Jameel Khan

Pharmacology Review (3 rd Semester):

MINI 1:

Pharmacokinetics effects of body on drug

Pharmacodynamics effects of drug on body

Transfer/Permeation:

1) Bulk flow – intracellular pores; depends on P gradient (passive)2) Aqueous diffusion – small molecules; aquaporins (<100 MW)3) Lipid diffusion – uncharged molecules (**H-H principle**)

pKa > pH = non ionized (lipid soluble) for W.A. (*THINK = ACID in more ACIDIC env. is uncharged)

Difference >3 3 2 1 0.5 0% ionized >99.9 99.9 99 90 76 50

pH stomach = 1.5 to 2; blood = 7.4; cell/cytoplasm = 7 (electroneutral)

Ion trapping build-up within cell due to differences in pH/pKa; drugs with low pKa (i.e., aspirin) build-up in GI epithelium = gastric ulcers; can use to increase drug elimination by trapping in urine

4) Carrier transport – large / charged molecules; facilitated or active; saturable5) Endocytosis – large / charged molecules; selective

Administration:

Parenteral = injection or infusion

1) Oral – 1st pass effect; absorption in small intestine; gastric emptying can be hastened or delayed2) IV – F = 13) IM – fast absorption; NO anticoagulants (e.g., heparin)4) SC – slower than IM (bulk flow); heparin OK5) SL – NO 1st pass6) Rectal (suppository) – partial 1st pass avoidance; lower absorption7) Inhalation – inhalers or gases8) Topical – local effect9) Transdermal – systemic effect; slow; avoids 1st pass

Blood flow: higher = faster absorption; epinephrine with local anaesthetics (AVOID near end capillaries!)

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Bioavailability (F) = AUC other / AUC iv (fraction of dose that reaches systemic circulation; CONSTANT for each drug)

Distribution:

Vd = D x F / Cp0

Can rearrange to solve for dose CONTSTANT, independent of dose! Cp0 can be obtained by extrapolating line to y-axis of Cp vs. time graph 3L = only in plasma (heparin); 13L = to ECF; 42L = TBW (ethanol); >42L = specific cells/tissues

Redistribution – IMPORTANT with lipid soluble anaesthetics in obese pts.

Protein binding – constant % bound = inactive, independent of dose; IMPORTANT with drugs with narrow T.I. (e.g., warfarin – 98% bound)

BBB – highly impermeable (intrathecal admin.); placenta is opposite

THINK: absorption & elimination occurring simultaneously!

Placental crossing: slowed by ionization, protein binding, size (esp. >1500 MW)

Metabolism:

Biotransformation conversion to a metabolite is form of elimination (in SER of hepatocytes)o Phase I – CYP450; makes polaro Phase II – conjugations: glucoronidation & acetylation **fast/slow acetylators =

genetic Individual differences! (e.g., pseudocholinesterase deficiency prolonged duration of

succinylcholine) Prodrugs are inactive, metabolized to active form Liver consider damage/cirrhosis & CYP 450 effectors

o INDUCERS (barbiturates & rifampin) faster metab., therefore lower amt. of drugo INHIBITORS (cimetidine, macrolides, grapefruit juice) slower metab., therefore higher

amt. of drug

Elimination:

Not equal to EXCRETION! biliary, renal*, pulmonary (e.g., anaesthetics), others = saliva, sweat

First Order – constant proportion; exponential decrease; the norm for most drugs

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Zero Order – constant amount; linear decrease; ethanol, phenytoin, toxic dose of aspirin

Compartment models: (use example Q)

One compartment – drug uniformly distributed; concentration of drug increases with constant proportion (single t1/2)

Two compartment – separate peripheral & central distribution; distribution phase & elimination phase (two distinct t1/2’s)

Clearance: CL(t) = CL(h) + CL(r) + CL(o)

CL(r) = Ud x V / Pd

GFR normally 125mL/min +/- 26; BUT if > 150 mL/min = secretion; <100 mL/min = reabsorption

**MUST adjust dose when elimination altered by disease based on fraction of drug eliminated by kidney & liver (do not consider CL(o))

Hepatic cirrhosis, disease or heart failure (reduced blood flow)

Renal impairment or heart failure (lowered CO); relate to creatinine CL & GFR

(provide question example)

Accumulation:

T1/2 = 0.693 (Vd/CL) CONSTANT for each drug!

Full elimination after 4 X t1/2

**Can determine from conc. vs time graph NOTE semilog scale (provide ex.)

**know how to determine based on Cp0 & Cp(after time)

Duration of action is proportional to t1/2 & administered dose

Continuous IV:

D / T = Css X CL

Css rate of infusion = rate of elimination; time to reach depends on t1/2; level depends on dose; reached after 4 x t1/2 (accumulation occurs provided that dosing interval is < 4 x t1/2)

1 x t1/2 50% Css2 x t1/2 75% Css3 x t1/2 87.5% Css

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4 x t1/2 94% Css Therefore, if it takes 20 h to reach Css t1/2 = 5 h

**IMPORTANT for drugs with low T.I. smaller (lower D) & more frequent doses (lower T) decrease fluctuations at Css

Css = F x D / CL x T

Loading Dose = Vd x Cp / F (used in emergencies or with drugs with low T.I.)

Maintenance Dose / T = CL x Css / F

Dose-Effect Relationship: **IMPORTANT to relate these properties to their effect on the graph

Emax = maximal effect

EC50 = concentration where 50% receptors bound, or Kd

Intrinsic activity = ability of a drug to initiate changes (once bound) which lead to a biological response

Agonist full (max response); partial (below max response – acts as antagonist in presence of full agonist); inverse (decreases basal activity)

Antagonist intrinsic activity = 0

a) Chemical – combines & inactivatesb) Pharmacokinetic – prevents absorption or stimulates eliminationc) Physiological (functional) – binds different receptor causing opposite biological responsed) Pharmacological (receptor-block) – compete for same receptor,

Competitive / reversible bind agonist receptor site; Increases Kd; right shift on graph

Non-competitive / irreversible allosteric binding site; decreased Emax (# of effective receptors); lowers slope on graph

Threshold dose – min dose to produce any response

Potency – proportional to affinity (inverse to Kd); increase potency = lower dose for effect (more left on graph)

Efficacy – proportional to intrinsic activity/Emax; Emax increases on y-axis

Therapeutic Index = RATIO between harmful & effective dose (REMEMBER to calculate = lethal or toxic dose / effective dose) – digoxin (very low T.I. of 3-5)

