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RECEPTORS Receptor Class 1 Mechanism/Second messenger DAG & IP3 IC Ca2+ Site Action Vasoconstriction-Blood vesselsTPR Mydriasis GIT,

, Contraction-urinary VASOCONSTRICTION Effect BP on stimulation/agonist Mydriasis-good in glaucoma Drug receptor selectivity Epinephrine> Norepinephrine >>>>>>>>> Isoproterenol

Blood Vessel Smooth Muscle-TPR (skin) Pupil Radial muscle Intestine, Prostate, Bladder sphincter cAMPNorepinephrine Presynaptic release receptorNor(auto)/Ach(hetero) INHIBITORY Pancreatic cellinsulin Fat, Platelet HeartIno, Chrono, AV nodal conduction velocity JG cellsRenin

Dopamine

3 D1 typeD1, D2 D2 typeD3, D4, D5

cAMP:adenylyl cyclase

adenylyl cyclase Open K channel Ca influx Cholinergic Nicotinic Agonist-small dose Nicotine Muscarinic Agonist-Muscarine Histamine H1

Blood Vessel SKELETAL, (coronary) Uterine Smooth muscle Respiratory Liver Pancreatic cell Ciliary muscle Fat cell Blood vessel-Smooth muscle: Renal, Splanchnic, CORONARY, Cerebral--RELAXATION Nerve terminal

Nor/Ach Neuromodulationinhibitory insulin & lipolysis (DOMINANT) Platelet aggregation BP, HR,conduction Reninfluid retentionvenous returnSVCOBP;Ang2TPRafterloadheart work,BP GIT smooth muscle relaxation Vasodilation Relaxation (tocolysis) Bronchodilation Glycogenolysis insulin (MILD) Relaxation-Mydriasis lipolysis Vasodilationblood flow (CORONARY)

blood sugar on stimulation insulin release

BP on stimulation/agonist

Isoproterenol> Epinephrine> Norepinephrine

blood flow to skeletal muscle/HEART air in lungs energy Good in glaucoma On stimulation/agonist

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

Norepinephrine release Autoregulator AchNorepinephrine at vasoconstrictor nerves AchM3NO/EDRF releasevasodilation (cavernous muscleerection) Sildenafril Smooth Muscle Contraction Blood Vessel: (Short Lasting) Vasodilation-NO, PG release capillary permeability, gap junction widening Smooth muscle: vasoconstriction-larger vessels Afferent Nerve Stimulation Gastric Gland-Gastric Acid Secretion Blood Vessels: (persistent) Vasodilation-smaller vessels Heart: +ve Chronotropy & +ve Inotropy, HR Presynaptic H3 Receptors-release several transmitters Skin of face, Neck, salivary Cholinergic glandsstimulate/agonistblushing drug-all vessels dilate Bronchoconstrict Sensory Nerve ion EndingsAllergies stimulation-pain Waking Amine Triple responseID Peptic Ulcer injectionRed spot, edema & flare BP(vasodilation ), sense of warmth, Headache

Antagonist-Large dose nicotine Antagonist-Atropine Smooth Muscle-intestine, airway Endothelium Brain

H2

H3

Gastric Parietal Cells Cardiac Muscle Smooth Muscle Brain Histaminergic Neurons Myenteric Plexus

Classification DIRECTLY ACTING

Drug Epinephrine

Class Catecholamines

Receptors All 1=2; 1=2

AGONISTS Action Low dose- actionvasodilation High dose- actionvasoconstriction

Effect 2-dilates coronaries & skeletal blood vessels-blood flow 1&2-consticts blood vessels of skin & mucosa

Norepinephrine

Isoproterenol

Dopamine

1=2 1>>>2 1,2,1 agonist 1=2>>>> Mainly ;Less D1=D2 >>1>> D1, , 1 agonist

1 vasoconstrictionTPR-BP

BP

Uses ANAPHYLACTIC SHOCK()(IM), local anaesthetic, GLAUCOMA(1), local bleed (nose)( 1&2) Physiological antagonist of Histamine Glauoma Heart block, cardiac arrest Local hemostasis(1) Shock Dopamine preferred Heart block, cardiac arrest

ADR/Interactions +COCAINECVS cardiac workeffects ischaemia, MI, heart failure BP HR Arrythmias Pulmonary edema

BP*barorecepto r*VagusREFLEX BRADYCARDIA (1)

Low dose: Inotrope D1-vasodilation-renal, splanchnicblood to kidney, viscera D2-presynaptic autoreceptorNorepinephrine release Moderate dose: (D1) contraction,conduction (heart) High dose: vasoconstriction Vasoconstriction of nasal mucosa Topical-long acting Vasoconstriction Mydriasis

Cardiogenic/Septic shock Inotrope-CO, xHR perfusion kidney, visceraurine output Acute HF

Selective Adrenergics

Xylometazoline, Oxymetazoline, Naphazoline Pseudoephederine, Phenylephrine Selective 1 agonist

Nasal decongestants

Initial sting BP Prolong: Atrophic rhinitis No cycloplegia BP

Nasal Decongestant Mydriasis-retinal exam GLAUCOMA

Methoxamine Clonidine

Selective 1 agonist Selective 2 agonist

2 vasomotor Central sympathetic sypatholytics centerBP, relax

Antihypertensive Antihypertensive TPR-relax GLAUCOMAperipheral blood apraclonidie

Withdrawal reaction of Opiates, Benzodiazepines

methylDOPA

Dobutamine

Selective 2 agonist methyl analogue of DOPA (precursor of DA, NE) Selective(relatively) 1 1 agonist >2>>>

peripheral blood vessels

vessels

Antihypertensivesynthetic-no ADR/interaction GLAUCOMA

No ADR/interaction therefore Coombs test/DAT globulin negative

intropy, conduction-CO No in O2 demand x HR, BP, TPR

Inotrope

Salbutamol, Terbutaline Isoxurine, ritodrine MIXED ACTION Ephederine

Selective 2 agonist

Brochodilation Uterine relaxation Long acting Less efficacy

Cardiogenic/Septic Sinus tachycardia, Arrhythmia /Renal shock CHF-inotrope Post MI shock/pump failure Cardiac surgery Asthma Skeletal muscle tremors Premature labor Postural Hypostension Ma Huang-weight loss, appetite suppression Nasal decongestant CNS: tremors, anxiety, insomnia, convulsions, anorexia

Mixed acting adrenergic

Direct + action Also indirect action

Release Norepinephrine + & stimulation

Pseudoephederine Mephentermine INDIRECTLY Release ACTING Amphetamines: Dex/Met Amp, Modafinil, Methylphenidate Tyramine

Mixed acting adrenergic & agonist Indiectly acting adrenergic Norepinephrine release CNS, alertness weight

Modafinil-Epilepsy Methyphenidate: ADHD

Drug of Abuse CNS: tremors, anxiety, insomnia, convulsions, anorexia Present in fermented food- cheese, wine, sausages Metabolized: Liver-MAO enzyme Drug of Abuse: Dopamine in brain neurons

Indiectly acting adrenergic Indirectly acting adrenergic

Norepinephrine release Reuptake at noradrenergic synapses

Reuptake

Cocaine

Type blocker

Class Nonselective

Drug Phenoxybenzamine Ergotamine Dihydroergotamine Phentolamine Chlorpromazine

ANTAGONISTS Uses/effect Phentolamine: Penile erection for impotence

Action 1 blockadeTPRCOBP Secondary shock-reflex vasoconstrictionhypovolemic shock CHF-short term relief Peripheral vascular disease

ADR/Interactions Postural hypostension-dizziness & syncope Nasal stuffiness-dilated blood vesselsextravasation Miosis-cholinergic-pupillae constrictor Diarrhea: cholinergic dominance Inhibition of ejaculation

