RECEPTORSReceptor Class Mechanism/Second

messengerSite Action Effect Drug receptor

selectivityα α1 ↑DAG & IP3↑ IC Ca2+ Blood Vessel Smooth Muscle-TPR

(skin)Pupil Radial muscleIntestine, Prostate, Bladder sphincter

Vasoconstriction-Blood vessels-TPRMydriasis↓GIT, Contraction-↓urinary

VASOCONSTRICTION ↑BP on stimulation/agonistMydriasis-good in glaucoma

Epinephrine>Norepinephrine>>>>>>>>>Isoproterenol

α2 ↓cAMP↓Norepinephrine release

Presynaptic receptor↓Nor(auto)/Ach(hetero)INHIBITORYPancreatic β cell↓insulinFat, Platelet

↓Nor/Ach—Neuromodulation—inhibitory↓insulin & lipolysis (DOMINANT)Platelet aggregation

↑blood sugar on stimulation↓ insulin release

β β1 Heart↑Ino, Chrono, AV nodal conduction velocityJG cells↑Renin

↑BP, ↑HR,↑conduction↑Renin↑fluid retention↑venous return↑SVCO↑BP;↑Ang2↑TPR↑afterload↑heart work,↑BPGIT smooth muscle relaxation

↑BP on stimulation/agonist Isoproterenol>Epinephrine>Norepinephrine

β2 Blood Vessel SKELETAL, (coronary)Uterine Smooth muscleRespiratoryLiverPancreatic β cellCiliary muscle

VasodilationRelaxation (tocolysis)BronchodilationGlycogenolysis↑insulin (MILD)Relaxation-Mydriasis

↑blood flow to skeletal muscle/HEART↑ air in lungs↑ energyGood in glaucoma On stimulation/agonist

Isoproterenol>Epinephrine>>>>>>>>>>Norepinephrine

β3 Fat cell ↑lipolysisDopamine D1 type-

D1, D2↑cAMP:↑adenylyl cyclase Blood vessel-Smooth muscle:

Renal, Splanchnic, CORONARY, Cerebral--RELAXATION

Vasodilation↑blood flow (CORONARY)

D2 type-D3, D4, D5

↓ adenylyl cyclaseOpen K channel↓Ca influx

Nerve terminal ↓Norepinephrine releaseAutoregulator

Cholinergic Nicotinic Agonist-small dose Nicotine Antagonist-Large dose nicotine Ach↓Norepinephrine at vasoconstrictor nervesAchM3NO/EDRF releasevasodilation (cavernous muscle-erection) Sildenafril

Skin of face, Neck, salivary glandsstimulate/agonistblushing

Cholinergic drug-all vessels dilate

Muscarinic Agonist-Muscarine Antagonist-Atropine

Histamine H1 Smooth Muscle-intestine, airwayEndotheliumBrain

Smooth Muscle ContractionBlood Vessel: (Short Lasting) Vasodilation-NO, PG releasecapillary permeability, gap junction wideningSmooth muscle: vasoconstriction-larger vesselsAfferent Nerve Stimulation

BronchoconstrictionAllergies

Sensory Nerve Endings-stimulation-painWaking AmineTriple response-ID injectionRed spot, edema & flareBP(vasodilation), sense of warmth, Headache

H2 Gastric Parietal CellsCardiac MuscleSmooth MuscleBrain

Gastric Gland-Gastric Acid SecretionBlood Vessels: (persistent) Vasodilation-smaller vesselsHeart: +ve Chronotropy & +ve Inotropy, HR

Peptic Ulcer

H3 Histaminergic NeuronsMyenteric Plexus

Presynaptic H3 Receptors-release several transmitters

AGONISTSClassification Drug Class Receptors Action Effect Uses ADR/Interactions

DIRECTLY ACTING Epinephrine Catecholamines Allα1=α2;β1=β2

Low dose-β action-vasodilationHigh dose-α action-vasoconstriction

β2-dilates coronaries & skeletal blood vessels-↑blood flowα1&2-consticts blood vessels of skin & mucosa

ANAPHYLACTIC SHOCK(α)(IM), local anaesthetic, GLAUCOMA(α1), local bleed (nose)(α 1&2)Physiological antagonist of HistamineGlauomaHeart block, cardiac arrestLocal hemostasis(α1)

+COCAINE↑CVS effects

↑cardiac work-ischaemia, MI, heart failure↑BP↑HRArrythmiasPulmonary edema

Norepinephrine α1=α2β1>>>β2α1,α2,β1 agonist

α1 –vasoconstriction-↓TPR-↑BP

↑BP ShockDopamine preferred

↑BP*baroreceptor*VagusREFLEX BRADYCARDIA (α1)

Isoproterenol β1=β2>>>>αMainly β;Less α

Heart block, cardiac arrest

Dopamine D1=D2>>β1>>α

D1, α, β1 agonist

Low dose:D1-vasodilation-renal, splanchnic↑blood to kidney, visceraD2-presynaptic autoreceptor-↓Norepinephrine releaseModerate dose: (D1)↑contraction,conduction (heart)High dose: α-vasoconstriction

Inotrope Cardiogenic/Septic shockInotrope-↑CO, xHR↑perfusion kidney, viscera↑urine outputAcute HF

Xylometazoline, Oxymetazoline, Naphazoline Pseudoephederine,

α Vasoconstriction of nasal mucosaTopical-long acting

Nasal decongestants

Initial sting↑BPProlong: Atrophic rhinitis

Selective Adrenergics Phenylephrine Selective α1 agonist

α1 VasoconstrictionMydriasis

Nasal DecongestantMydriasis-retinal examGLAUCOMA

No cycloplegia ↑BP

Methoxamine Selective α1 agonist

Clonidine Selectiveα2 agonist

α2Central sypatholytics

↓vasomotor sympathetic center↓BP, relax peripheral blood vessels

Antihypertensive↓TPR-relax peripheral blood vessels

AntihypertensiveGLAUCOMA-apraclonidie

Withdrawal reaction of Opiates, Benzodiazepines

αmethylDOPA Selectiveα2 agonistαmethyl analogue of DOPA (precursor of DA, NE)

Antihypertensive-synthetic-no ADR/interactionGLAUCOMA

No ADR/interaction therefore Coombs test/DAT globulin negative

Dobutamine Selective(relatively) β1 agonist

β1>β2>>>α

↑intropy, conduction--↑CONo ↑ in O2 demandx HR, BP, TPR

Inotrope Cardiogenic/Septic/Renal shockCHF-inotropePost MI shock/pump failureCardiac surgery

Sinus tachycardia, Arrhythmia

Salbutamol, Terbutaline

Selective β2 agonist

β2 Brochodilation Asthma Skeletal muscle tremors

Isoxurine, ritodrine Uterine relaxation

Premature labor

MIXED ACTION Ephederine Mixed acting adrenergic

Direct α+β actionAlso indirect action

Release Norepinephrine + α&β stimulation

Long actingLess efficacy

Postural HypostensionMa Huang-weight loss, appetite suppression

↑CNS: tremors, anxiety, insomnia, convulsions, anorexia

Pseudoephederine Mixed acting adrenergic

Nasal decongestant

Mephentermine α & β agonist

INDIRECTLY ACTING

↑Release Amphetamines:Dex/Met Amp, Modafinil, Methylphenidate

Indiectly acting adrenergic

↑Norepinephrine release

↑CNS, alertness↓weight

Modafinil-EpilepsyMethyphenidate: ADHD

Drug of Abuse↑CNS: tremors, anxiety, insomnia, convulsions, anorexia

Tyramine Indiectly acting adrenergic

↑Norepinephrine release

Present in fermented food- cheese, wine, sausagesMetabolized: Liver-MAO enzyme

↓Reuptake Cocaine Indirectly acting adrenergic

↓Reuptake at noradrenergic synapses

Drug of Abuse: ↑Dopamine in brain neurons

ANTAGONISTSType Class Drug Uses/effect Action ADR/Interactions

α blocker Nonselective PhenoxybenzamineErgotamineDihydroergotaminePhentolamineChlorpromazine

Phentolamine:Penile erection for impotence

α1 blockade↓TPR↓CO↓BP

Secondary shock-reflex vasoconstriction-hypovolemic shockCHF-short term reliefPeripheral vascular disease

Postural hypostension-dizziness & syncopeNasal stuffiness-dilated blood vessels-extravasationMiosis-cholinergic-pupillae constrictorDiarrhea: cholinergic dominanceInhibition of ejaculation

Selective

α1 blocker Prazosin HypertensionPheochromocytoma

Tamsulosin BPHTerazosine

α2 blocker Yohimbineβ blocker Propanolol Hypertension ↓vasodilation-β2 blockade

↓Renin-↓Ang2-↓TPR-↓BP-β1 blockadeHeart β1 blockade-↓CO-↓BP

Anticholinergic M3: vascular endothelial cell

Atropine No marked effect on BP Normal dose-Blocks Ach agonist-↓vasodepressor action (↓TPR; INDIRECT)Large dose: Direct Vasodilator

Anti Histamin

ergic

H1 Blocker

First generation DipenhydrinateDipenhydramineHydroxineCyclizineMeclizineCinnarazineChlorpheneraminePromethazineCyproheptadine

Anti Allergic-(type 1 HS-Histamine)Allergic reactions-Allergic Rhinitis (hay fever), urticarial, Drug induced allergy (type 1 HS)Atopic Dermatitis: Dipenhydramine (sedative-reduces itchiness sensation)

