PharmDrug List Complete SGU-UST
PharmDrug List Complete SGU-UST
PharmDrug List Complete SGU-UST
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
Carbamate esters of
alcohol (Most common AChE for)
Pyridostigmine CNS Toxicity
Myasthenia gravis
quaternary ammonium
Drug Name Receptor Chemical Structure Mechanism of Action Effects Indications Pharmacokinetics Adverse Effects
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)
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
Drug Name Receptor Chemical Structure Mechanism of Action Effects Indications Pharmacokinetics Adverse Effects
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
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
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
Drug Name Receptors Chemical Structure Mechanism of Action Effects Indications Pharmacokinetics Adverse Effects Contraindications
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
Class of Drugs: Adrenergic Antagonists (α1 and β-Adrenergic Blockers, Partial agonists)
Drug Name Receptors Chemical Structure Mechanism of Action Effects Indications Pharmacokinetics Adverse Effects Contraindications
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
Drug Name Receptors Chemical Structure Mechanism of Action Effects Indications Pharmacokinetics Adverse Effects Contraindications
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
Class: Misc
Drug Description Mechanism of Action Indications Drug of Choice Pharmacokinetics Bacterial Resistance Mechanism Combo therapy Adverse Effects
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)
Drug Description Mechanism of Action Indications Drug of Choice Pharmacokinetics Bacterial Resistance Mechanism Combo therapy Adverse Effects
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
Drug Description Mechanism of Action Indications Drug of Choice Pharmacokinetics Bacterial Resistance Mechanism Combo therapy Adverse Effects
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
Drug Description Mechanism of Action Indications Drug of Choice Pharmacokinetics Bacterial Resistance Mechanism Combo therapy Adverse Effects
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
Drug Description Mechanism of Action Indications Drug of Choice Pharmacokinetics Bacterial Resistance Mechanism Combo therapy Adverse Effects
Class: Clindamycin
Drug Description Mechanism of Action Indications Drug of Choice Pharmacokinetics Bacterial Resistance Mechanism Combo therapy Adverse Effects
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: Trimethoprim
Drug Description Mechanism of Action Indications Drug of Choice Pharmacokinetics Bacterial Resistance Mechanism Combo therapy Adverse Effects
Class: Cotrimoxazole
Drug Description Mechanism of Action Indications Drug of Choice Pharmacokinetics Bacterial Resistance Mechanism Combo therapy Adverse Effects
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
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.
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
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)
Drug Drug Class Description MOA Indications Pharmacokinetics Adverse Effects Contraindications
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
Studies show rate control has better benefit-to-risk outcome than rhythm control
Anti-Arrhythmic Drugs (Part 3)
Drug Drug Class Description MOA Indications Pharmacokinetics Adverse Effects Contraindications
↓ 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
↓ 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)
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
Sumatriptan (Prototype)
5-HT1D/1B Receptor suffix - tryptan
Drug of choice for acute severe migraine
Agonist attacks
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
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
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
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
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
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)
rate)
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)
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
Drug Drug Class Description MOA Indications Pharmacokinetics Adverse Effects
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)
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
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
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)
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
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
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
Analgesic, antipyretic
Acetaminophen Non-opioid Hepatotoxicity with excess DoC for low back pain, osteoarthritis, fever in young people
analgesic use, overdose
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
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:
Pharmaco-
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
-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)
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
Drug Drug Class Description MOA Indications Pharmacokinetics / Dosage Resistance Adverse Effects Contraindications
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
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)
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)
Drug Drug Class Description MOA Indications Pharmacokinetics / Dosage Resistance Adverse Effects Contraindications
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
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
Zidovudine (start immediately after birth, Treat for 1 month after injury (best treated within 1-2 hours of injury)
administer for 6 weeks)
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
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
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
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
1. Prednisolone (Glucocorticoids)
2. Azathioprine, Methotrexate, Sirolimus (Cytotoxics)
3. Cyclosporine, Tacrolimus (Antibiotics)
4. Muromonab (antibody)
Cyclophophamide
Chlorambucil
Glucocorticoids
Inhibit MHC expression → ↓
Prednisone IL-1, 2, 6 → Th cells not
activated
Immunopharmacology (Part 3)
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
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
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
Investigational New Drug Application (IND) – seeking approval to initiate clinical trial in US
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
Drug Development – Part 3
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
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
Off-label Use
Use of approved drug for any purpose, or in any manner, other than what is described in the labeling
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
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
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
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)
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
Drug Drug class Description MOA Indications Pharmacokinetics Adverse Effects Contraindications
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
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
-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)
Drug Drug class Description MOA Indications Pharmacokinetics Adverse Effects
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
Drug Drug class Description MOA Indications Pharmacokinetics Adverse Effects
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
Drug Description MOA Indications Pharmacokinetics Adverse Effects Notes
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
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
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
↓ (Seizure continues) . Surgery Most extreme, last resort Removal of local area of abnormal brain from which seizures originate
↓ (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
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
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
Drug Class MOA Indications Pharmacokinetics Adverse Effects Notes
IV Anesthetics
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
Diazepam Enhance action at GABAA receptors Sedation Reduce muscle spasms of almost any origin
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
Aspirin
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
Toxin MoA Effect Treatment
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.
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