Selecti ve

1 blocker

Prazosin Tamsulosin Terazosine Yohimbine Propanolol

Hypertension Pheochromocytoma BPH

2 blocker blocker

Hypertension

Anticholinergic

M3: vascular endothelial cell First generation

Atropine

No marked effect on BP

Anti Histamin ergic

H1 Blocker

Dipenhydrinate Dipenhydramine Hydroxine Cyclizine Meclizine Cinnarazine Chlorpheneramine Promethazine Cyproheptadine

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, Promethazinetremor,rigidity(Anti Chloinergic) Pregnancy Nausea/Vomiting: Doxylamine, Promethazine Motion Sickness: Dipenhydramine/inate, Promethazine, Cyclizine, Meclizine Pomethazine: Vestibular Disturbances: Cinnarazine (AntiHistaminic, AntiCholinergic, Anti5HT)

vasodilation-2 blockade Renin-Ang2-TPR-BP-1 blockade Heart 1 blockade-CO-BP Normal dose-Blocks Ach agonistvasodepressor action (TPR; INDIRECT) Large dose: Direct Vasodilator AntiAllergic-(Histamine=type 1 S) Sedative Highly: Dipenhydramine/inate, Promethazine Moderately: Pheniramine, Cyproheptadine, Meclizine, Cinnarazine Anticholinergic: Dipenhydramine/inate, Promethazine AntiHistaminergic+AntiMuscarinic = AntiEmetic/AntiNauseaDoxylamine (Promethazine) Adrenoreceptor Blocker: Promethazine Serotonin Blocker: Cyproheptadine Wide Distribution Greater CNS entry Duration of action: 4-6 hours (Meclizine: 12-24 hours) Block Autonomic Receptors Reversible Competitive Antagonism H1 Selectivity Rapid Acting No AntiCholinergic effects Absence of Sedation

Unsuitable for daytime use, car driving, machinery workers psychomotor performance (AntiHistamine H1) CNS: alertness & concentration, motor incoordination, fatigue Promethazine: Adrenoreceptor BlockerOrthostatic hypotension, reflex tachycardia AntiHistamine/AntiSerotonin: Appetite AntiMuscarinic: Dry Mouth, Altered Bowel & Bladder, Vision Blurring

Second generation

Fexofenadine Loratidine, Desloratidine Cetrizine,

Narrow Spectrum of Uses: Allergic rhinitis (hay fever) Conjunctivitis Urticaria, atopic eczema

Terfenadine/astemezol + CYP3A4 inhibitors (ketoconazole/erythromycin/itraconazole) -Ventricular Arrhythmias (Torsades de

Levocetrizine Azelastine Ebastine

Acute Allergic reactions to Drugs & Food

Additional AntiAllergic mechanisms: Inhibit cytotoxic mediator release, Eosinophil Chemotaxis, inhibit platelet activating factors CNS entry Metabolized by CYP3A4Drug Interactions Long Acting: 12-24 hours Active Metabolites of Drugs available: Loratidine-Desloaratidine Cetrizine-Lovocetrizine Terfenadine-Fexofenadine Reversible Competitive Antagonism

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 No role in Asthma: Asthma due to Leukotriene & PAF Low concentration at site of action No role in other humoral & cell mediated allergies

Adrenalin e

Physiologic antagonist of Histamine

Anaphylaxis/Anaphylactic Shock Caused by Histamine, Leukotriene, Prostaglandin Administer: Adrenaline Followed by- AntiHistamine: Chlorpheneramine Glucocorticoids: Hydrocortisone BP, Bronchodilation, Laryngeal edema release of mediators

Class Nitrates

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

blocker

Calcium Channel Blockers

Phenylalkylamine : Verapamil

Dihydropyridine: Nifedipine, Amlodipine, Lercanidipine

Benzothiazepines: Diltiazem

MYOCARDIAL INFARCTION/ANTI-ANGINAL Site/Mechanism Uses ADR Angina Pectoris Throbbing headache Venodilationpreload NSTEMI Tolerance Arteriolar Hypertensive dependance dilationTPRAfterload emergency Coronary dilation LV failure Abdominal Colic Cyanide Poisoning Anti-adrenergic Classical & Unstable TG angina CO/cardiac work and quality of life MI myocardial O2 requirements Worsening Peripheral Mild CHF reninangiotensin vascular disease Hypertension CHF Arrythmia Heart block Dissecting Aortic Tiredness & reduced Aneurysm exercise Hypertrophic obstructive cardiomyopathy Migraine, thyrotoxicosis, Anxiety, tremors, glaucoma Ca2+ CCB: interfere w/ Cardiac arrhythmia channel Ca2+ entry in the Migraine, nocturnal blockcellblood vessel leg cramp NERVE cell relaxationCO SA,AV node Block L type SMOOTH & voltage channel Angina pectoris Weak uterine contraction, CARDIAC Hypertension foetal hypoxia, muscle Premature labor tachycardia, hypotension Hypertrophic placental perfusion cardiomyopathy, Reynauds disease Broad Cardiac arrhythmia spectrum: Angina pectoris nerve + Hypertension muscle Hypertrophic cardiomyopathy Visceral+vascular smooth muscle dilation Arterial+veno dilation Dilation of epicardial & deeper vessels coronary blood flow Nitrate + CCB Nitrate - preload CCB - afterload Hypertension MI-nicorandilcardioprotective

Interaction +sildenafil/Viagra=death +other antihypertensives=BP

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

+blockercardiac depression-death

Nifedipine: tachycardia & death

+blockercardiac depression-death

K+ channel openers

Nicorandil Pinacidil

Combinations

blocker + Long acting nitrate blocker-x nitrate tachycardia

blocker + nitrate + CCB Nitrate - preload CCB - afterload +

AVOID verapamil+ diltiazem

Prehosptal/Emer gency management

Nitrate- x blocker cardiac dilation & blood flow Aspirin: 162-325 mg-chewed &swallowed Nitroglycerine: sublingual0.4mg/5min O2 Morphine

Vasospastic angina

coronary blood flow blocker - cardiac work Anti-thrombotic therapy: Antiplatelets: clopidogrel (ADP), abciximab (Gp 2b/3a), Apirin (COX) Anticoagulant: heparin/enoxaparin Anti-ischemic/Cadioprotective therapy: Cardioselective blockers, ACE inhibitors, Nitrates PCI: first preference Favored after 3 hrs w/in 90 mins-door to balloon angioplasty/stent placement Fibrinolytics: w/in 30 mins- door to needle after 6 hrs- poor efficacy Prevention of Recurrence: Aspirin: lifelong blockers: metoprolol2 years ACE inhibitors Antihyperlipidemics: statins Thrombolytic: rTPA-alteplase-STEMI <6hrs of onset mortality/preserve LV function Aspirin: antiplatelet-irreversibly acetylating COX cardiovascular events mortality following AMI Morphine: opioid-analgesic anxiety, cardiac metabolic demands sympathetic activity Nitrates: coronary vasodilation coronary blood flow ventricular load-venodilation blockers: Atenolol, Metoprolol cardiac work & O2 demandinjury & death & infarct size- myocardial salvation Maintain coronary flow to subendocardium acute mortality, prevent recurrence automaticity: delay in AV conduction/cardioprotective sudden ventricular fibrillation ACEI: w/in 24 hr6 weeks Reverses remodeling caused by Ang2 early & long term mortality Clopidogrel, unfractionated heparin(PCI)

NSTEMI: Stabilize acute coronary lesion Rx residual ischemia Prophylaxis

In hospital management

Complete bed rest Aspirin & Heparin: after fibrinolysis(x reocclusion) blocker: w/in 24 hrs2 years ACE inhibitors: STEMI-w/in 24 hrs Antihyperlipidemic drugs

STEMI: Reperfusion therapy

Class Class 1 Na channel blocker

Phase of action Phase 0 Phase 4 (Phase 0 & 3)

Mechanism rate of conduction in tissue w/ fast potential Ignores slow potential - SA, AV nodes

Drugs 1a Quinidine Procainimide (phase 0 & 3)