Parkinsonism: Dipenhydramine/inate, Promethazine- tremor,rigidity(Anti Chloinergic)

Pregnancy Nausea/Vomiting: Doxylamine, Promethazine

Motion Sickness: Dipenhydramine/inate, Promethazine, Cyclizine, MeclizinePomethazine:

Vestibular Disturbances: Cinnarazine (AntiHistaminic, AntiCholinergic, Anti5HT)

AntiAllergic-(Histamine=type 1 S)

SedativeHighly: Dipenhydramine/inate, PromethazineModerately: Pheniramine, Cyproheptadine, Meclizine, Cinnarazine

Anticholinergic:Dipenhydramine/inate, Promethazine

AntiHistaminergic+AntiMuscarinic = AntiEmetic/AntiNausea-Doxylamine (Promethazine)

Adrenoreceptor Blocker: Promethazine

Serotonin Blocker: Cyproheptadine

Wide DistributionGreater CNS entryDuration of action: 4-6 hours(Meclizine: 12-24 hours)

Unsuitable for daytime use, car driving, machinery workers psychomotor performance(AntiHistamine H1)

CNS: alertness & concentration, motor incoordination, fatigue

Promethazine: Adrenoreceptor Blocker-Orthostatic hypotension, reflex tachycardia

AntiHistamine/AntiSerotonin: Appetite

AntiMuscarinic: Dry Mouth, Altered Bowel & Bladder, Vision Blurring

Block Autonomic ReceptorsReversible Competitive Antagonism

Second generation FexofenadineLoratidine, DesloratidineCetrizine, LevocetrizineAzelastineEbastine

Narrow Spectrum of Uses:Allergic rhinitis (hay fever)ConjunctivitisUrticaria, atopic eczemaAcute Allergic reactions to Drugs & Food

H1 SelectivityRapid ActingNo AntiCholinergic effectsAbsence of SedationAdditional AntiAllergic mechanisms:Inhibit cytotoxic mediator release, Eosinophil Chemotaxis,inhibit platelet activating factorsCNS entryMetabolized by CYP3A4Drug InteractionsLong Acting: 12-24 hoursActive Metabolites of Drugs available:Loratidine-DesloaratidineCetrizine-LovocetrizineTerfenadine-Fexofenadine

Reversible Competitive Antagonism

Terfenadine/astemezol + CYP3A4 inhibitors (ketoconazole/erythromycin/itraconazole)-Ventricular Arrhythmias (Torsades de Pointes)due to blockage of IKr (HERG) potassium channels responsible for repolarization of heart

+CNS depressants: additive effect

Autonomic blockade of older Antihistamines are additive w/ AntiMuscarinics

Terfenadine, Astmezol banned-vent arrhythmia-TdP

Adrenaline

Physiologic antagonist of Histamine

Anaphylaxis/Anaphylactic ShockCaused by Histamine, Leukotriene, ProstaglandinAdminister:AdrenalineFollowed by- AntiHistamine: ChlorpheneramineGlucocorticoids: HydrocortisoneBP, Bronchodilation, Laryngeal edema release of mediators

No role in Asthma:Asthma due to Leukotriene & PAFLow concentration at site of action

No role in other humoral & cell mediated allergies

MYOCARDIAL INFARCTION/ANTI-ANGINALClass Drug Site/Mechanism Uses ADR Interaction

Nitrates Short acting: Glyceryl Dinitrate, isosrbide dinitrate ( sublingual)Long acting: oral, transdermal

VenodilationpreloadArteriolar dilationTPRAfterloadCoronary dilation

Angina PectorisNSTEMIHypertensive emergencyLV failureAbdominal ColicCyanide Poisoning

Throbbing headacheTolerancedependance

+sildenafil/Viagra=death+other antihypertensives=BP

β blocker Anti-adrenergicCO/cardiac work and myocardial O2 requirementsreninangiotensin

Classical & Unstable anginaMIMild CHFHypertensionArrythmiaDissecting Aortic AneurysmHypertrophic obstructive cardiomyopathyMigraine, thyrotoxicosis, Anxiety, tremors, glaucoma

TGquality of lifeWorsening Peripheral vascular diseaseCHFHeart blockTiredness & reduced exercise

+verapamil/diltiazem=SA & AV nodal depressioncardiac arrestdeath+insulin & oral antidiabeticsdelay recovery from hypoglycaemiaBlocks warning symptoms of hypoglycaemia: tremors, seating, tachycardia+α agonists (cold remedies: ephedirine/phenylephrine)=BP (unopposed action)+NSAIDS=β blocker effectPropanolol=lignocaine metabolism

Calcium Channel Blockers

Phenylalkylamine : Verapamil

Ca2+ channel block-NERVE cell – SA,AV node

CCB: interfere w/ Ca2+ entry in the cellblood vessel relaxation↓COBlock L type voltage channel

Cardiac arrhythmiaMigraine, nocturnal leg cramp

+βblockercardiac depression-death

Dihydropyridine: Nifedipine, Amlodipine, Lercanidipine

SMOOTH & CARDIAC muscle

Angina pectorisHypertensionPremature laborHypertrophic cardiomyopathy, Reynaud’s disease

Weak uterine contraction, foetal hypoxia, tachycardia, hypotension↓placental perfusion

Nifedipine: tachycardia & death

Benzothiazepines: Diltiazem

Broad spectrum: nerve + muscle

Cardiac arrhythmiaAngina pectorisHypertensionHypertrophic cardiomyopathy

+βblockercardiac depression-death

K+ channel openers

NicorandilPinacidil

Visceral+vascular smooth muscle dilation

HypertensionMI-nicorandil-

Arterial+veno dilationDilation of epicardial & deeper vessels↑coronary blood flow

cardioprotective

Combinations β blocker + Long acting nitrate

Nitrate + CCB β blocker + nitrate + CCB

AVOID verapamil+ diltiazem

βblocker-x nitrate tachycardiaNitrate- x β blocker cardiac dilation & ↓blood flow

Nitrate - ↓ preloadCCB - ↓ afterloadVasospastic angina

Nitrate - ↓preloadCCB - ↓afterload + ↑coronary blood flowβ blocker - ↓ cardiac work

Pre-hosptal/Emergency management

Aspirin: 162-325 mg-chewed &swallowedNitroglycerine: sublingual-0.4mg/5minO2Morphine

NSTEMI:Stabilize acute coronary lesionRx residual ischemiaProphylaxis

Anti-thrombotic therapy:Antiplatelets: clopidogrel (ADP), abciximab (Gp 2b/3a), Apirin (COX)Anticoagulant: heparin/enoxaparinAnti-ischemic/Cadioprotective therapy: Cardioselective β blockers, ACE inhibitors, Nitrates

Prevention of Recurrence:Aspirin: lifelongβ blockers: metoprolol2 yearsACE inhibitorsAntihyperlipidemics: statins

Thrombolytic: rTPA-alteplase-STEMI<6hrs of onset↓mortality/preserve LV functionAspirin: antiplatelet-irreversibly acetylating COX↓cardiovascular events↓mortality following AMIMorphine: opioid-analgesic↓anxiety, cardiac metabolic demands↓sympathetic activityNitrates: coronary vasodilation↑coronary blood flow↓ventricular load-venodilationβ blockers: Atenolol, Metoprolol↓cardiac work & O2 demand↓injury & death & infarct size- myocardial salvationMaintain coronary flow to subendocardium↓acute mortality, prevent recurrence↓automaticity: delay in AV conduction/cardioprotective↓sudden ventricular fibrillationACEI: w/in 24 hr6 weeksReverses remodeling caused by Ang2↓early & long term mortalityClopidogrel, unfractionated heparin(PCI)

In hospital management

Complete bed restAspirin & Heparin: after fibrinolysis(x reocclusion)β blocker: w/in 24 hrs2 yearsACE inhibitors: STEMI-w/in 24 hrsAntihyperlipidemic drugs

STEMI:Reperfusion therapy

PCI: first preferenceFavored after 3 hrsw/in 90 mins-door to balloonangioplasty/stent placementFibrinolytics:w/in 30 mins- door to needleafter 6 hrs- poor efficacy

ANTI-ARRHYTHMICSClass Phase of

actionMechanism Drugs Effects Uses ADRs/Interactions/Contraindications

Class 1Na channel blocker

Phase 0Phase 4(Phase 0 & 3)

↓rate of conduction in tissue w/ fast potentialIgnores slow potential - SA, AV nodes

1aQuinidineProcainimide(phase 0 & 3)

↑AP duration & refractoriness↓conduction through ventricle↓Repolarization rate↑ QRS & QT intervals

Atrial & Ventricular arrythmias ↓myocardial contractility, cardiac arrest+diureticshypokalemiatorsades de PointesGIT side effectsHypersenstivity

1bLidocaineMexiletine(phase 3)

↓AP duration and refractoriness↓conduction through ventricles↓Repolarization rate↓automaticity in ectopic foci

Ventricular arrythmiasIneffective in atrial arrythmias

Neurological: dizziness, drowsiness, nausea, blurred vision, paraesthesia, confusion, convulsionBradycardiaHypotension

1cFlecainide(phase 0)

↓conduction in all cardiac tissues

Atrio-ventricular re-entrant tachycardia

GI symptoms, blurred vision, tremorsContraindicated-Sick sinus syndrome, heart failure, MI

