarial
Anti-Fungals (Part II) - Azoles, Echinocandins (for systemic infections)
Drug Drug Class Description MOA Indications Pharmacokinetics Adverse Effects Resistance
Strong inhibitor of Relatively non-toxic

Oral
CYP3A4 (can potentiate Minor GI upset
Superficial mycoses (topical creams)Best absorbed at LOW pH
toxicities of other drugs,
Imidazole i.e., warfarin &
(Antacids, H2 blockers, PPIs
↓ plasma tetosterone --> gynecomastia,
Chronic mucocutaneous candidiasis & interfere with absorption)
Ketoconazole (Azoles) cyclosporine)
dermatophytes
↓ libido, loss of potency in men;
menstrual irregularities in women
Poor CSF penetration
Imidazoles are less specific
(increase membrane for fungal P450 Other azoles usually preferred
High doses may inhibit adrenal steroid
permeability) Hepatic elimination
--> more adverse effects synthesis & ↓ plasma corƟsol
Miconazole Superficial mycoses (Candida albicans, Most commonly used topically

Topical Rare
Clotrimazole Pityrosporum orbiculare) Negligible absorption
DoC for:
Inhibits fungal CYP450,
-Esophageal, oropharyngeal & High oral bioavailability
14-α-sterol Moderate inhibitor of CYP3A4
vulvovaginal candidiasis Also IV
demethylase --> -Coccidioides NOT effective against
Fluconazole Good for meningitis STRONG inhibitor of CYP2C9 -->
prevents conversion of -Prophylaxis & treatment against Good CSF penetration Aspergillus or other
↑ plasma phenytoin, zidovudine, &
cryptococcal meningitis filamentous fungi
lanosterol to ergosterol --> warfarin
-Prophylaxis in bone marrow 90% RENAL elimination
distrupts of membrane
function, ↑ permeability transplant and AIDS patients
Oral; poor bioavailability, poor CSF
DoC for Mycoses due to dimorphic
penetration
Triazoles fungi Blastomyces, Sporthrix, &
Best absorbed at LOW pH
Doesn't affect mammalian Histoplasma STRONG inhibitor of CYP3A4
(Azoles) steroid synthesis
(Antacids, H2 blockers, PPIs
Fatal arrythmias if given with cisapride or Not effective against
Itraconazole interfere with absorption)
Dermatophytoses & onychomycosis quinidine Zygomycetes
(increase membrane Potent antifungal (Still less than ketoconazole)
Hepatic elimination (CYP3A4)
permeability) Replaced by voriconazole for
Accumulates in nails --> can use
Aspergillus
pulse dosing
DoC for
Rash, ↑ liver enzymes,
Aspergillus (invasive aspergillosis) IV & Oral
Transient visual disturbances (30%)
Well absorbed (BA > 90%) Not effective against
Voriconazole including blurring, changes in color vision
Some Candida spp. (krusei) Hepatic elimination (CYP: 2C19, Zygomycetes
or brightness
2C9, 3A4)
Inhibits CYP: 2C19, 2C9, 3A4
Fusarium
Similar to Itraconazole, but active Oral
Posaconazole Inhibits CYP3A4
against Zygomycetes, i.e., Mucor Must take with figh-fat meal
Newest class
Inhibits synthesis of β(1,3)-
Not active against
Caspofungin Echinocandins Large cyclic peptides D-glucans in fungal cell Candida & Aspergillus IV only Cryptococcus
linked to a long-chain fatty wall --> disruption of cell wall - neoformans
acid -> death
-conazole Water solubility Absorption CSF:Serum [ ] Ratio Half life (hours) Elimination Formulations
Keto Low Variable < 0.1 7-10 Hepatic Oral
Flu High High > 0.7 22-31 Renal Oral, IV
Itra Low Variable < 0.01 24-42 Hepatic Oral, IV
Vori High High 6 Hepatic Oral, IV
Anti-Viral Drugs (Part I)
Drug Drug Class Description MOA Indications Pharmacokinetics / Dosage Resistance Adverse Effects Contraindications
Influenza A, B, & RSV
Orally active prodrug (hydrolyzed in GI disturbances, nausea
Treatment of Respiratory Viral Infections (RAZOR)
Analogs/Inhibitors of (Respiratory Syncytial Virus)

Oseltamivir liver) (alleviated when taken
Neuraminidase sialic acid substrate Excreted unchanged in urine Less infective + virulent with food)
Can be used for prophylaxis
Inhibitors for neuroaminidase --> neuraminidase mutations
or within 24-48 hours after
inhibit release of virus Inhaled, intranasal No GI effects
Zanamivir infection --> modest effect in Severe asthma, COPD
↓ symptoms Excreted unchanged in urine Airway irritation
Monitor drug in
EXCLUSIVELY for Influenza A Oral CNS: Insomia, dizziness,
Don't impair immune Blocks viral membrane Up to 50% of people Psychiatry pt, cerebral
virus Widely distributed, crosses BBB ataxia --> hallucinations,
response to Influenza A (+5% on first dose) atherosclerosis, renal
Amantidine protein, M2 (H+ channel) (2nd line drug, after above) seizures)
impairment, epilepsy
vaccine
Ion Channel Channel is required for NOT extensively metabolized &
Cross-resistance between Pregnancy, nursing (FDA
Blockers fusion of viral with cell Effective in treatment and excreted in urine (may accumulate) GI intolerance
Resistance is a drugs occurs Category C)
prophylaxis (70-90%)
problem: Use as LAST membrane --> endosome NOT widely distributed
RESORT (prevents uncoating) Mutation of M2 channel Pregnancy, nursing (FDA
Rimantidine Amantidine: Parkinsonism Does NOT cross BBB GI intolerance
Category C)
Metabolized/excreted by kidney
Ribavirin-triphosphate Oral, IV, aerosilized Pregnancy (FDA

--> inhibits guanosine Absorption ↑ with a fatty meal Dose-dependent Category X)
Synthetic triphosphate formation transient anemia (binds
Converted to ribavirin- --> prevents viral mRNA RNA + DNA viruses (RSV, HCV,
Ribavirin Guanosine triphosphate Lassa Fever)
Drug retention in all tissues except to RBC) Severe teratogen, must
capping --> inhibition of brain be 6 month lag between
Analog Drug & metabolite eliminated in Elevated bilirubin ceasing drug and getting
RNA-dependent RNA
polymerase urine pregnant
Uses innnate immune IV, Subcutaneous, Intralesion

response Hepatitis A,B,C,D,E -Interferes with hepatic
(Not oral)
Does NOT target viral drug metabolism -->
Naturally occuring
gene products directly Interferon α (HCV, HBV, Flu-like (fever, chills, toxic accumulation of
glycoproteins/ Cellular uptake & metabolism by liver
condyloma accuminata, hairy- myalgias, GI upset) theophylline
cytokines Inhibits RNA + DNA + kidney --> little in plasma
Treatment of Hepatic Viral Infections (I LATE)
Interferons α, β, γ Interferons cell leukemia, Kaposi's

synthesis by sarcoma) Fatigue & mental -May potentiate
γ made only by activating/inducing Negligible renal elimination
depression myelosuppression by
immune cells protein expression that Interferon β - Multiple zidovudine (Nucleoside
inhibit virus infection (e.g. Sclerosis PEGYLATED to improve PK profile
analog)
PKR) (allows smaller dose)
Competitively inhibits Well absorbed orally, widely
Headache
Lamivudine HBV DNA HBV distributed (t1/2 ≈ 9 hrs)
Dizziness
polymerase 70% excreted unchanged in urine
Incorporated into viral Admin once daily (↑ compliance)

Severe exacerbation of Renal dysfunction, may
Adefovir DNA --> termination of HBV Excreted in urine (45% active
hepatitis (25%) ↑ blood levels
DNA synthesis compound)
Nucleotide/ Must be Competes with

phosphorylated to Severe hepatitis
deoxyguanosine Lamivudine-resistant strains of Avoid drugs with renal
Entecavir Nucleoside triphosphate (active) Renal function must be asessed (monitor after
triphosphate for viral HBV toxicity
Analogs form discontinuation)
reverse transcriptase
Competes with
endogenous thymidine
Oral (once/day)
triphosphate
Not effective against HIV or
Telbivudine OR
Eliminated unchanged by glomerular other viruses
Incorporates into viral
filtration
DNA --> terminate DNA
chain elongation
Anti-Viral Drugs (Part II) - Treatment of Herpesvirus Infections
No drug can treat latent

Monophosphorylated by Herpes Simplex 1 & 2
infection (only active)
herpes virus-encoded Varicella-zoster virus (VZV) Topical = local irritation
thymidine kinase --> only Some Epstein-Barr Viral IV, Oral, Topical
Altered or deficient
infected cells susceptible Infections (HHV-4) Oral = headache,
Prototype antiherpetic thymidine kinases & DNA
Well distributed (including CSF) diarrhea, nausea,
Acyclovir polymerases (most
Competes with dGTP; DoC for HSV Encephalitis vomiting
Guanosine analog commonly in
causes chain termination Partially metabolized --> urine (can
immunocompromised)
when incorporated into Genital herpes infections & accumulate with renal failure) Renal dysfunction at
DNA; inhibits viral DNA prophylaxis in transplant & high doses
Cross resistance to other
polymerase immunocompromised patients
cyclovirs
HSV
Adenovirus
NOT phosphorylated by IV, intravitreal (for retinitis)
CMV-induced retinitis in
viral kinases DNA chain terminator +
HIV/AIDS Mutation in viral DNA
Cidofovir Viral DNA polymerase Must be co-admin with Probenicid Nephrotoxicity
polymerase
Activation by host cell inhibitor (blocks renal tubular secretion) to
Effective against HSV &
kinases avoid nephrotoxicity
Gancyclovir-resistant
Purine/ organisms
Pyrimidine Valganciclovir =
Phosphorylated by viral
IV
prodrug with ↑ Well distributed (including CSF) Reduced phosphorylation
Analogs bioavailability
(UL97) & cell kinases
DoC for CMV retinitis & Urinary excretion via glomerular & (mutations in
Myelosuppression
Ganciclovir Pregnancy (FDA Category
CMV prophylaxis in tubular secretion phosphotransferase, UL97)
(Valganciclovir) DNA chain terminator + Severe, dose- C)
Analog of acyclovir (8- immunocompromised or mutations in viral DNA
viral DNA polymerase dependent neutropenia
20x activity against Valganciclovir rapidly hydrolysed in polymerase
inhibitor
CMV) intestine + liver --> ganciclovir
Inhibits HSV DNA Penciclovir (Topical only, t1/2 = 20- Headaches
Penciclovir Famciclovir = prodrug
polymerase/chain HSV-1, 2, VZV 30x acyclovir) Low occurrence Nausea
(Famiclovir) of penciclovir
terminator Famciclovir (Oral prodrug) Diarrhea
HSV, CMV, VZV
Inhibits viral DNA Superficial punctate
synthesis after Limited to treatment of keratitis
Vidarabine Adenine analog Ophthalmic ointment
conversion to immunocompromised with Pain
triphosphate herpetic & vaccinal keratitis & Photophobia
HSV keratoconjunctivitis
HSV-1, 2, & vaccinia virus Transient irritation of
Ophthalmic ointment (too toxic for
the eye
Incorporated into viral systemic use)
Trifluridine Thymidine analog DoC for HSV
DNA --> fragmentation
keratoconjunctivitis & Palpebral (eyelid)
t1/2 ≈ 12min (applied frequently)
epithelial keratitis edema
Iritis (25%)
Binds to CMV mRNA --> Vitritis
Antisense Last resort when other Intravitreally
Fomivirsen inhibits CMV protein Changes in vision
oligonucleotide therapies for CMV retinitis fail t1/2 ≈ 55 hours
synthesis ↑ intraocular pressure
(15-20%)
Nephrotoxicity
Organic analog of CMV retinitis in Hypocalcemia
Selectively inhibits virus-
inorganic immunocompromised Anemia
Pyrophosphate specific DNA IV (poor oral absorption) Point mutation in
Foscarnet pyrophosphate (does Acyclovir-resistant HSV + CMV Nausea + fever
analog polymerase & reverse Well distributed (including CSF) polymerase
NOT require retinitis, ganciclovir-resistant CNS: hallucinations,
phosphorylation) transcriptase CMV & VZV seizures, headache
(25%)
Anti-RetroViral Drugs (Part I) - NRTIs
Toxicity potentiated by
Well absorbed orally
Bone marrow probenacid,
Penetrates BBB
Prophylaxis in exposed suppression acetominophen,
individuals (neutropenia, anemia) lorazepam, cimetidine,
Zidovudine t1/2 ≈ 1 hr (intracellular
indomethacin
(ZDV, AZT) t1/2 ≈ 3 hr) --> frequent dosing
Prevention of prenatal Headaches
infection Stavudine & ribavirin
Glucuronylated by liver & excreted in
GI intolerance activated by same
urine
pathways
↓ mitonchondrial DNA
synthesis --> toxicity
STRONG inhibitor of Completely absorbed orally, crosses
Peripheral neuropathy
Stavudine BBB
β and γ DNA Lipoatrophy &
(d4T) Most common: mutation at
polymerases hyperlipidemia
~50% cleared in urine viral codon 184. Admin
Neuromuscular
lamivudine (restores
weakness
sensitivity to zidovudine &
tenofovir)
Pancreatitis (monitor
Analogs of native Absorption best in fasting state (acid Cross resistance between serum amylase)
labile) or combined with antacid analog of same agent can
ribosides (lack 3'OH)
Didanosine HIV adults/children in combo occur Stavudine (similar
(ddI)
Nucleoside/ with other agents
Peripheral neuropathy
toxicities)
Phosphorylated --> Penetrates CSF (less than AZT) (dose-limiting)
-tide Reverse 55% excreted in urine
General PK: Renally excreted GI intolerance
Transcriptase incorporated into viral
DNA by reverse
Inhibitors transcriptase --> Renal insufficiency
Nucleotide Analog With food (↑ bioavailability) General AE: due to
(NRTIs) mitochondrial DNA Only NRTI with
Termination of DNA
Tenofovir Inhibits HIV elongation Long t1/2 --> once/day dosing GI (nausea, vomiting, significant drug
(TDF) polymerase inhibition diarrhea, flatulence) interactions: ↑ [ddl] -->
reverse Excreted mostly unchanged in urine (peripheral neuropathy, reduce dosage;
transcriptase (filtration & active secretion) pancreatitis, lipoatrophy); ↓ [atazanavir] --> boost
with ritonavir
Liver toxicity (lactic acidosis,
Terminates synthesis of
hepatomegaly with
proviral DNA chain &
steatosis)
inhibits HIV & HBV RT
(does NOT affect High resistance with Do not use with other
Lamivudine (3TC) HIV, in combo with AZT
mitochondrial DNA single A.A. substitutions cytosine drugs
synthesis or bone
marrow precursor
cells)
Emtricitabine Structural analog of
Once daily dosing
(FTC) 3TC
GI, headache, dizziness

Guanosine analog
Hypersensitivity (5%) Do not rechallenge
Abacavir (rash, GI, malaise, sensitized person
Cross resistance with
(ABC) respiratory distress) (reaction is worse each
strains resistant to AZT
(genetic screening time)
& 3TC
available)
Anti-RetroViral Drugs (Part II) - NNRTI, PI
Hepatoxicity, Fever,
CD4+ counts >250
Rash (16%), Headache
Well absorbed otally (NOT affected (women) or >400 (men)
by food or antacids)
Advantages: Target site is HIV-1 specific Steven-Johnson
Use in combo with other ARTs Inducer of CYP3A4
Non-nucleoside -No effect on blood- & not essential to enzyme syndrome & toxic
Nevirapine (NVP) Highly selective for HIV-1 treatment in Widely distributed (including CNS) (Protease inhibitors,
Reverse forming cells --> resistance develops epidermal necrolysis
noncompetitive inhibitors adults/children OCs, Ketoconazole,
-No cross-resistance quickly (14-day titration at 1/2
Transcriptase with NRTIs of HIV-1 Reverse
Excreted mainly in urine as
dose required to ↓ risk
Methadone, Metro-
metabolites (CYP 3A4 & 2B6) nidazole, Quinidine,
Inhibitors Transcriptase of serious epidermal
Theophylline, Warfarin)
Disadvantages: reactions)
(NNRTIs) -Cross-resistance with
Does not require
other NNRTIs CNS (50%) (Dizziness, Potent inducer of
Not included: activation Oral
-Drug interactions Headache, Vivid CYP3A4
Delaviridine, Etravirine Preferred NNRTI on DHHS Absorption ↑ with a fatty meal
-Hypersensitivity dreams, Loss of Pregnancy (FDA category
Efavirenz (EFV) guidelines (↑ CD4+ counts, ↓ Once daily dosing (t1/2 > 40 hrs)
concentration) --> D);
viral load) Extensively metabolized
resolves in few weeks can be used after 1st
99% bound to plasma albumin
Rash (25%) trimester if necessary)
PK enhancer/booster Potent inhibitor of CYP3A4 N/V, Diarrhea

Ritonavir (RTV) of other PI's (inhibits Poor oral bioavailability Headache, Circumoral Numerous (CYP)
their metabolism) t1/2 = 3-5 hrs parethesia
Accumulation of stepwise
mutations of protease gene - Rifampin, rifabutin,
Absorption ↑ with a fatty meal -> high resistance levels Headache, fatigue,
Saquinavir (SQV) Admin with low dose of RTV nevaripine (drugs that
t1/2 = 7-12 hrs nausea, GI
enhance metabolism)
GI, Headache
Least protein bound (60%) General AE: Nephrolithiasis &
Admin with RTV to ↑ Parasthesias hyperbilirubinemia
Indinavir (IDV) Protease absorption & permit 2/day Absorption ↓ with a faƩy meal Nausea/Vomiting (adequate hydration
dosing Diarrhea
Inhibitors t1/2 = 1.8 hrs Disturbance in lipid
important)
Fat redistribution
metabolism (diabetes,
Major metabolite (CYP Absorption ↑ with a faƩy meal Diarrhea (controlled by
hyperTAG,
Nelfinavir (NFV) General PK: Poor oral 2C19) is anti-viral equal CANNOT be boosted by RTV Metabolized by several CYPs Loperamide)
Reversible inhibitors of hypercholesterolemia) Can inhibit metab. of
bioavailability to parent t1/2 = 5 hrs Flatulence, Nausea
HIV aspartyl other drugs
Fosamprenavir Pro-drug --> Chronic admin --> Headache, fatigue, N/V,
Admin with RTV
(fAPV) Bound to plasma proteins amprenavir protease (cleaves fat redistribution --> parasthesias
(α1-acid glycoprotein - viral polyprotein into RT, St. John's Wort (enzyme
(cushingoid)
can ↑ in response to Preferred PI GI
protease, & integrase) Admin with RTV Poor intrinsic bioavailability inducers)
Lopinavir (LPVr) trauma & surgery --> less Oral prep contains Hypertriglyceridemia
Pregnancy t1/2 = 1.8 hrs Disulfram
free drug) EtOH Insulin resistance
Prevents maturation --> General Contraindications Metronidazole
Non-infective virions Potent inhibitors of CYP Competitive inhibitor of
Substrates for CYP 3A4
Well absorbed orally (↑ with food) e.g., rhabdomyolysis glucuronyl
(little excreted Most popular (simvastatin, lovastatin); Must be >12 hrs apart
unchanged) transferase (benign
Atazanavir (ATV) ATV + RTV is only once-daily Highly protein bound (86%) excessive sedation from H2 blockers,
Structurally different hyperbilirubinemia &
t1/2 = 7 hrs (midazolam, triazolam); antacids, or PPIs
Substrates for from other Pis jaundice)
Metabolized by & inhibits CYP3A4 respiratory depression
P-glycoprotein pump Prolongs PR interval &
(fentanyl)
slow HR
Inhibits HIV protease resistant Adjust Warfarin, Sildenafil, & Severe, fatal HEPATITIS
Well absorbed with food
to other PIs Phenytoin doses
Tipranavir (TPV) Inducer of CYP450
Intracranial
t1/2 = 6 hrs
2/day dosing with RTV Do not take Rifampin & St. hemorrhages
John's Wort
Well absorbed with food
Inhibits HIV protease resistant
Darunavir (DRV) t1/2 = 15 hrs (with RTV) Rash
to other PIs
Metabolized by/inhibits CYP3A4
Anti-RetroViral Drugs (Part III)
Structurally similar to gp41
(HIV protein that mediates Treatment experienced adults Injection-related
Enfuvirtide
Inhibits viral entry membrane fusion) --> with evidence of HIV SC injections (2/day) Hypersensitivity
(T-20)
prevents membrane replication Eosinophilia
fusion
Fusion Inhibitor Blocks CCR5
coreceptor that binds Well absorbed orally
Maraviroc gp41 to facilitate HIV Hepatoxicity
entry (only CCR5- Metabolized by CYP3A4 (↓ dose
expressing cells can be when given with PI)
treated with maraviroc)
Integrase Strand Inhibits final step in Treatment experienced &
2/day dosing (t1/2 ≈ 9 hrs)
Nausea
Metabolism - UGT1A1-mediated
Raltegravir Transfer Inhibitor integration of viral DNA Treatment naïve patients with
glucuronidation --> no CYP450
Headache
into host cell DNA evidence of HIV replication Diarrhea
(INSTI) interactions
Preferred Regimen for Treatment-naïve Patients Alternative Regimens

NNRTI-based Regimens
1. NNRTI + 2 NRTI 1. Efarvirenz + abacavir/zidovuidne + lamivudine
Efarvirenz + (tenofovir + emitricitabine)
2. Nevirapine + zidovudine/lamivudine
PI-based Regimen
2. PI (boosted with ritonavir) + 2 NRTI 1. Ritonavir-boosted atazanivr + abacavir/zidovudine + lamivudine
Ritonavir-boosted atazanavir + (tenofovir + emitricitabine)
Ritonavir-boosted darunavir + (tenofovir + emtricitabine) 2. Ritonavir-boosted fosamprenavir + abacavir/zidovudine + lamivudine or
tenofovir/emtricitabine
3. Ritonavir-boosted lopinavir + abacavir/zidovudine + lamivudine or

3. INSTI + 2 NRTI tenofovir/emtricitabine
Raltegravir + (tenofovir + emitricitabine)
4. Ritonavir-boosted saquinavir + tenofovir/emtricitabine
Recommendations During Pregnancy HIV Prophylaxis Following Needle Stick

Ritonavir-boosted lopinavir (2/day) + zidovudine/lamivudine Exposure Type HIV Positive HIV Status Unknown
Less severe (e.g., solid needle, 2 NRTI's

superficial injury) (e.g., AZT + Lamivudine) Generally nothing;
consider 2-drug
Recommendations for Infant Born to HIV- More severe (e.g., large-bore 3-drugs (e.g., 2 NRTIs + PI treatment
infected Mother hollow needle, deep puncture) or NNRTI)
Zidovudine (start immediately after birth, Treat for 1 month after injury (best treated within 1-2 hours of injury)
administer for 6 weeks)
HIV Prophylactic Vaccines: Pneumococcal, hepatitis, influenza

Do NOT give: Live vaccines such as oral polio & varicella
Anti-Malarial Drugs (Part I)
Drug Description MOA Indications Pharmacokinetics Resistance Adverse Effects Contraindications
Use severely compromised by DoC for both treatment & P.falciparum -

Concentrates in food Pruritis (common in Africans)
resistance prophylaxis of all P. vivax & P. mutations in
vacuoles --> prevents Oral (well absorbed &
ovale malaria infections (non- putative transporter, Psoriasis
biocrystalization of rapidly distributed to N/V, abdominal pain, headache,
Highly effective blood falciparum) PfCRT expels Porphyria (may
Hgb breakdown tissues) anorexia, malaise, blurring of vision,
schizonticide chloroquine from precipitate attacks)
Chloroquine product heme to non- urticaria
NOT active against liver stage DoC for sensitive, uncomplicated food vacuole
toxic hemozoin Excreted in urine
parasites falciparum malaria Retinal or visual field
Toxic heme lyses Hemolysis (if G6PD-deficient)
Preferred chemoprophylactic in Some drugs (e.g. abnormalities
parasite and RBC t1/2 = 3-5 days
Safe in pregnancy & young areas with no resistant falciparum Verapamil) can
(See diagram) ECG changes
children malaria reverse resistance
Do NOT use with

Cinchonism (tinnitus, headache, nausea, dizziness, flushing, mefloquine
visual distrubances) Discontinue if signs of:
Hypersensitivity (rashes, urticaria, angioedema, brochospasm) severe cinchonism;
Derived from cinchona tree First line therapies for SEVERE
Not fully understood Oral Blackwater fever (hemolysis + hemoglobinuria) (specific for hemolysis;
bark falciparum disease (parenteral)
Rapidly absorbed quinine + malaria) hypersensitivity
Quinine
Thought to be similar Well distributed Hematologic abnormalities - hemolysis (G6PD deficiency), Adoid if:
Quinidine Rapidly acting, highly effective Oral treatment in Chloroquine-
to Chloroquine (toxic leukopenia, agranulocytosis, thrombocytopenia Visual/auditory
(stereoisomers) blood schizonticide resistant areas
free heme IV admin for severe Hypoglycemia (stimulates insulin release) problems
accumulation) infections Uterine contractions, FDA category C (still DoC for severe Use with caution if:
Resistance is uncommon Class 1A Anti-arrhythymic
falciparum in pregnancy) Underlying cardiac
Severe hypotension, QT prolongation abnormalities
Can raise plasma warfarin & digoxin ↓ dose in renal
insufficiency
Weekly dosing (N/V, dizziness,