ANTI-ARRHYTHMICS Effects AP duration & refractoriness conduction through ventricle Repolarization rate QRS & QT intervals AP duration and refractoriness conduction through ventricles Repolarization rate automaticity in ectopic foci conduction in all cardiac tissues Slow gradual Ca2+ influxautomaticity blocker: Ca2+ influx PR interval; no change in QRS

Uses

ADRs/Interactions/Contraindications myocardial contractility, cardiac arrest +diureticshypokalemiatorsades de Pointes GIT side effects Hypersenstivity Neurological: dizziness, drowsiness, nausea, blurred vision, paraesthesia, confusion, convulsion Bradycardia Hypotension

Atrial & Ventricular arrythmias

1b Lidocaine Mexiletine (phase 3)

Ventricular arrythmias Ineffective in atrial arrythmias

Class 2 blocker

Phase 4

Class 3 K+ channel blocker

Phase 3

receptorsattached to Ca2+ channels blocker: Ca2+ influx similar to class 4 (CCB) K+ effluxprolongs repolarization & ERP

1c Flecainide (phase 0) Propanolol Esmolol (short acting)

Atrio-ventricular re-entrant tachycardia Supraventricular arrhythmias associated w/ exercise, emotion & stress Sinus tachycardia Extrasystoles

GI symptoms, blurred vision, tremors Contraindicated-Sick sinus syndrome, heart failure, MI Severe bradycardia cardiac contractility, cardiac arrest

Amiodarone

K+ efflux Repolarization & ERP PR, QRS, QT interval

Class 4 Ca2+ channel blocker

Phase 2 (Phase 4)

Similar effect as blocker

Verapamil Diltiazem

Adenosine ( 1 agonist)

Very short acting purine nucleotide

Digoxin

Na/K ATPase inhibitor

SA/AV automaticity AV nodal conductivity ERP PR interval Breaks reentrant circuit Hyperpolarization of membrane conduction velocity via slow potential/Ca2+ channels No effect on fast potential/Na+ channel PR interval Inhibits Na/K ATPase of myocardial fibers intracellular Na+ intracellular Ca2+ (via

Supraventricular and Ventricular arrhythmia Resistant ventricular tachycardia Recurrent ventricular fibrillation Atrial fibrillation: maintain sinus rhythm Paroxysmal Supraventricular Tachycardias (PSVT) Poor efficiency in ventricular arrythmia Paroxysmal Supraventricular Tachycardias (PSVT) involving AV node-alternative to verapamil

Bradycardia, Heart block Hypothyroidism: amiodarone has Iodine GI related Photosenstivity Skin & corneal pigmentation Peripheral neuropathy Pulmonary alveolitis & fibrosis (serious) Hypotension, Bradycardia Additive AV block Negative inotropic effect

Transient dyspnea, Chest pain BP Ventricular standstill or fibrillation

Paroxysmal Supraventricular Tachycardia (PSVT) Atrial flutter/fibrillation

GI related Disturbances in color vision Atrial Arrhythmia Gynaecomastia, hyperkalemia

Na/Ca exchange pump) contractility & excitability of contracting cells generation & propagation of impulse in SA & AV conduction velocity PR interval, depresses ST segment Enhance Vagal activity: INDIRECTLY

ANTI-HYPERLIPIDEMICS Action Endogenous Class Statins Drug Simvastatin(PrD) Atorvastatin(LnAct) Rosuvastatin(LnAct) Lovastatin(PrD) Mechanism Hmg CoA red Hepatic Cholesterol synthesis LDL receptors on hepatocytes plasma LDL clearance PPAR- Lipopritien Lipase Synthesis clearance of VLDL and Chylomicrons Actions Total Cholesterol LDL TG HDL Adverse Myopathy Hepatitis-serum transaminase GI disturbance Rash, Insomnia, Angioedema Rash, Nausea, Dyspepsia, Diarrhea, Myopathy testosteroneimpotence liver enzymes Flushing & pruritus GI disturbance Hepatotoxicity Hyperuricemia Impaired glucose tolerance Therapeutic Contraindications/ Interactions

Hypercholestrolemia Anticoagulants & IIa, IIb Antidiabetics 95% PP binding TERATOGENIC

Fibric Acid Derivatives

Gemfibrozil Bezafibrate Clofibrate Fenofibrate

TG HDL

HyperTGemia IIb, III, IV, V

Hepatic & Renal Disease Pregnancy & lactation oral anticoagulants Myopathy

Nicotinic Acid

Adipose:Binds to NA recptors-FFA mobilization-TG & VLDL synthesis Liver:Inhibits DAG acyltransferase-2 (key TG synthesis enzyme)-VLDL synthesis Plasma:Lipoprotein Lipase activityclearance of VLDL & chylomicrons Ezetimibe (oral) Interferes with cholesterol transport protein NPC1L1 (intestine) cholesterol absorption

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

HDL HyperTGemia IIb, V

Exogenous

Cholesterol Uptake Inhibitors

Diarrhea , Headache, Hypercholestrolemia Myalgia Combined with statins-synergistic IIa

Bile Acid Binding Resins

Cholestyramine Colestipol Colesevelam (no dug interaction)

Bind to Bile acidLDL interrupt NE TG enterohepatic circulation excretion of bile in feces cholesterolbile hepatic cholesterol-LDL receptor on hepatocytesclearance of LDL Statins Fibrates Ezetimibe Fibrates Nicotinic Acid

Constipation, Hypercholesterolemia Delasy absorption Flatuence Patients who cannot of Warfarin, Impaired fat soluble tolerate other drugs Digoxin, vit absorption Chlorothiazide gallstones

LDL

TG

Class Renin inhibitors ACE inhibitors

Drugs blockers Aliskrenin (oral unapproved) Enalapril, Captopril, Benazepril

Mechanism Inhibit rennin secretion Inhibit ACEno Angiotensin II

Features

ANTI-HYPERTENSIVES Effects

Uses

ADR

Interactions/Contraindi cations

angiotensin bradykinin

ARB

Losartan, Valsartan, Irbesartan

Competitive antagonist of AT-1 receptor Block L-type channels Arteriolar vasodilation coronary tone myocardial O2 requirements LV wall stress HR Smooth Muscle Relaxation: Bronchiole, Uterine, GIT Afterload only

Inhibit angiotensin II No effect on bradykinin

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

Hypertension, CHF: TPR first line MI: reduce mortality Diabetic nephropathy Progressive renal impairment: ESRD, protienuria, Systemic resistance

Hypotension (CHF w/ diuretics) Hyperkalemia (renal pts) Cough (bradykinin) Teratogenic ARF (bilateral renal artery stenosis)

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

Hypertension w/ cough (ACEI)

Hypotension , Hyperkalemia, Teratogenic

Calcium Channel Blockers

Verapamil

Cardiac>vascular smooth muscle

Diltiazem

Cardiac=vascular smooth muscle inotropy vs Verapamil

AV nodal conduction: in Supraventricular Reentry tachycardia Atrial fibrillation-ventricular response Sympathetic blockade Typical Angina Atrial tachycardia/flutter/fibrillation Migraine AV nodal conduction: in Supraventricular Reentry tachycardia Atrial fibrillation-ventricular response Sympathetic blockade Typical Angina Variant Angina Atrial tachycardia/flutter/fibrillation Less effect on AV nodal conduction Typical Angina Variant Angina Hypertension Pregnancy induced Hypertension

Ca2+ influx in heart Cardiac depression/arrest/failure HR AV block

AV conduction abnormalities Overt Heart Failure Verapamil/Diltiazem + blockerAV blockventricular function

Ca2+ influx in heart Cardiac depression/arrest/failure HR AV block Constipation

Dihydropyridi ne

Nifedipine 1 gen Short acting

Reflex Sympathetic Stimulation: Reflex Tachycardia, BP swing MORTALITY in CAD

Cardiac<vascular smooth muscle

Reflex Sympathetic Stimulation: Reflex Tachycardia, BP swing MORTALITY in CAD MI risk in hypertensive Vasodilation: flushing, headache, ankle edema, BP Elderly: Urine retention Can be used in overt heart failure