Class 2β blocker

Phase 4 β receptors-attached to Ca2+ channelsβ blocker: ↓ Ca2+ influx similar to class 4 (CCB)

PropanololEsmolol (short acting)

Slow gradual Ca2+ influxautomaticityβ blocker: ↓ Ca2+ influx↑PR interval; no change in QRS

Supraventricular arrhythmias associated w/ exercise, emotion & stressSinus tachycardiaExtrasystoles

Severe bradycardia↓cardiac contractility, cardiac arrest

Class 3K+ channel blocker

Phase 3 ↓K+ effluxprolongs repolarization & ERP

Amiodarone ↓ K+ efflux↑Repolarization & ERP↑PR, QRS, QT interval

Supraventricular and Ventricular arrhythmiaResistant ventricular tachycardiaRecurrent ventricular fibrillationAtrial fibrillation: maintain sinus rhythm

Bradycardia, Heart blockHypothyroidism: amiodarone has IodineGI relatedPhotosenstivitySkin & corneal pigmentationPeripheral neuropathyPulmonary alveolitis & fibrosis (serious)

Class 4Ca2+ channel blocker

Phase 2(Phase 4)

Similar effect as β blocker

VerapamilDiltiazem

↓SA/AV automaticity↑AV nodal conductivity↑ERP↑PR intervalBreaks reentrant circuit

Paroxysmal Supraventricular Tachycardias (PSVT)Poor efficiency in ventricular arrythmia

Hypotension, BradycardiaAdditive AV blockNegative inotropic effect

Adenosine (α 1 agonist)

Very short acting purine nucleotide

Hyperpolarization of membrane↓conduction velocity via slow potential/Ca2+

Paroxysmal Supraventricular Tachycardias (PSVT) involving AV node-alternative to verapamil

Transient dyspnea, Chest pain↓BPVentricular standstill or fibrillation

channelsNo effect on fast potential/Na+ channel↑PR interval

Digoxin Na/K ATPase inhibitor

Inhibits Na/K ATPase of myocardial fibers ↑intracellular Na+↑intracellular Ca2+ (via Na/Ca exchange pump)↑contractility & excitability of contracting cells↓generation & propagation of impulse in SA & AV conduction velocity↑PR interval, depresses ST segmentEnhance Vagal activity: INDIRECTLY

Paroxysmal Supraventricular Tachycardia (PSVT)Atrial flutter/fibrillation

GI relatedDisturbances in color visionAtrial ArrhythmiaGynaecomastia, hyperkalemia

ANTI-HYPERLIPIDEMICS

Action Class Drug Mechanism Actions Adverse Therapeutic Contraindications/Interactions

Endogenous Statins Simvastatin(PrD)Atorvastatin(LnAct)Rosuvastatin(LnAct)

Lovastatin(PrD)

↓Hmg CoA red↓Hepatic Cholesterol synthesis↑LDL receptors on hepatocytes↑plasma LDL clearance

↓Total Cholesterol↓LDL↓TG↑HDL

MyopathyHepatitis-↑serum transaminaseGI disturbanceRash, Insomnia, Angioedema

HypercholestrolemiaIIa, IIb

Anticoagulants & Antidiabetics95% PP bindingTERATOGENIC

Fibric Acid Derivatives

GemfibrozilBezafibrateClofibrate

Fenofibrate

PPAR-α↑Lipopritien Lipase Synthesis↑clearance of VLDL and Chylomicrons

↓TG↑HDL

Rash, Nausea, Dyspepsia, Diarrhea, Myopathy↓testosterone-impotence↑liver enzymes

HyperTGemiaIIb, III, IV, V

Hepatic & Renal DiseasePregnancy & lactation↑oral anticoagulants↑Myopathy

Nicotinic Acid Adipose:Binds to NA recptors-↓FFA mobilization-↓TG & VLDL synthesisLiver:Inhibits DAG acyltransferase-2 (key TG synthesis enzyme)-↓VLDL synthesisPlasma:↑Lipoprotein Lipase activity-↑clearance of VLDL & chylomicrons

↓VLDL(hepatic secretion)↓LDL↓TG (synthesis)↓FFA (from adipose tissue)↑HDL

Flushing & pruritusGI disturbanceHepatotoxicityHyperuricemiaImpaired glucose tolerance

↑HDLHyperTGemia

IIb, V

Exogenous Cholesterol Uptake Inhibitors

Ezetimibe (oral) Interferes with cholesterol transport protein NPC1L1 (intestine) - ↓cholesterol absorption

Diarrhea , Headache, Myalgia

HypercholestrolemiaCombined with

statins-synergisticIIa

Bile Acid Binding Cholestyramine Bind to Bile acid- ↓LDL Constipation, Hypercholesterolemia Delasy absorption

Resins ColestipolColesevelam (no dug

interaction)

interrupt enterohepatic circulation↑excretion of bile in feces↑cholesterolbile↓hepatic cholesterol-↑LDL receptor on hepatocytes-↑clearance of LDL

NE TG FlatuenceImpaired fat soluble vit absorption↑gallstones

Patients who cannot tolerate other drugs

of Warfarin, Digoxin, Chlorothiazide

↑ LDL StatinsFibrates

Ezetimibe

↑ TG FibratesNicotinic Acid

ANTI-HYPERTENSIVES

Class Drugs Mechanism Features Effects Uses ADR Interactions/Contraindications

Renin inhibitors

β blockersAliskrenin (oral unapproved)

Inhibit rennin secretion

ACE inhibitors

Enalapril, Captopril, Benazepril

Inhibit ACEno Angiotensin II

↓angiotensin↑bradykinin

No reflex sympathetic stimulation↓BP:↓TPR, ↓angiotensin II, ↓vasoconstriction, ↓aldosterone↑Vasodilation (bradykinin)Renal:↑vasodilation, ↓protienuria, no electrolyte disturbance

Hypertension, CHF: ↓TPR first lineMI: reduce mortalityDiabetic nephropathyProgressive renal impairment: ↓ESRD, ↓protienuria, ↓Systemic resistance

Hypotension (CHF w/ diuretics)Hyperkalemia (renal pts)Cough (↑bradykinin)TeratogenicARF (bilateral renal artery stenosis)

+NSAID:↓PG synthesis, ↓vasodilation+K sparing diuretic (spironolactone):↑K

ARB Losartan, Valsartan, Irbesartan

Competitive antagonist of AT-1 receptor

Inhibit angiotensin IINo effect on bradykinin

No Cough (bradykinin metabolized)

Hypertension w/ cough (ACEI) Hypotension , Hyperkalemia,Teratogenic

Calcium Channel Blockers

Verapamil Block L-type channelsArteriolar vasodilation↓coronary tone↓myocardial O2 requirements↓LV wall stress↓HRSmooth Muscle Relaxation: Bronchiole, Uterine, GIT↓Afterload only

Cardiac>vascular smooth muscle

↓AV nodal conduction:in Supraventricular Reentry tachycardiaAtrial fibrillation-↓ventricular responseSympathetic blockadeTypical AnginaAtrial tachycardia/flutter/fibrillationMigraine

↓Ca2+ influx in heartCardiac depression/arrest/failure↓HRAV block

AV conduction abnormalitiesOvert Heart Failure

Verapamil/Diltiazem + β blockerAV block↓ventricular function

Diltiazem Cardiac=vascular smooth muscle↓inotropy vs Verapamil

↓AV nodal conduction:in Supraventricular Reentry tachycardiaAtrial fibrillation-↓ventricular responseSympathetic blockadeTypical AnginaVariant AnginaAtrial tachycardia/flutter/fibrillation

↓Ca2+ influx in heartCardiac depression/arrest/failure↓HRAV blockConstipation

Dihydropyridine

Nifedipine1 genShort acting

Reflex Sympathetic Stimulation:Reflex Tachycardia, BP swingMORTALITY in CAD

Cardiac<vascular smooth muscle

Less effect on AV nodal conductionTypical AnginaVariant AnginaHypertensionPregnancy induced Hypertension

Reflex Sympathetic Stimulation:Reflex Tachycardia, BP swingMORTALITY in CAD↑MI risk in hypertensiveVasodilation: flushing, headache, ankle edema, ↓BPElderly: Urine retention

Unstable Angina: ↑ risk of adverse cardiac events

Amlodipine2 genHR, CO not affected

Can be used in overt heart failure

Direct Hyadralazine/dihydralazine ↓TP ↓TP Arteries & Arterioles Moderate Hypertension Lupus Syndrome ↓BP

Vasodilators

R↓BPReflex sympathetics↑contractility, HR, O2 consump↑MI, angina, Heart failure(counteract: β blocker)↑Renin↑salt&H2O retention(counteract: diuretic)

R↓diastolic BP

Pregnancy Induced Hypertension Palpitation↑HR, AnginaFluid retentionEdema

Sodium NitroprussideForms NO

Forms NOIV: T1/2 is small (2-5 min) continuous infusion↓TPR&CO↓sys & dias BP

Arteries & Veins↓BPReflex tachycardia↓Preload & Afterload

Hypertensive Emergencies MetabolismCN_ ionLarge dose: Toxicity+thiosulphateThiocynatekidneys excreteLight sensitive: protect from light

DizoxideK channel opener

K channel openerIVLong acting (6-24 hrs)