Chemoprophylaxis (P. falciparum) sleep/behavioral disturbances, Epilepsy
Oral only epigastric/abdominal pain, diarrhea, Psychiatric disorders
Only drug recommended for headache, rash) Arrhythmias
Chemically related to quinine chemoprophylaxis in pregnant Highly protein bound, Uncommon Cardiac conduction
women in chloroquine-resistant extensively distributed, Higher doses (leukocytosis, defects
Mefloquine Unknown
Safe in pregnancy & young areas eliminated slowly Related to Quinine thrombocytopenia, aminotransferase Sensitivity to related
children (FDA category C) resistance elevations, arhythmias, bradycardia) drugs
Mefloquine + artesunate = t1/2 = 20 days Do NOT co-admin with
uncomplicated malaria in S.E. (weekly dosing) Neuropsychiatric toxicities (depression, quinine, quinidine, or
Asia confusion, acute psychosis, seizures, < halofantrine
0.1%)
Anti-Malarial Drugs (Part II)
Drug Description MOA Indications Pharmacokinetics Resistance Adverse Effects Contraindications
DoC for eradication of dormant Nausea, epigastric pain, abdominal

Oral
liver forms of P. vivax & P. ovale cramps, headache G6PD deficiency (drug
Well absorbed
causes oxidative stress;
Unknown
Acute therapy & prophylaxis for Leukopenia, agranulocytosis, test first)
Test for G6PD deficiency prior Rapidly metabolized &
Primaquine vivax & ovale malaria leukocytosis, cardiac arrhythmias
to prescribing Metabolites may be excreted in urine
Pregnancy (treat
oxidants
Chemoprophylaxis (all strains - Hemolysis (more likely with metabolites) dormant liver form after
t1/2 = 3-8 hrs
used only when other drugs are or methemoglobinemia (especially if delivery)
too toxic) G6PD deficient)
Tissue & erythrocytic schizonts

Abdominal pain
Disrupts Oral only Nausea/Vomiting
Chemoprophylaxis can be
Malarone = Atovaquone + mitochondrial discontinued after 1 week after
(absorption ↑ with Diarrhea
Atovaquone fatty food) Headache
proguanil electron exposure
Rash
transport Treatment & prophylaxis of P.
t1/2= 2-3 days
FDA Category C (safe)
falciparum
Inhibts folate synthesis Inhibits dihydro- GI disturbances

Chemoprophylaxis (only in combo) Oral Rashes, Itching
Sulfadoxine Weakly active against pteroate Intermittent preventive therapy Sulf: t1/2 = 170 hrs Proguanil (mouth ulcers, alopecia)
erythrocytic schizonts
synthesis (high risk patients)
Common for
Pyrimethamine-Sulfadoxine (erythema
Inhibts folate synthesis Inhibit Chloroquine-resistant falciparum multiforme, Stevens-Johnson syndrome, All are safe in pregnancy
P.falciparum
malaria (pyrimethamine- toxic epidermal necrolysis),
Pyrimethamine
Act slowly on erythrocytic plasmodial Oral
forms of all malaria species sulfadoxine used) Pyr: t1/2 = 3-5 days megaloblastic anemia
Proguanil (pro-drug)
Proguanil: some activity dihydrofolate NOT for severe malaria Prog: t1/2 = 16 hrs Sulfadoxine (hematologic, GI, CNS,
against hepatic forms reductase dermatologic, & renal toxicity)
Doxycycline + quinine for GI

Active against erythrocytic
Severe P. falciparum malaria Candidal vaginitis
schizonts of all human malaria Binds reversibly to Pregnancy (FDA Cat D)
Doxycycline Photosensitivity
(Tetracyclines)
parasites 30S Used to complete treatment after Discoloration & hypoplasia of teeth,
Children < 8 years
Inhibits tRNA binding severe malaria is treated (teratogenic)
stunting of growth
NO effect on hepatic stages
w/quinine, quinidine or artesunate Fetal hepatotoxicity (in pregnancy)
Iron-catalyzed
Derived from qinghaosu plant
cleavage of drug's
Artesunate -
endoperoxide bridge
NO effect on hepatic stages Severe, multi-drug resistant P. Oral, IV, IM, Rectal Nausea, vomiting, diarrhea
by heme iron -->
Artemisinins falciparum malaria
production of free
-Artesunate Combine with longer acting Artemether - Very High Doses (neurotoxicity, QT
radicals in
-Artemether drug --> protect against Oral, IM, Rectal prolongation)
plasmodium food
-Dihydroartemisnin resistance
vacuole
Dihydroartemisinin - Safe in 2nd, 3rd trimesters of pregnancy
OR
Coartem = artemether + Oral only
Inhibition of parasite
lumefantrine
calcium ATPase
Clindamycin Alternative to doxycylcine
Irregular absorption
Halofantrine Cardiac toxicity Pregnancy (teratogen)
(limits use)
Erythrocytic stages of all parasites
Fixed dose combo with
Lumafantrine Minor QT prolongation
artemether only
Parasite Life Cycle Signs and Symptoms (P. falciparum )
1. Anopheline mosquito inoculates plasmodium sporozoites to initiate human infection -Most severe disease (microvascular effects)
↓ -Only species likely to cause fatal disease if untreated
2. Circulating sporozoites rapidly invade human liver cells -Cerebral malaria (irritability --> seizures --> coma)
↓
3. Exoerythrocytic stage tissue schizonts mature in the liver e.g. respiratory distress syndrome, diarrhea,
↓ severe thrombocytopenia, spontaneous abortion,
4. Merozoites are released from the liver & invade erythrocytes hypoglycemia
↓
5. Gametocytes develop in erythrocytes before being taken up by mosquitoes
P. falciparum + P. malariae P. vivax + P. ovale

-only one cycle of liver cell invasion -have dormant hepatic stage
-liver infections ceases in < 4 weeks -erythrocytic and hepatic parasites have to be
-only erythrocytic parasites have to be eliminated eliminated
CDC Malaria Treatment Guidelines

Clinical Diagnosis/
Resistance Recommended Drug
Species
Uncomplicated
Chloroquine-sensitive
P. falciparum
Chloroquine/hydrochloroquine
Uncomplicated
All regions
P. malariae
Uncomplicated
P. vivax All regions (Hyrdoxy)Chloroquine + Primaquine
P. ovale
1. Atovaquone-proguanil
2. Artemether-lumefantrine
Uncomplicated Chloroquine-resistant or 3. Quinine + doxycylcine
P. falciparum unknown 4. Mefloquine
Pregnancy, 1st trim: Quinine ± Clindamycin
2nd-3rd trim: Artesunate/Quinine + Clindamycin
1. Quinine + doxycycline + primaquine
Uncomplicated 2. Atovaquone-proguanil + primaquine
Chloroquine-resistant
P. vivax 3. Mefloquine + primaquine
Pregnancy: Quinine only
Quinidine + doxycylcine/tetracycline/clindamycin
All regions Artesunate + atovaquone-proguanil /
doxycycline / mefloquine
Severe malaria
Pregnancy, 1st trimester Quinine or artesunate
Pregnancy, 2nd-3rd Artesunate
trimester Artemether (2nd choice)
Chloroquine-sensitive Chloroquine
Chemoprophylaxis
Chloroquine-resistant Mefloquine, Doxycycline, Primaquine
Anti-Parasitic Drugs (Part I) - Amebiasis
Drug's nitro group acts as

DoC - Kills E. Histolytica Oral
electron acceptor to ameba's Nausea, vomiting, epigastric
trophozoites Well distributed (vaginal &
Used in combo with luminal ferrodoxin-like, low redox- distress, abdominal cramps
seminal fluids, breast milk,
drug potential, electron-transport
Giardia lamblia CSF)
Metronidazole Mixed proteins (which participate in
Trichomonas vaginalis
Unpleasant metallic taste
Safety in pregnancy not metabolic removal reactions) Oral moniliasis
Antiamebics Anaerobic cocci & anaerobic Undergoes hepatic oxidation &
established (Category B) --> Reduced cytotoxic Dark urine
gram-ve bacilli glucoronidation (P450)
compounds (bind proteins & Leukopoenia, dizziness, ataxia
(acts on lumenal and H. pylori (combo) t1/2 = 6-8hrs
DNA) --> cell death
systemic disease)
2nd generation Amebiasis
nitroimidazole Amebic liver ascess
Tinidazole t1/2 = 12-14 hours
Better tolerated than Giardiasis
metronidazole Trichomoniasis
Rash
Luminal trophozoite & cyst
Diarrhea
forms of E. histolytica
Iodoquinol Oral Dose-related peripheral
(alternative to diloxanide for
neuropathy (rare optic neuritis)
mild-severe infections)
Avoid long term use
Converted in gut to freebase

Diloxanide furoate Asymptomatic amebiasis Mild (GI distress)
Luminal active form
Antiamebics Luminal forms of E. histolytica
Amebicidal & tapeworm GI distress, Diarrhea
Causes cell membranes to leak
(mechanism unknown) With tetracyclines for mild Headaches
Paromomycin Aminoglycoside antibiotic
intestinal disease Dizziness
↓ intesKnal flora populaKon (↓ Rashes
food for ameba) Alternative for Arthralgia
cryptosporidiosis in AIDS
Used with metronidazole & Eliminates trophozoites in liver Liver abscesses

Chloroquine Resistance can be a problem
diloxanide furoate abscesses (mechanism unknown) Intestinal wall infections
Systemic
Antiamebics IM (preferred), SC
Pain at injection site
Transient nausea
Inhibits protein synthesis by Concentrates in liver (persists
Emetine (Treats liver abscesses Backup drugs for severe Cardiotoxicity
Used with a luminal agent blocking ribosomal movement for 1 month)
Dehydroemetine & intestinal wall intestinal or hepatic infection Neuromuscular weakness
along mRNA Slowly metabolized &
infections) Dizziness
eliminated
Rash
Plasma t1/2 = 5 days
Disease Form DoC Alternative

Asymptomatic, Intestinal Diloxanide furoate Iodoquinol, paromomycin
Mild-moderate, intestinal Metronidazole + luminal Tinidazole/tetracyclin/erythromycin + luminal
Severe, intestinal Metronidazole/tinidazole + luminal Tetracycline/(dihydro)emetine + luminal
Hepatic abscess/other extraintestinal Metronidazole/tinidazole + luminal (Dihydro)emetine + chloroquine + luminal
Anti-Parasitic Drugs (Part II) - Antihelminthics
Short (1-3 days): mild &

transient (nausea)
Oral (erratic absorption,
DoC for Cestodal infections enhanced by fatty meal)
Hydatid treatment (3 mos):
hepatotoxicity, agranulo-cytosis Pregnancy
Antihelminthics e.g., cysticercosis (Taenia Extensive first-pass
Albendazole or pancytopenia Children < 2 years
solium larvae) & hydatid metabolism (metabolite is
(FDA Category C)
Nematodes: disease (Echinococcus also active)
Inflammatory response to dying
Elongated roundworms with granulosis )
Inhibits microtubule synthesis & parasites in CNS (headache,
complete digestive system 3 mos treatment for hydatids
glucose uptake --> kills worms vomiting, hyperthermia,
(mouth to anus). Infects convulsions, mental changes)
intestines, blood, tissue
Dead worms expelled in feces
Benz-
Whipworm (Trichuris trichiura)
imidazoles Trematodes: Pin worm (Enterobius
Oral (nearly water insoluble, Pregnancy (Category C)
Leaf-shaped flatworms vermicularis)
take with fatty meal)
(flukes). Infects liver, Hookworms (Necator Abdominal pain
Mebendazole Use with caution in
intestinal, blood americanus & Ancylostoma Diarrhea
Firstpass metabolism --> children < 2 &
duodenale)
Metabolite is inactive patients with cirrhosis
Cestodes: Roundworm (Ascariasis
Flat, segmented body. lumbricoides)
No mouth/digestive system.
Attaches to host’s intestine. Threadworm (Strongyloides) Dizziness, Anorexia, N/V
Pregnancy (Category C)
Oral (readily absorbed, nearly CNS distrubances
Thiabendazole Affects microtubular aggregation
Cutaneous larva migrans water insoluble) Erythema multiforme
Kidney, liver disease
Early stages of trichinosis Steven-Johnson syndrome
Pregnancy
Meningitis (may cross
DoC for
BBB when inflamed)
River blindness (Onchocerca Mazotti-like reaction (fever,
Ivermectin ↑ Cl- influx --> HyperpolarizaKon volvulus) Oral (does not cross BBB) dizziness, somnolence,
Concomitant use of
--> Cutaneous larva migrans hypotension)
other GABA agonists
GABA agonist Parasite paralysis Strongyldoides
(e.g., barbituates,
benzodiazepines)
Worm expelled by peristalsis
Piperazine Alternative drug for Ascariasis Seizure disorders
Persistent activation of parasite's

Roundworms
Acts as depolarizing, nicotinic receptors by release of Oral (poorly absorbed) -->
Pyrantel Pamoate Pinworms Nausea, vomiting, diarrhea
neuromuscular blocker Ach & inhibition of works in intestinal tract
Hookworms
cholinesterase
Fever, malaise, myalgias, rash,
Immobilizes microfilariae DoC for
Oral (rapidly absorbed with arthralgias, headache
Lymphatic filariasis
Diethylcarbamazine meals) Leukocytosis
Renders them susceptible to host Loiasis
Excreted in urine Co-admin antihistamines to
defense mechanisms Tropical eosinophilia
mitigate AE
Oral (rapidly absorbed with
Acts indirectly by killing Wuchereria Bancrofti
meals)
Doxycycline Tetracycline Microfilaricidal Wolbachia (intracellular bacterial
Excreted in urine (40%) & bile
symbiont of filarial parasites) Onchocerciasis
(60%)
Anti-Parasitic Drugs (Prt III)
Oral
DoC for Pregnancy
↑ permeability of cell Well distributed (also CSF)
ALL schistomiasis Nursing mothers
membrane to Ca2+ --> Drowsiness, dizziness, malaise
Most trematode & cestode
Praziquantel Extensive metabolism (CYP), Anorexia, GI upsets
Ocular cysticercosis
Contracture & paralysis of short t1/2 Drug interactions (CYP450)
Cysticercosis (albendazole is (destruction of organism
parasite Inactive metabolites excreted
preferred) damages eye)
via urine & bile
DoC for fasciolosis (sheep liver
Inhibits helminth's electron fluke)
Bithionol
transport chain (probably) Alternative for pulmonary
paragonimiasis
Avoid alcohol within 1
Not available in US Inhibits parasite's mitochondrial Oral
day of dose
Always admin laxative first to
Niclosamide Lethal for cestode's scolex &
ADP phosphorylation; 2nd line for most cestode
purge bowel of dead segments
Anaerobic metabolism may infections Safety in pregnancy/
segments of cestodes, but & to prevent
also be inhibited children <2 not
NOT for ova digestions/liberation of ova
established
Drugs for Treatment of Nematode Infections Drugs for Treatment of Trematode Infections
Disease/Causative Agent Drug of Choice Other Disease/Causative Agent Drug of Choice
Ascariasis (roundworm) Albendazole (PP) Mebendazole, Pyrantel pamoate Fasciola hepatica (sheep liver fluke) Bithionol
Ancylostoma/Necator (hookworm) Albendazole (PP) Mebendazole, Pyrantel pamoate Schistosomiasis (New World) (S. mansomi, S. japonicu)
Trichuriasis (whipworm) Albendazole Mebendazole Schistosomiasis (Old World) (S. hematobium)
Praziquantel
Toxicariasis (Visceral larva migrans) Albendazole Clonorchis sinensis (Oriental liver fluke)
Trichinosis (Trichinella) Albendazole Mebendazole (+ Corticosteroids) Paragonimus westermani (Lung fluke)
Cutaneous larva migrans (Creeping
Albendazole Ivermectin
eruption, dog/cat hookworm), Ancylostoma
Enterobiasis (pinworm) Pyrantel pamoate Mebendazole Drugs for Treatment of Other Protazoal Infections
Wuchereria (Lymphatic filariasis) Diethylcarbamazine Doxycycline Indications Drug
Loiasis (African Eye Worm) Diethylcarbamazine Mucotaneous trypanosomiasis & late CNS stage
Melarsoprol
Onchocerciasis (River blindness) Ivermectin (African sleeping sickness)
Strongyloidiasis (threadworm) Ivermectin Hemolymphatic trypanosomiasis & P. jiroveci Pentamidine
Trypansomiasis (T. cruzi) Nifurtimox
Hemolymphatic trypanosomiasis (T. brucei
Drugs for Treatment of Cestode Infections Suramin
gambiense, T. rhodesiense)
Disease/Causative Agent Drug of Choice Toxoplasmosis Pyrimethamine + Clindamycin
Echinococcosis Albendazole Other opportunistic infections or Sulfadiazine + folinic acid
Cysticercosis Albendazole Sodium

Leishmaniasis (all stages)
Taenia solium larvae Praziquantel stibogluconate
Taeniasis Trimethoprim-
Pneumocystic jiroveci
Taenia solium (pork tapeworm) Praziquantel sulfamethoxazole
Taenia saginata (beef tapeworm) Niclosamide Giardia lamblia & Trichomonas vaginalis Metronidazole
Diphyllobothriasis (fish tapeworm)
CELL-CYCLE SPECIFIC AGENTS (CCS) - for rapidly growing tumors
Drug Description MOA Pharmacokinetics Indications Adverse Effects Notes
Antimetabolies (Block S phase)
Renal damage (↑ dose) Avoid in pregnancy (X)
Folic acid analog/Folate inhibitor Inhibits dihydrofolate Oral, IM, IV, IT
ALL, ChorioCA, Burkitt's, Cirrhosis (long term)
Methotrexate Needs P-glycoprotein (MDR1) pump reductase → Not CSF (unless IT)
Breast, Head & Neck CA Pulmonary toxicity Give leucovorin 24hrs later to
to enter cell ↓ DNA/RNA synthesis Minimal metabolism
Neurologic irritation rescue bone marrow
Thiol analog of Hypoxanthine → Oral, erratic absorption ALL (induction [1st step]
6-Mercaptopurine -Non-functional RNA/DNA Allopurinol prevents
converted to t-IMP by HGPRT Not CSF; Metabolized by therapy)
(6-MP) -Inhibits de-novo purine metabolism
t-IMP → t-GMP xanthine oxidase Crohn's disease Bone marrow depression
synthesis (feedback)
Metab. by thiopurine AML Hepatotoxicity (jaundice)
6-Thioguanine HGPRT converts drug to t-GMP -Inhibits AMP/XMP formation Must genotype for TPMT
from IMP methyltransferase excreted (with Daunorubicin &
(6-TG) t-GMP → t-GDP → t-tGTP Can be given with allopurinol
in urine cytarabine)
IV, topical Oral/GI ulcerations
Slow growing solid tumors Given with leucovorin to ↑
5-Fluorouracil Rapidly metabolized to fluoro- Hand/foot syndrome
Uracil analog Forms ternary complex (5- Superficial basal cell CA, stability of ternary complex →
(5-FU) β-alanine (urine) and CO2 (erythematous
FdUMP + thymidylate synthase premalignant keratoses ↑ efficacy
(exhaled) desquamation)
+ Leucovorin) --> Inhibits
Avoid in pregnancy (D), &
5-FU prodrug, needs thymidine thymidylate synthase Metastatic Colon CA Bone marrow depressed,
Capecitabine Oral People taking
phosphorylase (tumor specific) Met. Breast CA (2nd line) Hand/foot syndrome
warfarin/phenytoin
Cytarabine Phosphorylated by deoxycytidine ARA-CTP Inhibits DNA IV, IT AML (with Daunorubicin & 6- Myelosuppression
(ara-C) kinase (dCTP analog) polymerase Not CNS (unless IT) TG) Leukoencephalopathy
Inhibits ribonucleotide IV; Deaminated metabolite Pancreatic AdenoCA Myelosuppression
Gemcitabine Phos. to dCTP analog
reductase (urine) NSC Lung, Breast, Ovarian ↑ AST/ALT
Antitumor Antibiotics (Block G2 phase), from Streptomyces
-Inhibits topoisomerase II Irreversible cardiotoxicity
Leukemias, solid tumors, Myelosuppression
Doxorubicin -Intercalates in DNA, inhibits from free radicals
Anthracyclines IV (widely used) Severe alopecia
synthesis Acute: arrhythmias
Cell-cycle NON-specific (CCNS) No CNS Cardiotoxicity
-Binds cell membrane, alters Chronic: dilated
Effluxed by P-gp (P-glycoprotein Red urine/veins Radiation recall reaction
fluidity/ion transport AML (adults only) cardiomyopathy
pump) Liver metabolism (Desquamation at sites of
Daunorubicin -Generates semiquinone + free (with aca-C & 6-TG) Co-admin with iron chelator
previous radiation)
radicals ALL (Dexrazoxane) to protect
Actinomycin D -Intercalates in DNA Wilm's tumor (with surgery

Bone marrow depression
Dactinomycin CCNS -Blocks RNA Polymerase + Vincristine)
Sensitizes to radiation
Efflux pump P-gp -Single strand breaks Gestational ChorioCA
Pulmonary fibrosis ↑ hydrolase in liver/spleen,

Bleomycin Copper chelating glycopeptides DNA scission (by radicals) SC, IM, IV Testicular CA (with BEP)
(Bleomycin lung) low in lung/skin
Epipodophyllotoxins (Block late S-G2 phase)

IV; No CNS Germ-cell, NSC Lung, H/NH
Etoposide Inhibits topoisomerase II - Lymphoma, Gastric
Letoukopenia
Water insolube (Cremohpor
-> Damages DNA Hepatic toxicity
Teniposide vehicle) Refractory ALL (2nd line)
Vinca Alkaloids (Block M phase)
Inhibits microtubule ALL (children), Wilm’s,
Vincristine (VX) Peripheral neuropathy
Ewing’s, H/NH Lymphoma
formation IV → rapid cytotoxicity Can cause hyperuricemia (use
Vinblastine Binds to tubulin Metastatic testicular CA Myelosuppression
Prevents partitioning to CYP450 allopurinol)
Vinorebine daughter cells Advanced NSC Lung CA Granulocytopenia
Taxanes (Block M phase)
Promotes microtubule IV Adv. Ovarian, Breast, SC Hypersensitivy
Paclitaxel
Binds irreversibly to β-tubulin polymerization → accumulate, No CNS Lung, Kaposi's sarcoma Myelosuppression Avoid in cardiac disease
Docetaxel nonfuntional CYP450 Same; fewer side effects Myelosuppression
Camptothecins (Block S phase)
Irinotecan Met. colon/rectal CA Diarrhea, Myelosuppres. Give with antidiarrheal
S-phase specific → arrest in G2 phase Inhibits topoisomerase I
Topotecan Ovarian, SCLung, Cervix Myelosuppressive
CELL-CYCLE NON-SPECIFIC AGENTS (CCNS) - for slow growing tumors

ALKYLATING AGENTS - transfer alkyl groups to cellular constituents & covalently bind to nucleophilic groups
Nitrogen Mustards
Hemorrhagic cystitis Most widely used
Pro-drug; CYP2B → acrolein + Lymphoma, Leukemia,
Cyclophosphamide Oral (acrolein → bladder Can cause (bladder) cancer
phosphoramide mustard Neuro/Retinoblastoma, etc.
fibrosis); Sterility Given with Mesna
Hemorrhagic cystitis
Analog of cyclophosphamide
Ifosfamide IV Testicular CA (3rd line) Neurotoxicity Given with Mesna
Prodrug (activated by CYP 3A4) Alkylates N7 of guanine →
Thrombcytoopenia
cross links DNA →
strand breakage Hodgkin's 1st nitrogen mustard (WW2)
Very unstalble Bone marrow supression
Mechlorethamine Binds 2 separate nucleotides Lymphosarcoma Tx blistering with Sodium
Little excreted Blistering → ExtravasaIon
CML, CLL thiosulfate
Melphalan Oral, IV Multiple Myeloma Hematologic toxicities