Unstable Angina: risk of adverse cardiac events

Amlodipine 2 gen HR, CO not affected

Direct Vasodilator s

Hyadralazine/dihydralazine Sodium Nitroprusside Forms NO

TPRBPRefle x sympatheticsco ntractility, HR, O2 consumpMI, angina, Heart failure (counteract: blocker) Reninsalt&H2 O retention (counteract: diuretic)

TPRdiast olic BP Forms NO IV: T1/2 is small (2-5 min) continuous infusion TPR&COs ys & dias BP

Arteries & Arterioles Arteries & Veins BP Reflex tachycardia Preload & Afterload

Moderate Hypertension Pregnancy Induced Hypertension Hypertensive Emergencies

Lupus Syndrome MetabolismCN _ ion Large dose: Toxicity+thiosul phateThiocynat ekidneys excrete Light sensitive: protect from light

BP Palpitation HR, Angina Fluid retention Edema

Dizoxide K channel opener

K channel opener IV Long acting (624 hrs) plasma & ECF volumeCOB Pgradual in TPR Sympathetic depressant HR, inotropy & COBP cardiac work & O2 consumption

Arteriole

Hypertensive Emergencies

Diuretics

blockers

Class Positive Inotrope

Cardiac Glycosides

Drugs Source/Comment Digoxin: Foxgrove Plant Fast acting (15Sugar Steroid 30 mins) Lactone ring Commonly used protein binding T1/2: 40 hrs Digitoxin: Slow onset Not commonly used protein bound T1/2: 5-7 days

CONGESTIVE HEART FAILURE Mechanism Effects Inhibits NA/K ATPaseI/C contractionventric NaNa/Ca pumpCa ular efflux &CA influx ejectionEDV&ESV CO: Sympathetic, HR, TPR Renal perfusion, Edema SA:rate Atria:refractory period AV:conduction velocity refractory period Purkinje/Ventricle: refractory period (slight) ECG: PR,QT interval venous tone Kidney: diuresis

Uses Heart failure CHF + Atrial fibrillation Severe/Chronic CHF + LV systolic dysfunction Atrial flutter/fibrillation: Av node conduction AV node ERP

ADRs & Antidote Initial: GIT: Anorexia Nausea, Vomiting Diarrhea CNS: Elderly-disorientation & hallucinations Color vision disturbance Antidote: Lower dose Cardiac: Delayed afterdepolarizations Ventricles: Bigeminy Fibrillation/tachycardia Heart block ECG: PVB, inverted T wave, depressed ST segment; tachycardia, fibrillation, arrest SA: rate Atria: refractory periodarrhythmias AV node: refractory periodarrhythmias Purkinje/Ventricles: Extrasystoles, tachycardia, fibrillations K+: Mild: skip 1-2 doses; oral K+ supplementation <5 meq/L Severe/Suicidal: K+ levels; not give K+ supplements Suicide/severe poisoning: Digoxin antibodiesFab fragments bind & inactivate drug Arrhythmias: Antiarrhythmic- lidocaine, phenytoin

Interactions + 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

1 agonists

Dobutamine

Drug + receptorcAMPactivatio n of PK-Aphosphorylation of Ca channelCa2+ flow into

CO ventricular filling pressure

Acute Heart Failure

Arrythmias Tachycardi a

Less arrythmogeni c & less tachycardia vs

Dopamine Phosphodiester ase Inhibitors Amrinone Milrinone

cellmyofibrilscontractio n force PDE are enzymes that inactivate cAMP & cGMP PDE inhibitors: X PDEcAMP & cGMP Non selective vasodilator: Arteries & Veins X ACE (kininase 2) angiotensin 2sympathetic activityVasodilationafte rload aldosteronesalt & water retentionvenous returnpreload

dopamine BP Inotropic agent Vasodilation Acute Heart Failure, raise BP Severe Heart Failure

Vasodilators

ACE inhibitors

Enalapril Lisinopril

Non selective vasodilator: CHF: Arteries & Veins First line afterload & preload ventricular dilation long term remodeling efficacy of diuretic treatment mortality & morbidity Asymptomatic patients w/ LV dysfunction + no edema Symptomatic patients: preload and afterload Hypertension MI Diabetic Nephropathy ACEI intoleration due to cough CHF: all stages Hypertension Dyspnea NOT FIRST LINE Patients w/ DRUGS Isosorbide increased dinitrate + fatigue Antihypert hydralazin erem ensiveodelling pregnancy + methyl (africans) DOPA CHF Hypertensive emergency CHF: FIRST LINE Furosemide/loop diuretic: Acute pulmonary edema, severe chronic failure Spirinolactone: Severe chronic heart failure, morbidity &mortality

Mortality Nausea, Vomiting Arrhythmias Liver enzyme Thrombocytopenia First dose hypotension (post diuretics) Cough (bradykinin) Hyperkalemia Dysguesia, rashes, urticarial Acute Renal Failure; angioedema TERATOGENIC

Angiotensin Receptor Blocker Nitrate Hydralazine

Losartan Valsartan Irbesartan Candesartan Isosorbide Dinitrate

No cough

Block AT-1 receptor (angiotensin-2 receptor) No effect on ACEBradykinin metabolized Venodilator preload Arteriole dilator

Hypotension K+ Angioedema TERATOGENIC: fetal damage

Venodilator Arteriole dilator Dilates arterioleCO cGMP-smooth muscle

Sodium Nitroprusside Diuretics Loop diuretics Furosemide Bumetanide Torsemide Chlorothiazide Hydrochlorothia zide Spirinolactone Eplerenone

Arteriole + Veno dilator

NOcGMP

Arteriole + Veno dilator afterload & preload

venous pressurepreloadsyste mic pulmonary edema cardiac sizepump efficiencyCO

Thiazide diuretics Aldosterone antagonist

Hypokalemia: leads to digoxin interaction Hypervolemia Ototoxicity Hyperuricemia: Gout Metabolic alkalosis Hyperlipidemia

blockers

Bisprolol Carvedilol Metoprolol

catecholamines: HRsymptoms Myocyte apoptosisremodelling

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

Stable chronic heart failure MI history Asymptomatic patients w/ LVEF

Neseritidine Bosentan survival in CHF ACEI, ARB, blockers, spirinoloactone, hydralazine+nitr ate

BNP, IV continuous infusion Endothelin receptor antagonist Stage A: High risk, No symptoms Risk factors Treat: hypertension, hyperlipidemia, diabetes, obesity (ACEI/ARB for vascular disease)

Chronic Heart Failure

work, Na & H20 ACEI or ARB Thiazide diuretic blocker (in stable class 2-4) Digitalis (if systolic dysfunction/atri al fibrillation) Nitrate/hydralaz ine (vasodilator) Cardiac resynchronizati on (if wide QRS)

Acute Heart Failure Can be due to AMI Anemia, fevermetab olic demand exertion, emotion, Na

Power: inotropes, vasodilators Pulmonary congestion: diuretics

Stage B: Structural disease, No symptoms Risk factors Treat: hypertension, hyperlipidemia, diabetes, obesity (ACEI/ARB, blockers)

Stage C: Structural disease, Symptoms Na, H20, Work Diuretics, ACEI, ARB Digitalis: systolic dysfunction + 3 HS/atrial fibrillation blockers ( in stable class 2-4) Spirinolactone Stage D: Refractory Symptoms Na, H20, Work Diuretics, ACEI, ARB Digitalis: systolic dysfunction + 3 HS/atrial fibrillation blockers ( in stable class 2-4) Spirinolactone Cardiac resynchronization Cardiac transplant