Arteriole Hypertensive Emergencies

Diuretics ↓plasma & ECF volume↓CO↓BPgradual ↓ in TPR

β blockers Sympathetic depressant↓HR, inotropy & CO↓BP↓cardiac work & O2 consumption

CONGESTIVE HEART FAILUREClass Drugs Source/Comment Mechanism Effects Uses ADRs & Antidote Interactions

Positive Inotrope

Cardiac Glycosides

Digoxin:Fast acting (15-30 mins)Commonly used↓protein bindingT1/2: 40 hrsDigitoxin:Slow onsetNot commonly used↑protein boundT1/2: 5-7 days

Foxgrove PlantSugar SteroidLactone ring

Inhibits NA/K ATPase↑I/C NaNa/Ca pump↓↓Ca efflux &↑CA influx

↑contraction↑ventricular ejection↓EDV&ESV↑CO:↓Sympathetic, ↓HR, ↓TPR↑Renal perfusion, ↓Edema

SA:↓rateAtria:↓refractory periodAV:↓conduction velocity ↑ refractory periodPurkinje/Ventricle: ↓refractory period (slight)ECG: ↑PR,↓QT interval↑venous toneKidney: diuresis

Heart failureCHF + Atrial fibrillationSevere/Chronic CHF + LV systolic dysfunctionAtrial flutter/fibrillation: ↓Av node conduction↑AV node ERP

Initial:GIT: AnorexiaNausea, VomitingDiarrheaCNS:Elderly-disorientation & hallucinationsColor vision disturbanceAntidote: Lower dose

Cardiac:Delayed afterdepolarizationsVentricles:BigeminyFibrillation/tachycardiaHeart blockECG: PVB, inverted T wave, depressed ST segment; tachycardia, fibrillation, arrestSA: ↓rateAtria: ↓refractory periodarrhythmiasAV node: ↑refractory periodarrhythmiasPurkinje/Ventricles: Extrasystoles, tachycardia, fibrillations

↓K+:Mild: skip 1-2 doses; oral K+ supplementation <5 meq/LSevere/Suicidal: ↑K+ levels; not give K+ supplements

Suicide/severe poisoning: Digoxin antibodiesFab fragments bind & inactivate drug

Arrhythmias: Antiarrhythmic- lidocaine, phenytoin

+ K+:↓ digoxin binding to Na/K ATPase+hypokalemia due to steroids/diuretics: ↑ toxicity

+ Ca2+:Hypercalcemia, ↑toxicity

+ other drugs: qunidine, amiodarone, tetracycline ↑toxicity due to ↑ digitalis concentration

β 1 agonists Dobutamine Drug + β recepto

↑CO↓ventricular filling

Acute Heart Failure ArrythmiasTachycardia

Less arrythmogeni

r↑cAMPactivation of PK-Aphosphorylation of Ca channel↑Ca2+ flow into cellmyofibrils↑contraction force

pressure c & less tachycardia vs dopamine

Dopamine ↑BP Acute Heart Failure, raise BP

Phosphodiesterase Inhibitors

AmrinoneMilrinone

PDE are enzymes that inactivate cAMP & cGMPPDE inhibitors: X PDE↑cAMP & ↑cGMP

Inotropic agentVasodilation

Severe Heart Failure ↑MortalityNausea, VomitingArrhythmias↑Liver enzymeThrombocytopenia

Vasodilators ACE inhibitors EnalaprilLisinopril

Non selective vasodilator: Arteries & Veins

X ACE (kininase 2)↓angiotensin 2↓sympathetic activityVasodilation↓afterload↓aldosterone↓salt & water retention↓venous return↓preload

Non selective vasodilator: Arteries & Veins↓afterload & ↓preload

CHF:First line↓ventricular dilation↓long term remodeling↑efficacy of diuretic treatment↓mortality & morbidityAsymptomatic patients w/ LV dysfunction + no edemaSymptomatic patients: ↓preload and afterloadHypertensionMIDiabetic Nephropathy

First dose hypotension (post diuretics)Cough (↑bradykinin)HyperkalemiaDysguesia, rashes, urticarialAcute Renal Failure; angioedemaTERATOGENIC

Angiotensin Receptor Blocker

LosartanValsartanIrbesartanCandesartan

No cough Block AT-1 receptor (angiotensin-2 receptor)No effect on ACEBradykinin metabolized

ACEI intoleration due to coughCHF: all stagesHypertension

Hypotension↑K+AngioedemaTERATOGENIC: fetal damage

Nitrate Isosorbide Dinitrate

Venodilator Venodilator↓preload

Dyspnea NOT FIRST LINE DRUGSIsosorbide dinitrate + hydralazine↓remodelling(africans)

Hydralazine Arteriole dilator Dilates arteriole↑CO↑cGMP-smooth muscle

Arteriole dilator Patients w/ increased fatigueAntihypertensive-pregnancy + α methyl DOPA

Sodium Nitroprusside

Arteriole + Veno dilator

↑NO↑cGMP Arteriole + Veno dilator↓afterload & ↓preload

CHFHypertensive emergency

Diuretics Loop diuretics FurosemideBumetanideTorsemide

↓venous pressure↓preload↓systemic pulmonary edema

↓cardiac size↑pump efficiency↑CO

CHF:FIRST LINEFurosemide/loop diuretic: Acute pulmonary edema, severe chronic failureSpirinolactone: Severe

Hypokalemia: leads to digoxin interactionHypervolemiaOtotoxicityHyperuricemia: GoutMetabolic alkalosisHyperlipidemia

Thiazide diuretics

ChlorothiazideHydrochlorothiazide

Aldosterone Spirinolactone

antagonist Eplerenone chronic heart failure, ↓morbidity &↓mortality

β blockers BisprololCarvedilolMetoprolol

↓catecholamines:↓HR↓symptoms↓Myocyte apoptosis↓remodelling

Start w/ low doses↓mortality in stable severe heart failure↑EF,↓HR, ↓symptomsLong term:↓death rate, ↓symptoms, ↑sense of well being, better clinical status

Stable chronic heart failureMI historyAsymptomatic patients w/ ↓LVEF

Neseritidine BNP, IV continuous infusion Acute Heart FailureBosentan Endothelin receptor

antagonistSevere Pulmonary Hypertension

↑survival in CHF

ACEI, ARB, β blockers, spirinoloactone, hydralazine+nitrate

Stage A: High risk, No symptoms↓Risk factorsTreat: hypertension, hyperlipidemia, diabetes, obesity

(ACEI/ARB for vascular disease)

Stage C: Structural disease, Symptoms↓ Na, H20, WorkDiuretics, ACEI, ARBDigitalis: systolic dysfunction + 3 HS/atrial fibrillationβ blockers ( in stable class 2-4)Spirinolactone

Drugs causing CHF NSAIDCCBAnti arrhythmic (some)Alcohol

Chronic Heart Failure

↓work, ↓Na & H20ACEI or ARBThiazide diuretic β blocker (in stable class 2-4)Digitalis (if systolic dysfunction/atrial fibrillation)Nitrate/hydralazine (vasodilator)Cardiac resynchronization (if wide QRS)

Acute Heart FailureCan be due toAMIAnemia, fever↑metabolic demand↑exertion, ↑emotion, ↑Na

↓Power: inotropes, vasodilatorsPulmonary congestion: diuretics

Stage B: Structural disease, No symptoms↓Risk factorsTreat: hypertension, hyperlipidemia, diabetes, obesity

(ACEI/ARB, β blockers)

Stage D: Refractory Symptoms↓ Na, H20, WorkDiuretics, ACEI, ARBDigitalis: systolic dysfunction + 3 HS/atrial fibrillationβ blockers ( in stable class 2-4)SpirinolactoneCardiac resynchronizationCardiac transplant

SHOCKType of Shock Mechanism Treatment

Hypovolemic/Oligemic shockLow Volume

Internal & external fluid loss↓preloadHemorrhagic/Non HemorrhagicTraumaNon traumatic: Vaginal, GI, GUBurns, DiarrheaVomitingDiuresis, SweatingThird Space Loss:Pancreatic, peritonitis, bowel obstruction

Volume resuscitation: rapid infusion-isotonic saline, ringers lactateNaHCO3-correct acidosisInotropic support following volume support-Dobutamine, DopamineO2Acute hemorrhage/anemia: Whole Blood & plasmaAbsence of Blood & plasma: Colloidal plasma expandersHuman albumin, Dextran, HydroxyethylstarchCrystalloid plasma substitute: superior to colloids-Normal saline, 5% dextrose, ringer lactate

Neurogenic shockLow Resistance

Cervical spinal cord injury/severe head injuryloss of sympathetic vasomotor tonearteriolar & venodilationpooling of blood in post capillary capacitance blood vesselpooling of venous system↓venous return & ↓cardiac output

Penylephruine/Norepinephrine↑vascular resistance↑MAPIV fluids for relative hypovolemia

Cardiogenic shockPump Failure

Severe LV dysfunctionsystemic hypoperfusionMI, acute myocarditis

MI:Morphine,O2, nitroglycerine, aspirin, alteplase (fibrinolytic), metoprolol (β blocker), captopril (ACEI), heparin (anticoagulant)Dopamine:Low dose-dilates renal vascular bedModerate dose- +ve chronotropic & inotropic effectsDobutamine: +ve chronotropic & inotropic effectsIV fluids: maintains adequate blood volume