Therapeutic Window = RANGE between min. therapeutic dose & min. toxic dose

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Signalling:

a) Intracellular receptors – lipid soluble drugs (e.g., steroids, NO)b) Ionotropic – Ach, nicotine c) Transmembrane linked – insulin TK receptord) G-protein coupled (metabotropic) – sympathomimeticse) Janus-kinase - cytokines

G-proteins:

Receptor Coupling protein Effector Response Result M1, M3, a1 Gq Phospholipase C Increase IP3, DAG Increase Ca2+ &

protein kinase activity

B (1,2,3), D1 Gs Adenylyl cyclase Increase cAMP Increase Ca2+ influx & enzyme activity

a2, M2 Gi Adenylyl cyclase decrease cAMP Decrease Ca2+ influx; increase K+ efflux

Regulation:

Chronic activation densensitization & down-regulation = TACHYPHYLAXIS or TOLERANCE

Chronic inhibition up-regulation (supersensitivity) **DO NOT suddenly stop pt from B-blocker Tx

Interactions:

a) Addition 1 + 1 = 2b) Synergism 1 + 1 > 2c) Potentiation 0 + 1 > 1 ; drug with no effect enhances otherd) Antagonism 1 + 1 < 2 ; partial & full agonist.. OR... 0 + 1 < 1 ; antagonist & agonist

Placebo Effect = always present! MUST always consider

Pt compliance 15-95% non-compliant!

Adverse Effects: (not high yield on exams)

Majority are pharmacological (70-80%); can be cytotoxic (5-15%) or immunological (5-15%)

Mainly occur in first 10 days of Tx MUST reduce dosage or can switch to night time administration (e.g., sedation)

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May be due to drug metabolite

Overdose toxicity most deaths in hospital; or idiosyncratic (e.g., genetically based)

Haptens = small molecule that elicits an immune response when attached to a larger protein (e.g., penicillin)

Allergy Types:

I) Immediate rxns IgEII) Ab-dep. cytotoxicity IgG or IgMIII) Immune complex-mediated IgG or IgM with complementIV) Delayed or cell-mediated T cell receptors

Pseudoallergic NO antibodies; anaphylactoid; dose-related

**IMPORTANCE of a detailed history

Teratogenesis – MW 800-1000 can cross placenta easily

Most sensitive stage = ORGANOGENESIS (17-80 days); before that is resistant

Most frequent mechanism is covalent bonds to DNA, RNA, enzymes, etc.

FDA Risk categories: (lowest) A, B, C, D, X (worst)

*AVOID all drugs unless deeply necessary in pregnancy

Carcinogenesis – dose-dep.; additive & irreversible; reactive intermediates

Abuse & Dependence increases in dopamine in the nucleus accumbens; shorter acting = more addictive

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Introduction to Autonomics:

SNS from T1-L5 (short pre-) paravertebral chain ganglia (Ach @ Nn, then long post-) adrenergic transmission (catecholamines, NE/Ep) alpha/beta receptors on effector

*REMEMBER: Ach to sweat glands (M) & adrenal medulla (Nn) (which releases catecholamines)

PSNS from III, VII, IX, X & S2-4 (long pre-) ganglia (Ach @ Nn, usually near target oran) cholinergic transmission M receptors on target organ

Somatic voluntary motor nerve Ach to Nm on muscle

Adrenergic Transmission:

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Tyrosine (tyrosine hydroxylase) DOPA dopamine (dopamine beta-decarboxylase) NE Ep

Termination:

1) Actively transported back into pre-synaptic cell (primary mechanism)2) Diluted & diffuse away3) Metabolized by MAO-A or B & COMT HVA and VMA (respectively)

Nicotine THINK nicotinic receptors post-ganglionic neurons = unmyelinated

ANS main regulator is the hypothalamus

**Receptors: KNOW the chart above with all the receptors & their corresponding G-proteins

CHOLINERGICNn Ganglionic neurons Evokes APNm Skeletal muscle endplates AP Muscle contractionM1 (Gq) Ganglionic neurons*M2 (Gi) Myocardium

Presynaptic terminals

Cardiac depression

Decrease NE & Ach release*M3 (Gq) Smooth muscle

Exocrine glands

Vascular endothelium

Bronchoconstriction & increased secretions, GI motility, gallbladder, urinary bladder, eye, sweat glands

Pancreatic secretions (exocrine & insulin)

Vasodilation (via NO), erection

ADRENERGICa1 (Gq) Vascular smooth muscle

Visceral smooth muscle

Arteriolar & venous constriction,

Ejaculation, ALL sphincter contractions, radial m. (eye)

a2 (Gi) Presynaptic terminals

platelets

Autoreceptors – inhibit NE/Ach release

AggregationB1 (Gs) Myocardium

JG cells

Increase cardiac function

Renin secretionB2 (Gs) Visceral smooth muscle Bronchodilation & increased

secretions

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Vascular smooth muscle

Liver

Mast cells

Vasodilation in skeletal m., venodilation,

Glycogenolysis & gluconeogenesis

Inhibits degranulationB3 (Gs) Adipocytes LipolysisD1 (Gs) Vascular smooth muscle Renal vasodilation

Key Organs/Systems:

Eye:

*Circular m. or sphincter pupillae m. M3 (contracts) MIOSIS (pupillary constriction)

*Radial m. or dilator papillae m. a1 (contracts) MYDRIASIS (pupillary dilation)

*Ciliary m. M3 (contracts) accommodation (zonula fibers relax & lens thickens) near vision

B2 (relaxes) no accommodation; far vision (lens flat)

*Ciliary epithelium B2 (increase aqueous humor production); a2 (decrease aq. humor production)

Lacrimal sac M3 tears (lacrimation)

Superior tarsal m. a1

Urinary Bladder:

Detrusor m. (motility & tone) M3 (contracts); B2 (relaxes)

Trigone m. & sphincter a1 (contracts); M3 (relaxes)

Uterus (pregnant):

B2 relaxes; a1 contracts

Heart:

Atria M2 decrease conduction & contractility

Ventricles B1>>B2 increase conduction & contractility

Vessels:

Skin, splanchnic vessels a1 (vasoconstricts); M3 (vasodilation via NO)

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Skeletal m. B2 (vasodilation)

Lung:

Bronchodilation & increased secretions B2

Bronchoconstrion & increased secretion M3

Key Conditions/Special situations:

Glaucoma: (3rds, just know the drugs pertaining to ANS pharm at this point)

Open-angled – excessive production of aq. humour

Epinephrine a2 vasoconstriction decrease aq. humour production

Apraclonidine a2 decrease aq. humour production

Timolol beta-blocker decrease aq. humour production

Acetazolamide, dorzolamide CA inhibitors (diuretics) decrease aq. humour production