Chlorambucil Slowest acting CLL Azoospermia, Amenorrhea
Alkyl Sulfonates
Myelosuppression
Busulfan Alkylate/cross-link DNA CML Addison’s-like syndrome Given with allopurinol
Azoospermia, Amenorrhea
Nitroosureas
Carmustine IV only (unstable), lipophilic Brain Tumors Renal toxicity
Biotransformed to active
Alkylate/cross-link DNA Multiple myeloma Hematopoetic toxicity
Lomustine alkylating/carbamoylating form
Oral H/NH Lymphomas Pulmonary fibrosis
Semustine
Triazenes
Forms methlycarbonium ions
Melanoma Myelosupression
Dacarbazine P450 activation → MTIC that attack nucleophilic groups IV
Hodgkin's Hepatotoxicity
→ DNA methylaKon
Methylhydrazines
Inhibits MAO (avoid wine Mutagenic/teratognic
Procarbazine Activated by oxidative reactions Cross-link DNA Hodgkin's lymphoma
and cheese) Avoid in pregnancy (D)
Platinum Coordination Complexes
Severe vomiting,
Solid tumors, Ovarian,
Cisplatin Amifostine reduces renal toxicity IV Nephrotoxicity, Tinnitus, Must monitor Mg, Ca, K, PO4
Bladder CA
Bind to & cross-link DNA Intraperitoneal Electrolyte dusturbances
Carboplatin Alternative if pt. can't be hydrated (for Ovarian CA) Myelosuppress only
Oxaliplatin Advanced Colorectal CA
HORMONAL AGENTS
Glucocorticoids
Dexamethasone Immunosuppression
Hydrocortisone Binds to receptors ALL (induction), Lymphomas Hyperglycemia
Steroids
Prednisolone Induce protein synthesis Autoimmune anemias Cataracts, Glaucoma
Prednisone (prodrug) Osteoporosis
Estrogens
Thromboemboli
Ethinylestradiol Block LH secretion (pituitary) ↓ androgen synthesis →
Prostatic CA Gynecomastia
Diethylstilbestrol Replaced by GnRH inhibitors Inhibits prostatic growth
Impotence
Estrogen Inhibitors
Selective Estrogen Receptor Bind to estrogen receptor → Estrogen receptor +ve
Tamoxifen Oral ↑ endometrial cancer Limited to 5 year use due to AE
Modulator (SERM) ↓ estrogen acKon Breast CA
Also inhibit hydrocortisone
Aminogluthemide Metastatic breast CA
(give supplement)
Aromatase Inhibitors
Inhibits aromatase Do not ↑ risk of
Anastrozole
↓ estrone synthesis (from endometrial CA or Non steroidal, reversible
Letrozole Effective postmenopausally (↓ Advanced estrogen receptor
androstenedione) in fat androgenic effects
esrogen from ovaries) +ve Breast CA
Exemestane Hot flashes
Steroidal, irreversible
Formestane Androgenic effects
Progestins
Hydroxyprogesterone Stimulates appetite (good if patient is Breast & endometrial CA
nd
Megestrol wasting) (2 line)
Angrogens
Fluoxymesterone Pallitative effect for Breast
Unknown
Testosterone CA
Androgen Inhibitors
↑ surge of test. & estrogen Impotence, hot flashes,
Leuprolide L: Sustained release SC/IM
Goserelin
GnRH analongs/super agonist → ↑ neg. feedback loop →
G: IM implant
Prostate CA early tumor flare (↑
↓↓ test. & estrogen levels testosterone)
Androgen Receptor Blockers
Androgen receptor antagonist
Competes with hormone for Liver failure Always combine with an
Flutamide Gynecomastia Oral Prostate CA
receptor binding Gynecomastia androgen inhibitor
Will ↑ LH & testosterone
Signal Transduction Inhibitors
Trastuzumab Inhib. HER2/neu (ErbB2) Met. Breast CA CHF, fever, chills
Monoclonal antibody
Cetuximab Colorectal, Head/Neck CA Difficulty breathing
Inhib. EGFR (ErbB1) tyrosine
Gefitinib NSC Lung CA
kinase
Erlotinib
NSC Lung CA
Inhib. both EGFR & HER2 ↑ AST/ALT, bleeding
Lapatinib Pancreas CA
(ErbB1 & B2)
Inhib. BCR-ABL, CML; Idiopathic Generally fewer side effects
Imatinib (Gleevac)
C-KIT, PDGFR hypereosinophilia due to specific targets
Inhib. RAS/MAP
Sorafenib Renal cell CA
(serine/threonine kinase)
Induces growth inhibition & Multiple myeloma
Bortezomib Proteasome inhib.
apoptosis Mantle cell lymphoma
Renal CA
Sunitinib Angiogenesis inhib. Inhib. VEGFR-1&2, PDGFR
GI stromal tumor
MISCELLANEOUS
Breaks down asparagine Deaminates asparagine to Hypersensitivity Normal cells have enough
L-Asparaginase ↓ asparagine in cancer cells (which ammonia + aspartic acid → ↓ IV or IM ALL (+ VX + prednisone) Ammonia toxicity (seizures, asparagine synthetase, and do
have ↓ Asn synthetase) protein synthesis coma) not require an external source
CML, blast crisis AML

Urea analog Inhibits ribonucleotide
Hydroxyurea Melanoma, Ovary CA, Myelosuppression
Effects in S phase reductase → ↓dNTPs Head/neck CA, Sickle cell
Interferon 2α Possible interaction with Hairy cell, Kaposi
Antiviral IM or SC Flu-like
Interferon 2β surface receptors CML (2α), Follicular (2β)
Arrthymia, ↑ QT, faKgue, Teratogenic
Arsenic Trioxide Induce differentiation + apoptosis APML M3 t(15:17)
fluid retention Avoid in pregnancy (D)
Drugs to Decrease Adverse Effects
Rescues bone marrow from
Leucovorin Folinic acid (folate analog) Methotrexate ↑ acKvity of 5-FU
methotrexate
Dexrazoxane ↓ anthracycline cardiotoxciKy Free radical scavenger Anthracycline, Antibiotics
Filgrastim Reverses neutropenia G-CSF (neutrophil growth) Most chemo. drugs
↓ effects of metabolite Ifosfamide &
Mesna ↓ hemorrhagic cysKKs
acroline Cyclophosphamide
Allopurinol Prevents hyperuricosuria/gout Inhibits xanthine oxidase Vinca alkaloids, Busulfan Will accumulate 6-MP
Phosphorylated to active thiol
Amifostine ↓ renal toxicity Scavenge Cisplatin metabolites Cisplatin
metabolite
Drug Combos: Drugs Use
Mechlorethamine, Vincristine Hodgkin’s Lymphoma/

MOPP
(Oncovin), Procarbazine, Prednisone Medulloblastoma
F-CL 5-fluorouracil, Leucovorin Colorectal CA

BEP Bleomycin, Etoposide, Cisplatin Testicular CA
Untreated tumor growth

Low dose/freuquency
treatment (1 log kill)
Higher dose/frequency
therapy (2 log kill)
Intensive adjuvant
chemotherapy
Cell Cycle Specific (CCS) for rapidly growing tumors

Cell Cycle Non-specific (CCNS) for slow growing tumors
Immunopharmacology (Part 1)
Types of Grafts Immunosuppression in organ transplant
Autograft → from self Induction → Before transplant (acute rejection likely from 2-12 weeks)
Syngeneticgraft (isograft) → from idenKcal twin Common Regimen → Cyclosporine + Prednisolone + Azathiaprine (or mAB)
Allograft → from same species Maintenance → Given for long time; may be lifelong; Use lower doses (↓ cost & AE)
Xenograft → from different species Use 1 of above 3 drugs (2 nd Line: Cyclophosphamide, chlorambucil, mycophenolate)
Breakthrough Rejection → High dose steroids , taper off gradually
AE: Risk of viral CMV, fungal/bacterial infections, lymphoma related malignancy
Desensitization – The process of decreasing a patient’s sensitivity to an allergen.

Used when there are no alternative therapies
Inject patient with gradually increasing amounts of allergen
Allergen is given with Insulin, Antibiotics or Aspirin
Keep Type 1 HS drugs on hand for safety
Symptoms: Urticaria, angioedema, rhinoconjunctivitis, bronchial asthma, anaphylactic reaction
-ASA allergy desensitized by gradually ↑oral dose
-Penicillin desensitization performed in hospital, IV or oral
Approach designed to ↓ IgE level by ↑ offending anKgen in SC injecKon over weeks/months.
Exact mechanism unknown
Immediate allergy (Type 1 HS)

Antibody mediated (Type 2) HS
Epinephrine (α1 acKvaKon → vasoconstricKon
Steroid + stop offending drug + transfusion
→ ↓ laryngeal edema)
(Drug mediated, e.g. hemolytic anemia by methyldopa)
β-Agonists (β2 acKvaKon → bronchodilaKon)
Exchange transfusion (Erythroblastosis fetalis)
Corticosteroids
Antibiotic + Aspirin (Rheumatic fever)
H1-R Antagonists
Immune complex (Type 3) HS Cell Mediated/Delayed (Type 4) HS

Complexes activate C' and attract PMNs → release lysosomal enzymes Sensitized T cells exposed to Ag → release lymphokines →
Serum sickness : ICs deposited in membranes → tissue damage macrophage activation
Arthus reaction : Intradermal injection of antigen → Ab complexes in skin Contact dermatitis, PPD testing, transplant rejections (GVHD), Stevens-
(lesions = induration, edema, hemorrhage and rarely necrosis) Johnson syndrome
Drug MOA Indications Adverse Effects Pharmacokinetics
T Cell Inhibitors (Antibiotics)
Renal Toxicity Topical & Systemic
Bind Cyclophilin → ↓ rejecKon in allograZs
HTN Combo with: steroids,
Inhibits calcineurin Gum hyperplasia, hirsutism, cytotoxic agents,
Psoriasis
Cyclosporine (cytoplasmic phosphatase) → Convulsions, Hyperglycemia, mycophenolate (replaces
Atopic dermatitis
(peptide) ↓ acKvaKon of T-cell Hyperkalemia, Peripheral AZA)
Keratoconjunctivitis sicca
Transcription factor → neuropathy, Nephro-/hepato-
Rheumatoid arthritis
↓ IL-2/3 & IFNγ toxicity, Choleithiasis, Opportunistic P450 inhibitor will ↑ plasma
Ulcerative Colitis
infections cyclosporine
Tacrolimus Does not bind cyclophillin No hirsutism or gum hyperplasia
(Macrolide) Inhibits calcineurin with Tacrolimus
Hyperlipidemia
Sirolumus Binds FKBP12 → binds mTOR
Kidney transplant Leukopenia
(Rapamycin) → ↓T-cell response to IL-2
Thrombocytopenia
1. Prednisolone (Glucocorticoids)
2. Azathioprine, Methotrexate, Sirolimus (Cytotoxics)
3. Cyclosporine, Tacrolimus (Antibiotics)
4. Muromonab (antibody)
Cytotoxic Drugs (Inhibit Proliferation/Differentiation of B/T cells)

Prodrug → Organ Transplant Nausea, rash, GI mucositis Combo with other
6-mercaptopurine (purine ALL, AML BM suppression → ↑ infecKons immunosuppressents for
Azathiorpine antimetabolite) → RA, IBD (CD/UC), MS, ↑ risk: NH lymphoma, skin organ transplant
↓ purine synthhesis, Autoimmune hepatitis, squamous cell, heptobilliary, & ↓ dose with allopurinol
↓ DNA/RNA synthesis Restrictive lung disease mesenchymal tumors Teratogen
Folic acid analog Myelosuppression, GI,

RA, psoriasis, CA of breast,
Methotrexate Hemmorhagic enteritis, Neurotoxic,
Inhibits DHFR lung, ovary, bladder, neck
Hepatotoxic
Prodrug → mycophenolic acid

Mycophenolate
inhibits IMP DH → Organ transplant
mofetil
↓ purine synthesis (alt. to cyclosporine)
(DMARD)
→ ↓ lymphocyte proliferaKon
Cyclophophamide
Chlorambucil
Glucocorticoids
Inhibit MHC expression → ↓
Prednisone IL-1, 2, 6 → Th cells not
activated
Drug MOA Indications Adverse Effects Pharmacokinetics
Polyclonal Antibodies
Ab targeting human IgG Rh(-) mother delivering Rh(+) baby
RhO(D)
against red cell Rho(D) antigen; Within 72 hours of delivery
Immunoglobulin Prevent hemolytic disease of newborn in next pregnancy (also
Inhibits Rh-Ab formation
used post miscarriage)
Antithymocite globulin
Monoclonal Antibodies
Infliximab RA & Crohn's Expensive Humanized Ab
Targets TNFα
Etanercept RA Chimeric (TNF-α-R + IgG)
Prevents coagulation in
Abciximab Targets GPIIb/IIIa on platelets
coronary angiography
Targets phosphoprotein CD20
Rituximab NH Lymphoma
on B cells
Daclizumab Targets IL-2-R on actived Acute rejection of kidney
Basiliximab T- cells (CD25) transplant
Palivizumab Targets RSV protein RSV infections in kids
Recombinant Cytokines
↑ lymphocyte differenKaKon Renal cell CA
IL-2 (Aldesleukin)
& NKs Metastatic Melanoma
Chemo induced
IL-11 Improves platelet function
thrombocytopenia
BM recovery from chemo
Filgrastim (G-CSF) ↑ granulocyte prolif/diff
induced neutropenia
Sargramostim (GM- ↑ granulocytes & BM recovery after transplant
CSF) macrophages & AML chemo
Anemia of chronic renal
Erythropoietin ↑ RBC producKon dysfunction, chemo, or
radiation
JAK/STAT pathway responds to Melanome, Leukemia, Combine with chemo +

IFN-α
cytokines of prolif/diff Kaposis, HBV, HCV radiation
IFN-β Anti-inflammatory ↑ BBB Integrity in MS

Macrophage activating factor
IFN-γ Chronic Granulomatosis
→ (+) TNF
Immune Response Modifiers

May ↓TNFα
ENL (Erythema nodosum
Anti-angiogenic
leprosum) (with Dapsone) Teratogen: Short limbs, "seal-like"
Thalidomide Anxiolytic Banned, but still used
Multiple myeloma appearance
Adjucant analgesic
↓ wasKng in cancer pts
Antipyretic
Superficial bladder CA,

intersitital cystitis, painful
BCG vaccine Intravesical instillation (injected into
↑ TNFα → Kills T-cells bladder syndrome Contraindicated: SCID
(for tuberculosis) bladder)
Maybe Type 1 DM
Activates immune cells via Toll- Actinic keratosis

Imiquimod Like Receptor 7 → secrete Superficial basal cell CA
IFN-α, IL-6, TNF-α External genital warts
Drug Development – Part 1
Drug Discovery – ID/screening of compounds for potentially active therapeutic agents
Hit – a compound that passes a discovery 'screen'
Lead – leading candidate for a successful new drug
Drug Discovery – Two basic strategies are used to identify ‘hits’

1. Compound-Centered Drug Design = compound identified + biological profile is explored
Natural compounds
Adv:
Likely biological activity
Easier to isolate than synthesize de novo
Can fine tune natural product
Disadv: Can be difficult/expensive to isolate + modify
May be difficult to predict assay for testing
Synthetic Compounds
Chosen from library of compounds based on structure
Analogues of Natural Ligands
Choose a natural ligand as starting point for development.
A 'skeleton' on which chemical modifications are made
2. Target-Centered Drug Design = likely drug target is identified first, used to search for hits
Adv:
Target associated with disease – hit has high likelihood of useful pharmacological activity
Easier to devise assays for testing
Structure-Based Drug design = Candidate discovered using target's 3D structure

Combinatorial Chemistry = Uses few precursor molecules to make many compounds
High-Throughput Screening = Rapid screening of many molecules
Uses target-based assay + robotic automation
Shotgun approach = High-throughput screening + Combinational chemistry
Drug Screening
- Biologic assays (molecular, cellular, organ system, whole animal levels)
- Define activity + selectivity + pharmacologic profile + toxic effects
- Select Lead
Lead Optimization
Refine 'lead' for physical, chemical, biological & pharmacological properties
Select single molecule to enter clinical testing
Phases of Drug Development

Discovery Chemistry (chemical properties)
Discovery Biology (receptors, biological assays)
Absorption, Distribution, Metabolism + Excretion (ADME)
Toxicology
Development Chemistry
Formulation
Preclinical Safety and Toxicity Testing
No-effect dose = Maximum dose at which specified toxic effect is not seen
Minimum Lethal Dose = Smallest dose that kills any experimental animal
LD50 = Dose that kills ~ 50% of animals
Acute toxicity – two species + two routes

Subacute/subchronic – 3 doses, 2 species, 2wks-3mos
Chronic - Rodent + nonrodent for > 6 months.
Effect on reproduction – 2 species (rodent + rabbit)
Carcinogenic potential – 2 years, 2 species
Mutagenic potential – Test genetic stability + mutations in bacteria or mammalian cells in culture
Investigative toxicology – Sequence + mechanism of toxic actions
Investigational New Drug Application (IND) – seeking approval to initiate clinical trial in US
Number of Subjects Length of Phase Purpose

Phase I 20-100 Several months Mainly safety
Phase II Up to several hundred Up to 2 years Effectiveness + short-term safety
Several hundred - Several
Phase III 1-4 yeats Safety, dosage, effectiveness
thousand
Subject + Observer Bias

Blind studies – Investigators or subjects do not know who receives which treatment
Double-blind Studies – Identity of intervention is unknown to both subject + investigator
Crossover design – each group is given test drug alternately with placebo
Subject Randomization – co-morbidities, histories, etc. do not affect trial
Prephase I Studies
Conducted under 'exploratory IND'
Very limited clinical investigations
Low doses + short duration
Facilitates efficient drug development
Phase I Studies
20-100 healthy normal subjects
Establish safety, toxicity, kinetics, major AE
May be non-blinded
Biomarkers of desired pharmacologic effect provide data on drug
Must yield maintenance dose + frequency for phases 2 & 3
Phase II Studies
Up to several hundred subjects with medical condition of interest
Get preliminary efficacy data
Monitor safety – less common adverse effects
Evaluate dose-response + dosing regimens
Single-/double-blind studies
Phase III Studies
'End of Phase II' Meeting – Establish safety
Hundreds to thousands of patients, multiple sites
Randomized, controlled, double-blind trials
In settings similar to those of drug's ultimate use
Specific (1°) endpoints: survival, improvement in function

Surrogate (2°) endpoints: markers for decreased disease (e.g. BP, lipid profile, enzyme activity)
New Drug Application (NDA) – required before market approval can be given
Requires full reports of all preclinical and clinical data
Phase IV Studies
Begins after market approval, no fixed duration
Continued under actual conditions of use
Observing rare/chronic dosing AE
Orphan Drugs = drugs for rare diseases, affects <200,000 people

Low priority due to low money-making possibility
Orphan drug act of 1983 – gov’t gives incentives
Fast-Track Status – ~½ review time

For drugs that may fulfill an unmet medical need for serious disease
Approval may be granted upon surrogate endpoints
Phase IV trials may be required
Can be withdrawn easily
Off-label Use
Use of approved drug for any purpose, or in any manner, other than what is described in the labeling
Black Box Warning

Studies indicate that the drug carries a significant risk of serious or life-threatening adverse effects
Schedule Reason Restriction

Has no accepted medical use in US All non-research use illegal under
1
Lack of accepted safety under medical supervision federal law
Abuse may lead to severe psychological or physical
2 No telephone prescriptions, no refills
dependence
Abuse may lead to moderate/low physical dependence Prescription must be rewritten after 6
3
or high psychological dependence months or 5 refills
Rewritten after 6 months or 5 refills

4 Abuse → limited physical/psychological dependence
(less penalties for illegal possession)
As any other nonopioid prescription

Abuse → limited physical/psychological dependence
5 (OTC) drug; Given without prescription
relative to drugs in schedule 4
unless state regulations apply
Hypothalamus/Pituitary Hormones - Part 1
Drug Description MOA Indications Pharmacokinetics Adverse Effects Notes
GH Analog
Growth failure (short child, >2.5 Children: hypothyroidism,
Recombinant GH Activate JAK/STAT →
Somatropin SD below average) intracranial HTN, scoliosis,
(original sequence) ↑ IGF-1 →
otitis media, pancreatitis, CYP450 inducer
↑ bone growth/density, SC, 3-7/week
GH deficiency (pituitary/ diabetic syndrome (chronic)
↑ muscle mass, ↑ GFR, Peak levels in 2-4 hrs
hypothalamic damage) Adults: peripheral edema, Contraindicated with
adipocyte differentiation, Persists for ~36 hrs
GH analog myalgias, & arthralgia in known malignancy
Somatrem anti-insulin actions,
(altered sequence) Wasting in HIV+ patients hands/wrists, proliferative
↑ immune system funcCon
Short bowel syndrome retinopathy (rare)
GHRH Analog
Less expensive, but
↑ GH from pituitary GH deficiency if Anterior pituitary Well tolerated
Sermorelin GHRH analog less effective than
(Gs → cAMP) can make GH (↓ GHRH) Same as GH analog
GH analog
IGF-1 Analog
Growth failure due to IGF-1 Hypoglycemia
Recombinant IGF-1 &
Mecasermin deficiency (GH receptor mutation SC, 2/day Intracranial HTN
IGF-Binding-Protein-3
or GH-R antibodies) ↑ liver enzymes
GH Receptor Antagonist
Causes incomplete
dimerization of GH-Rs, JAK
Pegvisomant Acromegaly, Giantism
cannot bind
↓ GH signaling
SOMATOSTATIN Analog
Acromegaly, Giantism t1/2 ≈ 80 mins (30x GI upset
45x more potent ↓ in
Octreotide (Small) hormone-secreting Biliary sludge + Gallstones
GH than somatostatin) Large ademomas
↓ release of GH, insulin, adenoma Sinus bradycardia + conduction
somatostatin; SC (every 8 hrs) require surgery or
clucagon, gastrin Control bleeding from disturbances
2x greater ↓ in radiation
esophageal varices Vit B12 deficiency (long term),
Octreotide acetate insulin Once/4 weeks
Lozalize neuroendocrine tumor Injection site pain
GONADOTROPIN (FSH, LH, hCG) Analog
Menotropins (hMG -
Ovarian hyperstimulation
human menopausal Purified FSH and LH
SC or IM, daily syndrome (enlargement,
gonadotropins)
Activate Gs → t1/2 = 10-40 hrs ascites, hypovolemia, Expensive and
Follitropin α + β Recombinant rFSH
↑ spermatogenesis and Infertility hemoperitoneum, complicated esp. for
Urofollitropin Purified uFSH
ovulation thromoembolism) women
hCG Purified from urine IM
Multiple Pregnancies
Choriogonadotropin α Recombinant rhCG SC Gynecomastia
Hypothalamus/Pituitary Hormones - Part 2
GnRH Analog
Headache, nausea, flushing,
Pulsatile: Male infertility
light-headedness;
Acetate salt of IV or SC More potent,
Gonadorelin Pulsatile → ↑ LH/FSH SC injection site swelling;
synthetic GnRH Sustained: Suppression of t1/2 = 4 mins longer lasting
Hypersensitivity; Pituitary
LH/FSH: than GnRH
Sustained → ↓ LH/FSH apoplexy + blindness
Endometriosis, Fibroids (L,G,N)
D-amino acid at (First 7 days, agonist "flare" Menopausal symptoms,
Ovarian hyperstimulation, central Contraindicated in
Goserelin (G) position 6 and response; later inhibitory SC, IM, SC implant diminished libido, pain, vaginal
early puberty (L,N) pregnancy & breast
Leuprolide (L) ethylamide (for Gly) action) Nasal spray (Naf) dryness,
Prostate CA (L,G) feeding
Nafarelin (N) at position 10 (except t1/2 ≈ 3 hrs Breast atrophy, ovarian cysts,
Adv. Breast/ovarian CA
Naf) Osteoporosis
GnRH Antagonist
Cetrorelix Competitive GnRH Ovarian hyperstimulation
↓ LH/FSH producCon SC Well tolerated
Ganirelix antagonists (↓ LH surge)
DOPAMINE Agonist
Prolactinoma Nausea (B > C), orthostatic
Bromocriptine Hyperprolactin infertility t1/2 ≈ 7 hrs hypotension, fatigue Oral (all other
High dose: cold-induced digital hormones are
Cabergoline Inhibit prolactin Acromegaly (alone, or with t1/2 ≈ 65 hrs vasospasm parenteral)
octreotide or surgery) Chronic: pulmonary fibrosis
ACTH Analog
-Diagnostic tool for 1o vs. 2o Limited use due to less

Cosyntropin MC2-R (Gs) → ↑ cAMP →
ACTH analog adrenal insufficiency (Addison) predictability and convenience
(Corticotropin) ↑ adrenal cortex secreCons
-Infantile spasm (West synd) than cortisol
OXYTOCIN Agonist
Gq → ↑ PG + LT release → Excess stimulation (fetal Contraindications:
↑ frequency/force of IV (labor) distress, uterine rupture) Fetal distress,
Induce/augment labor
Oxytocin uterine contractions; IM (bleeding) ADH actions (at high dose) Prematurity,
Postpartum bleeding
With high doses: Sustained t1/2 = 5 mins Hypotension (give as slow, Cephalopelvic
contraction dilute IV) disproportion
OXYTOCIN Antagonist
Atosiban Oxytocin antag. Prolong intrauterine life Not available in US
ADH Agonist
V1 = vasopressor Esophageal variceal + colonic Headache, nausea, abdominal
Vasopressin (ADH) V1 & V2 activity IV, IM, t1/2 = 15 mins
V2 = antidiuretic diverticular bleeding cramp, allergy
V2R in renal tubule cells → Central diabetes insipidus IV, SC, nasal, oral, OD = H20 retention, HTN, Antidiuretic-to-
Desmopressin Mostly V2 activity
↑ water reabsorpCon Hemophilia A, vWF disease t1/2 = 1.5-2.5 hrs hyponatremia, seizure pressor: 4000x
VASOPRESSIN Antagonist
Conivaptan High affinity Blocks V1 & V2 Hyponatremia (SIADH)
Hypothalamic-Pituitary Endocrine System
Growth hormone receptor

Mediates effects via surface receptors that activate JAK/STAT cascade
JAK2 Janus kinase 2
IRS-1 Insulin receptor substrate-1
PI3K Phosphatidyl inositol-3 kinase
STAT Signal transducer and activator of transcription
MAPK Mitogen-activated protein kinase
SHC Src homology containing
Thyroid Hormones
Thyroxine T4 Hypothyroidism Always use T4 before
Arrhythmias, thyrotoxicosis
Triiodothyronine T3 (more potent) Myxedema coma adding T3
Block iodination & coupling DOC Hyperthyroidism Rash, arthralgia, vasculitis,

Methimazole Oral, 1/day agranulocytosis,
(peroxidase) Agranulocytosis
Thioamides hepatotoxicity, lupus
(Goitrogens) Above (but more severe)
Above + blocks peripheral DOC for thyroid storm and in Takes 2-3 weeks for
Propylthiouracil (PTU) Oral, 3/day Hypoprothombinemia
T4 → T3 (5'-deiodinase) pregnancy full effect
(Bleeding)
Chronic iodide intoxication,