Acute Heart Failure Severe Pulmonary Hypertension Drugs causing CHF

NSAID CCB Anti arrhythmic (some) Alcohol

SHOCK Type of Shock Hypovolemic/Oligemic shock Low Volume Mechanism Internal & external fluid losspreload Hemorrhagic/Non Hemorrhagic Trauma Non traumatic: Vaginal, GI, GU Burns, Diarrhea Vomiting Diuresis, Sweating Third Space Loss: Pancreatic, peritonitis, bowel obstruction Cervical spinal cord injury/severe head injuryloss of sympathetic vasomotor tonearteriolar & venodilationpooling of blood in post capillary capacitance blood vesselpooling of venous systemvenous return & cardiac output Severe LV dysfunctionsystemic hypoperfusion MI, acute myocarditis Treatment Volume resuscitation: rapid infusion-isotonic saline, ringers lactate NaHCO3-correct acidosis Inotropic support following volume support-Dobutamine, Dopamine O2 Acute hemorrhage/anemia: Whole Blood & plasma Absence of Blood & plasma: Colloidal plasma expanders Human albumin, Dextran, Hydroxyethylstarch Crystalloid plasma substitute: superior to colloids-Normal saline, 5% dextrose, ringer lactate Penylephruine/Norepinephrinevascular resistanceMAP IV fluids for relative hypovolemia

Neurogenic shock Low Resistance

Cardiogenic shock Pump Failure

Septic/Bacteremic/Endotoxic shock

Severe infection & tissue hypoperfusion GN (E coli)>GP (staph)

Anaphylactic shock

Histamine release & other mediators

MI: Morphine,O2, nitroglycerine, aspirin, alteplase (fibrinolytic), metoprolol ( blocker), captopril (ACEI), heparin (anticoagulant) Dopamine: Low dose-dilates renal vascular bed Moderate dose- +ve chronotropic & inotropic effects Dobutamine: +ve chronotropic & inotropic effects IV fluids: maintains adequate blood volume Infection treatment, Hemodynamic & Respiratory support w/in 1hr of presentation Antimicrobial: Empirical: effective against both GN & GP microorganism After microbial culture: appropriate antimicrobial treatment Remove focal source of infection NaHCO3-corrects acidosis Vasopressor-for hypotension O2 Recombinant activated protein C: Sepsis associated w/ excess inflammatory response & altered coagulation & fibrinolysis Anti-inflammatory & Anti-apoptotic Septic shock w/ adrenal insufficiency: Glucocorticoids (hydrocortisone 100 mg IV TID) Adrenaline: 0.5 mg of 1:1000 IM reversal of hypotension, bronchospasm, laryngeal edema IV fluids Hydrocortisone hemisuccinate: 100mg IV/IM- inhibit late phase of allergic reaction Chlorpheneramine: 10-20 mg slow IV O2, assisted ventilation Norepinephrine 1, 2, 1 Strong vasoconstrictionBP Shock w/ severe hypotension

Dopamine D1, D2, 1, 1 Low dose: 2 g/Kg/minD1dilates renal vascular bed Moderate dose: 2-10 g/Kg/minD1,1+ve chronotropic & inotropic effect

Dobutamine 1 selective inotropic w/ afterload reduction(peripheral vasodilator)minimize cardiac O2 consumption Cardiogenic shock-pump failure due to MI

Phenylephrine 1 agonist Strong vasoconstrictor

Hypovolemic, Cardiogenic, Septic

Neurogenic shock

Vasopressin: Catecholamine resistant shock Milrinone: PDE inhibitor Potent inotrope & chronotrope Shock treatment: Early recognition ABC resuscitation Fluid restoration Vasopressors (AFTER fluid restoration) Restore O2 delivery Control inciting pathological process Maintain vital organ function
Hypovolemic shock Volume replacement Dopamine Dobutamine YES Endotoxic shock YES Cardiogenic shock NO Anaphylactic shock

POSSIBLY

YES POSSIBLY

YES YES

YES YES

POSSIBLY NO

Adrenaline

NO

NO

NO

YES

Glucocorticoids

NO

YES

NO

YES

Antihistaminics

NO

NO

NO

YES

HEMATINICS Oral Fe Ferrous Sulphate (32%) Ferrous Fumarate (33%) Ferrous Gluconate (12%) Colloidal Ferric Hydroxide (50%) Preferred Ferrous>Ferric absorption Empty stomach Upper intestineabsorbed ADRs Epigastric pain Nausea, vomiting, heartburn Metallic taste Staining of Teeth Bloating ADRs Local: Pain Skin Pigmentation Sterile abscess Systemic: Fever, headache, joint pain, flushing Palpitation, chest pain, dyspnea LN enlargement Anaphylaxis Renal DiseaseX Fe sorbitol

Parenteral Iron Dextran Fe IV/IM

Iron Sorbitiol-Citrate IM

Fe overload

MW MW IM(locally bound)/IV IM-Not locally bound Not excreted 30 % excreted Absorbed through Absorbed through Lymphatics Circulation Not transferrin bound Transferrin bound Taken up by macrophagesslowly Directly available available to erythron Normal-2.5-3mg >7 mgtissue damage Acute Fe Poisoning: >60mg/Kg Vomiting, Abdominal Pain, Hematemesis Diarrhea, Lethargy Cyanosis, Dehydration, Acidosis Convulsions Shock, CVS collapse

IM-deep gluteal injection Z technique-avoid skin staining 2ml-daily/alternate days 5 ml each side on same day IV-0.5 ml Fe Dextran after test dose over 5-10 min Infusion-diluted in 500 ml glucose/saline Fe sorbitol-not iv

USES Fe deficiency anemia (treatment & prophylaxis) Megaloblastic anemia FeCl3-astringent in throat pain

Megalobl astic state

B12/Cobalamin deficiency: Gastric failure: Pernicious anemia Total gasterectomy Ileal failure: Crohns disease: regional enteritis Ileal resection Tropical sprue Competing organism: Bacterial overgrowth (blind loop) Diphyllobothrium latum

Folate deficiency: Folate poor diet: Alcoholism, poverty Folate requirement: Pregnancy Severe hemolytic anemia Severe psoriasis Drug therapy Tropical sprue

Management: Prevent further Absorption: Induce vomiting/gastric lavage Oral egg yolk & milkcomplex iron Activated charcoal useless Bind & remove absorbed Fe: Chelating Agent: Desferroxamine DTPA/Ca edetate BAL contraindicated Supportive Measures: Correct fluid/electrolyte balance CVS support Convulsions: Diazepam Clinical features: B12 & Folate: Megaloblastic anemia Fatigue, weight loss, fundal hemorrhage, diarrhea, fever, sore tongue, appetite loss, jaundice B12 deficiency: Paraesthesia, neuropathy, dementia, demyelination of spinal cord Pernicious anemia: Family & personal history of vitiligo, Autoimmune thyroid disease

Hemopoetic GF Erythropoetin: peritubular cells of kidneyRBC MCSF, GCSFWBC Thrombopoetinplatelets Stem cell factor IL

Treatment: Transfuse (care) B12-oral or parenteral Folate tablets Severe cases: hypokalemia

Epoetin: r Human Erthropoetin Uses: Chronic Renal Failure Cancer Chemotherapy AIDS anemia Premature infants Dose: 25-100 IU/Kg/SC IV 3x a Wk Adverse Flu like symptoms Mild Hypertension Encephalopathy Thrombosis Fe & Folate demand

Disease/Condition G6PD-Hemolytic anemia

Immune Hemolytic Anemia

Causative Drugs/Causes Antimalarials: Primaquine Chloroquine Fansidar Maloprim Sulfonamides: Sulfacetamide Co-trimexazole Dapsone Antibiotics: Chloramphenicol Furazolidone Niridazole Nalidixic acid Nitrofurantoin Antidiabetics: Glibenclamide Analgesics; High dose ASPIRIN Vitamin K analogues Naphthalene Penicillin-High Dose: Ab against drug-RBC complex Quinidine Rifampin: Drug-ag-ab deposits complement on RBC surface Methyldopa Fludarabine