Closed-angled – blockage of aq. humour flow through Canal of Schlemm

Carbachol, pilocarpine, physostigmine M3 contract ciliary m. increase aq. Humour outflow

Latanoprost prostaglandin increased aq. humour outflow through uveoscleral route

Mannitol osmotic diuretic increase aq. humour outflow

Urinary inconintence:

Over-flow incontinence – due to an obstruction, bladder so full that it leaks urine

Tamsulosin (“Tamiflow”) a1 blocker Tx: prostatic hyperplasia

Bethanacol cholinergic (M3) Tx: urinary retention

Urge incontinence – inflammation of M3 receptors, involuntary activation

Darifenacin antimuscarinic (tertiary) Tx: neurogenic bladder, urge incontinence

Asthma:

Albuterol & Salmeterol (long-acting) B2>>>B1 CI: palpitations

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Ipatropium (M3-antag) does not reduce secretions or mucociliary clearance

Beta-blockers are CI bronchoconstriction

NSAIDs are CI LT build-up

Pheochromocytoma:

ALWAYS administer alpha-blocker first, then the beta-blocker (must relieve vasoconstriction then Tx tachycardia)

Posionings: LOOK AT THE PUPILS!

1) Organophosphate/parathion (irreversible cholinesterase inhibitor, causes AGING) FARMER miosis, lacrimation, salivation, flushed, sweating, nausea, vomiting, erection, hypotension, ataxia, slurred speech

Tx: praladoxime (cholinesterase reactivator) – provided enzyme not AGED

2) Muscarin poisoning CHILD who eats mushrooms miosis, spasm of accommodation, bronchoconstriction, bradycardia, sweating, vasodilation, tearing

Tx: atropine

3) Atropine (antimuscarinic) mydriasis, blurred vision, dry mouth, tachycardia, nausea, ataxia, confusion, hallucinations

Tx: physostigmine (anti-AchE) give IV

4) Nicotine poisoning CHILD who gets to parents nicotine patches nausea, vomiting, pallor, sweating, dyspnea, palpitations, tachypnea, hypertension, seizures, drooling (similar to organophosphate poisoning)

Tx: gastric lavage (if swallowed); prognosis depends on how much nicotine taken in

Myasthenia Gravis:

Dx Tensilon Test Edrophonium (anti-AchE)

Diabetes Mellitus:

CI: beta-blockers will shut down gluconeogensis & glycogenolysis

Septic shock:

Dopamine especially when there is decreased renal perfusion

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ANS Drugs:

SNS - ADRENERGIC

AGONISTS ANTAGONISTSa B a/B a B (“EAM”) =

selectivea/B

Phenylephrine (a1) – Tx: hypoTn, decongestant

Isoproteronol (B1,2,3) – Tx: torsade de pointes, HF

*increase CO & HR; massive vasodilation in skel. m. (B2) large increase in PP

Epinephrine (B1,2,3 > a1,2) – Tx: anaphylactic shock

*overall increase CO & HR, decrease TPR (B2) increase PP but overall increase BP

Phenoxybenzamine (a1) – Tx: pheochromocytoma (irrev. blockade), Raynaud’s

Propanolol (B1,2) – Tx: hyperTn, migraine, angina, arrhyth.

Labetolol (a1, B1,2) – Tx: hyperTn from preg. (emergencies – IV)

Clonidine (a2) – Tx: hyperTn, drug withdrwl

Prazosin (a1) – Tx: HyperTn

Pindolol (B1,2) – partial ag.

Cavedilol (a1, B1,2) – Tx: HF

Aproclonidine (a2) – Tx: open-angle glaucoma

Tamsulosin (a1) – Tx: overflow incontinence

Timolol (B1,2) – Tx: closed-angle glaucoma

Dobutamine (B1) – Tx: HF, cardiogenic shock

Norepinephrine (B1>a1,2) – Tx: hypoTn, delay abs. of local anaesth.

*REFLEX bradycardia, due to massive increase TPR (no B2) small increase in PP

Yohimbine (a2) – non-clinical

Sotalol (B1,2) – Tx: cardiac arryth. (K+ channel block)

D Albuterol (B2) – Tx: asthma, COPD

Esmolol (B1) – Tx: IV, short t1/2

Dopamine (D1) – Tx: septic shock with renal shutdown

Salmeterol (B2) – Tx: asthma (long-acting)

Atenolol (B1) – Tx: hyperTn, a-fib

Retrodrine (B2) – Tx: labor, relaxes uterus

Metoprolol (B1) - enters CNS

OTHERS:

Indirect acting (agonists): tyramine (increase NE release) – cheeses, wine; methyldopa (a2-ag.); cocaine (inhibits reuptake of catecholamines) – Tx: local anaesthetic; amphetamine (stimulates release of DA, NE, 5-HT, blocks reuptake of catecholamines) – Tx: ADHD, narcolepsy

Mixed adrenergic: ephedrine (a1,2, B1,2) – increase NE release – Tx: nasal decongestant, fat burner, enuresis

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Indirect acting (antagonists): metyrosine ( inhibits catecholamine synthesis) – Tx: pheochromocytoma, HyperTn

PSNS – CHOLINERGIC

AGONISTS ANTAGONISTSM Anti-AchE Anti-M Gangionic

StimulantCholinesterase

RectivatorAch (M1,2,3,N) – Tx: glaucoma

Edrophonium (4, reversible, 2-10 m) – Dx: Tensilon Test, MG

Atropine (3, M1,2,3) – Tx: visceral hypermot., ophthal.

Nicotine (Nn & Nm)

Pralidoxime – Tx: organophosphate poisoning

Carbachol (M1,2,3,N) – Tx: glaucoma, miosis

Physostigmine (3 – CNS effects), reversible, 1-6 h) – Tx: MG, glaucoma, AD

Scopolamine (3, M1,2,3,N) – Tx: motion sickness, ophthal. (mydriasis, cycloplegia)

Bethanecol (M1,2,3) – Tx: urinary ret. due to bladder atony

Neostigmine (4, reversible, 1-6 h) – Tx: MG

Homatropine (3, M1,2,3,N) – Tx: ophthal.

Ganglionic Blocker

Muscarine (M1,2,3) - poison

Donepizil (reversible) – Tx: AD

Glycopyrrolate (4) – Tx: visceral hypermot., cardiovasc.

Mecaylamine (Nn) – unpredictable outcomes, Tx: Tourette’s, smoking cessation

Pilocarpine (M1,2,3) – Tx: closed-angle glaucoma

Parathion/ Organophosphate (irreversible aging) - poison

Darifenacin (3, M3) – Tx: neurogenic bladder, urge incontinence

Ipatropium (4, M1,2,3,N) – Tx: asthma, does not decrease mucociliary clearance

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MINI 2:

AUTOCOIDS:

Histamine:

H1-antagonists (Gq) H2-antagonists (Gs)1st generation

(SEDATIVE, 4-6 h, M and alpha block!)