High doses block iodination, anaphylactoid (angioedema, Only lasts 10-14 days
Iodine Reversible, transient, Used to ↓ size & vascularity of Used with PTU & β-
coupling reactions, & larynx/eyelid swelling), Brassy (Wolff-Chaikoff
Iodide salts (KI) paradoxical effect thyroid gland before excision blockers in thyrotoxicosis
secretion taste, teeth burning, enlarged effect)
parotid gland
Radioactive iodine Emission of beta-particle → Hypothyroidism
131 Refractory hyperthyroidism, Only permanent
I Sequestered in Permanent tissue Do not use in pregnancy or
Graves' disesase treatment
thyroid destruction nursing mother
Diatrizoate Block T4 → T3 Oral
Iodinated
Iohexol Thyroid storm Rapid onset
radiocontrast media (5'-deiodinase) Oral, IV
Ipodate
Perchloarate Block iodine trapping by
Thiocyanate Hyperthryoidism Aplastic anemia
blocking NIS transporter
Pertechnetate
Propranolol Decrease sympathetic
β-blocker Hypeythyroid tachycardia Esmolol has short t1/2
Esmolol symptoms
Glucocorticoids Block T4 → T3 Thyroid strom
Amiodarone Goitrogens:
May provoke autoimmune or inflammatory
Interferon α, IL-2 Cabbage, cassava (contain thiocyanate)
thyroiditis, inducing hypothyroidism
Lithium Sulfodimethoxine
In pregnancy, surgical treatment is preferred (minimal risk to fetus). PTU is preferred drug, if needed.
Step Steps in synthesis Mechanism of action of anti-thyroid drugs
Iodine trapping in follicular cells of thyroid A process of selective cell destruction by 131I, Perchlorate,
1
(Na+/I–symporter; NIS) thiocyanate
2 Iodination of tyrosine residue on thyroglobulin Inhibited by PTU & Methimazole (Thioamides)
Inhibited by ↑levels of Iodide salts; Iodine (paradoxical
3 Coupling reactions to form DIT, T3 & T4
effect) & Thioamides
4 Proteolytic release of T4 & T3 from thyroglobulin Inhibited by Ipodate and iodide
Conversion of T4 to T3 through 5’-deiodinase in Inhibited by diatrizoate, iohexoland Ipodate, ↑↑ PTU,

6
peripheral tissues Propranolol, & glucocorticosteroid
Corticoid Hormones
Corticosteroid Agonists Glucocorticoid:Mineralcorticoid activity ratio
Inhaled, for nasal Short acting
Beclomethasone Penetrates airway Binds cytosolic receptors,
Adrenal insufficiency (Acute, mucosa, sinuses, Minimal systemic
Budesonide mucosa complex binds GREs Diabetes, muscle wasting,
Addison's disease) bronchi, lungs toxicity
Short acting (glucocort. response osteoporosis, peptic ulcer,
Hydrocortisone Congential adrenal hyperplasia 1:1
glucocorticoids elements) in nucleus necrosis of femoral head,
(suppress ACTH)
Cortisone (8-12 hrs) Anti-inflammatory: ↓ PLA2 Topical for eye, skin, cataracts, Cushing's syndrome 0.8 : 0.8
Inflammatory/autoimmune
→ ↓ PG & LT synthesis; mucous membranes Growth retardation
Prednisone conditions 4 : 0.3
Immunosupp: ↓ IL-2, IL-3, Anti-emetic (chemotherapy)
Prednisolone Intermediate-acting PAF, ↓ WBCs, ↑ PMN, Oral (prednis(ol)one) Avoid chronic use, taper off to 5 : 0.8
Hematological cancer
glucocorticoids (Lymphotoxic); prevent adrenal failure
Methylprednisolone (18-36 hrs) Parenteral (IV, IM) 5 : 0.5
Metabolic effects: ↑ Ashma (Beclo)
Triamcinolone lipolysis, gluconeogenesis & Give “stress dose” to patient 5:0
Fetal lung maturation (Betam)
protein catabolism, ↓ Intralesional/ with adrenal insufficiency in
Betamethasone Long-acting Hodgkin’s (Predni) 35 : 0
glucose use (anti-insulin); intraarticular serious illness or pre-surgery
glucocorticoids Cerebral edema (Dexa)
Dexamethasone Salt-retaining effects: 30 : 0
(1-2 days)
Reabsorb Na+, HCO3-, & H20
Aldosterone in exchange for K+ in renal HTN, Hypokalemia, & CHF 3 : 3000
Mineralocorticoids Adrenal insufficiency
tubules (due to fluid retention)
Fludrocortisone 10 : 125
Corticosteroid Antagonists
RECEPTOR ANTAGONISTS
Spironolactone Steroid derivatives Block intracellular receptors Hyperaldosteronism in CHF &
Antiandrogenic
Eplerenone K+ sparing diuretic in collecting tubules cirrhosis
Cushing’s syndrome
Mifepristone Competitive Block glucocorticoid & Not abortifacient in
Post-coital contraception (<49
(RU-486) antagonist progesterone receptors USA
days, used in small doses)
SYNTHESIS INHIBITORS
Breast, prostate, adrenal CA, Antifungal (↓
Ketoconazole ↓ steroid synthesis Inhibits P450 enzymes
Hirsutism ergosterol)
Blocks cholesterol → Inhibits side chain cleavage
Aminoglutethimide Adrenal CA
pregnenolone enzyme
↓ 11-deoxycort. →
Metyrapone Inhibits 11β-hydroxylation Cushing’s syndrome
corticosterone
Gonadal Hormones & Inhibitors - Part 1
Drug Description MOA Indications Physiologic Effects Adverse Effects Notes
Estrogens
1° hormone from
Estradiol (Estrace) Development of female
ovary Absolute
Female hypogonadism sex organs & 2° sex
Conjugated estrogen contraindications:
characteristics CV disease (stroke, CHD)
(Premarin) History of
Oral contraceptive ↑ risk of endometrial & breast
Ethinyl estradiol Bind cytosolic receptors; thromboembolism
Regulate menstrual cycle CA
(Estinyl) complex travel to nucleus to Pregnancy
Postmenopausal hormome
Quinestrol (Estrovis) modulate gene expression Liver disease
replacement therapy Epiphyseal closure, Migraines, gall stones,
Other natural Breast CA
Estrone prevent bone loss cholestasis, depression
estrogens made by 15+ cigarettes & 35+
Estriol Prostate CA, acne, dysmenorrhea Increase coagulation
females years old
(More below)
Mestranol
Progestins
Progesterone Stimulate endometrial
Norgestrel Endometriosis secretory changes
Norgestimate Dysmenorrhea Maintains pregnancy
Weight gain, edema,
Medroxyprogesterone Contraception ↓ uterine contracClity
High dose: suppress LH/FSH depression, acne, HTN, ↓ HDL,
acetate (Provera) Progestins Hormone replacement therapy ↓ gall bladder
secretion thrombophlebitis, cholestatic
Norethindrone (HRT) contraction
jaundice Synthetic
(Norlutin) High doses suppress
Norethindrone acetate Promote/maintain pregnancy gonadotropins, cause
(Agestin) anovulation
Androgens/Anabolic Steroids
Testosterone Anabolic: ↑ muscle mass Over-masculinization 19 carbon steroid
& RBC Hirsutism, acne, BPH,
Androgenic: Develop amenorrhea, clitoral
Methyltestosterone
male sex organs & 2° sex enlargement
Oxandrolone Bind cytosolic receptors; Hypogonadism
characteristics Feminization
Stanozolol Androgens complex travel to nucleus to Osteoporosis
Growth of skeleton & Hepatic adenoma
Fluoxymesterone modulate gene expression Increase muscle mass & RBCs Synthetic
larynx, darkens skin Cholestatic jaundice
Oxymetholone
Feminization (↑ feed- Closure of epiphysis
Nandrolone
back inhibition & Drug dependence
Phenpropionate
conversion to estrogen) Contraind: pregnancy
More effects of estrogens:

Maintain normal skin and blood vessels (inhibits proliferation of vascular smooth muscle cells)
Coagulation: ↑ F2, 7, 9, 10, 12 ↑ HDL and TAG; ↓ LDL (but no protecCon from CVD)
↓ anCthrombin 3, protein C & S. ↑ cholesterol in bile (gall stones)
↑ NO, PGI (vasodilaCon) ↑ corCsol binding, SHBG (sex-hormone), & TBG (thyroid binding)
Gonadal Hormones & Inhibitors - Part 2
GnRH ANALOGS
Drug Description MOA Indications Adverse Effects Notes
Leuprolide Pulsatile → ↑ LH/FSH Combo with
Pulse: Male infertility Menopausal sympt.
Gonadorelin GnRH analogs Sustained → ↓ LH/FSH androgen receptor
Sust: Endometriosis, Fibroids, Diminished libido
Nafarelin (more potent) (reversible medical inhibitor to ↓ iniCal
Prostate CA Osteoporosis
Goserelin castration) increase in LH/FSH
Antiestrogens & Antiprogestins
Antagonist on breast N/V, hot flushes,
Tamoxifen Agonist on bone DoC ER+ve Breast CA Thrombosis
Selective estrogen
Agonist on endometrium Risk of endometrial CA
receptor modulators
Toremifene
(SERMs)
Antagonist on breast AND Breast CA prophylaxis Thromboembolisms
Raloxifene
endometrium & osteoporosis No risk of endometrial CA
Pure estrogen Tamoxifen resistant breast
Fulvestrant
receptor antagonist cancer
Letrozole
Anastrozole
Aromatase Selectively block estrogen ER+ Breast CA
inhibitor synthesis (2nd line)
Exemestane
Estrogen antag. in ↓feedback inhibition → ↑ Multiple births, ovary
Clomiphene CNS (hypothalamus & GnRH, LH/FSH → sCmulates Infertility enlargement, visual
pituitary) ovulation disturbances
Competitive Also inhibits
Abortion with PG-E/F Excessive bleeding, GI (N/V,
Mifepristone (RU-486) progestin receptor glucocorticoid
("Morning after" pill) vomiting, anorexia, abd. pain)
antagonist receptors
Steroid synthesis
Danazole Endometriosis
inhibitor
Antiandrogens
Flutamide Blocks effects of Use with GnRH super-
Prostate CA w/ GnRH analogs,
Bicalutamide Androgen receptor testosterone, but will ↑ LH analog to inhibit
Hirsutism
Nilutamide antagonist & testosterone synthesis synthesis
Cyproterone Hirsutism
Hirsutism, fluid retention, HTN,
Spironolactone Diuretic Blocks DHT binding
CHF
Finasteride (Propecia) 5α-reductase
Blocks conversion to ↓ DHT BPH, Male baldness
Dutasteride inhibitor
Steroid synthesis Adrenal CA, Cushing's disease,
Ketoconazole Inhibits P450 enzymes
inhibitor Prostate CA
Anti-Diabetic (Part 1)
Diabetes = ↑ fasting blood glucose due to relative or absolute insulin deficiency Insulin secretion stimulated by:
-Glucose (most important stimulus)
Type 1 Diabetes = Absolute deficiency of insulin (autoimmune attack on β cells) -Amino Acids
-Hallmarks: ↑ blood glucose & ketone bodies -GI hormones (Incretins) →
-Must rely on exogenous insulin injected SC to control hyerglycemia & avoid ketoacidosis released after ingestion of food
Incretins = Glucagon-like peptide-1
Type 2 Diabetes = insulin resistance + dysfunctional β cells (GLP-1) & gastric inhibitory peptide (GIP)
-Insulin levels may be HIGH, esp. early on in the dx
-Hallmark: peripheral insulin resistance & ↑ liver glucose producCon make insulin levels Mechanism of Insulin secretion:
inadequate to normalize plasma glucose → β cells stress/injury → ↓ insulin producCon --> Hyperglycemia →
hyperglycemia; insulin levels suppress lipolysis and ketogenesis ↑ ATP levels in β-cells
close ATP-dependent K+ channels →
Maturity-onset diabetes of the young (MODY) = heterogenous group of disorders marked by membrane depolarization →
impaired insulin secretion with minimal or no defects in insulin action opening of voltage-gated Ca2+ channels →
Autosomal Dominant inheritance, 6 genetic loci, occurs before age 25. Ca2+ influx → PulsaCle insulin exocytosis
Physiologic Effects
Insulin Regimens:
-Inhibiys gluconeogenesis & glycogenolysis, increased glycolysis & glycogen synthesis
Basal-bolus Insulin Regimens
-Increases GLUT4 transporters in muscle and adipose
-One daily shot of glargine or detemir to provide basal coverage
-Inhibits Hormone Sensitive Lipase, increases Lipoprotein Lipase levels
-Doses of regular, lispro, or aspart to provide coverage for each meal
-Increases fatty acid/TAG synthesis & storage
-ADMIN at BEDTIME or in MORNING
-Stimulates (branched) amino acid uptake (Val, Leu, Ile) & protein synthesis
-If patient skips a meal, omit premeal bolus; if eats larger meal, ↑
premeal bolus; adjust doses to accomodate snacks, exercise patterns, &
Sources
acute illnesses
Human insulin made from recombinant DNA in E. Coli
Modified sequences produce insulin with different pharmacokinetic properties
Insulin Pump Therapy
-Optimal way to mimic normal insulin secretion by pancreas
Insulin Administration:
-Battery-operated pump & computer programs pump to deliver
-Insulin is a polypeptide → degraded in GI tract if taken orally
predeterminied amounts of insulin 0-15 mins before eating
Thus usually admin sub-cutaneously
-Rapid-acting insulin analogs are preferred for use in pump
-In hyerglycemic emergency, regular insulin is admin IV
Adverse Effects of Insulin:

-Hypoglycemia (most common); Management: Drug Interactions worsening Drug Interactions:
→ MILD = orange juice, glucose, or any sugar-containing beverage or food hypoglycemia: Drugs can cause hypo-/hyperglycemia or may alter the response of
→ SEVERE with unconsciousness/stupor = 20-50 mL of 50% IV glucose -Ethanol (inhibits diabetic patients to their therapeutic regimens
(if unavailable, 1mg glucagon SC or IM) gluconeogenesis)
-β-blockers (block Three most commonly cause hypoglycemia via:
-Allergic Reactions gluconeogenesis and -EtOH inhibits gluconeogenesis
→ Immediate type (1) hypersensiCvity glycogenolysis activation; mask -β-blockers block stimulatory effects of catecholamines on
→ Rare; oZen due to non-insulin protein contaminants sympathetic warning signs) gluconeogenesis & glycogenolysis; also mask sympathetic-mediated
→ Human/analog insulins → ↓ incidence of insulin allergy -Salicylates (enhance panceatic β- symptoms of hypoglycemia (e.g., tremor & palpitations)
cell sensitivity to glucose, -Salicylates enhance β-cell sensitivity to glucose & potentiate insulin
-Lipodystrophy at Injection Site potentiate insulin secretion) secretion; also have weak insulin-like activity in the periphery
→ Atrophy of SC fa[y Cssue; Rare since intro of neutral pH human/analog insulin
Anti-Diabetic (Part 2): Insulin Agents
Drug Drug class Description Onset/Peak/Duration (hours) Pharmacokinetics Notes
Endogenous insulin is metabolized by
Soluble crystalline insulin hexamer
Usually SC insulinase, 60% in the liver, 30-40% by
Regular Insulin
Short-Acting around central zinc
Admin IV in emergencies
0.5-0.7 / 1.5-4 / 5-8 the kidneys
Insulin Safe in pregnancy
t1/2 in serum is 3-5 mins Parenteral insulin is reversed (60% by
kidneys)
Phosphate buffer
Lispro Lysine/proline at pos B28/29 reversed 0.25 / 0.5-1.5 / 2-5 SC or IV
Used in insulin pumps
Aspart Rapid-Acting Proline (B28) replaced by Aspartate 0.25 / 0.6-0.8 / 3-5 SC Phosphate buffer
Insulin Asparagine (B3) replaced by lysine SC
Glulisine 0.25 / 0.5-1.5 / 1-2.5 No Zinc
Lysine (B29) replaced by glutamate Shortest duration of action
Amorphous precipitate of insulin with
Semilente Suspension
zinc ion in acetate buffer
Isophane Suspension Intermediate- Suspension of crystalline zinc insulin at SC only Protamine decreases solubility, delays
(neutral protamine neutral pH with a positive polypeptide - 1-2 / 6-12 / 18-24 (can clog veins) absorption, and increases duration of
Hagedorn - NPH)
Acting Insulin Protamine Cloudy appearance action
(Cloudy Appearance)
Mixture of 30% semilente + 70%
Lente 1-2 / 6-12 / 18-24 Poorly soluble crystal of zinc
ultralente
Very slow onset & prolonged action

Ultralente 4-6 / 16-18 / 20-36
Cloudy appearance
Provide low basal concentration of
insulin throughout the day
Protamine zinc insulin Very unpredictable action
suspension Long-acting Insulin 4-6 / 14-20 / 24-36
Protamine bound
SC → Crystalline depot Soluble in acidic solution, precipitate at
+2 Arginine at C' end of B chain
Insulin Glargine 2-5 / No peak / 18-24 Cannot be mixed due to acidic neutral pH of SC tissue
Asparagine (A21) replaced by Gly
pH Less hypoglycemia
Modifications increase self-aggregation;
Terminal Threonine (B30) removed
Insulin Detemir 1-2 / No peak / > 24 Binds albumin
Myristate attached to B29 Lysine
Phosphate buffer
Receptors in liver, GS activation → ↑
Indications:
cAMP → glycogen metabolism, Transient nausea, vomiting (mild)
Severe hypoglycemia
gluconeogenesis
-Emerg. treatment for T1DM
→ ↑ blood glucose
Endocrine Diagnosis
-Test β-cell reserve in T1DM
No effect on
β-Blocker poisoning skeletal muscle
Glucagon
-1st line antidote (β-adr
effects, ↑ cAMP in heart) Causes release of:
Radiology of the Bowel -insulin from β-cells
-Large doses relaxe smooth -catecholamines from
muscles of the intestine → pheochromocytoma
better images of the bowel -calcitonin from
medullary carcinoma
Anti-Diabetic (Part 3): Non-Insulin Oral Antidiabetic Agents
Drug Drug class Description MOA Pharmacokinetics Adverse Effects
Short duration of action
Tolbutamide Prolonged hypoglycemia, rarely
t1/2 = 4-5 hrs
Bind SUR1 subunit & block the Hypoglycemia (especially in elderly)
ATP-sensitive K+ channel in Contraindicated in elderly or hepatic or
1st generation the β cell membrane → renal failure
Treat T2DM
Sulfonylureas Effective at reducing FPG & HBA1C less K+ leaves cell → Jaundice at doses >500 mg/day
cell depolarizes → Long t1/2 = 32hrs Hyperemic flush (when EtOH is ingested);
Chlorpropamide
Insulin Secretagogues Tachyphylaxis - 5-10% per year Ca2+ channels open → Slow liver metabolism due to inhibition of (or low) aldehyde
become secondary failures Ca2+ entry triggers exocytosis → dehydrogenase
(sulfonylureas lose efficacy, insulin Stimulates Insulin release from Apparent SIADH (common), by
therapy required) β cells potentiating vasopressin
Transient hematologic toxicity (rare)
Glyburide 2nd generation Decreases serum glucagon
Hypoglycemia (20-30%)
(Glibenclamide) Mechanism unclear, may be due
Sulfonylureas
Glipizide to Somatostatin release, inhibiting Shortest t1/2 (= 2-4 hrs) Less likely to cause hypoglycemia
Up to 100x potency α-cells
Glimepiride Insulin Secretagogues Best compliance, most convenient Once daily use Hypoglycemia in only 2-4%
Same as above, different binding Rapidly absorbed & cleared Hypoglycemia
Repaglinide Rapid onset, short duration
site on SUR1 Peak in 30-60 mins Weight gain
Meglitinides Postprandial glucose regulators
Must be taken before each
Insulin Secretatgogues Contain NO SULFUR; may be used
Less effective than sulfonyl-ureas meal; if the meal is missed, Weight gain
Nateglinide with sulfur or sulfonylurea allergy
in reducing FPG & HbA1C dose must be omitted Less effective than Repaglinide
GI: nausea, vomiting, (contributes to
DoC in Type 2 DM management Effects mediated by activation of weight loss) anorexia, abdominal
-Does NOT cause insulin secretion Oral, not protein bound, not
AMP-dependent protein discomfort, diarrhea (upto 20%)
Thus, low risk of hypoglycemia metabolized, urine excretion
-Equivalent efficacy to sulfonylureas in kinase (AMPK)
Metformin
Biguanide ↓ FPG & HbA1C Activated AMPK inhibits ↓ gluconeogenesis & ↑
Can Interfere with Vit B12 absorption
Insulin Sensitizer gluconeogenesis & lipogenesis (long term use)
insulin action in muscle & fat
Only hypoglycemic agent shown to ↓ while promoting fatty acid ↓ plasma TAGs (15-20%)
oxidation & lipolysis Contraindicated in renal/hepatic disease
macrovascular events in type 2 DM ↓ body weight
Decreases insulin resistance % alcoholism due to risk of severe Lactic
Allows ovulation in PCOS (PCOD)
acidosis
Effects on lipids more favorable than ↓ insulin resistance Fluid retention, weight gain, edema
Rosiglitazone Agonists of peroxisome
Pioglitazone Exacerbates CHF
↑ HDL
↓ TAG
proliferator-activated Slow onset due to nuclear Contraindicated in Class 3 or 4 CHF
receptor-γ (PPAR-γ) action
Use restricted due to ↑ CV risk
Thiazolidinediones Risk of MI with nitrates (Re: fibrates activate PPAR-α) FDA requires monitoring of liver function
(Nuclear receptor found in Oral with Tzd therapy
Rosiglitazone (Tzds) Risk of edema with insulin
Liver metabolism
↑ HDL, No effect on TAG muscle, fat, & liver)
Glitazones ↑ LDL
Risk of hypoglycemia with insulin
Insulin Sensitizers Expression of genes involved in Can resume ovulation in
lipid/glucose metabolism, insulin PCOS/PCOD Same as above
First Tzd
Troglitazone signaling, & adipocyte Exacerbates CHF
Withdrawn
differentiation Withdrawn due to severe hepatotoxicity
Anti-Diabetic (Part 4): Non-Insulin Antidiabetic Agents
Drug Drug class Description MOA Pharmacokinetics Adverse Effects
Competitive inhibitors of intestinal α- ↓ postprandial digesCon of starch Flatulence, diarrhea, abdominal pain
glucosidases & disaccharides Hypoglycemia if with sulfonylurea
Acarbose α-Glucosidase Acarbose - use alone or with ↓ postprandial hyperglycemia & Oral Contraindicated in IBD, renal disease
Miglitol Inhibitors sulfonylureas, metformin, insulin hyperinsulinemia Taken prior to meal Reversible hepatic enzyme elevation
Miglitol - use alone or with Periodic liver function monitoring
sulfonylureas Modest ↓ in FPG & HbA1C required with Acarbose
Analog of glucagon-like-polypeptide
↑ glucose-dependent insulin
1 (GLP-1)
secretion
Injectable, 2/day
Derived from salivary gland of the Gila
Suppresses postprandial glucagon 2 injections/day
Exenatide Incretin Analog monster, 53% homology with human,
release Admin with other drugs for GI effects
longer action
Slow gastric emptying T2DM
↓ appeCte
Resistant to human dipeptidyl
May stimulate β cell proliferation
peptidase IV (DPP-IV)
↑ circulaCng GLP-1 & insulin Oral
Dipeptidyl peptidase IV (DPP-IV) ↓ glucagon levels Admin alone or with
Sitagliptin DPP-IV Inhibitors degrades incretins ↑ responsiveness of insulin metformin or
release to oral glucose load thiazolidinedione (Tzd)
Amylin = peptide co-secreted with Injectable
Inhibits food intake, gastric 3 injections/day
Pramlintide Amylin Analog insulin from β cells in response to
emptying, & glucagon secretion
Admin with insulin, for T1DM
GI effects
nutrient stimuli & T2DM
Constipation, nausea, dyspepsia,
Colesevelam Bile-acid sequestrant ↓ LDL MoA for Type 2 DM unclear
↑ TAG, interfere with absorption
American Diabetes Association Anti-Diabetic Drugs in Pregnancy .