DRUGS AFFECTING BLOOD ELEMENTS Treatment/Therapeutic Drugs Stop drug Treat underlying infections Severe anemiablood transfusion Hemoglobinuriamaintain good renal flowavert renal damage Neonatal jaundicephototherapy

Adverse effects

Chemical AgentsHemolysis

Dapsone-High Dose

Stop Drug CORTICOSTEROIDS: PrednisoneFIRST LINE Azathioprine, Cyclosporin, Cyclophosphamideused when other measures fail Splenectomy Severe Cases: Blood Transfusions Folate Stop Drug Severe Anemia: Blood Transfusion

Wilsons Disease-Cu-High Dose

Poisoning: Pb, Chlorate, Arsine

Thalassemia

Regular Blood Transfusion Folate-regular use Splenectomy: 6yrs+ Hepatitis B vaccine Allogenic BM transplant

Iron OverLoad: Liver damage Endocrine: growth failure, delayed/absent puberty, DM, hypothyroidism, hypoparathyroidism Myocardium Siderosis Iron Chelator: Parenteral: Desferoxamine 1-2g IV or 20-40 mg/Kg SC w/ each unit of blood

Adverse : Rapid IV: hypotension Idiosyncratic reactions: Flush, Rash Pulmonary, Neurosensory toxicity Oral: Defipirone, Deferasirox Endocrine therapy: GH, insulin, Ca, Vitamin D Aplastic Anemia Chemicals: Benzene, DDT, insecticides, Hair Dye Drugs: Anticancer: Busulphan Cyclophosphamide Anthracyclines Nitrosoureas Idiosyncratic: Chloramphenicol Sulphonamide Gold General Treatment: Stop Drug/Chemical Anemia: Blood transfusions, Platelet concentrates Infections: Prevent & Treat-cultures, Broad spectrum prophylactic antibiotics, antifungals, GCSF Severe Thrombocytopenia Fibrinolytic Inhibitors: Tranexamic Acid or Aminocaproic Acid Platelet transfusion Allogenic Stem Cell Transplantation Specific Treatment: Anti Lymphocyte Globulin (ALG) & Anti Thymocyte Globulin (ATG): cytotoxic T cells Adverse: Fever & Chills: Prednisolone Serum 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 Transplantation General Treatment: Stop Drug Prevent & Treat infections: Bacterial Usually Can also be: Viral, Fungal, Protozoal Specific Treatment: GCSF GM-CSF Autoimmune Neutropenia: Corticosteroids & Splenectomy Rituximab: Anti CD-20 (Monoclonal Antibody)

Neutropenia

Anticancer Drugs: Alkylating agents-non selective neutropenia Antibiotics: Chloramphenicols Sulfonamides Co-trimexazole Cephalosporins Antipsychotics: Chlozapine Chlorpromazine Antithyroids: Carbimazole Anti-Inflammatory: Phenylbutazone Gold Salts Anti-Epileptic: Phenytoin Carbamazepine

Thrombocytopenia

Penicillamine Ticlopidine Bone Marrow Suppression: Anticancer, Ethanol Chloramphenicol, Co-trimoxozole, Arsenic Immune: Analgesics, Anti-inflammatory: Gold Salts Antibiotics: penicillin, trimethopterin, sulfonamides Antiepileptic: Diazepam, Carbamazepine Diuretics: Acetazolamide, Furosemide Antidiabetics: Chlorpropamide Digoxin, Heparin, Methyldopa, Quinidine Platelet Aggregation: Heparin Myeloid Growth Factor: rG-CSF: Filgrastim neutrophils rGM-CSF: Sargramostim neutorphils, eosinophils, monocytes Uses: Post chemotherapy, radiotherapy, autologous SC transplant Peripheral mobilization of SC for autologous SC transplant (G-CSF) Severe neutropenia, Aplastic anemia

Erythropoetin: Hb, Erythropoesis, circulatory reticulocytes EPOETIN , DARBOPOETIN : IV, SC Uses: Anemia due to CRF/AIDS, cancer/drugs Anemia in premature babies Pre-Operationto blood transfusions Adverse: Thrombosis, BP

General Treatment: Blood Transfusion/Platelet Concentrates Specific Treatment: Corticosteroids: Prednisolone (High Dose) Splenectomy: Patients w/ steroid failure or in need of high dose steroids Immunoglobulin: Rituximab (anti CD 20); high dose modify autoAb production Immunosuppression: Azathioprine, Cyclosporin, Cyclophosphamide when other measures fail Megakaryocyte Growth Factor: OPRELVEKIN (IL 11) Megakaryocyte Growth Factor: Oprelvekin: IL-11 Thrombopoetin Uses: Thrombocytopenia /after cancer therapy Adverse Effects: Fatigue, Headache, Dizziness, Fluid Retention CVS effects: Dilutional anemia, dyspnea, Transient Atrial Arrythmia

ANTI-PARASITIC Disease Antimalarial Class Erythrocitic Schizonticide Drug Chloroquine Mechanism Degradation of RBC HB Fast & Long Acting Uses Prophylaxis & Cure of ALL types of Malaria Infectious Mononucleosis Rheumatoid Arthritis Multidrug Resistant Plasmodium falciparum malaria Multidrug Resistant malaria Cerebral malaria + Tetracycline=effect Nocturnal muscle cramps, varicose veins, myasthenia gravis P. falciparumcurative Toxoplasmosisfirst choice Adverse Effects toxicity; side effects GIT-A/N/V, epigastric pain CVS: IV; BP; arrhythmia CNS: toxicity Eye: retinal damage Ear: Hearing Defects Not Parenteral Avoid in cerebral/complicate malaria Resistance effective, toxicity than chloroquine Highly toxic8-10 g-fatal Cinchonism: CTZ damage, vomiting, tinnitus Hemolysis PregnancyAbortion

Mefloquine

Intermediate & Long Acting

Quinine

Sulfonamide Slow and Long (sulfamethopyrazine/sulfadoxine)+Pyremethamine acting (S/P) Erythrocytic phase of P. falciparum Antifolate (like Cotrimoxazole) Tetracyclines Weak & Slow acting

SulfonamideSerious toxicityExfoliative dermatitis, Steven Johnson syndrome Not prophylactic Single Dose

Blood Schizonticide

Halofantrine

Mefloquine like activity

Artemesinin Derivatives Artisunate: Water SolubleOral, IV, IM Artemether: Lipid Soluble Arteether: IM

Tissue/Liver Phase acting/Exoxryhtrocytic Filariasis Diethyl Carbamazine

Primaquine

Fastest and Short acting Prodrugs Damage ER & Protein synthesis in parasites Kills falciparum gametes Effective against Gametocytes & Hypnozoites Selectively

All Plasmodium species +Quinine or S/PChloroquine resistant Falciparum Doxycycline (100 mg/day): Second Line ProphylacticChloroquine resistant Falciparum malaria Multidrug Resistant P. falciparum P. vivax Used when other drugs not working Multidrug Resistant Falciparum malaria treatment

X Pregnant, Lactating X Children <7 years NEVER USED ALONE

GIT Ventricular Arrhythmia

+ enzyme inhibitors/anti-arrhythmic/antipsychotic/anti-depressants arrhythmias Not useful in prophylaxis

Prevent & Cure malaria relapse Filariasis

GIT G6PD: hemolysis GIT

Leishmaniasis

Sodium Stibogluconate

Trypanosomiasis

Pentamidine

sensitize microfilariae for phagocytosis Inhibits SH dependant enzymes of parasite Inhibits topoisomerase 2 & aerobic glycolysis

Tropic Pulmonary Eosinophilia Kala Azar (L. donovanii)

Fever, Rash LN enlargement N/V, abdominal pain Pancreatitis Kidney & Liver Damage Highly Toxic Strong alkaline naturereleases Histamineanaphylaxis Heart, Liver, Kidney damage