2nd generation (NON-SEDATIVE, long-acting,

less lipid soluble, no ANS effects)

Take before you “DINE” reduce gastric acid secretion“table for 2” H2**Tx: gastic ulcers BUT less effective than PPI’s

Cyclizine-antiemetic-post-op with opioids

Cetrizine (Zyrtec)

Cyproheptadine-ALSO a 5-HT2 antagonist

Fexofenadine (Allegra) Cimetidine-inhibits P450*-antiandrogenic effects* (galactorrhea, gynecomastia, loss of libido, impotence)-crosses blood-brain barrier-decrease renal excretion of creatinine

Dimenhydrinate (Dramamine)-Tx of motion sickness

Loratadine (Claritin) Famotidine

Diphenhydramine (Benadryl)-prevention of motion sickness & chemo induced emesis-anti-Parkinsonian effect -local anaesthetic

Nizatidine

Meclizine-long acting (12-24 h)-antiemetic

Ranitidine-can inhibit androgen receptor-inhibits hepatic drug metabolizing enzymes-decreases renal excretion of creatinine

Promethazine-prevents motion sickness-anti-adrenoceptor action-local anaesthetic

Release Inhibitors decrease mast cell degranulation (effective vs. asthma/COPD)

-cromolyn; nedocromil; B2-agonists

Physiological Anatagonists use in anaphylaxis epinephrine (a1,a2,B1,B2)

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Serotonin:

5-HT Agonists (Gi) Triptans 5-HT Antagonists*Buspirone-partial 5-HT 1A ag.-anti-anxiety (Tx: GAD)

-Tx: severe migraine (D.O.C.)-cerebral vasoconstriction-1-3 hrs-CI = cardiac pts., possible coronary vasospasm

Cyproheptadine (5-HT2)-antimuscarinic-sedative (H1 antag.)-Tx: carcinoid tumour; cold-induced uticaria

Ergotamine*increase oral bioav. w caffeine-5-HT2 partial ag.-Tx: 1st sign of migraine attack-CI = cardiac pts.-a-adrenoreceptor & dopaminergic also

Eletriptan *Ondansetron (5-HT3)-Tx: n & v associated with cancer chemo. or post-op.(“So you can DANCE on”)

Dihydroergotamine-Tx: 1st sign migraine attack

Naratriptan Ritanserin-alters bleeding time & TXA formation by altering platelet fxn

Ergonovine-Tx: post-partum bleeding-Dx: variant angina-a-adrenoreceptor activation increases uterine contraction

*Sumatriptan-Tx: CLUSTER headaches (as well as migraines)

Phenoxybenzamine (5-HT2)-irreversible blockade-Tx: pheochromocytoma (a-antag.); carcinoid tumour

LSD-drug of abuse (hallucinations)

Phenothiazines/Butyrophenones-Tx: schizophrenia & mania

Ecosanoids:

Prostaglandins Ecosanoid Inhibitors*Alprostadil (PGE1)-Tx: erectile dysfunction (penile injection); maintains PDA until surgery (due to T of GVs)-AE: priaprism

Zafirlukast-LT receptor inhibitor Tx: asthma

*Carbaprost (PGF2a)-Tx: 2nd trimester abortion (IM injection)

Montelukast -LT receptor inhibitor Tx: asthma

*Dinoprostone (PGE2)-Tx: ripening of cervix for labour; 2nd trimester abortion (vaginal admin.)

Zileuton-5-LOX inhibitor Tx: asthma

*Epoprostenol (PGI2 = prostacyclin)-Tx: primary pulmonary HT (life saving!); antiplatelet effects (dialysis) IV infusion

Glucocorticoids-inhibit phospholipase A2 (all pathways)-Tx: asthma, organ/graft rejection, closes PDA

*Latanoprost (PGF2a)-Tx: open-angle glaucoma (ophthalmic admin.)-AE: browning of iris

Cromolyn-inhibits ecosanoid & histamine release Tx: asthma & COPD

*Misoprostol (PGE1) NSAIDs

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-Tx: NSAID peptic ulcers, abortificient (w RU-486)-AE: diarrhea, uterine cramping

-COX-blockers reduce inflammation*Tx: dysmenorrhea

ANTI-INFLAMMATORIES:

Recall:

Membrane lipids (phospholipase A2) AA (COX-1 & 2) PGE/Fs, PGIs, TXAs

(LOX) LTs

NSAIDs:

Salicylates ***Aspirin-irreversible inhibition of COX-1 & -2 (pKa = 3.5)Tx: anti-thrombotic (low dose); analgesia & antipyretic (med dose); anti-inflamm (high dose)AE: GI & renal tox.; increased BT (CI in clotting disorders); HS due to increased LTs bronchospasm; tinnitus; hyperventilation; coma in O.D.

SulfasalazineTx: ulcerative colitis; Crohn’s dz

Proprionic Acids **Ibuprofen (MOTRIN)Tx: closes PDA; dysmenorrhea (antipyretic, analgesic, anti-inflamm.)AE: GI & renal tox., HS due to increased LTs

Flurbiprofen-non-selective COX inhib.-Tx: arthritis, sore throat-AE: cog-wheel rigidity

*NaproxenTx: anti-inflamm., analgesic, antipyretic (longer t1/2)

Oxaprozin-Tx: gout

Acetic Acids **Diclofenac-non-selective COX inhib, low levels of LOX inhib., ROS inhibTx: anti-inflamm, analgesic, antipyretic (used w misoprostol) – RA, AS, OA

**KetorolacTx: ANALGESIC effects (reduce opioid requirement)AE: renal tox w chronic use

SuldinacTx: familial intestinal polypsAE: Stevens-Johnson

Indoles **Indomethacin-non-selective inhibition of COX, inhibits PLA & PLC-decreases neutrophil migration and T & B cell proliferationTx: closes PDA, gout, AS, RA (ANTI-INFLAMM effects)AE: dizziness, pancreatitis, hematologic reactions

Oxicams *Meloxicam-COX-2 selectivityTx: OA

Piroxicam -non-selective COX inhib (longer t1/2)-inhibits PMNs & ROS formation at high doses

Coxibs ***Celecoxib-selective COX-2 inhibitor (lower GI tox.!)Tx: analgesic, antipyretic & anti-inflam.AE: CARDIOVASCULAR RISK, increased thrombosis (black box warning!)