Treatment Algorithm for T2DM Drug Category
Step 1 - Lifestyle intervention + Metformin Insulins
Step 2 Lispro & Aspart B
-If HbA1C ≥ 7% in 2-3 months, add second agent: insulin or Regular Insulin B (DoC in Pregnancy)
sulfonylurea (glimepiride, glipizide) NPH Insulin B
-If HbA1C ≥ 8.5%, start insulin Glulisine, glargine, detemir C
Note: Stop secretagogues when starting insulin Noninsulin antidiabetics
Step 3 Sulfonylureas C (Glyburide = B)
-If glycemic goal not achieved: start/intensify insulin Meglitinides C
-Addtion of 3rd oral agent may be considered, but NOT Metformin B
preferred Thiazolidinediones (Tzd) C
Insulin is the MOST effective diabetes medications in
lowering glycemia Exenatide C
-Can ↓ any level of ↑ HbA1C to therapeutic goal Sitagliptin B
-There is NO maximum dose of insulin beyond Pramlintide C
which a therapeutic effect will not occur
-Large doses of insulin may be necessary to
overcome insulin resistance of T2DM
Calcium & Phosphate Metabolism (Part I)
Vitamin D
Parathyroid Hormone (PTH) Hypercalcemia
-A pro-hormone (1,25-Dihydroxycholecalciferol or calcitrol is active form)
MoA: binds Gs receptors → ↑ cAMP in bone & renal tubular cells Usually ASYMPTOMATIC, but if
-Binds Vit D receptor in nuclei; expressed in kidney, GI, bone, parathyroid gland, brain, etc.
- Kidneys: INHIBITS Ca2+ excretion, PROMOTES PO4- excretion serum Ca2+ > 11mg/dL, may
-Vit D3 (cholecalciferol) synthesized from UV light exposure
- ↑production of 1,25-(OH)2-Vit D (calcitriol) via 1α-hydroxylase exhibit:
-Vit D2 (ergocalciferol) ingested from vegetable sources
- Bone: ↑ osteoclasts & osteoblasts activity via RANK ligand, a TNF cytokine groans (constipation);
-Both are converted to 25-OH vit D (calcifediol, the storage form) in liver
moans (psychotic sound);
& to 1,25-(OH)2 vitamin D (calcitriol) in kidney
- High continuous dose - net bone resorption bones pain (esp. if PTH is ↑);
-Renal synthesis is ↑ by PTH & FGF23 (fibroblast growth factor made by osteoblasts &
- Low pulsatile release - net bone formation (used in osteoporosis) stones (kidney stones);
osteoclasts)
psychiatric overtones
-Required for normal mineralization of bone;
PTH Regulation: (depression & confusion);
deficiency → rickets (kids) & osteomalacia/bone softening (adults)
- ↓ in free serum Ca2+ sƟmulate PTH secreƟon NOTE: Thiazides contraindicated
- 1,25-(OH)2-Vit D plays secondary role in regulating PTH secretion by inhibiting PTH in hyPERcalcemic conditions
Effects: ↑ serum Ca2+ & PO4- by intestinal absorption & ↓ renal excreCon (greater effect on GI)
Hypocalcemia: Chronic renal failure, Hypoparathyroidism, ↓ Vit D, Malabsorption, Unintentional

Risk factors for osteoporosis: Caucasians, Asians, Postmenopausal, ↓ exercise, Small-boned thin woman, Excess parathyroid gland removal, DiGeorge syndrome
alcohol, Hyperthyroidism, Aluminum antacids, Thyroid hormone, Glucocorticoids, Anticonvulsants Causes muscular excitability, tetany, paresthesias, laryngospasm, seizures,
Chvostek's/Trousseau's signs
Drug Drug class Description MOA Indications Pharmacokinetics Adverse Effects

Teriparatide PTH Recombinant PTH PTH → ↑ bone formaCon Osteoporosis
Calcipotriol Calcipotriene Psoriasis Topical
Cholecalciferol Vit D3 Added to Ca2+ supplements &
Inactive precursors
Ergocalciferol Vit D2 dairy products Hypercalcemia,
2° hyperparathyroidism in patients hyperphosphatemia (chronic
Calcitriol Vitamin D 1,25 Dihydroxy Vitamin D3 with chronic renal and/or liver Oral & parenteral overdose)
disease
Doxercalciferol 1 α-Hydroxy Vitamin D2
19 nor-1,25 Dihydroxy
Paricalcitol
Vitamin D2
Osteoporosis Salmon calcitonin has
Inhibits bone resorption & renal Acute hypercalcemia longer t1/2 & greater
Salmon calcitonin Calcitonin Peptide hormone excretion → ↓ serum Ca2+ & With bisphosphonate for Paget's potency
PO4- Disease, Multiple Myeloma
Spine fractures Injection, nasal spray
Direct regulation of osteoblasts
& ↑ synthesis, of collagen,
osteocalcin, & alkaline
Prevent bone loss in post- Osteoporosis in post-menopausal
Estrogens Estrogens menopausal women
phosphatase
women
Small ↑ in factors 2, 7, 9, 10, 12;
↓ anCcoagulaCon factors
Protein C, S, & ATIII
Selective Estrogen Estrogen antagonist in breast Breast CA ↑ risk of endometrial CA &
Tamoxifen
Agonistic in bone & uterus Osteoporosis thromboembolism
Receptor Modulators Favorable effects on breast & Post-menopausal women with
Raloxifene (SERMs) Agonistic at bone only Thromboembolism
endometrium osteoporosis
Calcium & Phosphate Metabolism (Part II)
Calcium chloride
IV for severe cases Severe hypocalcemia IV admin
Calcium gluconate
Calcium carbonate
Calcium citrate
Calcium Salts Prophylaxis of osteoporosis
Oral prep for mild cases Oral admin
Calcium phosphate Mild hypocalcemia
Calcium lactate
Loop diuretic +
Loop Diuretics Thiazide dieuretics are
(Furosemide)
Loop Diuretic DoC in acute hypercalcemia Rehyration with saline
contraindicated in hypercalcemia
diuresis
Erosive esophagitis (Tx: fluid
Alendronate Daily Disrupts mevalonate pathway intake, remain in upright position
→ ↓ osteoclast H+ ATPase after dose)
Etidronate Daily → Inhibits osteoclast acCvity Mineralization defects
↓ resorpCon + Malignancy with hypercalcemia (osteomalacia) with long term use
Pamidronate Bisphosphonates Weekly ↑ hydroxyapatite formation Paget's Disease of Bone
Parental admin (>12 months)
(P,I,R,A,T,E,Z) (inorganic component of bone, Osteoporosis
Zoledronic acid Yearly = preferred
mostly CaPO4; Stores 90% of All Bisphosphonates: Bone pain in
Tiludronate
bone Ca2+) → in Paget's disease, esp. around
Ibandronate Monthly ↑ Bone formation Pagetic lesions
Risedronate
Activates Ca2+ sensing Secondary hyperparathyroidism in

Hypocalcemia
Cinacalcet receptors in parathyroid cells → chronic renal disease &
↓ bone cell acCvity
↓ PTH synthesis/release parathyroid carcinoma
Acute toxicity = GI & neuro

symptoms
New bone synthesis in chronic
exposure Dental caries Drinking water
Fluoride Chronic toxicity = (fluorosis)
Converts hydroxyapatite to Prophylaxis of osteoporosis 5-10 ppm
ectopic bone formation &
fluorapatite (denser, but brittle)
exostosis (formation of new bone
on top of a bone)
Inhibits bone resorption Nephrotoxicity (Amphotericin B,
Ganite Gallium Nitrate ↓ serum Ca2+
Cancer related hypercalcemia
aminoglycosides may ↑ risk)
Thrombocytopenia →
↓ serum Ca2+
hemorrhage
Inhibits effects of PTH on
Mithracin Plicamycin Cytotoxic Antibiotic
osteoclasts
Hepatic/Renal toxicity
GI (Nausea, Vomiting, Loss of
Blocks effects of Vit. D
appetite)
↓ intesCnal absorpCon & Hypercalcemia (2° to sarcoidosis &
Glucocorticoids Glucocorticoids ↓ serum Ca2+
↑ renal excerCon of Ca2+ lymphoma)
Osteoporosis
Intro to CNS Drugs
Fast-Acting Neurotransmitters (NT) (ionotropic)
-Activate ligand-gated receptors →
Slow-Acting Neurotransmitters (metabotropic)
influx of ion (mostly cations) into post-synaptic cell
-Activate receptors linked to G proteins
-milliseconds
-Act directly on voltage gated ion channels or alter synthesis of second
3 subtypes:
messengers via certain enzymes
1. Kainate
adenylyl cyclase → cAMP
2. AMPA
phospholipase C → IP3 & DAG
3. NMDA
Present at most excitatory synapses in brain
Excitatory NTs (e.g., glutamate) → influx of Na+ ions → excitatory
Communication between neurons in the CNS occurs via chemical
postsynaptic potential (EPSP) → depolarizes postsynaptic cell to threshold,
synapses
generates an all-or-none action potential
-The released NT diffuses in cleft → binds to receptors on postsynapCc
Inhibitory NTs (e.g., GABA, glycine) → influx of Chloride ions → inhibitory
membrane on target cell (Ca2+-mediated)
postsynaptic potential (IPSP) → opposes generation of action potential
Cellular Organization of the Brain Sites of Drug Action

(Neuronal Systems divided into 2 categories) Storage
Hierarchical Systems -Reserpine depletes synapses of monoamines by interfering w/storage
-Pathways involved in sensory perception & motor control) Metabolism
-Glutamate = principal excitatory NT; -Vigabatrin inhibits degradation of GABA
Small, local curcuit neurons are usually inhibitory Release
-GABA = prinicipal inhibitory NT -Amphetamine induces release of catecholamines
-Carbamazepine blocks voltage-gated Na+ channels & inhibits glutamate
Non-specific or Diffuse Neuronal Systems release
-NTs are monoamines: NE, DA, or Serotonin (5-HT) Uptake & degradation
-Control global function, i.e., sleeping, walking, attention, appetite, & -TCAs block uptake of NE & serotonin
emotional states -Anticholinesterases block degradation of ACh
Monoamines
Central Neurotransmitters -Dopamine = generally inhibitory
Neutral Amino Acids (inhibitory) -Norepinephrine = inhibitory or excitatory
-Glycine receptor is a Cl-channel -Serotonin = inhibitory or excitatory
-GABA (2 subtypes):
-GABAa receptor is a Cl- channel Peptides
-GABAb receptors are coupled to Gi proteins that -Opioid peptides, neurotensin, Substance P, Somatostatin, Cholecystokinin,
inhibit Ca2+ channels or activate K+ channels Neuropeptide Y, Thyrotropin releasing hormone
-Often coexist with conventional transmitter in same neuron
Acidic Amino Acids (excitatory)
-Glutamate & Aspartate Nitric Oxide (Role unclear in synaptic transmission & synaptic plasticity)
-Bind to either Ionotropic or Metabotropic (Gq or Gi) receptors
Acetylcholine (ACh)
-Most receptors in CNS are G-protein-coupled muscarinic receptors
Anti-Depressants (Part I)
Monoamine Hypothesis:
Norepinephrine & Serotonin = candidate monoamines
"Depression may be due to lowered actual or functional monoamine neurotransmitter at brain synapses and
treatment of depression may be achieved by restoring the monoamine levels or actions to normality"
Tricyclics: block monoamine (NE/serotonin) reuptake pumps of amine neurotransmission →
i.e., monoamine depletion → depression; monoamine preservation → mood elevaon
↑ lifespan of the amines
Evolving Monoamine Hyopthesis:
Monoamine inhibitors: block the major degradative pathway for monoamine NTs →
Depression may be linked to defect in signal transduction →
accumulation of amines in presynaptic stores, more for release
↓ response of target neurons to neurotransmission → depression
Reserpine
Unipolar (Depressive symptoms only) Note: pharmalogical actions of TCAs & MAOIs are immediate;
-Used for HTN; found to preciptate depresion
-Major depression however, clinical effects of the drugs take 2-4 weeks to manifest, and 6-8 weeks to achieve
-Depletes dopamine, serotonin, & NE in rat brain
-Dysthymia benefit
Isoniazid & Iproniazid
-Used for TB
Bipolar (Depression interspersed w/mania) Note: Antidepressants are helpful to treat bulemia, but NOT for anorexia nervosa
-Inhibits monoamine oxidase (MAO)
Drug Drug class Description MOA Indications Pharmacokinetics Adverse Effects Contraindications
Drowsiness
Phenelzine Hydrazine Orthostatic hypotension Combo of MAOI with SSRIs, SNRIs,
Inactivates monoamine
Blurred vision TCAs, or meperidine → Serotonin
oxidase enzyme → NE, DA, 5-
Isocarboxazid Irreversible Effects take 2-4 weeks Dry mouth Syndrome (hyperthermia, muscle
HT escape degradation → ↑
Dysuria rigidity, myoclonus) due to
activation of NE & 5-HT
Depression unresponsive to Extensive first pass Constipation overstimulation of 5-HT1 & 5-HT2
receptors
MAOIs other anti-depressants metabolism → Gut MAO receptors (Tx: Cyproheptadine (5-
HT2-blocker))
inhibited → Tyramine MAOI + Sympathomimetics (OTC
Non-hydrazine MAO-A deaminates NE, Epi, 5-
pressor effect cold preparations with
Irreversible HT
Tranylcypromine Rarely used in clincal pseudophedrine (Sudafed) & Cheese Reaction: Tyramine (found
Amphetamine-like metabolite (also
setting due to toxicity & phenylpropanolamine) → significant in aged cheese, chicken liver, soy
Selegiline) MAO-B deaminates
potentially lethal food, HTN products, pickled fish, red wines)
Dopamine, Tyramine, &
drug interactions usually inactivated by MAO → no
above amines
degradation with MAOIs → release
of catecholamines → tachycardia,
Inhibiting MAO-A is more
Tranyl + Selegiline: HTN, arrhythmia, seizure, stroke
Non-hydrazine, Reversible effective for treating Depression Transdermal, sublingual
Selegiline Agitation, insomnia (from (treat with Phentolamine or
MAO-B selective (low doses) depression Early Parkinsons forms avoid gut
metabolite) Prazosin)
Little affinity for NET

Binds potently to SERT Narrow TI: Give limited quantities to
Clomipramine Approved for OCD Oral Blockade of muscarinic suicidal patients & monitored
MOST serotonergic → most sexual Depression Lipophilic receptors: closely
problems (alternative to SSRI/SNRI) Widely distributes, Blurred vision, xerostomia, urinary Elevated with CYP2D6 inhibitors (or
Neuropathic pain including CNS
Block SERT & NET by retention, constipation, aggravation slow CYP2D6 polymorphism)
Amitriptyline Most weight gain Enuresis (Bed wetting) Variable half life & first
competition for the binding of narrow-angle glaucoma ----------------------------------
site on the carrier protein → pass
Desipramine Effects: (take 2 weeks)
↑ monoamine in cleZ ↑ catecholamine acCvity → death Block α1-adrenoreceptors →
Elevate mood, Liver microsomal
TCAs More selective for NET
↑ mental alertness, enzyme metabolism +
by Cardiac overstimulation Orthostatic hypotension, reflex
Nortriptyline Block α-adrenergic, tachycardia, esp. in elderly
↑ physical acCvity glucuronic acid
muscarinic, histamine, & 5- Overdose → Block fast-Na+
NET selective, anticholinergic HT receptors → adverse conjugation Block H1 receptors → SedaCon &
No CNS stimulation or mood channels (slows pahse 0, wide
Amoxapine Postsynaptic D2 blocker effects (thus not 1st line) Excreted by kidneys
elevation in normal people QRS) → Cardiac arrhythmias → Tx: weight gain, especially
(antipsychotic) amytriptyline
Little dependence or monitor, airway support, gastric
Maprotiline NET selective, anticholinergic
tolerance lavage; sodium bicarbonate to
reverse conduction block Sexual effects (common), especially
Imipramine t1/2 = 4-17 hrs clomipramine
Anti-Depressants (Part II) - Heterocyclics (2nd/3rd generation)
All are well absorbed
orally, well distributed Nausea
Citalopram
Low potential for interactions (thus DoC for Depression & Renally excreted GI upset
can give to elderly!) Anxiety disorders t1/2 ranges 16-36 hrs Diarrhea Allow 2 week wash-out before/after
OCD ↑ serotonergic tone in spinal cord taking MAOI
Note: SSRIs are not effective for Blocks serotonin reuptake
Escitalopram Panic disorder S-enantiomer of above → ↓ sexual funcƟon & interest
Selective chronic pain 2 weeks for effect
Posttraumatic stress
Upto 12 weeks or more for Only one with first-pass
Sertraline
Serotonin- disorder
effect
Weight gain, esp. paroxetine
max benefit
Reuptake Social anxiety disorder
1/2 fecal excretion
Premenstrual dysphoric Overdose: seizures (antidepressants
Inhibitors (SSRIs) 300-3000x affinity for SERT t1/2 = 50 hrs
disorder (Fluoextine & may lower seizure threshold)
Fluoxetine over NET (& other receptors) Active metabolite, S- Inhibit CYP2D6
All SSRIs have potential to cause Sertraline)
(Prototype) norfluoxetine (t1/2 = 10 CI: TCAs, neuroleptics,
serotonin syndrome when Bulemia nervosa Serotonin syndrome (with MAOIs),
days), is potent antiarrhythmics, β-blockers
combined with a MAOI or other (Fluoxetine) (Tx: Cyproheptadine - 5-HT2
Paroxetine serotonergic drug 1/3 fecal excretion blocker)
Inhibits CYP1A2, CYP2C19, &
Fluvoxamine
CYP3A4
SSRI at theraputic doses
Nausea, somnolesence, diziness,
Venlafaxine Serotonin & Higher doses → blocks NE uptake Blocks reuptake of NE & Alternative drug for
anxiety, sexual disturbances, HTN
WEAK inhibitor of DA uptake serotonin depression where SSRIs are
Norepinephrine
Ineffective
Reuptake Inhibits 5-HT & NE at all doses
(like TCA, but no blocking at Nausea, dry mouth, constipation, ↓
First antidepressant approved to Extensive hepatic
Duloxetine Inhibitors (SNRIs) H1, M, & α1 receptors) Chronic pain appetite, fatigue, sweating, asthenia (↓ Hepatic insufficiency
treat pain of diabetic neuropathy & metabolism
strength), dizziness, sexual dysfunction
fibromyalgia
Note: not associated with sexual
Blocks reuptake of NE & DA Depression
Norepinephrine & dysfunction as it lacks serotonin
Sexual dysfunction by other
component (thus, someone taking Metabolite
Dopamine Also ↑ NE & DA release antidepressant
Bupropion Prozac + having sexual problems can (hydroxybupropion) is Seizures (overdose)
Reuptake use Bupropion instead) active
↓ craving and withdrawl of Smoking cessation
Inhibitor (NDRI) nicotine (extended release Zyban)
Not effective for anxiety
Nefazodone 5-HT1A receptors (raphe) help treat Potent 5-HT2 antagonist, Hepatotoxicity Nefazodone inhibits CYP3A4
5-HT2 Antagonist/ depression weak NET/SERT inhibitors
Reuptake Inhibitor 5-HT2 receptors cause agitation, Also blocks α1 & H1 →
Trazadone is a substrate, but NOT a
Trazodone anxiety (forebrain) & sexual ↓ AE of of 5-HT2 receptor Extreme Sedation
(SARI) potent inhibitor of CYP3A4
dysfunction (spinal cord) stimulation Priapism
Antagonist at:
Noradrendergic & Depression
TCA with extra ring α2,
Specific 5-HT2,
Blocks H1 →
5-HT3
Mirtazapine Serotonergic Potent antagonist of central
H1
Sedation
presynaptic α2 receptors → Weight gain
Antidepressant receptors
↑ release of NE & 5-HT
(NASSA) No reuptake inhibition
Anti-Depressants (Part III) - Lithium
Leukocytosis (always)
Alternatives: Inositol depletion theory:
UNcompetitive inhibition of Confusion & motor impairment →
Valproate & Carbamazepine Oral admin as carbonate
coma → convulsions & death @ Pregnancy (category D)
inositol polyphosphatase salt
plasma conc. at 3-5 Mm Nursing mothers
Atypical anti-psychotics (Olanzapine (catalyzes transformation of
& Aripiprazole) inositol 1,4-bisphosphate Completely absorbed in
Prophylactic for manic Tremor, Sedation, Ataxia, Aphasia Valproate during pregnancy can
(IP2) to IP1) & inositol gut, cleared by kidneys
episodes in bipolar disorder cause neural tube defects
Atypical anti-psychotics (Quetiapine, monophosphatase t1/2 = 20 hrs
Thyroid enlargement (dysfunction
Lithium Lithium Risperidone, & Ziprasidone) for (catalyzes conversion of Hypomania is rare) Carbamazepine not recommended
ACUTE mania or mixed episodes inositol monophosphate (IP1) Narrow therapeutic
during pregnancy (last resort only)
to free inositol) → window
Mania Reversible nephrogenic diabetes due to major malformations (neural
Olanzapine + Fluoxetine for ↓ PIP2 → ↓ IP3 & DAG → insipidus (in the DCT) tube defects, low birth weight,
depression with bipolar disorder thus ↓ signal transduction Effective at 0.5-1 mM in
neonatal vitamin K deficiency
plasma, toxic above 1.5
Edema (hemorrhage))
Lamotrigine for maintenance of Blocks action of NT mM
Acneiform skin eruptions
bipolar disorder responsible for mood swings Congenital cardiac abnormailites
of fetus
UNcompetitive = Lithium only binds to neurons with active

receptors (i.e., substrate is bound to enzyme)
Anti-Psychotic Drugs (Part I) - General
Pyschosis = set of symptoms in which a person's mental capapcity, affective response, & capacity to recognize reality, Dopamine Pathways in the Brain
communicate, & relate to others is impaired Mesolimic pathway
Schizophrenia = breakdown of integration between emotions, thought, & actions -Brainstem → limbic areas
Negative symptoms: Positive symptoms: Note: positive symptoms -Role in emotional behaviors; Hyperactivity = postive pshychotic symptoms
-Poverty of speech -Delusions typically respond to treatment -Blockade of postsynaptic D2 receptors in this pathway = antipsychotic efficacy of anti-psychotic
-Loss of emotional -Thought disorder drugs
responsiveness -Perceptual distrubances (hallucinations)
-↓ motor funcCon -Incongruous mood Nigrostriatal Pathway
-Social withdrawal -↑ motor funcCon -Substantia nigra → basal ganglia
-Associated with frontal -Symptoms linked to overactivity of dopaminergic -↓ in Parkinsons → extrapyramidal symptoms
cortex hypoactivity neurons in the mesolimbic dopamine pathway -Control motor movements
-Disorders of movement appear if postsynaptic DA receptors are blocked
Drugs that ↑ dopaminergic activity produce ↑ positive psychotic symptoms -Pathway is part of extrapyramidal nervous system; thus, motor adverse effects due to blockade of
Amphetamine & Cocaine taken repeatedly can cause a paranoid psychosis indistinguishable from schizophrenia D2 receptors are called extrapyramidal reactions (EPRs)
Drugs that ↓ dopaminergic acCvity ↓ or stop posiCve symptoms -EPRs = acute dystonia (spastic retrocollis, torticollis), akathisia (uncontrollable restlessnes), &
Antipsychotic druga used to treat positive psychotic symptoms are D2 dopamine receptor blockers Parkinsonian-like syndrome (tremors, bradykinesia, rigidity)
Antipsychotic actions
-↓ hallucinaCons & agitaCon by blocking DA receptors in the mesolimbic system Mesocortical Pathway
-Produce calming effect & reduce spontaneous physical movement -Brainstem → limbic cortex
-Unlike CNS depressants (i.e., barbituates), neuroleptics do NOT depress intellectual function -Negative symptoms may be due to ↓ DA in this pathway
-Motor incoordination is minimal -Blockade of D2 receptors here may cause or exacerbate negative or cognitive symptoms
-Antipsychotic action onsets within first 24 hrs, magnitude of action grows with time (emotional blunting & cognitive problems)
Antiemetic effects
-via blockade of D2 receptors of medullary chemoreceptor trigger zone; Exception: aripiprazole & thioridazine Tuberoinfundibular Pathway
-Hypothalamus → anterior pituitary
General Pharmacokinetics -Physiologically INHIBITS prolactin secretion
-Most completely metabolized by CYP2D6, 1A2, & 3A4; Clinical doses don't alter metabolism of other drugs -Blockade of D2 receptors here → ↑ prolacCn → galactorrhea (amenorrhea-galactorrhea syndrome
-Usually admin orally, incompletely absorbed, highly protein bound (92-99%) in women), infertility, impotence, loss of libido
General Adverse Effects (high TI, generally safe)

EPR motor effects: Relative excess of cholinergic influence, ↓ inhibiCon by dopamine
→ Typical Parkinson's syndrome (Treat with anCmuscarinic Benztropine, NEVER levodopa)
→ Akathisia (Treat with benztropine, propanolol, benzodiazepines)
→ Acute dystonic reacCons (Treat with benztropine or diphenhydramine)
Tardive dyskinesia: Irreversible choreoathetoid movements due to long term DA blockade → ↑ DA receptors
→ Treatment: Stop drug; eliminate central anCcholinergics, esp. anCparkinsonian & TCAs; Diazepam may help
Neuroleptic Malignant Syndrome: Rare, potentially fatal, due to excessively rapid DA blockade
→ Muscle rigidity, fever, altered mental status, stupor, unstable BP, myoglobinemia
→ Treatment: DisconCnue drug, Dantrolene, Bromocriptine may help; Switch to atypical antipsychotic
-Sedation, due to H1 blockade