Trypanosoma cruzi Nifurtimox/Benznidazole-Acute disease Trypanosom Early disease: IV suramin gambiense/rhodensiense Late disease + CNS involvement: suramin + melarsoprol (crosses BBB) + corticosteroids (prevents reactive encephalopathy) Toxoplasmosis Sulfadiazine + Pyrimethamine +Falinic acid (prevents BM suppression) Causal Prophylaxis: Suppressive Prophylaxis: Clinical cure: terminate episode of malarial fever Pre/exo-erythrocytic Erythrocytic Phase Erythrocytic Schizonticides phasecause of malaria suppressionprevents Fast acting High efficacy: used alone Prevent clinical attacks malarial fever Chloroquine, Mefloquine, Quinine, Amodiaquine, Proguanil: P. falciparum Clinical symptoms Halofantrine, Lumefantrine, Artemesinine, Primaquine: all malarial suppressed; Atovaquone. species exoerythrocytic phase Slow acting Low efficacy: used in combination not affected Proguanil, Sulfonamides, Pyrimethamine, Chloroquine: Tetracycline 300mgx2tabs/wk; 1wk before & 1 month after endemic area return Radical Cure: total eradication of parasite from Resistant cases: body Proguanil 200 mg daily + Exo-Erythrocytic drugs + Erythrocytic drugs = total Chloroquine 300 mg cure weekly P. falciparum & P. malariae: clinical Mefloquine 250 mg cure=erythrocytic schizonticides=erythrocytic weekly-4wks after parasite elimination is enough. No exoerythrocytic endemic area return phase Doxycycline 100 mg 1day P. vivax & P. ovale: Relapsing before to 4 weeks after malariaerythrocytic & exoerythrocytic/hypnotic endemic area return parasite elimination Exo-Erythrocytic drugs + Erythrocytic drugs Falciparum Malaria: Multi Drug Resistant Vivax Malaria: Chloroquine sensitive: Falciparum Malaria: Chloroquine sensitive: Chloroquine + Primaquine Uncomplicated Acute Chloroquine + Primaquine (gametocidal) Multidrug Resistant Chloroquine Resistant: Chloroquine resistant: Falciparum Malaria: Quinine + Doxycycline + Primaquine -Artesunate ACT-Artemesinine based +Sulfadoxine+pyrimethamine Combination Therapy (S/P)+Primaquine Artemesinine + -Artesunate + Mefloquine Erythrocytic

Trypanosomiasis Leishmaniasis AIDS patients: Pneumocystis jiroveci pneumonia Chagas disease Sleeping sickness

Gametocidal Elimination of male & female gametes from patients blood Not beneficial to patient; Reduces transmission to mosquito Primaquines & Artemesinines: Gametocidal to all species Chloroquine & Quinine: Vivax gametes

Congenital/disseminated disease Antimalarial Classification: 4-aminoquinolines: Chloroquine Quinoline Methanol: Mefloquine Cinchona Alkaloid: Quinine Biguanides: Proguanil Diaminopyridine: Pyrimethamine 8-aminoquinolines: Primaquine Sulfonamides: Sulfadoxine, Sulfamethopyrazine Tetracycline Sasquiterpine Lactone: Artesunate, Atemether, Arteether Amino Alcohol: Halofantrine Mannich Base: Pyronaridine Naphthoquinone: Atovaquone Most Antimalarials: Hemolysis in G6PD deficiency

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 DoxycyclineAreas w/ multidrug resistant P. falciparum PrimaquineTerminal Prophylaxis of P. vivax & P. Ovale

-Artemeether + Lumefantrine -Quinine + Doxycycline Cerebral malaria: Chloroquine sensitive malaria drugs IV

Schizonticide

Class Nucleoside & Nucleotide Reverse Transcriptase Inhibitor

Drugs Zidovudine (AZT)

Stavudine Didanosine

Mechanism Deoxythymidine Analog AZTThymidine KinaseTriphosphate form Competitive Inhibition of dTTP for Reverse Transcriptase Enzyme Causes Chain Termination Thymidine Analog Synthetic Deoxyadenosine Analog

ANTIRETROVIRALS Uses Adverse Effects IV & Oral Myelosuppression: Neutropenia, Anemia HIV 1, HIV 2, HTLV GI intolerance: N/V Headaches, Insomnia HIV treatment: progression & Crosses BBB survival Metabolite in urine Prevents Mother to Child HIV transmission Peripheral Neuropathy Lipidystrophy Pancreatitis Peripheral Neuropathy D/N/V Abdominal Pain Peripheral Neuropathy N/V Headache Fatal Hypersensitivity Prevents HIV transmission from mother to neonate at labor/delivery TERATOGENIC

Resistance Mutations in reverse transcriptase gene Prolong therapy & Monotherapy

Zalcitabine

Cytosine Analog

Lamivudine Abcavir Non-Nucleoside Reverse Transcriptase Inhibitors Nevirapine

Delavirdine Efavirenz

Protease Inhibitors

Indinavir Ritonavir Squavinavir Nelfinavir Amprenavir

Cytosine Analog Guanosine Analog More effective Binds to Viral Reverse TranscriptaseRNA & DNA dependent DNA polymerase blockade Substrate & Inhibitors of CYP3A4 Do not compete w/ nucleoside triphosphates Do not require Phosphorylation Protease: Cleaves large precursor polyprotein moleculefunctional componenets Inhibit Protease (late step in replication) prevent spread of infection

Nephrolithiasis Fatigue Inhibits CYP3A4 Photosensitivity

Lipidystrophy: Abdominal Obesity, Buffalo Hump, Limb & Face wasting Dyslipidemia GI intolerance Dizziness Numbness Rashes Headache Limb & Facial tingling Asthenia Hyperlipidemia Insulin resistance

Fusion/Entry Inhibitor

Enfuvirtide (T-20)

Binds to gp-41 subunit of viral glycoprotein envelopeprevents conformational changes required for fusion of viral & cellular membranes Blocks FusionPrevents entry into/infection of CD 4 cells

Integrase Inhibitor

Raltegravir

Anti HIV regimens: Zidovidine + Lamuvudine + Lopnavir (PI) Zidovidine + Lamuvudine + Efavirenz (NNRTI)

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

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

Class Thrombolytics / Fibrinolytics

Drug Streptokinase

THROBOLYTICS, ANTITHROMBOTICS AND COAGULANTS Description Action Uses Non enzymatic AMI: Thrombolytic Therapy-w/in 6 protein hrs of symptoms hemolytic Peripheral Arterial Thrombosis streptococci Catheter & Shunt patency Proactivator PE + Hemodynamic Instability plasminogen Severe DVT complexcatalyzes Acute Ischaemic Stroke: rTPA w/in 3 formation of hrs of symptoms plasmin Peripheral Vascular Disease

ADR Action blocked by Antistreptococcal Ab 1Year should be elapsed before next use Allergy, Hypotensiongenerating Kinins

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

Contraindications Absolute Contraindications: Neurosurgery/Head trauma <2 mts Severe Active Bleeding/ Internal Hemorrhage Cerebrovascular Hemorrhage <6 mts Cerebral tumor/aneurysm Relative Contraindications: Recent Major Trauma Invasive Surgery < 10 days GI/genitourinary bleeding Recent CardioPulmonary Resuscitation Peptic Ulcer <3 mts Pregnancy Uncontrolled Hypertension Thrombocytopenia

Urokinase

Recombinant Tissue Plasminogen Activator: Alteplase Duteplase Reteplase

Enzyme-Human urine Cultured Human Renal CellsNonAntigenic Potent Direct Plasminogen Activator rDNA technology Expensive

Non Antigenic

Anistreplase

Anti-Coagulant Parenteral Indirect (AntiThrombotic) Anticoagulant Thrombin Inhibitor