Analgesic-Antipyretic

***Acetaminophen (aka. Paracetamol) (TYLENOL)-weak COX inhibitor, MOA unknownTx: antipyretic, analgesic (NO ANTI-INFLAMM!)

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AE: hepatotoxicity in OD or w alcohol (antidote is NAPQI)

*** DO NOT give aspirin to CHILDREN for FEVER (especially if due to viral illness) REYE’s SYNDROME = fatty liver, encephalopathy, kidney dz, hypoglycemia coma and even death!!!!

Sx’s of Over-Dose:

Aspirin OD HYPERthermia, headache, hyperglycemia, vertigo, bradypnea, tinnitus, tachycardia, hypotension, acidosis

Acetaminophen OD n & v, diarrhea, appetite loss, sweating, irritability; may lead to liver failure (jaundice, dark urine, confusion, hypoglycaemia, bleeding)

Glucocorticoids: ALTER GENE EXPRESSION!

-inhibit Phospholipase A2

-Increase neutrophils; decrease lymphocytes, eosinophils, basophils and monocytes (immunosuppressive!)

Short-Medium Acting Intermediate Acting Long-ActingCortisone Triamcinolone BexamethasoneHydrocortisoneMethylprednisolone Dexamethasone

Dx: suppression test for Cushing’s(+ve with no decrease in cortisol after admin.)

PrednisolonePrednisone

ANTI-NEOPLASTICS:

CCS Tx fast growing tumors

CCNS Tx slow growing tumors (lung & colon)

Log-kill hypothesis reduce the # of cancerous cells in a step-wise manner (Tx on, then off)

1) Allows body to recover from toxicity2) More of the tumor cells enter cell cycle, once some of died (blood supply available to replenish)

CCS drugs:

S phase Antimetabolites (inhibit DNA synthesis)

G2 Bleomycin (generates free radicals DNA fragmentation & synthesis inhibition)

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M Vinca alkaloids, taxanes (disrupt microtubule assembly and disassembly, respectively)

AntimetabolitesTox: myelosuppression

**Methotrexate-Inhibits DHFR-must be polyglutamated

**5-Fluorouracil- inhibits thymidylate synthase*potentiated by leucovorin(folinic acid)

Cytarabine- inhibits DNA polym.Tx: AMLTox: neurotoxic

Capecitabine-oral prodrug 5-FU-less myelotoxic

Alkylating Agents MOA: cross-link DNA inhibiting synthesis

**Cyclophosphamide **Cisplatin CarmustineTx: CNS tumors (lipophilic)

TemazolamideTx: malignant gliomas

Cytotoxic Ab’sMOA: free radical formation binds DNA

*Doxorubicin-inhibits topo II-Tox: vesications with IV infusion

*DaunorubicinTx: leukemia

*Bleomycin Dactinomycin

Natural Products *Vincristine-prevent microtubule assembly

*Vinblastine-prevent microtubule assembly

*Paclitaxel-prevent microtubule DISassembly

Etoposide-stabilizes Topo II complexTopotecan-inhibits Topo I

Hormones/ Antihormones

Tx: breast CA (top)ORprostate CA (bottom)

*Tamoxifen-SERMTox: increase risk of endometrial CA

Anastrazole-inhibitis aromatase (estrogen synth.)

Prednisone-triggers apoptosis

Fulvestrant-anti-estrogen

Flutamide-NSAA inhibits translocation of steroid receptors to nucleus

Finasteride-inhibits 5-alpha reductase (synthesis of DHT)

Leuprolide-partial agonist at GnRH (blocks release of FSH & LH)

MAB’s Rituximab-anti CD20 B cellsTx: non-Hodgkins lymphoma

**TrastuzumabTx: metastatic breast CA (inhibits EGF binding to HER-2/neu receptor)Tox: cardiotoxic

Others AsparginaseTx: ALLTox: hypersensitivity, pancreas, CNS (w higher dose)

Imantinib Mesylate-inhibits bcr-abl TK in CML (Philadelphia chromosome)

Hydroxyurea-inhibits ribonuclease reductaseTx: CML

Methods of resistance: alteration ofpolyglutamate (methotrexate); mdr gene increase efflux (doxorubicin)

*As a rule, estrogen-dependent tumors are Tx with estrogen antagonists or androgens; testosterone-dependent tumors are Tx with testosterone antagonists or estrogens.

Jameel Khan

***Major Toxicities (Toxicity Bear): MAJORITY OF TEST QUESTIONS! (along with MOA’s)

Drug Toxicity AntidoteCisplatin Ototoxic & nephrotoxic Amifostine

Bleomycin Pulmonary fibrosisDoxorubicin/Daunorubicin Cardiotoxic Dimethyl sulfoxide (free radicals)

Dexrazoxane (Fe chelator)Cyclophosphamide Hemorrhagic cystitis Mesna

Methotrexate Renal toxicity LeucovorinVincristine Peripheral neuropathyVinblastine Myelosuppressive

Recall: cells that are rapidly turning over are affected alopecia; GI disturbances (n&v); myelosupp.

ANTI-VIRALS

Anti-Virals

Anti-Herpes(Antimetabolites)

Anti-CMV Anti-Hepatitis Anti-Influenza Other

Acyclovir-guanosine analog.-activated (tri-P) by viral thymidine kinase (TK) to inhibit vDNA pol.Tx: HSV-1,2; VZVAE: n & d; renal & CNS tox. (IV)

Cidofovir-ONLY activated by host cell kinases (less resistance)Tx: CMV, HSV, adenovirus, HPVTox: nephrotoxic

IFN-alpha-degrades vRNA via activation of host cell RNAase-IM injectionTx: HBV & HCVAE: flu, depression, alopecia, myalgia

Amantadine-blocks M2 proton channels (no acidification), NO uncoatingTx: Influenza A (not B)-adjust dose in elderly w renal fail

Palivizumab-parenteralTx: RSV in high-risk infants

Penciclovir-same as above (no chain term.)Tx: recurrent herpes labialis

Ganciclovir-activated by vTK (HSV) or UL97 (CMV)-intraocular implant (retinitis)Tx: CMV & HSVTox: myelosupp., CNS & hepatic tox.

Adefovir-inhibits HBV DNA pol.-oral-slower actionTox: lactic acidosis, nephrotox., hepatotox.