-Seizures (esp. chlorpromazine & clozapine)
-Not addicting, but physical dependance may occur (Withdrawl = malaise, difficulty sleeping); Little tolerance
-Rabbit Syndrome: Perioral tremor (after months or years of use)
-ANS effects (esp. thioridazine, chlorpromazine, clozapine, olanzapine) due to muscarinic receptor blockade,
(though this may be protective against extrapyramidal reactions)
-α1 receptors blockade → orthostatic hypotension, light headedness, & impaired ejaculation, esp. chlorpromazine
-Poikilothermia: Impaired ability to regulate temperature (hypo- or hyperthermia)
-Weight gain (T2DM, HTN, hyperlipidemia), galactorrhea, infertility, impotence, ↓ libido
Anti-Psychotic Drugs (Part II)
Less 1st-pass metab. →
Haloperidol Block DA receptors in brain &
High-porency drugs: more likely to periphery 65% bioavailability
See general AE
Thiothixene produce extrapyramidal reactions
-Schizophrenia
Fluphenazine D1-like DA receptors: D1 & D5 -Alcoholic hallucinosis
Activate adenylyl cyclase (Gs) → -Tourette's Syndrome Corneal & lens deposits
↑ cAMP -Huntington's Disease Seizures
Low-potency drugs: Less likely to
Chlorpromazine -Alzheimer's senile dementia 25-35% bioavailability Jaundice (mild, obstructive)
Classical produce extrapyramidal reactions
D2-like DA receptors: D2, D3, D4 -Control agitation/psychosis in Orthostatic hypotension, impaired
Anti-Psychotics Inhibit adenylyl cyclase (Gi) → ↓ depressed patientsts (in combo ejaculation
Also less EPR due to strong
cAMP with antidepressants)
antimuscarinic activity Retinal deposits may resemble retinitis
All except Thioridazine: Nausea pigmentosa ("browning" of vision)
MORE likely to produce sedation Note: the efficacy of classic
Thioridazine neuroleptics correlates with their & vomiting 25-35% bioavailability
& postural hypotension Cardiotoxicity:
(by blocking H1 & H2, respectively) ability to block D2 receptors in
Prolonged QT waves, T-wave changes,
the MESOLIMBIC pathway
Rare ventricular arrhythmia
Common properties of atypical Agranulocytosis (requires weekly blood

antipsychotics: High affinity for D1, D4, 5-HT2, Same as classicals + counts), 1-2%, reversible, MoA unknown,
muscarinic, & α-adrenergic Bipolar disorder use reserved for refractory cases
Clozapine
-most are antagonists at receptors
(prototype)
Safer for use in pregnancy Seizures
5-HT2A & D2 receptors (a.k.a. Also a D2 bocker (category B) (all others are C) Weight gain
SDA: serotonin-dopamine
Sedation
antagonists)
Compared to clozapine:
Blocks 5-HT2 MORE than D2 Antipsychotic of choice
-Exert part of their action by Active metabolie is More antidopaminergic
Risperidone
blocking 5HT receptors Paliperidone (below) Less antimuscarinic
5-HT2A, D2, α1, & H1 antagonist Same indications as above
Atypical (More EPR and ↑ prolacƟn)
-Less likely to cause
Anti-Psychotics 9-hydroxyrisperidone (active Used for 10% who are poor
Paliperidone extrapyramidal reactions than
metabolite of Risperidone) metabolizers of Resperidone
classical agents
Olanzapine Antimuscarinic Weight gain, ANS effects
Quetapine -Less likely to cause tardive -Schizophrenia
dyskinesia D2 & 5-HT2 antagonist -Bipolar disorder
-Less likely to cause ↑ prolacCn 5-HT1A agonist -Alcoholic hallucinosis
Ziprasidone Least weight gain
Moderately inhibits 5-HT & NE -Tourette's Syndrome
SNRI-like Rare QT elongation
-More effective at treating uptake → SNRI antidepressant-like -Huntington's Disease
negative symptoms feature -Alzheimer's senile dementia
Partial agonist at D2 & 5-HT1A -Control agitation/psychosis in Activity due to parent &
Aripiprazole -Effective in refractory populations receptors depressed patientsts metabolite
Antagonist at 5-HT2A-R (dehydroaripiprazole)
Fluphenazine decanoate Outpatients
Haloperidol decanoate Slow release (up to 2-4 weeks) Patients not compliant with Admin IM Less risk of EPR
Risperidone microspheres oral meds
Sedative-Hypnotics - Part 1
Benzodiazepines (BZRA)
Diazepam Long acting (1-3 days) -Anxiolytic (inhibit circuits in -Pharmocologic dependence Metabolism slowed by
Flurazepam (Active metabolites) limbic system) Lipophilic -Limited benefit in OCD or PTSD, CYP3A4 inhibitors
Bind GABAA receptors -Sedative/Hypnotic Good oral absorption & short-term use only
(chloride channel) at BZ1/2 -Anticonvulsant (seizure distribution -Drowsiness & confusion
sites in CNS → Potentiate GABA states, Lorazepam = DoC for Alprazolam may cause
-Ataxia (incoordination of muscle
Alprazolam rebound anxiety and
Intermediate acting (10- activity allosterically → Cl- influx status epilepticus) Phase 1 by CYP3A4 activity)
Lorazepam causes hyperpolarization withdrawl symptoms
20 hrs) -Muscle relaxant (↑ Phase 2 glucuronidation -Cognitive imapirment
Temazepam No phase 1 for
presynaptic inhibiton in spinal
Loraz/Temaz
cord, especially Diazepam) Meabolized in liver Paradoxical effects: nightmares,
Effect on sleep:
-Anesthesia (as an adjuvant) Excreted in urine anxiety, garrulousness, irritability,
Oxazepam -Faster sleep onset No phase 1 for
-Ethanol dependence (diazepam, tachycardia, sweating, bizarre
Short acting (3-8 hrs) -Longer stage 2 sleep
Triazolam oxazepam) Use cautiously with liver uninhibited behaviour, hostility Oxazepam
-Less REM sleep
-Less stage 4 NREM sleep disease, alcohol, or other and rage, (disinhibition or
Clonazepam Epileptic seizures CNS depressants discontrol reactions), paranoia, Fluraz, Temaz, and Triaz
Anesthesia adjuvant (also depression, suicidal ideation are Category X
Midazolam
Diazepam) Others Category D
IV only
Blocks CNS depressant effects Benzodiazepine overdose Dizziness, confusion, nausea, Synthetic
Benzodiazepine/NBBRA Rapid onset, short duration,
Flumazenil of benzodiazepines Hasten recovery from use as vomiting, agitation; Withdrawl in benzodiazepine
antagonist rapid hepatic clearance (t1/2
Competitive, reversible anesthetics dependent people, seizure derivative
≈ 1 hr)
Inverse agonist of
β-carboline Experimental use only
benzodiazepines
Barbiturates
Seizures (tonic-clonic, status, Coma in toxic doses
eclampsia) Duration >1 day Suppress hypoxic/hypercapnic
Hyperbilirubinemia & chemoreceptor response → Also blocks high-
Phenobarbital
kernicterus (↑ glucuronyl Redistribute from brain to respiratory depression → death frequency Na channels
Same as benzodiazepines, transferase & bilirubin-binding Y terminate action Induce P450
Mostly replaced by protein) (also N-phenylbarbital) Can cross placenta and depress fetus
Different binding site
benzodiazepines Cardiovascular collapse (rapid IV)
Pentobarbital Drowsiness, impaired concentration,
Don't raise pain threshold
Secobarbital Pregnancy Category D Sedation/hypnosis Short acting (3-8 hrs) mental/physical sluggishness
Oral, wide distribution
No analgesia
Amobarbital Paradoxical excitement
Meabolized in liver
Hypersensitivity
Addiction, Hangover
(except phenobarbital)
Onset within seconds ↑ porphyrin synthesis Excreted in urine
Thiopental Induce anesthesia
Very short acting (30min) May worsen perception of pain
Sedative-Hypnotics - Part 2
Non-Benzodiazepine Benzodiazepine-Receptor Agonists (NBBRA)
Short acting (t1/2 = 1.5-3.5 Nightmares, agitation, headaches, Little withdrawl or
Insomnia with difficulty in
Zolpidem Hypnotic only hrs) GI upset, dizziness, daytime rebound insonmia, no
sleep induction
Metabolized by CYP3A4 drowsiness tolerance
Act only on BZ1 subtype Rapid elim. (t1/2 ≈ 1 hr)
Fewer residual psychomotor & All 3 are pregnancy
Zaleplon Similar to Zolpidem (GABAA-R with α1) receptors Metabolized by CYP3A4 &
cognitive effects category C
Short-term treatment of aldehyde oxidase
(S)-enantiomer of insomnia Anxiety, dry mouth, headache, ↓ sleep latency,
Eszopiclone zopiclone, 50x affinity of t1/2 ≈ 6 hrs peripheral edema, somnolence, Improved sleep
(R)-enantiomer unpleasant taste maintenance
5-HT-1A Receptor Agonists
Anxiolytic only Agonist at 5-HT1A Receptors Advantages:

No hypnotic,
Slow onset has led to belief Less psychomotor impairment
Manage anxiety disorder anticonvulsant, or
No interaction with that Buspirone acts by No interaction with EtOH of other
Buspirone (2nd line for general anxiety Onset: 2-3 weeks muscle relaxant activity
GABA-R adaptive neuronal/receptor sedative-hypnotics
disorder (GAD))
events rather than just No dependence
Pregnancy Category B
MoA like antidepressants receptor activation No withdrawl or rebound anxiety
Melatonin-Receptor Agonists
Activity at MT1 & MT2 is Selective agonists at MT1 and Fluvoxamine inhibits
Rapidly absorbed, extensive Dizziness, somnolence, fatigue,
thought to promote MT2 receptors in Insomnia with difficulty in CYP1A2
Ramelteon first-pass (CYP1A2) to form endocrine changes (↓
sleep suprachiasmatic nuclei of the sleep onset ↓ abuse potential, can
active metabolite testosterone, ↑ prolacCn)
Pregnancy category C brain be used long term
Older Sedative-Hypnotics
Chloral hydrate,
Meprobamate,
Paraldehyde
Other (Off-label use)
Specific phobias
Propranolol β-adrenergic antagonists No CNS disturbances
Performance anxiety
Clonidine Partial α2 agonist Modify autonomic expression Anxiety
Antihistamine, Anxiety, psychoneurosis
Hydroxyzine
antiemetic associated tension
Diphenhydramine
Antihistamine Mild insomnia Anticholinergic
Doxylamine
Sedative - reduce anxiety, calming effect, NO effect on motor/mental functions, minimal CNS depression (at regular doses)
Hypnotic - produce drowsiness, encourage/maintain sleep (resembling natural sleep), more pronounced CNS depression
Decarboxylated
in gastric juice
t1/2 = 40 hrs
A = older sedative-hypnotics, including Barbiturates

B = newer drugs, including Benzodiazepines
t1/2 = 30-100 hrs
Anxiolytics
Goals DoC DoC Benefits DoC Notes Alternatives Alternatives' Notes Other
GAD - Generalized anxiety disorder
Acute, short-term treatment of
Benzodiazepines Use while effects of SSRI
GAD; Improve sleep; Abuse
Acute: reduce severity & No risk for dependency (Alprazolam) are becoming apparent
SSRIs potential
duration of anxiety Effective in various comorbid
symptoms; restore conditions 2nd line; No abuse potential or
Antidepressants Onset delayed 2-4 weeks
overall functioning Reduce psychic symptoms, Buspirone withdrawl; Does not potentiate
(Venlafaxine & SSRIs
Long term: achieve + modest effect on autonomic alcohol or sedatives; 2 week onset
preferred over TCAs)
maintain remission & somatic symptoms
3rd line; Antihistamine &
Hydroxyzine, Pregabalin
Antiepileptic, respectively
PD - Panic disorder
Reduce severity &
TCA, MAOI 2nd line, if SSRI are ineffective
frequency of panic
attacks; Reduce 3rd line, not for long term; Used
SSRI Benzodiazepines
anticipatory anxiety; with antidepressants,
Long term: sustain Rebound anxiety, withdrawl
Alprazolam
remission syndrome (seizure)
SAD - Social Anxiety Disorder
Acute: reduce
physiologic symptoms of
anxiety & fear;
SSRI Onset delayed 8-12 weeks
Long term: restore social
functioning; improve
quality of life
OCD - Obsessive-compulsive disorder
Reduce frequency of Fluoxetine Treatment may only partially
Clomipramine (TCA) Same efficacy, few more AE
obsessive thoughts & Fluvoxamine imrpove OCD thoughts, but
SSRI
time spent on Paroxetine patient can feel remarkably Benzodiazepines
Added for highly anxious patients
compulsive acts Sertraline improved Antipsychotic
PTSD - Post-traumatic stress disorder
Reduce anxiety Venlafaxine
Treatment may only partially
provoking thoughts or TCAs Also effective, more AE
imrpove OCD thoughts, but
imagery, nightmares, SSRI MAOIs
patient can feel remarkably
hypervigilance, and Sertraline Treat acute & long-term PTSD
improved
situation avoidance Paroxetine Treat acute PTSD
Performance Anxiety
Propranolol Lipophilic β-blocker Other β-blocker
Anti-Epileptics (Part I)
Seizure = finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons; thought to arise from cerebral cortex
Epilepsy = recurrent seizures
Mechanism of Seizures: defective synaptic function → seizure (i.e, ↓ inhibitory (GABA) synapCc acCvity or ↑ excitatory (glutamate) acCvity)
Classicification of Seizures: Partial Seizures Classification of Seizures: Generalized Seizures: no evidence of localized onset,
usually immediate loss of consciousness
Simple Partial Seizure (Partial = localized) Tonic-clonic Seizures (Grand Mal)
-Group of hyperactive neurons exhibiting abnormal electrical activity, -Sustained muscles contractions throughout body, followed by periods of muscle
confined to single locus in brain; patient does NOT lose consciousness contraction alternating with periods of relaxation
-Abnormal activity of single limb or muscle group -Most common and dramatic form of epilepsy
-May show SENSORY distortions -Seizure rsults in loss of consciousness followed by tonic, then clonic seizures
-Occurs at any age -Seizure followed by period of confusion & exhaustion
-Duration: 20-60 seconds -Duration: 1-2mins
Complex Partial Seizures
Absence Seizures (Petit Mal)
-Seizures includes comlex sensory hallucinations, mental distortion, &
-Brief, abrupt, & self-limiting loss of consciousness
loss of consciousness
-Onset occurs at age 3-5, lasting until puberty
-Motor dysfunctions may involve chewing movements, diarrhea, urination
-Patient stares & exhibits rapid eye blinking
-Majority arise from temporal lobe
-Duration: less than 10 seconds
-Duration: 0.5-2 mins
-EEG shows 3-Hz spike & wave pattern that emerges abruptly & ceases after a few seconds
Partial with Secondarily Generalized Tonic-Clonic Seizures
Atypical Absence Seizures
-Simple or complex partial seizure → evolves into a generalized tonic-clonic
-Marked by more intense muscle involvement & longer recovery time
seizure with loss of consciousness (see right)
-Responds poorly to treatment, often has severe neurologic impairment
-Duration: 1-2 mins
Other Generalized Seizures Principles of Therapy:
Atonic Seizures: sudden loss of postural tone; often in children, but may be in adults -Start with 1 drug
-Titrate dosage gradually to maximally tolerated dose
Tonic Seizures: muscles contract & consciousness is altered for ~10sec, Status Epileticus: -Monitor regularly
but seizures do NOT progress to clonic or jerking phase -repeated and/or prolonged -Combo therapy only if 2 single therapies have failed
seizure lasting ≥30 mins
Clonic Seizures: very rare; mainly in kids; muscle spasms, but not tonic ridigity -most common types is When to Discontinue Antiepileptic therapy:
Generalized Tonic-clonic status -Seizure free for 3-5 years
Myoclonic Seizures: short (~1 sec) episodes of muscle contractions that may reoccur for
epilepticus (can be fatal) -Discontinuation should be slow (i.e., taper off)
several minutes; rare & occur at ANY age; often result of permanent damage as a
-requires immediate -Discontinue Benzodiazepines & barbituates gradually to avoid withdrawal seizures
result of hypoxia, uremia, encephalitis or drug poisoning
cardiovascular, respiratory & -If on combo therapy, withdraw drugs one-at-a-time
Infantile Spasms: marked by sudden flexion & adduction of arms & forward flexion of the metabolic management +
trunk; seen in mentally retarded babies; Duration = few sec; recur many times a day pharmacologic therapy Overdose toxicity
-Rarely lethal
Febrile convulsions: kids <6 years with high fever >38°C, no infection or metabolic -Most dangerous effect is respiratory depression
abnormality; generalized tonic-clonic convulsions, short duration; treat if >15 mins -Supportive therapy ONLY (do NOT use stimulants)
Anti-Epileptics (Part II) - Na+ channel blockers
Drug Drug class MoA Indications DoC Pharmacokinetics Adverse Effects
Nystamus, diplopia, ataxia
Gingival hyperplasia (swollen gums)

Zero Order elimination
Coarsening of facial features in children
kinetics
Hirsutism
Phenytoin
Fetal Dilantin Syndrome (↓ growth, cleft
Partial seizure Inhibition of vasopressin
palate)
(simple, complex, 2° release
Newborn Hemorrhagic Disease (excessive
generalized tonic- Hyperglycemia
bleeding in newborn due to oxidative
clonic)
degradation of Vit. K in fetus (Treat with Vit.
K in final month of pregnancy/newborn)
Carbamazepine &
Phenytoin:
3 Blood Dycrasias:
Generalized Tonic-Clonic
Aplastic Anemia
Seizures CI in pregnancy
Agranulocytosis
Neuropathic pain (teratogenic)
Carbamazepine Prolongation of inactive state of Thrombocytopenia
Bipolar disorder
Blockage of Voltage- voltage-gated Na+ channels following
P450 inducer
action potential + prolongation of Skin rash (SJS)
gated Newborn Hemorrhagic Disease
refractoriness
Oxcarbazepine Na+ channels
Steven-Johnson Syndrome (SJS)
(Structurally related to ↓ release of glutamate
Toxic epidermal necrolysis (TEN)
Carbamazepine)
Generalized tonic-clonic
Absence seizures Partial seizures
Lamotrigine SJS (rashes)
Infantile spasms Atonic seizures
Bipolar disorder
Adjunct for: Partial seizures
Zonisamide (simple, complex, SJS/TEN
2° generalized tonic-clonic)
Alternative (due to AEs) for:
Block Na+ channels Pre-synaptic: Sedation
Phenobarbital Generalized Tonic-Clonic
Enhance GABAA Block voltage-gated Na+ channels to P450 Enzyme induction Depression
(Barbiturate) Partial seizure, simple/complex
↓ glutamate release Agitation
Block glutamate Myoclonic seizures
. Non-selective drugs Blockage of glutamate receptors, Alternatives for: Acute myopia & glaucoma
Inhibits excitatory responses Partial seizures Somnolence, fatigue
(simple, complex, Dizziness, Parasthesias
Topiramate Teratogenic
Post-synaptic: 2° generalized tonic-clonic) Renal stones, Oligohydrosis
Enhances GABAa signlaing Hyperthermia
Topiramate: Metabolic acidosis
-Generalized tonic-clonic Inhibits CYP450 (↓
-Absence seizure Tonic-Clonic metabolism of several
Block Na+ channels Hepatotoxicity (esp. if < 2 yrs & if taking
-Migraine Myoclonic drugs, including itself)
Blocks Na+ channels multiple antiepileptic drugs)
Valproate Block T-type Ca2+ Blocks T-type Ca2+ channels
Absence Teratogenic (spina
Displaces phenytoin from plasma proteins
channels Valproate: Atonic bifida) folic acid
Fine tremor, Weight gain
-Atonic Seizures Atypical Absence supplements
-migraine recommended
Anti-Epileptics (Part III)
Drug Drug class MoA Indications DoC Pharmacokinetics Adverse Effects
Absence seizures involve oscillatory
SJS
neuronal activity between thalamus
Ethosuximide Blockage of T-type Ca+ channels Absence seizures SLE
& cortex, governed by a low-
(rare)
threshold Ca2+ current
Benzodiazepines Diazepam (Diastat

Diazepam: Febrile convulsions AcuDial): breakthrough & Diazepam: IV or rectal
(Lorazepam & Withdrawal seizures if discontinued
May help, or worsen atonic febrile seizures
Diazepam) Post-synaptically suddenly
Direct action on the GABAA receptor
Barbituates All 3: Drug-induced
Sedation, Tolerance
seizures in NON-
(i.e., Phenobarbital)
epileptics
Dizziness, Difficulty concentrating
Pre-synaptically
Tiagabine Enhance GABAergic Inhibition of GABA reuptake
Rarely used Tremor
Psychosis (rare)
Neurotransmision Pre-synaptically
and/or Irreversible Inhibitor of GABA
Vigabatrin Infantile spasms Irreversible visual field defects (33%)
↓ Glutamatergic aminotransferase (GABA-T) →
Inhibition of degradation of GABA
Neurotransmission
Pre-synaptically Postherpetic neuralgia
↓ glutamate release (possibly by Fibromyalgia
Gabapentin
blocking presynaptic Ca2+ channels Adjunct for Partial seizures
Pregabalin (simple, complex,
↑ GABA release (unknown MoA) 2° generalized tonic-clonic)
Other drugs Alternative for Atypical Absence Sedation (prominent)

Clonazepam
(Benzodiazepines) Infantile spasms Tolerance
Acetazolamide Alternative for Atypical Absence Tolerance
Atonic seizures (3rd line) Aplastic Anemia
Felbamate Other drugs Infantile spasms Hepatotoxicity
Pyridoxine
Corticotrpoin Infantile spasms
Glucocorticoids
Steroids Infantile spasms
Status Epilepticus = Continuous Seizure Non-Pharmacological Approach for Seizure Control

1. IV Lorazepam (Benzo) (Initial) Type Description MoA
↓ (Seizure continues) . Surgery Most extreme, last resort Removal of local area of abnormal brain from which seizures originate
2. IV Phenytoin or Fosphenytoin Ketogenic Diet

Fat : Carb : Protein = High fat content & extremely low carbohydrate content → ketosis →
4:1:1 anti-seizure effect
↓ (Seizure continues) .
Use device when sense Intermittent electrical stimulation of LEFT vagus nerve with implanted
Vagus Nerve Stimulation
3. IV Phenobarbital imminent seizure pacemaker-like device
↓ (Seizure continues) .
4. IV General Anesthesia
Midazolam, propofol, or barbituates (last resort)
Anti-Parkinsonism Drugs (Part 1)
DA Receptors = D1, D2
Parkinson's Disease 4 features of Parkinsonism:
-D1 activates activate adenylyl cyclase (Gs)
Etiology: Unkown -Resting tremor
-D2 inhibits adenylyl cyclase, activates K+ current & ↓ Ca2+ currents (Gi)
Pathogenesis: Loss of neurons in substantia nigra pars compacta (provides -Muscle rigidity
Secondary Parkinsonism:
dopaminergic innervation to the striatum) → ↓ inhibitory influence of DA on -Bradykinesia
Viral encephalitis; multiple small vascular lesions;
cholinergic neurons in the striatum → ↓ control of muscle movement -Impaired postural balance
Classical anti-psychotic drugs (C.I. in Parkinsonian patients)
General Treatment Strategies:
-Restore dopaminergic input in the basal ganglia (striatum) & antagonize the Dopamine Synthesis:
excitatory effect of cholinergic neurons → reestablish DA/Ach balance -Originates from precursor tyrosine (neutral amino acid)
-Tyr, Phe, & Leu are transported by L-system across BBB in a Na+-independent manner
-Rate-limiting step in DA synthesis: L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) by tyrosine
hydroxylase; converted to dopamine by DOPA decarboxylase (very fast)
-DOPA levels are usually negligible in the brain; thus, can ↑ formaCon of DA by providing DOPA
decarboxylase w/↑'ed amts of L-DOPA
-Vesicular monamine transporter 2 (VMAT2) transports DA into vesicles for release
-DA is metabolized by COMT, MAO, & aldehyde dehydrogenase;
Homovanillic acid (HVA) = principal metabolite
Note: The levels of tyrosine in the brain are high & above the Km for tyrosine hydroxlase; under normal
conditions, dopamine synthesis cannot be ↑ much by ↑ tyrosine in the brain
DOPA levels are usually negligible in the brain; thus, excess L-DOPA can be given to ↑ formaƟon of DA
NOTE: DA does NOT cross the BBB
Peripheral: Nausea, vomiting, cardiac

arrhythmias, hypotension, tachycardia,
Rapidly absorbed from small
Levorotatory stereoisomer of ventricular extrasystoles
intestine, delayed by food
DOPA CNS: visual, auditory hallucinations
Metabolic precursor of DA & NE dyskinesia
Certain amino acids can compete
Symptomatic relief of Contraindications:
Drug transported into CNS → with levodopa for absorption &
*Only works if there is enough Parkinson only -MAO inhibitors (causes HTN)
converted to DA in brain → Restores transport from the blood to the
residual dopaminergic neurons to -Psychotic (have excess DA)
DA levels in extrapyrimidal centers brain
Levodopa convert levadopa to DA (early Does not stop progression -Angle closure (acute angle) glaucoma
stage of Parkinson's) -Melanoma (levodopa is melanin precursor)
Dopamine Much of drug is decarboxylated to DA Vit B6 ↑ peripheral metabolism of
Tx usually works for 3-5 -Peptic ulcers (can cause GI bleeding)
Precursors in periphery → Peripheral AE levodopa & ↓ its effecCveness
Fluctuations in response: related years
to timing of drug intake = "wearing- On/off phenomenon = off-periods of
t1/2 = 1-3 hrs
off reactions" or "end-of dose akinesia for few hours followed by on-
2/3 appears in urine, 1-3% reaches
akinesia" periods of ↑ mobility with dyskinesia (seen
brain
in persons who respond well to initial
treatment)
↓ metabolism of levodopa in GI &