Septic/Bacteremic/Endotoxic shock

Severe infection & tissue hypoperfusionGN (E coli)>GP (staph)

Infection treatment, Hemodynamic & Respiratory support w/in 1hr of presentationAntimicrobial:Empirical: effective against both GN & GP microorganismAfter microbial culture: appropriate antimicrobial treatmentRemove focal source of infectionNaHCO3-corrects acidosisVasopressor-for hypotensionO2Recombinant activated protein C: Sepsis associated w/ excess inflammatory response & altered coagulation & fibrinolysisAnti-inflammatory & Anti-apoptoticSeptic shock w/ adrenal insufficiency: Glucocorticoids (hydrocortisone 100 mg IV TID)

Anaphylactic shock Histamine release & other mediators Adrenaline: 0.5 mg of 1:1000 IMreversal of hypotension, bronchospasm, laryngeal edemaIV fluidsHydrocortisone hemisuccinate: 100mg IV/IM- inhibit late phase of allergic reactionChlorpheneramine: 10-20 mg slow IVO2, assisted ventilation

DopamineD1, D2, α1, β1Low dose: 2 µg/Kg/minD1dilates renal vascular bedModerate dose: 2-10 µg/Kg/minD1,β1+ve chronotropic & inotropic effectHypovolemic, Cardiogenic, Septic

Dobutamineβ1 selectiveinotropic w/ afterload reduction(peripheral vasodilator)minimize cardiac O2 consumptionCardiogenic shock-pump failure due to MI

Norepinephrineα1, α2, β1Strong vasoconstriction↑BPShock w/ severe hypotension

Phenylephrineα1 agonistStrong vasoconstrictorNeurogenic shockVasopressin:Catecholamine resistant shockMilrinone:PDE inhibitorPotent inotrope & chronotrope

Shock treatment:Early recognitionABC resuscitationFluid restorationVasopressors (AFTER fluid restoration)Restore O2 deliveryControl inciting pathological processMaintain vital organ function

Hypovolemicshock

Endotoxic shock

Cardiogenic shock

Anaphylactic shock

Volume replacement

YES YES NO POSSIBLY

Dopamine YES YES YES POSSIBLY

Dobutamine POSSIBLY YES YES NO

Adrenaline NO NO NO YES

Glucocorticoids NO YES NO YES

Antihistaminics NO NO NO YES

HEMATINICSOral Fe Ferrous Sulphate (32%)

Ferrous Fumarate (33%)Ferrous Gluconate (12%)Colloidal Ferric Hydroxide (50%)

PreferredFerrous>Ferric absorptionEmpty stomachUpper intestineabsorbed

ADRsEpigastric painNausea, vomiting, heartburnMetallic tasteStaining of TeethBloating

Parenteral Fe

Iron DextranIV/IM

Iron Sorbitiol-CitrateIM

IM-deep gluteal injectionZ technique-avoid skin staining2ml-daily/alternate days5 ml each side on same dayIV-0.5 ml Fe Dextran after test dose over 5-10 minInfusion-diluted in 500 ml glucose/salineFe sorbitol-not iv

ADRsLocal:PainSkin PigmentationSterile abscessSystemic:Fever, headache, joint pain, flushingPalpitation, chest pain, dyspneaLN enlargementAnaphylaxisRenal Disease-X Fe sorbitol

USESFe deficiency anemia(treatment & prophylaxis)Megaloblastic anemiaFeCl3-astringent in throat pain

↑MWIM(locally bound)/IVNot excretedAbsorbed through LymphaticsNot transferrin boundTaken up by macrophagesslowly available to erythron

↓MWIM-Not locally bound30 % excretedAbsorbed through CirculationTransferrin bound

Directly available

Fe overload

Normal-2.5-3mg>7 mgtissue damageAcute Fe Poisoning:>60mg/KgVomiting, Abdominal Pain, HematemesisDiarrhea, LethargyCyanosis, Dehydration, AcidosisConvulsionsShock, CVS collapse

Management:Prevent further Absorption:Induce vomiting/gastric lavageOral egg yolk & milkcomplex ironActivated charcoal uselessBind & remove absorbed Fe:Chelating Agent: DesferroxamineDTPA/Ca edetateBAL contraindicatedSupportive Measures:Correct fluid/electrolyte balanceCVS supportConvulsions: Diazepam

Hemopoetic GFErythropoetin: peritubular cells of kidney↑RBCMCSF, GCSF↑WBCThrombopoetin↑plateletsStem cell factorIL

Megaloblastic state

B12/Cobalamin deficiency:Gastric failure:Pernicious anemiaTotal gasterectomyIleal failure:Crohn’s disease: regional enteritisIleal resectionTropical sprueCompeting organism:Bacterial overgrowth (blind loop)

Folate deficiency:Folate poor diet: Alcoholism, poverty↑ Folate requirement:PregnancySevere hemolytic anemiaSevere psoriasisDrug therapyTropical sprue

Clinical features:B12 & Folate:Megaloblastic anemiaFatigue, weight loss, fundal hemorrhage, diarrhea, fever, sore tongue, appetite loss, jaundiceB12 deficiency:Paraesthesia, neuropathy, dementia, demyelination of spinal cordPernicious anemia: Family & personal history of vitiligo, Autoimmune thyroid disease

Treatment:Transfuse (care)B12-oral or parenteralFolate tabletsSevere cases: hypokalemia

Epoetin:r Human Erthropoetin Uses:Chronic Renal FailureCancer ChemotherapyAIDS anemiaPremature infantsDose: 25-100 IU/Kg/SC IV 3x a WkAdverseFlu like symptomsMild HypertensionEncephalopathyThrombosis

Diphyllobothrium latum ↑Fe & Folate demand

DRUGS AFFECTING BLOOD ELEMENTSDisease/Condition Causative Drugs/Causes Treatment/Therapeutic Drugs Adverse effectsG6PD-Hemolytic anemia

Antimalarials:PrimaquineChloroquineFansidarMaloprim

Stop drugTreat underlying infectionsSevere anemiablood transfusionHemoglobinuriamaintain good renal flowavert renal damageNeonatal jaundicephototherapy

Sulfonamides:SulfacetamideCo-trimexazoleDapsoneAntibiotics:ChloramphenicolFurazolidoneNiridazoleNalidixic acidNitrofurantoinAntidiabetics:GlibenclamideAnalgesics;High dose ASPIRINVitamin K analoguesNaphthalene

Immune Hemolytic Anemia

Penicillin-High Dose:Ab against drug-RBC complex

Stop DrugCORTICOSTEROIDS:PrednisoneFIRST LINEAzathioprine, Cyclosporin, Cyclophosphamideused when other measures failSplenectomySevere Cases:Blood TransfusionsFolate

QuinidineRifampin:Drug-ag-ab deposits complement on RBC surfaceMethyldopaFludarabine

Chemical AgentsHemolysis

Dapsone-High Dose Stop DrugSevere Anemia: Blood Transfusion

Wilson’s Disease-Cu-High Dose

Poisoning: Pb, Chlorate, Arsine

Thalassemia Regular Blood TransfusionFolate-regular useSplenectomy: 6yrs+Hepatitis B vaccineAllogenic BM transplant

Iron OverLoad:Liver damageEndocrine: growth failure, delayed/absent puberty, DM, hypothyroidism, hypoparathyroidismMyocardium Siderosis

Iron Chelator:Parenteral: Desferoxamine1-2g IV or 20-40 mg/Kg SC w/ each unit of bloodAdverse :Rapid IV: hypotensionIdiosyncratic reactions: Flush, RashPulmonary, Neurosensory toxicityOral: Defipirone, Deferasirox

Endocrine therapy: GH, insulin, Ca, Vitamin D

Aplastic Anemia Chemicals:Benzene, DDT, insecticides, Hair Dye

General Treatment:Stop Drug/ChemicalAnemia: Blood transfusions, Platelet concentratesInfections: Prevent & Treat-cultures, Broad spectrum prophylactic antibiotics, antifungals, GCSFSevere ThrombocytopeniaFibrinolytic Inhibitors:Tranexamic Acid or Aminocaproic AcidPlatelet transfusionAllogenic Stem Cell Transplantation

Drugs:Anticancer:BusulphanCyclophosphamideAnthracyclinesNitrosoureas

Idiosyncratic:ChloramphenicolSulphonamideGold

Specific Treatment:Anti Lymphocyte Globulin (ALG) & Anti Thymocyte Globulin (ATG): ↓cytotoxic T cellsAdverse:Fever & Chills: PrednisoloneSerum Sickness: spiking fever, arthralgia, skin rashes

Cyclosporin: primary treatment + ATG + steroids

Combination Immunotherapy: ATG (4 days) + cyclosporine (6 months) + Methylprednisolone (2 weeks)

Hemopoetic Growth Factors

Stem Cell TransplantationNeutropenia Anticancer Drugs:

Alkylating agents-non selective neutropeniaGeneral Treatment:Stop DrugPrevent & Treat infections:Bacterial UsuallyCan also be:Viral, Fungal, Protozoal

Antibiotics:ChloramphenicolsSulfonamidesCo-trimexazoleCephalosporinsAntipsychotics:ChlozapineChlorpromazine

Specific Treatment:GCSFGM-CSFAutoimmune Neutropenia: Corticosteroids & SplenectomyRituximab: Anti CD-20 (Monoclonal Antibody)