Rimantadine-same as above(4-10x’s more active)

Famciclovir-prodrug, coverted to penciclovirTx: genital herpes, herpes zoster

Fomivirsen-antisense to CMV RNA-intravitreal injection

Entecavir-same MOA as above-oral-more effective,

Oseltamavir-inhibits neuraminidase, blocks releaseTx: Influenza A&B

Imiquimod-topical-stimulates peripheral lymphocytes

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Tx: CMV retinitis improves liver Tx: genital & perianal wartsTrifluridine

-tri-P by host cell enzymes-active in infected & non-infected cells-ophthalmic admin

Foscarnet-inhibits vRNA pol, vDNA pol, HIV-RT(block pyro-P binding site)Tx: CMV retinitis (ganciclovir-R); HSV & VZV (acyclovir-R); HIVTox: nephrotoxic; Ca & Mg chelation; CNS

Ribavirin-multiple antiviral actions-inhalational-Tx: RSV in kids, HCV, Lassa fever, measles enceph.Tox: haemolytic anemia, teratogen

Zanamavir-same as above-inhalationalAE: bronchospasmCI: children <7y.o.

Resistance: changes to DNA pol; lack of thymidine kinase (TK- strains); mutations of HBV DNA pol.

Anti-Retrovirals Tx with multiple drugs (HAART) – usually NRTIs + PIs

NRTI NNRTI Protease Inhibitor Entry Inhibitor Integrase Inhibitor

Inhibit HIV-RT after –P by cellular

enzymesHIV-1 & 2

Inhibit HIV-RT, no –P required;

HIV-1 (not HIV-2)CYP450 metab.

Inducers (eg. Phenytoin, rifampin) &

inhibitors (eg. azoles, PIs) alter

duration of action“Never Ever

Deliver Nuc’s”

AE: Cushingoid appearance

HIV-1 & 2CYP450 metab.

All inhibit CYP3A4Many drug-drug

interactions

Enfuvirtide-binds gp41 on viral envelope, preventing fusion-HIV-1Tox: injection site reactions, hypersensitivity, bacterial pneumonia

Raltegravir-binds integrase-HIV-1 & 2-last resort drugTx: multi-drug resistant HIVCI: with rifampin & antacids

Abacavir-guanosine analog.AE: HS rxnsDidanosine-take on empty stomachAE: pancreatitis

Atazanavir-NO fat redistrib.AE: neuropathy, GI

EmtricitabineTx: HBV & HIVCI: pregnancy; young; renal or hepatic dysfxn

Delavirdine-decreased bioav. with antacids-other drug interactionsAE: rash, teratogen

Indinavir-food decreases bioav.-AE: hyperbilirubinemia; nephrolithiasis, thrombocytopenia

Maraviroc-binds CCR5, blocking viral attachment-HIV-1-CYP3A4 metab.Tox: cough, diarrhea, myalgia, arthralgia

LamivudineTx: HIV & HBVAE: pancreatitis

Efavirenz-fatty meal enhance bioav.AE: teratogenic

Lopinavir-combo w ritonavirAE: GI

Stavudine-thymidine analogAE: peripheral neuropathy

Ritonavir-highest inhibition of CYP3A (added to PI Tx’s)

Zidovudine (AZT)Tx: HIV + its

NevirapineTx: prevents

Saquinavir-combo w ritonavir

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transmission to baby, dementiaAE: myelosupp.

vertical transmission of HIVAE: rash, SJ synd.

AE: GI distress & diarrhea

IMMUNOMODULATORS

Immunosuppressants:

Pancytotoxic Lymphotoxic **Immunophilin Inhibitors**

Molecular Targets

MAB’s that bind cytokines

Azathioprine-antimetabolite (CCS)-prodrug of 6-MP inhibits PRPP synthetase & amidotransferase, therefore blocking purine synth. & salvage pathway NO clonal expansion of B & T cellsTx: prevents graft rejection; SLE; Crohn’s

**competes with allopurinol for metab. by xanthine oxidase (MUST reduce dose MP when using allopurinol for hyperuricemia)AE: myelosupp.; hepatotoxicity; infections; HS; carcinogenic!

ALG-antilymphocytic-binds T cells complement destruction-Ab’s raised in horsesTx: prophylaxis for GVHDAE: HS, serum sickness

Cyclosporine-binds to cyclophilin A1, inhibits calcineurin CAN’T enter nucleus to increase IL-2 prod’nTx: organ tx, GVHD, AI dz’sTox: nephrotoxic!

Etanercept-fusion protein“RECEPTS” / binds TNF-alpha-dimer of human TNF receptor fused to human IgGTx: RA, psoriasis, AS, added to MTX in cancer TxAE: injection site rxns

Infliximab-binds TNF-alpha preventing it from activating receptorTx: IBD (Crohn’s & ulcerative colitis), RA (w MTX), AS, psoriasisAE: HS, serum sickness, infectionCI: infections

Ig IV-polyclonal AB, most IgG, from donor poolTx: passive immunization; AI dz; etc.

Tacrolimus (FK506)-same as above, BUT binds to FKBP-12-more effective & less toxicTx: atopic dermatitis

Rho(D) Ig-RhoGAM (IgG)Tx: hemolytic dz of newborn -admin to Rho(D) neg. mom soon after birth to prevent Ab prod’n

Sirolimus-binds FKBP-12 & mTOR-inhibits IL-2 pathway, Ab prod’n & B cell prolif.Tx: stentsTox: hyperTGemia, hepatotox., diarrhea, myelosupp (non-nephro)

Daclizumab-binds IL-2 receptor on T cells, preventing activationTx: renal transplantAE: dyspnea, fever, GI distress

Muromonab-CD3-Ab to CD3 Ag on thymocytes, blocking T cell killing actionTx: acute renal allograft rejectionAE: HS, neuropsych., anaphylaxis

Mycophenylate mofetil-inhibits IMD (no de novo GTP synth)-suppresses B & T cellsTx: organ tx, GVHD, AI dz’sTox: GI, neutropeniaAsparginase

Jameel Khan

-see chemoTx CI: pregnancyGlucocorticoids: affect cellular immunity more than humoral decrease synthesis of prostaglandins, leukotrienes, cytokines, PAF, T cell proliferation, IgG levels; Tx for organ transplants, GVHD & hematologic cancers; Tox: adrenal suppression, growth inhibition, muscle wasting, osteoporosis, salt retention, glucose intolerance & behavioural changes.

Immunostimulants:

BCGTx: bladder CA (intravesicle admin); TB vaccine

Recombinant Cytokines Interleukins Colony Stimulating Factors

Interferons

Aldesleukin-recombinant IL-2Tx: adjuvant in metastatic melanoma & renal cell CA

Erythropoietin (Epoetin-alpha)-Tx: anemia (w Fe supp); chronic renal failureAE: heart & liver tox. w chronic use

Class 1: alpha-2aTx: Hairy Cell Leukemia;Hep B & ; CML; KSGenital warts

*Thrombopoietin-stimulates megakaryocytesTx: bone marrow suppression by chemo

Levamisole (Ergamisole)-stimulates maturation of T cells (antiparasitic)-adjuvant with 5-FU & leucovorinTx: colon cancer; nephrotic syndAE: myelosupp.