DOPA decarboxylase inhibitor ↓ daily requirements of Admin with levodopa
Carbidopa peripheral tissues →
Does not cross the BBB levodopa Allows 10% to reach brain
↑ availability in the CNS
Sinemet Carbidopa + levodopa DoC for Parkinson's Dx Fixed proportion (1:10 or 1:4)
Anti-Parkinsonism Drugs (Part 2)
GI disturbance (N/V, anorexia)
Used with levodopa CV effects (postural hypotension)
Dopamine Receptor Ergot DA agonist (Little response if patient Usually admin with levodopa Dyskinesias, Mental disturbances
Pure D2 agonist
Agonist does not respond to Headache, ↑ arousal, nasal congestion
Bromocriptine
Decrease fluctuations & levodopa) No toxic metabolites Pulmonary Infiltrates, Vasospasms
Does not require exzymatic conversion
dyskinesias of long term therapy No transport competition Pleural & retroperitoneal fibrosis
Ergot derivative Hyperprolactinemia Erythromelalgia (red, swollen, painful
hands & feet)
Affinity for D3 receptors Initial treatment of Erythromelalgia
Pramipexole Note: older people more
Treats mild Parkinson's Parkinson's in younger Vasospasms
vulnerable to AEs of DA agonists
Ropinirole Dopamine Receptor Pure D2 receptor agonist patients Metabolized by CYP450 Pleural & retroperitoneal fibrosis
Transdermal Recalled in 2008 due to formation of
Rotigotine Agonists 2nd line drugs
Smooth out fluctuations Once daily use rotigotine crystals on the patches
(Non-Ergot) Highly Emetogenic (pretreat with
Rescue therapy for "OFF"
SC QT prolongation
Apomorphine trimethobenzamide or Avoid 5-HT3 antagonists (casue Dyskinesia, Drowsiness, Sweating,
episodes of akinesia
domperidone (antiemetic)) hypotension, loss of conscious) Hypotension, Injection site bruising
Selegiline No MAO-A blocking (no
(Deprenyl) hypertensive crisis) Selectively and irreversibly inhibits
↓ motor fluctuaCons in
MAO Inhibitors Modestly helpful taken alone early MAO-B (metab. Dopamine) → ↑ DA in
advanced disease
Use as adjunct to levodopa
Rasagiline in disease or as adjunct in the brain
advanced disease
Inhibition of Dopa-Decarboxylase →
Rapidly absorbed, bound to
activation of other pathways of Hepatotoxicity (Talcapone) → ↑ liver
Fluctuations in levidopa plasma proteins
levodopa metabolism: enzymes (must monitor liver function)
Smoother response, ↑ "on-Cme" therapy
Tolcapone Catechol-O - & ↓ total daily levodopa dose
COMT → ↑ 3-O-methyldopa
Talcapone = peripheral & central
Dyskinesias, Confusion
Methyltransferase 3-O-MD competes for transport across
↓ motor fluctuaCons in effects
Nausea, Diarrhea, Abdominal Pai
Entacapone Entacapone preferred for less AE advanced disease
Inhibitors (COMT) (no hepatotoxicity)
intestinal mucosa & BBB
Entacapone = peripheral ONLY
Orthostatic hypOtension
Sleep disturbances
↓ levodopa dose ~30% Entacpaone available as fixed dose
Prolongs duration of levodopa by ↓ Orange-colored urine
w/levodopa/carbidopa
peripheral metabolism
Restlessness, Agitation
Confusion, Hallucinations
Acute toxic psychosis (high doses)
Antiviral drug
Livedo reticularis (mottled reticulated
vascular pattern that appears like a lace-
Less efficacious than levodopa,
↑ synthesis, release or reuptake of DA like purplish discoloration of the lower
Amantadine Ion Channel Blocker Rapid tolerance, fewer side effects
from surviving neurons extremities)
Use with caution in patients with
Urinary retention
history of seizures or CHF
Perhipheral edema (use diuretics)
Heart failure, Orthostatic hypotension
Headache
GI disturbances
Tremor
Mood changes
Rigidity
Benztropine Adjuvant in anti-parkinsonian Contraindications: Xerostomia
Drooling
mesylate therapy Glaucoma Pupillary dilation
Antimuscarinics Patients using
Benign Prostatic Hypertrophy Confusion, Hallucinations
antipsychotics
Trihexyphenidyl Little effect on bradykinesia Pyloric stenosis Urinay retention
(drug induced
Dry mouth
Parkinson's)
General Anesthetics (Part 1)
Features of Inhaled Anesthetics
Minor procedures: "monitored anesthesia care" Balanced Anesthesia: (goals) • ↓ cerebrovascular resistance, ↑ brain perfusion
or conscious sedation, using oral or parenteral -IV agent bolus used for induction since partial pressure of inhaled • Bronchodilation, ↓ minute venClaCon
sedatives with local anesthetics agent takes time to build up in brain • ↑ Potency → ↑ liposolubility → ↓ Rate of onset
-Halogenated hydrocarbons usually produces inadequate analgesia, • Recovery from effects is due to redistribution from the brain
Extensive surgeries: Pre-op benzodiazepine for supplemental agent needed (opioid or N2O) • After long time, partial pressure of anesthetic in all tissues
induction (IV thiopental or propofol), maintenance -Neuromuscular blocking agent must be given is equal to that in the inspired gas (equilibrium)
with inhaled + IV anesthetics, including a -Minimize CV and respiratory response to drugs (minimize dose of • While the partial pressures are equal,
neuromuscular blocker halogenated hydrocarbons) concentration of anesthetic in various
tissues will be different (partition coefficient)
Drug Class MOA Indications Pharmacokinetics Adverse Effects Notes

Inhaled Anesthetics
All inhaled: Least likely to cause typical AE

Not metabolized by
Major route of Expands air cavities → avoid in
Low anesthetic potency human tissues
elimination is pneumothroax, obstructed bowel
Nitrous oxide (N2O) Gas Strong analgesic, amnesic,
expiration Hematotoxicity (inhibits methionine
& sedative actions Highest MAC [minimum
Liver metabolism may synthase): Megaloblastic anemia
alveolar concentration]
contribute with chronic exposure (dentists)
Airway irritation, Low volatility Peripheral vasodilator

Least metabolised
Desflurane Enhance GABAA & glycine receptors (boiling point), requires special Least suitable due to
(except N2O)
vaporizer pungency
(on inhibitory neurons)
Most inhibit nicotinic receptors Degraded to vinyl Peripheral vasodilator
Nephrotoxic (fluoride released
Sevoflurane ether "Compound A" Bronchodilation →
Maintain anesthesia during metabolism)
Typical Effects: by CO2 → Renal damage preferred
↓ arterial blood pressure Not good analgesics Some excreted by Pungent, nephrotoxic, Seizure-like
Enflurane Respiratory depression (N2O least) Myocardial depressant
kidney activity (not a problem)
Bronchodilation Use w/ neuromuscular
Volatile ↑ intracranial pressure (N2O least) blocking agents for All VHH: malignant hyperthermia
halogenated ↓ GFR & renal blood flow adequate paralysis with succinylcholine (AD defect in
↓ hepaCc blood flow Peripheral & coronary
hydrocarbons “balanced anesthesia” ryanodine receptor → ↑ Ca)
Isoflurane Little metabolised vasodilator (Good for
- Treat with dantrolene
(VHH) VHH = Uterine relaxants Halo & Sevo for patients - Screen with caffeine-halothane
ischemic heart disease)
with airway problems muscle contracture test
Children (sevo)
Sensitize heart to catecholamine →
40% metabolised Pleasant odor
arrhythmias (also Isoflurane, but
Halothane Forms trifluoro-acetic Myocardial depressant
less)
acid, Cl-, Br- ions Bronchodilation
Life-threatening hepatitis (no tx)
70% metabolised by
Methoxyflurane Nephrotoxic (fluoride released) Lowest MAC
liver
Signs & Stages of Anesthesia MAC = minimum alveolar concentration = concentration (i.e. % of partial
1. Stage I: Analgesia. Amnesia. pressure) resulting in immobility in 50% of patients upon noxious stimulus =
2. Stage II: Excitement, Delirium, Irregular respiration, Vomiting. Avoided by IV thiopental ED50 on dose-response curve
3. Stage III: Surgical anesthesia. Unconsciousness. (Loss of eyelash reflex, regular respiration) Though only 50% at 1.0 MAC, 95% anesthetized at 1.1-1.3 MAC
4. Stage IV: Medullary depression. No eye movement. Respiratory and cardiovascular failure.
MAC ↓ with age (not affected by sex, height, weight), adjuvant drugs,
hypothermia, hypothyroidism, pregnancy
MAC ↑ with anxiety, thyrotoxicosis
Speed of anesthetic induction depends on: MAC values are additive
A) Solubility
Anesthetic MAC λ(oil:gas) λ(blood:gas) Onset/Recovery
Nitrous oxide (N2O) 104 1.4 0.47 Rapid, Incomplete anes
Desflurane 6 19 0.42 Rapid
Sevoflurane 2 51 0.69 Rapid
Enflurane 1.7 98 1.8 Medium
Isoflurane 1.4 98 1.4 Medium
Halothane 0.75 224 2.3 Medium
Methoxyflurane 0.16 960 12 Slow
↓ MAC = ↑ potency = ↑ λ(oil:gas) liposolubility = ↑ λ(blood:gas) = slow onset

↑ Solubility = longer Cme to reach parCal pressure equilibrium = slow onset
B) Concentration in inspired air

C) Pulmonary ventilation rate C)
Slight increase in arterial tension if anesthetic has low blood solubility (4x vent. = ↑ N2O 15% @ 10 mins)
Significantly increase tension if moderate or high blood solubility (4x vent. = doubles halothane @ 10 mins)
D) Pulmonary blood flow

↑ blood flow slows rise in arterial tension (↑ "capacity") → Slows onset
E) Concentration (partial pressure) gradient of anesthetic between

arterial and venous blood (high solubility = ↑ anestheCc uptake in
tissues = high atriovenous gradient = slow onset)
Rate of Elimination depends on:

A) Elimination from the brain (reverse process of uptake)
B) If solubility is low, duration of anesthesia does not matter
C) If solubility is high,recovery will depend on duration of anesthesia, as depot will have formed in tissues
D) Patient will be arousable when partial pressure is MACawake
Malignant hyperthermia with succinylcholine; AD defect in ryanodine receptor (RYR-1 gene on Chr 19) →
↑ Ca in muscle cells → Rigidity, hyperthermia, hyperkalemia, death by lactic acidosis
- Screen with caffeine-halothane muscle contracture test → muscle biopsy contraction with 3% halothane or 2 mM caffeine
is positive
Dantrolene prevents Ca2+ and calmodulin from activating the RyR-1, blocking release of Ca2+ from the SR
General Anesthetics (Part 2) - IV Anesthetics
IV Anesthetics
Exacerbate acute intermittent Effect ended by redist-

Highly liposoluble
Thiopental Ultra-short acting Induce anesthesia & short porphyria (induces ALA synthase) ribution, but hepatic
Can ↓ intracranial pressure Acts on brain within 1
Methohexital barbiturates surgical procedures Apnea, coughing, chest wall spasm, metabolism required for
min
laryngo/bronchospasm elimination
Diazepam Premedication for
Flumazenil used to
Lorazepam Benzodiazepines anxiolytic & anterograde Can prolong post-operative recovery
accelerate recovery
Midazolam amnesia effect
Morphine
Fentanyl Can ↑ chest wall rigidity & cause
Anesthetic agents
Sufentanil Opiods Good analgesic action postoperative respiratory depression
Strong analgesia effect
Alfentanil (treat with naloxone)
Remifentanil
Causes state of quiescence, ↓ anxiety, &
Use with fentanyl & N2O for Innovar = fentanyl + Antidopaminergic
Droperidol Neuroleptic indifference; adrenergic-blocking,
neurolept anesthesia droperidol Antipsychotic
antiemetic, anticonvulsant
Anesthesia onset similar to Outpatient procedures, Rapid liver Hypotension
Propofol Antiemetic actions
benzodiazepines, recovery faster Induction metabolism Negative inotropic effects
Nausea and vomiting
Rapid-onset, short-duration Minimal CV and resp.
Etomidate Injection site pain
anesthesia depression
Adrenocortical suppression
Dissociative anesthesia (out-of-
Blockade of NMDA receptors
Patients in cardiogenic or body, illusions, vivid dreams = Only anesthetic with CV
Ketamine Sympathetic activation by Norepi
septic shock "emergence phenomenea") stimulation
reuptake inhibition
↑ cerebral blood flow → ↑ ICP
Adjuvants
Pancuronium
Neuromuscular blockers Achieve muscle relaxation
Succinylcholice
Diphenhydramine H1 blocker Prevent allergic reactions
Ranitidine H2 blocker Reduce gastric acidity
Prevent aspiration of
Ondansetron Antiemetic 5-HT3 blocker stomach contents
Prevent salivation,
Scopolamine Antimuscarinic Amnesic effect bronchial secretions, &
brandycardia
Local Anesthetics
Infiltration anesthesia and Ester links broken Short-acting
dental procedures down easier than 1x potency
Procaine Ester-linked* Unprotonated (uncharged) form enters CNS stimulation (diazepam prevents
2-chloroprocaine = amide (shorter Hydrophilic → Rapid
nerve cell → protonated (+) form blocks seizures) →
epidural duration) dissociation & removal
Na channel from inside → abolishes leads to CNS depression
Metabolized by Intermediate-acting
pseudocholinesterase action potentials Ophthalmic & topical
Cocaine Depress cardiac excitability & 2x potency
anesthesia Weak bases (pKa ≈ 8-
conduction (esp. Bupiva), Only Vasoconstrictor
PABA metabolite causes Reversibly block nerve conduction of 9), preped as water
Spinal/topical anethesia Hypotension (not Prilo), treat with Long-acting
allergic reactions & sensory impulses (motor in higher soluble salts with
Tetracaine inhibits sulfonamide concentrations) in a limited area Highly hydrophobic → Slow hydrochlorides (weak Epinephrine 16x potency
release from tissues Cocaine causes HTN and arrhythmias Highly hydrophobic
action acid)
↑ liposolubility → ↑ potency → fast due to reuptake inhibition
Benzocaine onset → longer duraCon of acCon Surface use only
Vasoconstriction
Most popular local Methemoglobinemia (due to
decreases clearance & Intermediate-acting
Lidocaine Open/inactive Na-channels have higher anesthetic o -toluidine metabolite of Prilo)
increases duration of Lido: 4x potency,
affinity for drug → greater effect at more Class 1 antiarrhythmic Treat with methylene blue
action low pKa
Amide-linked* rapidly firing axons Part of EMLA cream with
Prilocaine Given with Epinephrine Prilo: 3x potency
lidocaine
Small unmyelinated C fibers (pain) > (vasoconstriction & α2 mediated
Metabolized by P450 Not commonly used
Small myelin. Aδ fibers (pain, temp) > inhibition of Substance P/sensory Long-acting
Bupivacaine (Cardiotoxic) Bupi/Ropi can cause
Aγ > Aβ > Aα (postural, touch, motor) neurons) → can cause hypoxic injury 16x potency
Epidural lethal arrhythmias
Binds to local proteins
Ropivacaine
*Esters have one “i” in their name TAC = Tetracaine, Adrenaline, Cocaine Convulsions: give oxygen & IV diazepam
*Amides have two “i” in their name EMLA = Lidocaine + Prilocaine Hypotension: give IV/IM vasoconstrictor (Epi)
Allergic rxn: give diphenhydramine or SC Epi
Skeletal Muscle Relaxants (Part I) - General
Neuromuscular blocker - used during surgical procedures and ICUs to cause paralysis
Genereal Uses of Effects of Disease & Ageing on Drug Response:
Spasmolytics - used to reduce spasticity in various neurologic conditions
Neuromuscular blockers: Myasthenia gravis, Advanced age,
Spasticity = ↑ tonic stretch reflexes and flexor muscle spasms, with muscle weakness (associated
Surgical relaxation (adjuvant) Aminoglycosides, Tetracylcines, Inhaled anesthetics→
with cerebral palsy, multiple sclerosis, stroke)
Control ventilation ↑ blockade
Convulsions
All neuromuscular blocking groups have 1-2 quaternary ammonium groups → Prevent trauma during ECT Severe burns & upper motor neuron disease →
Highly polar, poor lipid solubility, poor membrane penetration → ↑ extrajuncConal receptors (receptors outside typical area) →
Do not enter cells or cross BBB, must be given IV or IM Genereal Uses of Spasmolytics: Resistance to non-depolarizing muscle relaxants →
Chronic spasms ↓ blockade (higher dose required)
Also, NO CNS effects
Skeletal Muscle Relaxants (Part II) - Neuromuscular Blockers

Drug Class MOA Pharmacokinetics Adverse Effects Notes
Hydrolysis by plasma Short-acting

Mivacurium Non-depolarizing: competitive pseudocholinesterase → NOT dependent on liver or kidney
Inactivation Laudanosine (atracurium metabolite) may cause (good for dysfunction)
antagonists, bind (but do not
hypotension, seizures
activate) nicotinic receptors,
preventing ACh from binding Hydrolysis by non-specific
Tubocurarine: Histamine release (also Miva,
Atracurium plasma esterases
Meto, & Atra release lower levels) → Erythema, ↓ Intermediate-acting
Benzylisoquinolines At [↑], may enter channel pore, t1/2 not ↑ in renal failure
BP, ↑ HR
("acur" or "ocur" in name) making blockade stronger Steroisomer of atracurium,
(Treat with antihistamines before neuromuscular Hoffman elimination =
more potent spontaneous reaction
Cisatracurium blockade)
Bind to nicotinic receptor → motor Forms LESS laudanosine (since
weakness → skeletal muscles become less drug is needed)
Tubocurarine/Metocurine:
Doxacurium flaccid, inexcitable to stimulation →
Ganglion blockade → ↓ BP, ↑ HR
Metocurine flaccid paralysis
Long-acting
Tubocurarine
(prototype) Can be overcome by increasing [ACh]
with neostigmine or edrophonium Contain ester groups that are
Vecuronium (AChE inhibitors) hydrolyzed by liver esterases Intermed. Acting
(Also add atropine or glycopyrrolate Cardiac M2 block → tachycardia, arrhythmias
Pipecuronium (M blocker) to prevent bradycardia) Renal/Hepatic elimination
Ammonio steroids (Mostly Pancuronium, Rapa & Ro slightly)
Pancuronium ("curonium" in name) Long-acting

Antagonized by Succinylcholine CVS effects of Pan usually not a problem
Rocuronium
Skeletal Muscle Relaxants (Part III) - Succinylcholine
Drug Class MOA Pharmacokinetics Adverse Effects Notes
Activation of ALL autonomic cholinoceptors:
Depolarizing: nicotinic receptors in both sympathetic &
Bind and activate nicotinic receptors, Use when short duration of parasympathetic ganglia, muscarinic receptors in
but release slowly → continuous action is desired heart
depolarization of junction →
fasciculations → flaccid paralysis Ultrarapid onset (<1 min) Bradycardia (Muscarinic activation) → Prevent by
("Phase 1 block" or "depolarization Ultrashort duration (5-10 mins) thiopental, atropine, ganglionic blockers, or non-
block") depolarizing muscle relaxant
Rapid hydrolysis by plasma
Succinylcholine = Not reversed by AChE inhibitors pseudocholinesterase Histamine release (slight) No CNS effects (unable to
Succinylcholine
Ach + Ach Muscle Pain (esp. in abdomen) due to muscular penetrate BBB)
With large/repeated/continuous Not metabolized effectively at damange
dose, membrane repolarizes, but is synapse ↑ K+ (↑ risk with burns or muscle trauma) →
desensitized (cannot be depolarized, cardiac arrest or circulatory collapse
channels stay closed) Patient may experience ↑ intraocular pressure (extraocular muscle
("Phase 2 block" or "desensitized prolonged paralysis if they have contractions)
block") abnormal variant of ↑ intragastric pressure → emesis and/or
butyrylcholinesterase aspiration
CAN be reversed by AChE inhibitors Malignant hyperthermia (See Anesthetics)
Treatment: dantrolene
Skeletal Muscle Relaxants (Part IV) - Spasmolytics

Drug Description MOA Adverse Effects Notes
Diazepam Enhance action at GABAA receptors Sedation Reduce muscle spasms of almost any origin
GABAB Agonist Spasticity of motor neuron disease or spinal cord

Baclofen Hyperpolarization → presynaptic Increased seizure activity injury; May reduce pain by inhibiting release of
inhibition substance P
Progabide Drugs acting on CNS Both GABAA & B agonist
Gabapentin ↑ GABA release Antiepileptic, Also indicated for MS
Tizanidine α2-adrenoreceptor agonist Related to clonidine
Glycine Inhibitory neurotransmitter Active orally, readily passes BBB
Idrocilamide Inhibits glutamate transmission in
Indicated for ALS
Riluzole CNS
Binds to ryanodine receptor → ↓

Dantrolene Drugs that act on Used for malignant hyperthermia
Ca2+ release from SR of muscle
skeletal muscle
Botulinum toxin Prevents Ach release Used for cerebral palsy
↓ acute spasm due to trauma or Sedation
Related to TCAs
Cyclobenzaprine strain Confusion
Strong anti-muscarinic
Acts on brainstem Transient visual hallucinations
Drugs of Abuse (Part 1)
CNS Depressants
Drug MoA/Examples Effects Intoxication Effects Addiction Withdrawl Treatment
Withdrawal:
Motor incoordination 6-12 hrs: tremor, nausea, Long-acting Benzodiazepines (diazepam &
Affects many receptors: Sedation, Sleep vomiting, sweating, chlordiazepoxide); (lorazepam & oxazepam for elderly &
GABAA-R agitation, anxiety liver failure)
Kir3/GIRK channels Chronic: liver disease, CV Acquired tolerance & Vistual, auditory, tactile
Initial stimulation (due to suppression
Ethanol adenosine reuptake disease, endocrine/GI physical dependence hallucinations Prophylaxis:
of inhibitory systems)
glycine-R effects, malnutrition, with heavy drinking 24-48 hrs: seizures Disulfiram (inhibits aldehyde dehydrogenase → nausea,
NMDA-R cognitive deficits 48-72 hrs: delirium vomiting)
5-HT3-R tremens → 5-15% Naltrexone (Opioid antagonist, ↓ craving)
Teratogen morality Acamprosate (NMDA antagonist, ↓ relapse)
Topiramate (antiepileptic, ↓ craving)
Normal (low) dose:
nausea, vomiting,
Can cause physical Long acting benzodiazepine: Diazepam
sweating, tremor,
Benzodiazepines Anxiolytic, sedative dependence over years
anorexia, restlessness,
Addiction is rare Withdraw alcohol after long-acting benzo is established
incoordination;
High dose: seizures,
Barbiturates Same as Benzodiazepines psychosis, depression
Dysphoria, sweating,
Strong tolerance and
Heroin, morphine, codeine, weakness, flu-like
dependence; Methadone, buprenorphine (long-acting opiods) or
Opioids oxycodone; Pinpoint pupils, Seizures symptoms, vomiting,
Behavioral disruptions, Clonidine, lofexidine (α2 agonists)
Doctors: meperidine, fentanyl tremor, hyperpnea
Unproductive life
Not life-threatening
Psychotimulants
Drug MoA/Examples Effects Intoxication Effects Addiction Withdrawl Treatment Notes
Used to treat chronic asthma, &
migranes with ergotamine (↑
Caffeine, theophylline, vasoconstriction) 2-5g: spinal cord
Fatigue, sedation Distributes widely, incl. CNS,
theobromine 100-200mg: ↓ faCgue, ↑ mental stimulation,
Methylxanthines Tolerance can be rapid placenta, & milk;
alertness Emesis, Convulsion
(Caffeine) Addiction is rare High dose: headaches, Metabolized by CYP1A2,
Block adenosine receptor → 1.5g: anxiety, tremors 10g (100 cups): death from
nausea excreted in urine
↑ NorEpi +ve chrono/inotropic arrhythmias
Mild diuresis
↑ HCl → pepCc ulcers
Irritability, risk of violence Dopamine depletion →
Intense euphoria No treatment needed
Tremors, convulsions craving Mild; sleepiness,
CNS stimulant → ↑ awareness, De-esterified & demethylated to
Inhibits reuptake of Respiratory depression bradycardia,
Cocaine involuntary motor activity, paranoia Antidepressant, benzoylecgonine, excreted in
Dopamine, NE, 5-HT Hyperthermia (via IV & freebase crack dysphoria, depression, urine (identifies user)
dopamine agonists have
hypothalamus smoking ↑ effect (↑ fatigue, craving
Activates sympathic system been tested
thermoregulation) bioavailability)
Insomnia, irritability,
Methamphetamine,
Used to treat ADHD and narcolepsy weakness, dizziness,
Phenmetrazine, Abstinence syndrome:
tremor, hyperreflex
Methylphenidate Tolerance can be ↑ appeCte, sleepiness, Generally none Cathinone (related alkaloid)
Amphetamines CNS stimulant
↑ release of catecholamines marked exhaustion, mental (Antidepressants) has similar effects
Activates sympathic system (CV & GI Confusion, delerium, panic,
(& dopamine) depression
effects) suicidal
May be a mild MAO-I
Psychosis, convulsions
Drugs of Abuse (Part 2)
Drug MoA/Examples Effects Intoxication Effects Addiction Withdrawl Treatment Notes
Help smoking cessation High doses: medullary Nicotine replacement Highly liposoluble (enters
Highly addictive
Nicotine receptor agonist Low doses: euphoria, arousal, (respiratory) paralysis, therapy (patch, gum, etc) CNS, placenta, milk)
Tolerance within days
Low dose: ganglionic relaxation, hypotension, ↓ GI & Mild: irritability, Bupropion atypical
Nicotine Activtes N-receptors on
stimulation (ANS) ↑ a[enCon, learning, problem bladder activity sleeplessness antidepressant 1-2mg/smoked cigarette
dopamine neurons in
High dose: ganglionic blockade solving, Chronic: CV, respiratory Varenicline (partial N
VTA
↓ appeCte disease, cancer agonist, ↓ rewarding) 60mg = lethal
Hallucinogens
Euphoria → drowsiness, relaxaCon Theraputic (dronabinol) Endogenous CB ligands:
Δ9-THC binds to CB1 (brain) & ↑ HR, ↓ BP, Reddening of Tolerance & mild
↑ appeCte, dry mouth use for anorexia in AIDS & anandamide, 2-
Marijuana CB2 (immune cells) → Gi → conjuctiva, physical dependence
↓ muscle strength & skilled motor nausea/vomiting in arachidonylglycerol
inhibits adenylyl cyclase Toxic psychosis with frequent use
activity cancer chemotherapy (Not stored)
Affect thought, perception, & mood;
LSD no psychomotor effects Not addictive
5-HT2-R agonism in CNS Treat agitation with
Mescaline Hallucinations, SNS effects (pupil “Bad trips” cause agitation Tolerance with 3-4 daily No withdrawl
Related to ergot alkaloids diazepam
Psilocibin dilation, ↑ blood flow/BP, piloerection, doses
↑ body temp)
Medically replaced by
Inhibits dopamine
Dissociative anesthesia & analgesia Ketamine
NMDA (glutamate receptor) reuptake
Phencyclidine (PCP) Numbness, staggered gait, slurred Tolerance develops Increased sensitivity to
antagonist Hostile/bizzare behavior
speech, muscular rigidity external stimuli may last for a
Stupor, coma
week
↑ HR, muscle aches, Degenerates
↑ 5-HT release Feelings of empathy & intimacy, no Depressed mood for Methlyenedioxy-
MDMA (ecstasy) agitation, hyperthermia, serotonergic neurons in
↑ affinity for SERT cognitive impairments weeks methamphetamine
seizures rats
Inhalants
Euphoria & analgesia → loss of Asphyxia, death (if 100%
Nitrous oxide Used by medical personelle
consciousness N2O is used)
Gasoline, paint thinner, glue
Volatile organic Cancer, Neuropathies, Teenage boys from lower
(aliphatic & aromatic Exhilaration & light headedness
solvents Cardio-/hepatotoxicity socioeconomic classes
hydrocarbons)
Organic nitrites Amyl, butyl nitrates Treat angina, Enhance erection Not addictive
Anabolic steroids Increase muscle size
Abuse: excessive self-admiistration of any substance for nonmedical purposes