Antithyroids:CarbimazoleAnti-Inflammatory:Phenylbutazone

Gold SaltsAnti-Epileptic:PhenytoinCarbamazepinePenicillamineTiclopidine

Thrombocytopenia Bone Marrow Suppression: Anticancer, EthanolChloramphenicol, Co-trimoxozole, Arsenic

General Treatment:Blood Transfusion/Platelet Concentrates

Immune:Analgesics, Anti-inflammatory: Gold SaltsAntibiotics: penicillin, trimethopterin, sulfonamidesAntiepileptic: Diazepam, CarbamazepineDiuretics: Acetazolamide, FurosemideAntidiabetics: ChlorpropamideDigoxin, Heparin, Methyldopa, Quinidine

Specific Treatment:Corticosteroids: Prednisolone (High Dose)Splenectomy: Patients w/ steroid failure or in need of high dose steroidsImmunoglobulin: Rituximab (anti CD 20); high dose modify autoAb productionImmunosuppression: Azathioprine, Cyclosporin, Cyclophosphamide when other measures failMegakaryocyte Growth Factor: OPRELVEKIN (IL 11)

Platelet Aggregation: Heparin

Erythropoetin:Hb, Erythropoesis, circulatory reticulocytesEPOETIN α, DARBOPOETIN α: IV, SCUses:Anemia due to CRF/AIDS, cancer/drugsAnemia in premature babiesPre-Operationto blood transfusionsAdverse: Thrombosis, BP

Myeloid Growth Factor:rG-CSF: Filgrastim neutrophilsrGM-CSF: Sargramostim neutorphils, eosinophils, monocytesUses:Post chemotherapy, radiotherapy, autologous SC transplantPeripheral mobilization of SC for autologous SC transplant (G-CSF)Severe neutropenia, Aplastic anemia

Megakaryocyte Growth Factor:Oprelvekin: IL-11ThrombopoetinUses:Thrombocytopenia /after cancer therapyAdverse Effects:Fatigue, Headache, Dizziness, Fluid RetentionCVS effects: Dilutional anemia, dyspnea, Transient Atrial Arrythmia

ANTI-PARASITICDisease Class Drug Mechanism Uses Adverse EffectsAntimalarial Erythrocitic Schizonticide Chloroquine Degradation of

RBC HBFast & Long Acting

Prophylaxis & Cure of ALL types of MalariaInfectious MononucleosisRheumatoid Arthritis

toxicity; side effectsGIT-A/N/V, epigastric painCVS: IV; BP; arrhythmiaCNS: toxicityEye: retinal damageEar: Hearing Defects

Mefloquine Intermediate & Long Acting

Multidrug Resistant Plasmodium falciparum malaria

Not ParenteralAvoid in cerebral/complicate malariaResistance

Quinine Multidrug Resistant malariaCerebral malaria+ Tetracycline=effectNocturnal muscle cramps, varicose veins, myasthenia gravis

effective, toxicity than chloroquineHighly toxic8-10 g-fatalCinchonism: CTZ damage, vomiting, tinnitusHemolysisPregnancyAbortion

Sulfonamide (sulfamethopyrazine/sulfadoxine)+Pyremethamine (S/P)

Slow and Long actingErythrocytic phase of P. falciparumAntifolate (like Cotrimoxazole)

P. falciparumcurativeToxoplasmosisfirst choice

SulfonamideSerious toxicityExfoliative dermatitis, Steven Johnson syndromeNot prophylacticSingle Dose

Tetracyclines Weak & Slow acting

All Plasmodium species+Quinine or S/PChloroquine resistant FalciparumDoxycycline (100 mg/day): Second Line Prophylactic-Chloroquine resistant Falciparum malaria

X Pregnant, LactatingX Children <7 yearsNEVER USED ALONE

Blood Schizonticide Halofantrine Mefloquine like activity

Multidrug Resistant P. falciparumP. vivaxUsed when other drugs not working

GITVentricular Arrhythmia

Artemesinin DerivativesArtisunate: Water SolubleOral, IV, IMArtemether: Lipid SolubleArteether: IM

Fastest and Short actingProdrugsDamage ER & Protein synthesis in parasitesKills falciparum gametes

Multidrug Resistant Falciparum malaria treatment

+ enzyme inhibitors/anti-arrhythmic/anti-psychotic/anti-depressants arrhythmiasNot useful in prophylaxis

Tissue/Liver Phase acting/Exoxryhtrocytic

Primaquine Effective against Gametocytes & Hypnozoites

Prevent & Cure malaria relapse

GITG6PD: hemolysis

Filariasis Diethyl Carbamazine Selectively sensitize microfilariae for phagocytosis

FilariasisTropic Pulmonary Eosinophilia

GITFever, RashLN enlargement

Leishmaniasis Sodium Stibogluconate Inhibits –SH dependant enzymes of parasite

Kala Azar (L. donovanii) N/V, abdominal painPancreatitisKidney & Liver Damage

Trypanosomiasis Pentamidine Inhibits topoisomerase 2 & aerobic glycolysis

TrypanosomiasisLeishmaniasisAIDS patients: Pneumocystis jiroveci pneumonia

Highly ToxicStrong alkaline naturereleases HistamineanaphylaxisHeart, Liver, Kidney damage

Trypanosoma cruzi Nifurtimox/Benznidazole-Acute disease Chaga’s diseaseTrypanosom gambiense/rhodensiense

Early disease: IV suraminLate disease + CNS involvement: suramin + melarsoprol (crosses BBB) + corticosteroids (prevents reactive encephalopathy)

Sleeping sickness

Toxoplasmosis Sulfadiazine + Pyrimethamine+Falinic acid (prevents BM suppression)

Congenital/disseminated disease

Causal Prophylaxis:Pre/exo-erythrocytic phasecause of malariaPrevent clinical attacksProguanil: P. falciparumPrimaquine: all malarial species

Suppressive Prophylaxis:Erythrocytic Phase suppressionprevents malarial feverClinical symptoms suppressed; exoerythrocytic phase not affectedChloroquine: 300mgx2tabs/wk; 1wk before & 1 month after endemic area returnResistant cases: Proguanil 200 mg daily + Chloroquine 300 mg weeklyMefloquine 250 mg weekly-4wks after endemic area returnDoxycycline 100 mg 1day before to 4 weeks after endemic area return

Clinical cure: terminate episode of malarial feverErythrocytic SchizonticidesFast acting High efficacy: used aloneChloroquine, Mefloquine, Quinine, Amodiaquine, Halofantrine, Lumefantrine, Artemesinine, Atovaquone.Slow acting Low efficacy: used in combinationProguanil, Sulfonamides, Pyrimethamine, Tetracycline

GametocidalElimination of male & female gametes from patients’ bloodNot beneficial to patient; Reduces transmission to mosquitoPrimaquines & Artemesinines: Gametocidal to all speciesChloroquine & Quinine: Vivax gametes

Antimalarial Classification:

4-aminoquinolines: ChloroquineQuinoline – Methanol: MefloquineCinchona Alkaloid: QuinineBiguanides: ProguanilDiaminopyridine: Pyrimethamine8-aminoquinolines: PrimaquineSulfonamides: Sulfadoxine, SulfamethopyrazineTetracyclineSasquiterpine Lactone:Artesunate, Atemether, ArteetherAmino Alcohol: HalofantrineMannich Base: PyronaridineNaphthoquinone: Atovaquone

Most Antimalarials: Hemolysis in G6PD deficiency

Radical Cure: total eradication of parasite from bodyExo-Erythrocytic drugs + Erythrocytic drugs = total cureP. falciparum & P. malariae: clinical cure=erythrocytic schizonticides=erythrocytic parasite elimination is enough. No exoerythrocytic phaseP. vivax & P. ovale: Relapsing malariaerythrocytic & exoerythrocytic/hypnotic parasite elimination Exo-Erythrocytic drugs + Erythrocytic drugs

Falciparum Malaria:Chloroquine sensitive: Chloroquine + Primaquine (gametocidal)Chloroquine resistant:

Multi Drug Resistant Falciparum Malaria:Uncomplicated Acute Multidrug Resistant Falciparum Malaria:

Vivax Malaria:Chloroquine sensitive:Chloroquine + PrimaquineChloroquine Resistant:Quinine + Doxycycline + Primaquine

Prevention Of Malaria in Travelers:ChloroquineAreas w/o resistant P. falciparum

Malarone=Atovaquone+ProguanilAreas w/ chloroquine resistant P. falciparum (WHO)MefloquineAreas w/ chloroquine resistant P. falciparum

-Artesunate +Sulfadoxine+pyrimethamine (S/P)+Primaquine-Artesunate + Mefloquine-Artemeether + Lumefantrine-Quinine + DoxycyclineCerebral malaria: Chloroquine sensitive malaria drugs IV

ACT-Artemesinine based Combination TherapyArtemesinine + Erythrocytic Schizonticide

DoxycyclineAreas w/ multidrug resistant P. falciparum

PrimaquineTerminal Prophylaxis of P. vivax & P. Ovale

ANTIRETROVIRALSClass Drugs Mechanism Uses Adverse Effects ResistanceNucleoside & Nucleotide Reverse Transcriptase Inhibitor

Zidovudine (AZT) Deoxythymidine AnalogAZTThymidine KinaseTriphosphate formCompetitive Inhibition of dTTP for Reverse Transcriptase EnzymeCauses Chain Termination