Class 2: B1a & 1bTx: MS

**Oprelvekin-recombinant IL-11Tx: thromobcytopenia

Filgrastim (G-CSF)-increases neutrophilsTx: neutropenia

Class 3: gamma-1bTx: chronic granulomatous dz

Sargramostim (GM-CSF)-increases granulocytes & macrophagesTx: myeloid recoveryCI: heart failure, pulm. edema, yeast HS

MINI 3:

HEMATOPOIETIC DRUGS

ANTIANEMIC

Microcytic hypochromic anemia deficiency of Fe (menstruation, vegetarians or malnourished)

Microcytic normochromic chronic blood loss

Megaloblastic anemia deficiency of vit B12 or folic acid

Pernicious anemia deficiency of intrinsic factor OR ileal or gastric resection

Jameel Khan

Fe preparations:

Oral ferrous sulphate, ferrous gluconate, ferrous fumarate

IV iron dextran, iron sucrose, sodium ferric, gluconate complex

Transferrin = transport protein

Ferritin = storage protein

*RECALL: there is NO mechanism for efficient Fe excretion DO NOT give Fe for haemolytic anemia

Acute Fe intoxication necrotizing gastroenteritis, shock, metabolic acidosis, coma & death

- Child who accidently ingested tablets

Tx: Deferoxamine (IV)

Chronic overload hemochromatosis heart, liver, pancreatic damage

- Inherited abnormality of Fe absorption- Frequent transfusions (eg., thalassemia major)

Tx: phlebotomy; Deferasirox or Deferoxamine (chronic admin.)

Vit B12 5 year reserve; essential for DNA synthesis (cofactor for formation of tetrahydrofolate, converts homocysteine to methionine & methylmalonyl CoA to succinyl CoA); megaloblastic anemia; neurologic defects (due to build up of methylmalonyl CoA)

- Folate supp’s will correct anemia, but NOT neurologic deficits, therefore MUST rule out B12 deficiency PRIOR to selecting Tx

Preps: Cyanocobalamin; Hydroxycobalamin (IV, longer t1/2, **used in Tx of pernicious anemia**)

*Schilling’s Test +ve result = pernicious anemia

Folate 1-6 month reserve; essential for DNA synthesis; megaloblastic anemia, neural tube defects

Preps: Folic acid (cofactor of DHFR, converts DHF to THF); Leucovorin (folinic acid; bypass DHFR; MTX rescue)

Jameel Khan

HEMATOPOIETIC GROWTH FACTORS

*All must be given IV (very low oral bioavailability proteins damaged by stomach acids)

Erythopoiesis-Stimulating Agents

Myeloid Growth Factors Megakaryocyte Growth Factors

Agonist of EPO receptorsTx: renal failure; aplastic anemia*give with Fe & folate supp*JAK/STATAE: Hypertension & thrombosis (maintain Hb <12 g/dL)

JAK/STATTx: neutropenia

AE: fatigue, headache, dizziness, anemia, pulmonary edema, transient atrial arryth’sOprevelkin (IL-11)JAK/STAT

Epoetin alpha-heavily glycosylated-1 dose/wk

Filgrastim (G-CSF)AE: bone pain

RomiplostimJAK/STATTx: chronic ITP

Darbepoeitn alpha-3 doses/wk

Pegfilgrastim*longer t ½

EltrombopagTx: ITPHEPATIX TOXICITY!

Promacta cares (licensing for admin)

Epoetin beta-1-2 doses/month

Sargramostim (GM-CSF)AE: fever, arthralgia, myalgia, capillary leak syndrome

NEUROPHARMACOLOGY:

GENERAL

GABA ion channel Chloride entry hyperpolarization (IPSP)

Glutamate ligand-gated ion channel (AMPA, NMDA, Kainate) depolarization (EPSP) LTP (NMDA)

Emesis centers:

1) Vomiting centre Tx with anti-Ach2) CRTZ Tx with D2 antag & 5-HT3 antag (e.g., ondansetron)

KNOW THESE NUCLEI:

1) Raphe nucleus 5-HT (sleep-wake cycle, pain modulation)2) Locus cereleus NE3) Nucleus Basalis of Maynar Ach

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4) Pendunculopontine nucleus Ach5) Nigrostriatal DA

Recall:

Tyrosine (tyrosine hydroxylase) DOPA dopamine (dopamine beta-decarboxylase) NE Ep

ANXIOLYTICS / SEDATIVE-HYPNOTICS

SEDATION (relief of anxiety) < HYPNOSIS (facilitation of sleep) < ANESTHESIA < COMA < DEATH

Barbituates Benzodiazepines Others-Increase DURATION GABA-A channel is open-do not req GABA’s presence-P450 INDUCERS!-narrow T.I.-suppress REM

-Increase FREQUENCY GABA-A channel is open-require GABA’s presence-large T.I. & ceiling effect-must taper off of Tx-no hyperanalgesia, lower REMCI: pregnancy, elderly, Parkinsons, MG, alcoholics, COPD/asthma, sleep apnea

Non-benzo: partial 5HT1A ag.**BuspironeTx: GADLOW SIDE EFFECTS (no sexual dysfxn)Decreases relapse rates7-10 d onsetCan drink alcohol

Long Acting:Phenobarbitol

Tx: prolonged sedation; seizure control (status epilepticus)

Long:Chlordiazepoxide – alcohol wd*Diazepam (Valium) – anxiety, alcohol wd; muscle spasm, status epilepticus*Clonazepam – seizures; panic; bipolar disorderFlurazepam - insomniaAlprazolam XR (Xanax) – sedative hypnotic; anxiety & panic

Z-drugs

Zolpidem (Ambien)Tx: sleep onset insomnia

Med Acting:Pentobarbitol

Tx: surgical anesthesia

Med:OxazepamTemazepamLorazepam – status epilepticusOTL Outside The Liver (no metabs); Rx: elderly, alcoholicsTx: anxiety, preanestheticFlunitrazepam – date rape amnesiaAlprazolam – anxiety; acute panic

Zaleplon (Sonata)Tx: “on demand” sleep induction

Short Acting:Thiopental

Tx: IV anesthesia (commonly used for induction)

Short: **high abuse liabilityTriazolamMidazolam-preanesthesia, sleep onset insomnia

**Eszopiclone (Lunesta)Tx: insomnia*NO tolerance / dependence

Jameel Khan

**Antagonist:FlumazenilTx: o.d. rescue; recovery from anesthesia; antagonize z-drugsInverse agonist:Beta-carbolines

*RamelteonMelatonin receptor antagonistReduces sleep onsetTx: jet lag; elderlyAE: endocrine changes (lowers testosterone; increased prolactin)

ANTIPSYCHOTICS

Theories of Schizophrenia:

1) Increased DA in limbic region (+)ve Sx’s = delusions, hallucinations, bizarre thoughts2) Decreased DA in prefrontal region, inhibition by 5-HT (-)ve Sx’s = blunted affect, apathy

Classical(D2 receptor affinity)

Atypicals(D2 & 5-HT receptor affinity)

Tx of (+)ve Sx’sM & a1 block dry mouth, blurred vision, orthostatic hypoTnhyperprolactinemia (galactorrhea & gynecomastia)Parkinsonian-like Sx’sEPS, tardive dyskinesia (enhanced by anti-muscarinics which help EPS) , akathisiaAll except Haloperidol = CARDIOTOXIC (increase QT interval)Still used because they are CHEAPER!