Abused substances usually produce desirable effects on the brain
(reinforcing properties) which initiate drug-seeking behavior
Physical dependence: Withdrawl syndrome is produced by abrupt cessation or use of an antagonist
Withdrawl syndrome: physiological & behavioral changes related
to cessation of psychoactive drug to which body had become adapted
Tolerance: Adaptation which results in diminution of a drug's effects over time
Physical dependence + Tolerance = Normal response with persistant use ≠ Use disorder or AddicCon
Pseudoaddiction: patients' behavior when pain is undertreated; resolves when pain is treated
Addiction = Primary, chronic, neurobiologic disease, with one or more of:
impaired control over drug use
compulsive use Mechanism of Addiction
continued use despite harm 1° target for addictive drugs = Mesolimbic dopamine system (activated by drugs)
cravings Ventral tegmental area → Nucleus accumbens, Amygdyla, Prefrontal cortex
Toxicology (Part 1) - Drugs
Drug MoA Effect Treatment
Common Drugs
Stimulates respiratory center → Hyperventilation → Respiratory alkalosis
IV fluids, gastric lavage & activated charcoal
↓ Krebs cycle, ↓ renal funcCon → ↑ ketones & lactate → Metabolic acidosis
Aspirin Moderate (150-200 mg/kg): IV sodium
↑ O2 use, CO2 producCon, Hyperpyrexia, VomiCng,
Uncouple oxidative phosphorylation → bicarbonate → alkalinize urine
tinnitius, hypotension
Severe (300-500 mg/kg): hemodialysis
High doses depress medulla → Central respiratory paralysis → Resp. acidosis
Acetaminophen ↑ NAPQI producCon via CYP2E1 24-36 hrs: ↑ AST/ALT, ↓ prothrombin N-acetylcysteine (↑ glutathione) (can have
150-200 mg/kg (kids) Normally cleared by glutathione S - Hepatic necrosis → hepaCc encephalopathy anaphylactoid reaction)
7 g (adults) transferase Renal tubular necrosis, hypoglycemia, death Gastric lavage, liver transplant
Amphetamines Hypertension → Phentolamine, Nitroprusside (vasodilate)
(Pseudo)Ephedrine Tachyarrhythmias, sweating → Propranolol, Esmolol (β-blocker)
↑ catchcolamines
Phenylpropanolamine Seizures (Muscle activity → → IV Benzodiazepines
Cocaine hyperthermia, rhabdomyolysis) Ammonium chloride (to acidify urine)
Tachycardia, dilated pupils, flushed red skin, dry Physostigmine (NOT for TCA overdose →
Antimuscarinics
mucous membranes, no sweating, hyperthermia, aggravate cardiotoxicity) (can cause
Atropine, TCAs, Block parasympathics
blurred vision, confusion, delerium bradycardia & seizures if given too fast)
antihistamines
Agitation → Benzodiazepine, antipsychotic
Block both β1 & β2 Bradycardia, hypotension
β-blockers IV glucagon (↑ cAMP without β receptor)
Propranolol = most toxic (lipophil) → Block Na+ channels (Class I), wide QRS; seizures
Calcium channel Disrupt membrane polarization ↓ Cardiac contracClity → IV Ca2+
blockers Depress sinus node automaticity ↓ Blood pressure, ↓ HR → Glucagon, epinephrine
Block muscarinic receptor → see above
TCAs α1-blockade, reuptake inhibition → Vasodilation, Hypotension → Seizures → Norepiephrine
Block fast Na+ channels in heart → ↓ conducCon & contracClity, wide PR, QRS, QT → Sodium bicarbonate
+Tyramine (cheese, wine, drugs) → Hypertensive crisis → Phentolamine (α-inh), labetalol (α+β inh)
MAO Inhibitors Cyproheptadine (5-HT2-R antagonist)
+Serotonergic drug (5-HT1A + 2-R) → Hyperthermia, muscle rigidity, myoclonus →
Benzodiazepines
Mild: Small pupils, ↓ BP & HR, lethargy 1st: Establish patent airway & ventilate
Opioids
High: Coma, Respiratory depression (apnea) Naloxone, Nalmefene
Sulfonylureas Glucose bolus; IV octreotide or diazoxide if
↑ insulin release Hypoglycemia
Meglitinides needed (inhibits insulin release)
Neuroleptics Withdrawl Hyperthermia, muscle rigidity, metabolic. acidosis,
Bromocriptine
(Antipsychotics) Neuroleptic malignant syndrome confusion
Aspirin
Occupational & Environmental Toxic Chemicals

Toxin MoA Effect .
Forms CarboxyHb (220x affinity for Hb) → Headache → Confusion →
Carbon monoxide Left shift of O2 sat. curve → ↓ O2 release Tachycardia, syncope →
>60% HbCO is fatal → Cell hypoxia, ischemia Convulsions, Respiratory failure
Binds cytochrom Fe2+ → Inhibits ETC
Treatment
Normally t1/2 = 6 hrs
100% O2 (t1/2 = 80 mins)
Hyperbaric (100%, 2-3 ATM) O2 (t1/2 = 20 mins)
Toxicology (Part 2) - Occupational & Environmental
Solvents
Toxin MoA Effect Treatment
Hypoglycemia, acidosis Manage vitals signs, prevent aspiration
EtOH metabolism depletes NAD+
Ethanol Wernicke-Korsakoff IV dextrose, thiamine, electrolytes
Inhibits glycolysis & gluconeogenesis
Malnutrition Naloxone if comatose
IV Ethanol, fomepizole (Inhibits alcohol
Methanol Formation of formic acid Acidosis, Blindness, Cessation of respiration
dehydrogenase)
Sodium bicarbonate (for acidosis)
Ethylene glycol Formation of aldehydes & oxalate Acidosis, Renal damage, Urinary oxalate crystals
Hemodialysis (if severe)
Ethylene glycol
→ Glycoaldehyde
→ Glycolate
→ Glyoxylate
→ Oxalate
→ Urinary Calcium Oxalate crystals
Pesticides
Inhibit AChE by carbomylation of M: DUMBELS: Diarrhea, Urination, Miosis + Muscle Atropine
Carbamates
active site (reversible, short act) weakness, Bronchospasm, Excitation, Lacrimation, Pralidoxime only if toxin is unknown
Seizures + Sweating + Salivation Atropine large doses
Phosphorylate AChE; Ageing = loss of
Organophosphates Death by respiratory paralysis Pralidoxime before ageing
alkoxy group = ↑ stability
N: HTN, Tachy/bradycardia, twitching, weakness No treatment for delayed neurotoxicity
Blocks Vitamin K Exposide reductase Vitamin K1 (not K3) (takes 6 hrs, 24 hrs peak);
Warfarin Delayed clot formation
(kids & pets) Fresh-frozen plasma if bleeding
Heavy Metals
Heavy metal cations inactivate enzymes & disrupt membranes. They combine with oxygen, sulfur, or nitrogen in ligands. Chelation by electronegative groups.
Lead Hypochromic anemia, ↑ plasma porphyrins Diazepam (seizures)

(Paint) Damage hematopoetic GI, liver, Acute: abdominal colic, CNS changes (children), Mannitol, dexamethasone (cerebral edema)
Organic: kidneys, & reproductive tissues acute encephalopathy Chelation: edetate calcium disodium
tetraethyl Lead, Inhibit ALA Synthase & Ferrochelatase Chronic: (plumbism) peripheral neuropathy (wrist (CaNa2EDTA infusion), dimercaperol (IM),
tetramethyl lead (old in heme synthesis drop), anorexia, anemia, tremor, GI effects succimer (oral), unithiol (IV)
gasoline) Organic: hallucination, headache, convulsions Edetate & dimercaprol used max 5 days
Acute: GI, vomiting, Cholera-like rice water stools, Water, electrolytes

As3+ Arsenite: react with sulfhydryl (-
capillary damage, dehydration, shock, sweet, → Chelation with unithiol, dimercaprol, or
SH) on lipoic acid of PDH
garlicky odor in breath, stools succimer
Arsenic As5+ Arsenate: uncouples MitoC ox.
3+ 5+
AsH3 > As > As > phos.; replaces phosphate, Chronic: Skin changes, hair loss, bone marrow
→ Dimercaperol chelation
Organic ADP → ADP-As (no ATP); Arsenate depression, anemia, GI effects, cancer
ester lysed (arsenolysis)
Massive hemolysis → Renal tubule damage → Renal
AsH3 Gas: Depletes RBC glutathione → → None
failure
Acute: (elemental inhalation) Chest pain, SOB,

nausea, vomiting, kidney damage, gastroentritis, CNS
damage
Mercuric chloride (salt): corrosive, deadly
hemorrhagic gastroenteritis, renal failure Severe: Oral/IV unithiol, IM dimercaprol
Mercury Chronic: TNG triad: Tremor (fine or chorea-like),
Interferes with sulfhydryl (-SH)
Vapor (elemental) Neuropsychiatric (memory loss, insomnia), Mild: Oral succimer
groups, inhibiting enzymes & altering
Salts Gingivostomatitis (gum inflammation)
membranes
Organic Acrodynia: (Pink disease) painful erythema in Metallic/Organic: do NOT use dimercaprol, as
extremities of children (with HTN, diaphoresis, it will redistribute Hg to CNS from other tissues
anorexia, insomnia, milirial rash)
Organic: Methylmercury affects CNS-paresthesias,
ataxia, hearing/vision loss, dysarthria; teratogen
(cerebral palsy-like syndrome)
Vomiting, GI bleeding, lethargy, gray cyanosis

Iron (Ferrous salt tablets Deferoxamine chelation
Severe: GI necrosis, pneumonitis, jaundice, seizures,
for anemia) Activated charcoal does not work
coma
Toxicology (Part 3) - Cyanide
Cyanide Antidote Kit (inhaled amyl nitrate, IV
Binds iron in ferric (Fe3+) state, esp. in
Hyperpnea, headache, hypoxic convulsion, sodium nitrate, sodium thiosulfate)
Cytochrome a,a3 in ETC
Cyanide lactic acidosis, cellular hypoxia + Methylene blue
Blocks transfer of e- to oxygen
death by respiratory arrest Cyanokit (Hydroxycobalamin)
Risk: plastics manufacturing
See bleow
Cyanide Antidote Kit

0. Cyanide binds ferric iron in cytochromes
1. Nitrates (amyl/sodium) oxidize hemoglobin (Fe2+) to

methemoglobine (Fe3+)
2. Methemoglobin competes with Cytochromes for cyanide,

making Cyanmethemoglobin
3. Mitochondrial
Rhodanese
(transsulfurase) make
the nontoxic Thiosulfate
4. Methylene blue is
given, which is reduced
to Leukomethylene blue
by NADPH
5. Methemoglobin is
returned to ferrous
(Fe2+) form by
Leukomethylene blue
Cyanokit
Active agent = hydroxocobalamin,
a vitamin B12 precursor
Reacts with cyanide to form
cyanocobalamin, which is excreted
in urine
Natural Meds & Botanicals
General description: Herbal meds regarded as nutritional supplements for maintenance of health in humans & other animals
-Sold without prescription, lack FDA approval (review for safety, efficacy, purity, or potency is not available, incomplete, or non-existent)
-Alternative medicine = therapies that fall outside conventional medicine (e.g., naturopathy, chiropractic, Unani, herbal medicine, trad'l Chinese medicine, yoga, biofeedback, hypnosis, homeopathy, acupuncture)
-Purified non-herbal supplements DHEA (dehydroepiandrosterone) & melatonin used in search of alternative medicine
Drug Active Ingredient Effects Uses Adverse Effects Notes
Flavonoids Activate cytokines → ↑ IL, TNF Unpleasant taste
Echinacea
Polyacetylenes Anti-inflam → ↑ immune funcCon → ↓ duraCon, Common cold GI symptoms "Echinacea juice"
(E. purpurea)
Caffeonyl conjugates intensity of common cold Headache, Dizziness
Bronchitis Insomnia, Dizziness, Palpitation, Banned from USA
Asthma Tachycardia Arrhythmias, Flushing Contraindicated in: Cardiac arrhythmias,
Ephedrine (prescription drug) Indirect acting sympathomimetics →
Ephedra (Ma Huang) Weight loss Urinary retention Hyperthyroidism, CHF, HTN, Glaucoma,
Pseudoephedrine (OTC) ↑ release NE from nerve endings
↑ athleCc performance ↑ doses: ↑BP, cardiac arrhythmias, Pregnancy, Diabetes mellitus, Bulemia,
Cold & flu (in China) toxic psychosis Anxiety states
Allicin ↓ hepaƟc HMG-CoA reductase
→ anticoagulant
(fibrinolytic, ↓ platelet aggregaCon)
Garlic Organic thiosulfinate → ↓ cholesterol levels Allergic reaction Drug interaction with anticoagulant or
↑ nitric oxide
(Allium satium) forms Allicin (accounts for smell) Artherosclerosis Hypotension, Nausea antiplatelet drugs
↓ cholesterol, ↓ BP, ↓ plaque formaCon
↓ carcinogenic acCvaCon
Anti-microbial
Epileptogenic
Antioxidant Intermittent claudication Drug interaction with anticoagulant or
Insomnia
Ginkgo Flavone glycosides ↑ NO formaCon Dementia/cognitive impairment antiplatelet drugs
Headache
(G. biloba) Terpenoids ↓ Blood viscosity Pretreatment for CABG →
Anxiety
Free radical-scavenging effects ↓ oxidaCve stress Contraindicated with epilepsy
GI disturbances
↑ mental & physical performance Estrogenic effects (i.e., mastalgia Drug interactions with anticoagulants,
Ginsenosides (triterpenoid saponin ↑ mental & physical performance
Ginseng Possible value in type 2 DM (breast pain), vaginal bleeding) hypoglycemics, antiHTN, & psychiatric
glycosides) (energy drinks)
Some immunomodulating effects Insomnia, Anxiety, HTN meds
↓ lipid peroxidaƟon, scavenges free radicals
Milk Thistle Protect against hepatic injury
↑ superoxide dismutase
(Seeds of Silybum Silymarin (flavonignans) (alcohol, Amanita mushroom Loose stools LEAST side effects
↓ leukotriene formaCon
marianum) poisoning, acetaminophen)
↑ hepaƟc RNA polymerase acƟvity
Hyperforin ↓ 5-HT reuptake; Induces P450 → ↓ effecCveness of OCs, Interacts with MAOI, SSRI, bipolar or
St. John’s Wort
Hypericin Chronic use → ↓ reg. of adrenoreceptors & ↑ cyclosporine, digoxin, protease psychotic disorders
(dried flowers of Mild to moderate depression
Hyperforin reg. of 5-HT receptors inhibitors, warfarin Contraindicated with fluoxetine & other
Hypercurium perforatum)
Hypericin: antiviral + anticancer effects GI disturbances, photosensitivity SSRIs
Saw Palmetto ↓ libido
Photosterols, aliphatic alcohols, ↓ 5-α reductase & androgen receptor antag
(Serenoa repens or Sabal BPH (replaces fenasteride) HTN, headache
polyprenes, flavonoids ↑ urinary flow, urologic funcCon
serrulata) GI distress & pain
Coronary Artery Disease
Coenzyme Q10 Cofactor for mitochondiral ETC Antioxidant Chronic stable angina Normally, HMG-CoA reductase is needed
GI symptoms
(Ubiquinone) Ubiquinol (reduced)= antioxidant ↓ BP (systolic + diastolic) Parkinson's disease to make CoQ10
Myopathy/myolysis by statins
Osteoarthritis
Diarrhea, Nausea
Glucosamine Forms glycosaminoglycan (GAGs) Major component of cartilage ↓ joint pain, tenderness, Nitrogen containing sugar
Allergy (rare)
stiffness, ± local inflam of OA
N-acetyl-5-methoxytryptamine = Improve sleep onset, duration, & quality Jet lag Sedation, following day drowsiness Contraindicated in pregnancy,
Melatonin
serotonin derivative ↓ mid-cyle surge of luteinizing hormone Insomnia (Sleep disorders) ↓ sperm quality with chronic use breastfeeding
Dizziness, Seizures, Headaches
Black Cohosh Analgesic, sedative, anti-inflammatory Premenstrual syndrome
Nausea, vomiting, diarrhea Tinctures or tablets of dried materials
(Actea racemosa) Binds & activates serotonin (5-HT) receptors Menopausal Sx
Liver damage
End of Life Care (Part I)
Breakthrough pain = transitory flares of pain Tolerance = normal physiological phenomenon in which ↑ doses are required to produce the same
-Use immed. Prep release of same opioid used for routine dosing (5-15% of effect
24hr dose)
-Offer every 1hr (orally), every 30min (SC, IM), or every 10-15 min (IV) Physical Dependence = normal physiological phenomenon in which withdrawal syndrome occurs when
an opioid is abruptly stopped or an antagonist is administered
Opioids
-ORAL preferred in terminal disorders Psychological Dependence & Addiction = pattern of drug use marked by continuous craving for an
-No max dose of pure opioid agonists opioid, manifested by compulsive drug-seking behavior → overwhelming involvement in the
-90-95% excreted renally (↓ dose for renal problems) procurement & use of the drug
-LIVER conjugates codeine, morphine, oxycodone, & hydromorphone into
glucoronides (some metabolites are active analgesics) Complex Pain Treatment
-Adverse effects may become intolerable (Nausea, Sedation, Constipation, Off-label combinations may be required (e.g., oral antiarrhythmics, α2 agonists, NMDA receptor
Respiratory depression) antagonists, corticosteroids, etc.)
-Opioids NOT recommended:
1. Meperidine (routine dosing → accum. of Normeperidine → sig. adverse Treatment of Stress
effects; -Compassion
2. Partial/Mixed opioid-agonist/antagonist (e.g. butorphanol, nalbuphine) -Information
should not be used with pure opioid agonist → induces withdrawl, has ceiling -Counseling
effect -Psychotherapy
End of Life Care (Part II) Pain Control Adjuvants

Drug Class/Description Indications Pharmacokinetics/Effects Adverse Effects Notes
NSAIDs WHO Step 1 (1-3):
Non-opioid analgesics mild/moderate pain Has ceiling effect
Acetaminophen NSAIDs: Bone pain (2°)
Codeine
Mild to Moderate Agonists Step 2 (4-6): moderate pain
Constipation - Always treat
Hydrocodone Tolerance & physical prophylactically with laxatives to
No ceiling effect
Oxycodone Opioid analgesics
dependence will occur prevent fecal impaction; detergent
Bone pain
Tramadol Weak µ agonist Psychological dependence & stool softeners (docusate) NOT
addiction is rare sufficient alone with doses often
Morphine given at end of life Rx for breathlessness
Hydromorphone
Full agonist Step 3 (7-10): ↑ dose unCl paCent is Nausea (use anti-emetics, e.g.,
Opioids moderate/severe pain confortable metoclopramide)
Levophanol
Respiratory Depression
Fentanyl
Do not admin with pure
Butorphanol
Mixed Opioid Agonist NOT recommended opioid agonist → induces Ceiling effect
Nalbuphine
withdrawal
Amitriptyline, Imipramine,
Burning, tingling pain
Nortriptyline, Desipramine
Burning, tingling, & shooting
Gabapentin
pain
Carbamazepine Shooting pain
Valproate
Analgesic adjunctive agents Neuropathic pain
Advanced illness: acute nerve compression, ↑ ICP, bone
Corticosteroids
pain, visceral pain, anorexia, nausea, depressed mood
Calcitonin Bone pain

End of Life Care (Part III) - Drugs to Treat Common Symptoms
Drug/Tx Description Indications Notes
Dexamethasone is DoC of corticosteroids
Dexamethasone
Corticosteroids Also used for Fatigue/weakness
Prednisone
Anorexia/Cachexia NOTE: Fatigue/weakness is most frequent distressing symptom
Dronabinol
Cannabinoid
Tetrahydrocannabinol
Oxygen
Morphine Causes: Anxiety, airway obstruction, bronchspasm, hypoxemia,
Anxiolytics
Breathlessness pulmonary edema, thick secretions, etc
(benzodiazepines)
Benzodiazepines Confusion/Anxiety Causes: Drugs, hypoxia, intrinsic CNS disorders, urinary retention,
Barbiturates Severe Terminal Agitation sleep deprivation, poorly controlled pain
Stimulant Laxatives Casanthranol, senna
Osmotic Laxatives Lactulose, Sorbitol
Detergent Laxatives Docusate
Prokinetic agents
Constipation Causes: drugs (opioids, Ca2+ channel blockres, anticholinergics)
Lubricant stimulants
Large-volume enemas
Psychologic support Depressive symptoms
Methylphenidate Stimulant Withdrawn, vegatative signs, fatigue/weakness Depression
TCA Antidepressant Anxiety + insomnia
Attapulgite
Transient/Mild diarrhea
Bismuth salts
Loperamide
Diphenoxylate/atropine Persistent/bothersome diarrhea Slows peristalsis
Tincture of opium
Octreotide +
Octreotide = somatostatin derivative Persistent, Severe secretory diarrhea
parenteral fluid support
Antihistamines
(e.g., diphenhydramine) Insominia
Neuroleptics (also use benzodiazepine, e.g., Lorazepam)
(e.g., chlorpromazine)
Dopamine antagonist/5HT4 agonist
Metoclopramide
(antiemetic/prokinetic)
Scopolamine M-block (anticholinergics) Also use antihistamine, e.g. meclizine, diphenhydramine
Nausea/vomiting
Ondansetron NOTE: ondansetron, granisetron is most often used by cancer
5-HT3 antagonist (also use antihistamine)
Granisetron ptients likely due to chemotherapy
Antacids
Cytoprotective agents
Metronidazole
Silver sulfadiazine Superficial infections
Avoid iodine-containing products
Charcoal-impregnated due to pressure ulcers
dressings

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Class of Drugs: Direct-Acting Cholinergic Agonists

Low dose: ganglion stim by CVS: sympathomemitic due to

Areocoline Natural Alkaloid

Stimulates GI, bladder

Activated in body by conversion

Pralidoxime is an AChE reactivator,

Eye: Mydriasis, unresponsiveness to

Class of Drugs: (Cholinergic) Nicotinic (Nm) Antagonists, a.k.a. NMJ BLOCKERS

Autonomic effects: Some agents are

Nm IV by continuous infusion; Malignant hyperthermia: AD disoder

Decamethonium (C10 analog of C6)

Blocks choline transporter →

Diseases with ↑ muscle tone

CVS: vasoconstriction (alpha1), ↑ peripheral

Class of Drugs: β Adrenergic Agonists

Racemic mixture of (+)

Class of Drugs: Indirect-Acting Adrenergic Agonists

Class of Drugs: Mixed-Acting Adrenergic Agonists

Can reverse antihypertensive

Nadolol Long term management of angina Long duration of action

Hypertensive pts with impaired

Class of Drugs: Indirect Adrenergic Antagonists (act presynaptically)

General PK: absorption impaired by food (except: amoxicillin, ampicillin, dicloxacillin)

Class: Cephalosporin (Cell wall inhibitor)

Treating STDs (DOC):

Class: Monobactams (Cell wall inhibitor)

Class: β-Lactamase Inhibitors

Slow (60-90min) IV for

Amikacin E. coli, Enterobacter, E. Coli, Enterobacter, Ototoxicity

Very potent and toxic Gram +/-, anaerobes, GI

Class: Streptogramins (Quinupristin/Dalfopristin)

Class: Linezolid (techinically, Oxazolidinone)

Miscellaneous Drugs (Metronidazole, Polymyxins)

Class: Sulfonamides (Anti-metabolites)

Sulfisoxasole (short acting) Simple UTI Crystalluria (nephrotoxicity);

Infection Sulfonamide ROA

Inhibits bacterial Penetrates CSF;

Long t1/2 (weekly dosing)

Dose-dependent visual disturbances

Nongouty polyathralgia (40%)

Drugs for Leprosy (Hansen's Disease)

GI upset + peptic ulcers

Potassium Sparing Blocks Na+ transport channels (↓ Same as spirinolactone + Leg

Contraindications for Anti-Hypertensives Positive Criteria for Drug Selection

Inhibits enzyme activity of renin → ↓ Hyperkalemia, renal impairment

Inhibits active transport of Na+ Very low theraputic window Treatment:

+ve inotropic effects, vasodilation

Steps in Treatment of Chronic HF CLASS

Slows conduction in all cardiac tissues

Drug Therapy of Atrial Fibrillation General Applications

Complex class I, II, & III effects (i.e.

In HF = +ve inotrope (↑ [Ca2+])

Bronchial Asthma Drugs

Monoclonal Antibodies Binds to IgE on sensitized mast cells &

Histamine Antagonists (Autacoids)

Very safe drugs (AE <3%)

ligand-gated ion channel receptor

5-HT1 - 5-HT7 → G-linked

Ondansetron 5-HT3 Receptor Most powerful anti-emetic

Eicosonoids & Eicosanoid Antagonists (Autacoids)

Coating removed in alkaline Inhibits metabolism of

Inhibits pepsin and increases

Binds to proteins, forming

Prevention of NSAIDs- Produces uterine