IV & OralHIV 1, HIV 2, HTLVHIV treatment: progression & survivalPrevents Mother to Child HIV transmission

Myelosuppression: Neutropenia, AnemiaGI intolerance: N/VHeadaches, InsomniaCrosses BBBMetabolite in urine

Mutations in reverse transcriptase geneProlong therapy & Monotherapy

Stavudine Thymidine Analog Peripheral NeuropathyLipidystrophy

Didanosine Synthetic Deoxyadenosine Analog

PancreatitisPeripheral NeuropathyD/N/VAbdominal Pain

Zalcitabine Cytosine Analog Peripheral NeuropathyN/VHeadache

Lamivudine Cytosine AnalogAbcavir Guanosine Analog

More effectiveFatal Hypersensitivity

Non-Nucleoside Reverse Transcriptase Inhibitors

Nevirapine Binds to Viral Reverse TranscriptaseRNA & DNA dependent DNA polymerase blockadeSubstrate & Inhibitors of CYP3A4Do not compete w/ nucleoside triphosphatesDo not require Phosphorylation

Prevents HIV transmission from mother to neonate at labor/delivery

DelavirdineEfavirenz TERATOGENIC

Protease Inhibitors Indinavir Protease: Cleaves large precursor polyprotein moleculefunctional componenetsInhibit Protease (late step in replication) prevent spread of infection

Nephrolithiasis Lipidystrophy: Abdominal Obesity, Buffalo Hump, Limb & Face wastingDyslipidemiaGI intoleranceDizzinessNumbnessRashesHeadacheLimb & Facial tinglingAstheniaHyperlipidemiaInsulin resistance

Ritonavir FatigueInhibits CYP3A4

Squavinavir PhotosensitivityNelfinavirAmprenavir

Fusion/Entry Inhibitor

Enfuvirtide (T-20) Binds to gp-41 subunit of viral glycoprotein envelopeprevents conformational changes required for fusion of viral &

cellular membranesBlocks FusionPrevents entry into/infection of CD 4 cells

Integrase Inhibitor RaltegravirAnti HIV regimens:Zidovidine + Lamuvudine + Lopnavir (PI)Zidovidine + Lamuvudine + Efavirenz (NNRTI)

Post Exposure Prophylaxis:Low Risk: Zidovidine (300 mg) + Lamuvidine (150 mg)2xdaily for 4 weeksHigh Risk:+ Indinavir (800 mg)3xdaily for 4 weeks

HAART:2 NRTI + 1 PI (+/- ritonavir)

2 NRTI + 1 NNRTI

THROBOLYTICS, ANTITHROMBOTICS AND COAGULANTSClass Drug Description Action Uses ADR ContraindicationsThrombolytics / Fibrinolytics Streptokinase Non enzymatic

proteinβ hemolytic streptococciProactivator plasminogen complexcatalyzes formation of plasmin

AMI: Thrombolytic Therapy-w/in 6 hrs of symptomsPeripheral Arterial ThrombosisCatheter & Shunt patencyPE + Hemodynamic InstabilitySevere DVTAcute Ischaemic Stroke: rTPA w/in 3 hrs of symptomsPeripheral Vascular Disease

Action blocked by Antistreptococcal Ab

1Year should be elapsed before next use

Allergy, Hypotension-generating Kinins

Serious Bleedingtreated w/ tranexamic acid, fresh plasma or coagulation factors

Absolute Contraindications:Neurosurgery/Head trauma <2 mtsSevere Active Bleeding/ Internal HemorrhageCerebrovascular Hemorrhage <6 mtsCerebral tumor/aneurysm

Relative Contraindications:Recent Major TraumaInvasive Surgery < 10 daysGI/genitourinary bleedingRecent CardioPulmonary ResuscitationPeptic Ulcer <3 mtsPregnancyUncontrolled HypertensionThrombocytopenia

Urokinase Enzyme-Human urineCultured Human Renal CellsNon-AntigenicPotent Direct Plasminogen Activator

Non Antigenic

Recombinant Tissue Plasminogen Activator:AlteplaseDuteplaseReteplase

rDNA technologyExpensive

Better than streptokinase & urokinase in dissolving older clotsDoes not act on circulating plasminogenNon Antigenic

Anistreplase Anisoyloted Plasminogen Streptokinase Activator Complex (APSAC)Complex: Purified Human Plasminogen + Bacterial Streptokinase

Rapid action Clot selectivity Activity on plasminogen associated clots than free blood plasminogenThrombolytic Activity

Allergies BleedingHypotension-Kinins

Anti-Coagulant(AntiThrombotic)

Parenteral Anticoagulant

Indirect Thrombin Inhibitor

Unfractionated Heparin(UFH)

MW: 5000-30,000

Sulfated Mucopolysaccharide

IV/SCNot given IMhematoma formationImmediate onset

HeparinActivates Anti Thrombin 3 (AT-3)Inhibits Factors 2a (Thrombin), 9a, 10aBleeding timeClotting timeaPTT

DVT & PE:Prophylaxis-for bed rest, high risk surgeries, Cancer- Low dose UFH, LMWH, FondaparinauxTreatment-UFH,

Bleeding: risk: careful patient selection, Dosage control, monitor aPTT

Heparin Induced Thrombocytopenia (HIT):Ab formed to Heparin & Platelet Specific Protien - Platelet Factor 4

Drug hypersensitivity, HITActive Bleeding/Risk,Intracranial Haemorrhage, Active TB, Hemophillia, TTP, Recent Surgery-CNS, eye, postateThreatened AbortionBrain & Spinal Cord InjuryAnaesthesia: Regional & Lumbar

4-6hrsMonitor:aPTT = 2-2.5 control

Does not cross Placenta

Inhibits Coagulation InVivo & InVitroInhibits Aldosterone SecretionLipemia clearingAnti-Inflammatory

LMWH for 5-6 days, then Warfarin for 3-6 mtsPregnant Women- Heparin-SC

Atrial Fibrillation w/ emboliztion

Artificial Heart Valves, PC angioplasty

Cardiac bypass: Aspirin, Heparin

Rheumatic Heart Disease

DIC: Heparin

Acute Unstable Angina: Aspirin 160 mg/day + Heparin, followed by Warfarin

(PF4)Systemic hypercoagulable stateLeads to Venous ThrombosisPerform platelet count frequentlyTreatment: Direct Thrombin Inhibitor, Fondaparinaux

Allergy: Animal Origin-asthma, urticariaTherapy-Transient Alopecia Osteoporosis: >6 mts use

blockSevere Hepatic & Renal Impairment

Low Molecular Weight Heparins (LPWH):EnoxaparinDalteparinTinzaparin

MW: 3000-7000

Heparin Fragments Inhibits Factor 10aLess effect on Thrombin (2a)

Equally efficacious as UFHNo effect on CT, aPTTNo lab test requiredSCBioavailabilityLong T1/2Less frequent dosing1/2 weeklyBleeding, HIT

Prevention of DVT, PECannula patency in Dialysis patients

Fondaparinaux Anti Thrombin 3 mediated selective inhibition of Factor 10aNo effect on Thrombin (2a)SCLong T1/2: 15 hrs

PE, DVTHITAMI

Direct Thrombin Inhibitor

Hirudin/Lepirudin (Bivalent DTI)Specific irreversible Thrombin Inhibitor

Hirudin: Leech SalivaLepirudin: recombinant form

Directly bind to active site of Thrombin

HITAnaphylaxis

Bivalirudin (Bivalent DTI)

Coronary Angioplasty

Argatroban (Univalent DTI)

HITCoronary Angioplasty in HIT patients

Oral Anticoagulant

Vitamin K Antagonist

Warfarin Inhibits Vit K EpoxideVit K Hydroquinone (active form)

Inhibits Vit K EpoxideVit K Hydroquinone (active form)

Bleeding: Common-Haematuria, Epistaxis, Bleeding Gums, Uterine, Intracranial Ulcer-FATALTreatment: Vitamin K (antagonist),

Inhibits synthesis of Vit K dependent Factors 2,7,9,10 (TENS)

Potentiating Factors (anticoadulation)-bleeding-Hepatic Disease: synthesis of clotting factors-Fever & Thyrotoxicosis: metabolism (destruction) of clotting factors-Malnourishment, Malabsorption, New Borns: Vitamin KInhibiting Factors (coagulation)-Thrombosis-Pregnancy: synthesis of Clotting factors-Hypothyroidism: metabolism (destruction) of clotting factors-Genetic warfarin resistance

Inhibits synthesis of Vit K dependent Factors 2,7,9,10 (TENS)

Slow Complete AbsorptionDelayed onset: (1-3 days)plasma protein bindingCrosses Placenta & Secreted in MilkMetabolized in Liver

Dose Regulation:Monitor PT-reduce to 25% of controlINRFull effect: 4-5 days even if INR reaches therapeutic level in 1-2 days

PK: Enzyme Induction & Inhibition, PP bindingPD: Synergism-impaired hemostasis/clotting factor synthesis (hepatic disease), Competitive antagonism-Vit K, Hereditary resistance to oral anti coagulants

Fresh Blood/Plasma Infusion

Teratogenic: Fetal Warfarin Syndrome- Fetal Hemorrhage, Abnormal Bone Formation

Necrosis: Thrombosis in Venules-Soft Tissues-Breast & Buttocks

Warfarin Sodium: Alopecia, Urticaria, Severe Dermatitis

+Rifampicin&Barbiturates (metabolism), Vitamin K(clotting factors)Thrombosis

+Phenylbutazone&Aspirin(platelet aggr), Cimetidine, Metrinidazole, Erythromicin, Cotrimoxazole, fluconazole (metabolism)Potentiate