Tx of (+)ve & (-)ve Sx’sNo tardive dyskinesia, minimal EPSNo increase in prolactinMore expensive Higher death rate in elderly dementia pts

ChlorpromazineAE: cholestatic jaundice; hyperglycemia; sedation

*ClozapineTx: pts resistant to other drugsAE: AGRANULOCYTOSIS! (weekly blood test req’d); aplastic anemia; seizures; ANS toxicity (hypersalivation)

TrifluoroperazineTx: anxiolytic activity; anti-emetic

OlanzapineTx: bipolar 1; acute mania; OCDAE: weight gain (5-HT2c affinity); NMS!

*FluphenazineTx: NON-COMPLIANT pts (IM depot injection)

QuetiapineTx: acute mania; psychosis & Parkinson’s-minimal weight gainAE: cardiotoxic

ThioridazineAE: BROWNING OF VISON; ejaculatory probs (strongest ANS effects); arrythmias

Risperidone-potent a2 receptor antagonist-minimal weight gainAE: hyperprolactinemia

Thiothixine ZiprasidoneTx: schizoaffective mood disorderAE: cardiotoxic (QT prolongation); hyperglycemia**Haloperidol MOST POTENT!

-no anticholineric effects (weakest ANS effects)

Jameel Khan

IM depot injection (non-compliant/aggressive pts)Tx: Tourette’s synd; stuttering; hypomaniaAE: EPS (TD) & NMS

NMS (Neuroleptic Malignant Syndrome) high fever, severe muscle rigidity, altered consciousness, ANS instability, elevated CK, myoglobinemia (Tx with DANTROLENE!!!!)

DRUGS FOR BIPOLAR

Bipolar I HIGH & LOW mania & MDE (more equally manic to depressive)

Bipolar II MORE LOW hypomania & MDE (normal to depressive)

Increase intracellular Na depression; decreased intracellular Na mania

Lithium Non-responders / Rapid CyclersMOA: inhibits IP3/DAG (Gq)-very narrow T.I.-onset takes 2-3 wks (tide pt with antipsychotic (eg. chlorpromazine or olanzapine) or benzo)-90% renal excretionAE: Nephrogenic diabetes insipidus thirst & polyuria; hypothyroidism goiter (both reversible); ACNE; wt. gain; dysmorphogenesis*Toxicity: abdominal pain (1st sign)!; coarse tremor; vomiting; ataxia; diarrhea; seizures; albuminuria; nephritis; arrhythmia; coma; death*CI: thiazide diuretics; AV blocks; NSAIDs; ACE inhibs; iodinated cough syrups; nursing mothers; pregnancy (cat.D)

“Very Good & Calm”Valproic Acid-most effective DOC in acute illnessCan be used in combo w Li+AE: hepatic dysfn; GI distress; wt gain; alopecia; inhibition of drug metab.Gabapentin-use in pregnancy (no teratogenicity)

CarbamezapineTx: prophylaxis of depressive phaseAE: hematotoxicity; ataxia; diplopia; induces drug metab.LamotrigineAE: rash; nausea; dizziness; headache CI: liver problems*Valproate inhibits metab (dose must be halved)*Carbamezapine stimulates metab (dose must be doubled)

ANTI-DEPRESSANTS

TCA’s1st genInhibit 5HT & NE (increase BDNF) reuptake; plus M, H1 & alpha

Tx: neuropathic pain (*5HT&NE reuptake)AE: sedation; wt. gain; ANS effects; suicidality

Imipramine5HT = NETx: enuresis

Amitryptyline5HT > NEAE: sedation

Clomipramine5HT >> NETx: OCDAE: sedating

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*not 1st choice Tx(narrow T.I., lethal in o.d.) *DO NOT use in elderly (>65)

Tox: 3 C’s (coma, convulsions, cardiotoxicity)

MAOI’s1st genTx: depression, social anxietyAE: Hypertensive crisis w TYRAMINE

PhenelzineMAO-A & MAO-B (non-selective)

*SelegelineMAO-B (low dose)Tx: Parkinson’s (increases DA); MDD skin patch; reverses sexual dysfxn

SSRI’sDown regulate & desensitize autoreceptors (depression may increase)Tx: MDD, GAD, OCD, panic, social phobias, PTSD, bulimiaAE: sexual dysfn, wd Sx’s, agitationCI: other agents that increase 5HT (SS)

*Fluoxetine (Prozac)*only one approved for children (others increase suicidality!)-inhibits P450

Paroxetine-inhibits P450AE: high rates of sexual dysfn

**Escitalopram-high efficacyTx: GAD

Sertraline-high efficacy

CitalopramAE: cardiotoxic in o.d.

SNRI’sBoth 5HT & NE reuptake blocked(no H1/a/M block)Tx: MDD; OCD; PTSD; neuropathic pain; fibromyalgia

**VenlafaxineTx: GAD-inhibits P450AE: CNS stim; hypertension; cardiotoxic; sedating; sever wd Sx

DuloxetineTx: pain of diabetic neuropathyAE: hepatotoxic warning

Atypicals **Trazadone-antag at 5HT2A/CAE: sedative, priaprism, arryth’s

**Buproprion-NE & DA uptake inhibTx: nicotine wd; depression (counter-acts sex dysfn)AE: lowers seizure threshold

**Mirtazapine-blocks 5HT2A/C & alpha 2Tx: sedationAE: wt gain

Agomelatine-melatonin ½ plus 5HT2CTx: restores circadian rhythms (not yet approved in U.S.)

Serotonin Syndrome (SS) severe muscle rigidity, myoclonus, hyperthermia, CV instability and marked CNS stimulation (seizures) due to SSRI + MAOI, TCA, meperidine, St.John’s wort, amphetamine, cocaine