Phenindione HypersenstivityDirect Thrombin Inhibitor

Dabigtaran No routine INR monitoring requiredFewer Drug Interactions compared to Warfarin

Prevent Stroke & Thromboembolism in Atrial Fibrillation

In Vitro Calcium Chelators

Ethylene Diamine Tetra Acetic Acid(EDTA)Citrate

Prevent Blood Clotting in Test Tubes

Lithium HeparinAntiPlatelet Prostaglandin Synthesis Aspirin Inhibits COX & MI Prophylaxis Arterial

Inhibitors Thromboxane Synthase IrreversiblyTXA2 synthesis in Platelets Bleeding Time in vivoLow Dose: 75-100 mgPlatelets exposed to aspirincannot synthesize new enzyme

Unstable AnginaCerebrovascular Disease

Thrombus-White Thrombus

Prevent Reinfarction in Active MI & IHD

Primary & Tertiary prevention of MI post MI

Prevent stroke in cerebrovascular disease & transient ischemic attacks

Patency of implanted bypass in CABG:Aspirin + Abciximab

ADP Receptor Blocker ClopidogrelTiclopidine

Inhibits Platelet Aggregation

(ADPCa2+ (2nd messenger)Gp 2b/3a active)

Blocks ADP Receptor (P2Y12)ADPplatelet aggregationADP-RBinhibits aggregation

Aspirin Intolerant PatientTransient Ischemic AttacksStroke, Unstable AnginaCoronary Stent

Nausea, Diarrhea, LeukopeniaThrombocytopenic PurpuraClopidogrel: Less ADR, Safer

Glycoprotien 2b/3a Receptor Inhibitor

Abciximab Chimeric Monoclonal Antibody

Chimeric Monoclonal Antibody against Gp 2b/3a receptor

PCIAMI/Acute Coronary Syndromes

EptifibatideTirofiban

Parenteral Occupies ReceptorInhibits Ligand Binding

PDE Enzyme inhibitor Dipyridamole Weak effect on Platelet Aggregation

Inhibits Platelet PDE enzyme cAMPPGI2Weak effect on Platelet Aggregation

+Aspirincerebrovascular ischemia+WarfarinArtificial Heart Valves

Prasugrel Platelet Inhibition Platelet InhibitionBetter Than ClopidogrelPlatelet Inhibition

ischemic eventsThrombolysis in AMI

Ticagrelor Oral, reversible Direct Inhibitor of ADP Receptor (P2Y12)Reversible

Fibinolytic Inhibitors / Antifibrinolytics

Amino Caproic Acid Treat Overdosage of FibrinolyticsHemophilics: Limit excessive bleeding after SurgeryPrevent recurrence of SubArachinoid HemorrhageAbruptio Placenta, Post-Partum hemorrhage, Menorrhagia

Tranexaemic Acid Oral7 x more potent than ACA

Aprotinin CABG Surgery: Blood LossProtamine Sulphate Heparin Antagonist Heparin Antagonist

Basic ProtienFish SpermSlow IV1 mg Protamine Sulphate for every 100 units of Heparin remaining in patient

Combines w/ Heparin as an ion pairStable complex devoid of anticoagulant activity

BP, HRDyspnea, Flushing

Coagulants Vitamin K K1-Phytonadione-Fat soluble-PlantsK2-Menaquinone-BacteriaK3-Menadione-Fat/Water soluble-Synthetic

Deficiency due to:Liver Disease, Malabsorption Syndromes, long term antibiotic use

Deficiency Symptoms:Bleeding: Urine, Nose, GIT, Skin-Ecchymoses

Synthesis of Clotting Factors:2, 7, 9, 10 (TENS)In Liver

Deficiency of Clotting FactorsNewbornWarfarin Overdose: Phytonadione

Toxicity: BP, FlushingMenodione: Kernicterus in Newborns-Treat by Phytonadione

Plasma Fractions Factor 8Anti-Hemophilic Factor

Treat Hemophilia A

Prothrombin Complex ConcentratesFactor 9 Complex

Treat Hemophilia B (Factor 7 deficiency)

Factor 7a Liver Disease, Blood LossFactor 7 deficiency

CryoprecipitateFibrinogen

Hemophilia ALiver DiseaseDIC

Megaloblastic Anemia:

Hb:RBC:WBC: =/Platelet: =/Reticulocyte: Hct: MCV: MCH: =/MCHC: =Serum LDH: Serum Bilirubin: B12 &/or Folate: B12<100pg/mlPBS: hypersegmented neutrophils, macroovalocytesBM: erythroid hyperplasiaPenicious Anemia:Serum Ab to parietal cellsSerum Ab to IFAchlorydia (HCl –ve)

Aplastic anemia:Congenital: FanconiSecondary: Radiation, Chemical, Drugs: Chloramphenicol, Infections: Parvovirus B19, HIV, Hep A, B, C

DD:Severe Megaloblastic anemia w/ pancytopeniaMDSPrimary MyelofibrosisMarrow Fibrosis secondary to any other disease

Hb:RBC: WBC:Platelet:PBSBM: Trephine-dry tap w/ hypocellular imprints

Fanconi:Kidney & Spleen hypoplasiaHypoplasia of bone: Thumbs/radiiShort stature

PRCA:Congenital: Diamond BlackfanAcquired-Primary-AI destruction of erythroid precursorsSecondary:-Thymic tumor-thymoma-Malignancy-CLL, lymphoma-drugs, pregnancy-AI-SLE-Virus: Parvovirus B19, EB

Myelophthisic anemia;Space occupying lesions:Marrow infiltration: metastatic tumor, granulomaMarrow Fibrosis: Primary, Secondary to hemmatopoetic malignancies

Anemia of Chronic Disease:Normocytic Normochromic/Mildly microcytic, hypochromicMCV: 77-82;rarely<75Hb rarely<9ReticulocytopeniaSerum FeTIBCSerum Ferritin: =/BM Fe store: Perl’s stain: =Hepcidin: caused by IL1 & TNF

Iron Deficiency Anemia:Microcytic HypochromicMCV: MCH: Hb: RBC: Serum Fe: TIBC:

Hereditary Spherocytosis:ADHb: Reticulocytosis: 5-20%PBS: spherocytesDAT: normalOsmotic Fragility:

PlasmodiumFalciparumMalariaeVivaxOvale

Malaria Female Anopheles Mosquito

Infective: SporozoitesDiagnostic: Trophozoites, Schizonts, gametocytes

Sexual:Gametogony: MosquitoSporogony: humansAsexual: Schizogony: humans

Sporozoites liver schizonts (hypnozoites) blood RBC trophozoites Schizonts (merozoites) or gametocytes mosquito gut ookinete oocysts sporozoites

Anemia, cyclic fevermerozoites lyse RBC & get released

Cerebral Malaria: falciparum-aggregates of RBCs occlude capillaries

Relapse: hypnozoites- Vivax Ovale

Toxoplasma gondii Congenital ToxoplasmosisToxoplasmosis

Cat-definitive hostHumans: intermediate host

Infective: Ocysts from cat feces/raw meattransplacental

Oocystcat ingests tachyzoitestissue bradyzoites/oocysts

Trophozoites: Brain, eye, LiverTissue Cysts-enlarge & cause symptomsEncephalitis in AIDS patients: impaired CMI

Trypanosoma cruzii Chaga’s Disease Reduviid Bug Infective: TrypomastigotesDiagnostic: Trypomastigotes/ Amastigotes

Blood meal Trypomastigotes Reduviid Bug Midgut: Epimastigotes Hind gut: Trypomastigotes defecated –human amastigotes trypomastigotes

Myocarditis: amastigotes kill myocytesNeuronal Damage: Megacolon, Megaoesophagus

Trypanosoma Brucie:Gambiense & Rhodensie

African Tryposomniasis: Sleeping Sickness

Tsetse Fly-both sexes

Gambiense: west Africa-HumanRhodensie: east Africa-Animal-antelope

Infective: metacyclic trypiomastigotesDiagnostic: trypomastigotes

Blood mealTrypomastigotes Midgut: epimastigotes (procyclic) salivary glands: trypomastigotes (metacyclic) Blood stream

Trypomastigottes infect braindemyelinatin Encephalitis

Cervical LN’opathy winterbottom’s sign

Leishmania donovanii

Kala- AzarVisceral Leishmaniasis

Sandfly- Phlebotomus, Lutzomyia

Animal: Dog, small carnivores, rodents

Human: India

Infective: PromastigotesDiagnostic: Amastigotes

Blood MealAmastigotes Midgut: promastigotes Migrate to pharynx/proboscis human: macrophages Amastigotes

Kill RE cellsLiver, Spleen, BM

Leishmania Tropicana & Mexicana

Cutaneous Leishmaniasis

Reservoir: Forest rodents

Leishmania Brazilensis

Mucocutaneous Leishmaniasis

Wuchereria bancrofti

Filariasis Female Anopheles & Culex Mosquito

Definitiev host: Humans

Infective: Larvae (L3)Diagnostic: Microfilariae

Mosquito bites wound infective larvaelymphatics: Adultsblood: microfilariae

Adult worms block Lymphatics