Unfractionated Heparin (UFH) MW: 500030,000

Anisoyloted Plasminogen Streptokinase Activator Complex (APSAC) Complex: Purified Human Plasminogen + Bacterial Streptokinase Sulfated Mucopolysaccharide IV/SC Not given IMhematoma formation Immediate onset 4-6hrs Monitor: aPTT = 2-2.5 control

Better than streptokinase & urokinase in dissolving older clots Does not act on circulating plasminogen Non Antigenic Rapid action Clot selectivity Activity on plasminogen associated clots than free blood plasminogen Thrombolytic Activity HeparinActivates Anti Thrombin 3 (AT-3)Inhibits Factors 2a (Thrombin), 9a, 10a Bleeding time Clotting time aPTT Inhibits Coagulation InVivo & InVitro Inhibits Aldosterone Secretion

Allergies Bleeding HypotensionKinins

DVT & PE: Prophylaxis-for bed rest, high risk surgeries, CancerLow dose UFH, LMWH, Fondaparinaux Treatment-UFH, LMWH for 5-6 days, then Warfarin for 3-6 mts Pregnant Women-

Bleeding: risk: careful patient selection, Dosage control, monitor aPTT Heparin Induced Thrombocytopenia (HIT): Ab formed to Heparin & Platelet Specific Protien - Platelet Factor 4 (PF4) Systemic hypercoagulable state Leads to Venous Thrombosis Perform platelet count frequently

Drug hypersensitivity, HIT Active Bleeding/Risk,Intracranial Haemorrhage, Active TB, Hemophillia, TTP, Recent SurgeryCNS, eye, postate Threatened Abortion Brain & Spinal Cord Injury Anaesthesia: Regional & Lumbar block Severe Hepatic & Renal Impairment

Does not cross Placenta

Lipemia clearing Anti-Inflammatory

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 PE, DVT HIT AMI

Treatment: Direct Thrombin Inhibitor, Fondaparinaux Allergy: Animal Origin-asthma, urticaria Therapy-Transient Alopecia Osteoporosis: >6 mts use

Low Molecular Weight Heparins (LPWH): Enoxaparin Dalteparin Tinzaparin MW: 3000-7000

Heparin Fragments

Inhibits Factor 10a Less effect on Thrombin (2a) Equally efficacious as UFH No effect on CT, aPTTNo lab test required SCBioavailability Long T1/2Less frequent dosing1/2 weekly Bleeding, HIT Anti Thrombin 3 mediated selective inhibition of Factor 10a No effect on Thrombin (2a) SC Long T1/2: 15 hrs Directly bind to active site of Thrombin

Prevention of DVT, PE Cannula patency in Dialysis patients

Fondaparinaux

Direct Thrombin Inhibitor

Hirudin/Lepirudin Hirudin: Leech Saliva (Bivalent DTI) Lepirudin: Specific recombinant form irreversible Thrombin Inhibitor Bivalirudin (Bivalent DTI) Argatroban (Univalent DTI)

HIT Anaphylaxis

Coronary Angioplasty HIT Coronary Angioplasty in HIT patients Inhibits Vit K EpoxideVit K Hydroquinone (active form) Inhibits synthesis of Vit K dependent Factors 2,7,9,10 (TENS) Bleeding: Common-Haematuria, Epistaxis, Bleeding Gums, Uterine, Intracranial Ulcer-FATAL Treatment: Vitamin K (antagonist), Fresh Blood/Plasma Infusion Teratogenic: Fetal Warfarin Syndrome- Fetal Hemorrhage, Abnormal Bone Formation

Oral Vitamin K Warfarin Anticoagulant Antagonist

Inhibits Vit K EpoxideVit K Hydroquinone (active form) 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 K Inhibiting Factors (coagulation) -Thrombosis -Pregnancy: synthesis of Clotting factors -Hypothyroidism: metabolism (destruction) of clotting factors -Genetic warfarin resistance

Slow Complete Absorption Delayed onset: (1-3 days) plasma protein binding Crosses Placenta & Secreted in Milk Metabolized in Liver Dose Regulation: Monitor PT-reduce to 25% of control INR Full effect: 4-5 days even if INR reaches therapeutic level in 1-2 days PK: Enzyme Induction & Inhibition, PP binding PD: Synergismimpaired hemostasis/clotting factor synthesis (hepatic disease), Competitive antagonism-Vit K, Hereditary resistance to oral anti coagulants

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

Direct Thrombin Inhibitor

Phenindione Dabigtaran

Hypersenstivity No routine INR monitoring required Fewer Drug Interactions compared to Warfarin Prevent Stroke & Thromboe mbolism in Atrial Fibrillation Prevent Blood Clotting in Test Tubes

In Vitro

AntiPlatelet

Ethylene Diamine Tetra Acetic Acid (EDTA) Citrate Lithium Heparin Prostaglandin Synthesis Aspirin Inhibitors

Calcium Chelators

Inhibits COX & Thromboxane Synthase Irreversibly TXA2 synthesis in Platelets Bleeding Time in

MI Prophylaxis Unstable Angina Cerebrovascular Disease

Arterial ThrombusWhite Thrombus Prevent Reinfarction in

ADP Receptor Blocker

Clopidogrel Ticlopidine

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

vivo Low Dose: 75-100 mg Platelets exposed to aspirincannot synthesize new enzyme Blocks ADP Receptor (P2Y12) ADPplatelet aggregation ADP-RBinhibits aggregation

Active MI & IHD Primary & Tertiary prevention of MI post MI Aspirin Intolerant Patient Transient Ischemic Attacks Stroke, Unstable Angina Coronary Stent PCI AMI/Acute Coronary Syndromes Prevent stroke in cerebrovascular disease & transient ischemic attacks Patency of implanted bypass in CABG: Aspirin + Abciximab Nausea, Diarrhea, Leukopenia Thrombocytopenic Purpura Clopidogrel: Less ADR, Safer

Glycoprotien 2b/3a Receptor Inhibitor

Abciximab

Chimeric Monoclonal Antibody Parenteral

Eptifibatide Tirofiban PDE Enzyme inhibitor Dipyridamole

Weak effect on Platelet Aggregation

Chimeric Monoclonal Antibody against Gp 2b/3a receptor Occupies ReceptorInhibits Ligand Binding Inhibits Platelet PDE enzyme cAMPPGI2 Weak effect on Platelet Aggregation Platelet Inhibition Better Than Clopidogrel Platelet Inhibition Direct Inhibitor of ADP Receptor (P2Y12) Reversible

Prasugrel

Platelet Inhibition

+Aspirincereb rovascular ischemia +WarfarinArtif icial Heart Valves ischemic events Thrombolysis in AMI

Ticagrelor Amino Caproic Acid

Oral, reversible

Fibinolytic Inhibitors / Antifibrinolytics

Tranexaemic Acid Aprotinin Protamine Sulphate

Treat Overdosage of Fibrinolytics Hemophilics: Limit excessive bleeding after Surgery Prevent recurrence of SubArachinoid Hemorrhage Abruptio Placenta, Post-Partum hemorrhage, Menorrhagia Oral 7 x more potent than ACA CABG Surgery: Blood Loss Heparin Antagonist Basic Protien Fish Sperm Slow IV 1 mg Protamine Sulphate for every Heparin Antagonist Combines w/ Heparin as an ion pairStable complex devoid of anticoagulant

100 units of Heparin remaining in patient

activity BP, HR Dyspnea, Flushing Synthesis of Clotting Factors: 2, 7, 9, 10 (TENS) In Liver

Coagulants

Vitamin K

K1PhytonadioneFat soluble-Plants K2MenaquinoneBacteria K3-MenadioneFat/Water soluble-Synthetic

Deficiency due to: Liver Disease, Malabsorption Syndromes, long term antibiotic use Deficiency Symptoms: Bleeding: Urine, Nose, GIT, SkinEcchymoses

Deficiency of Clotting Factors Newborn Warfarin Overdose: Phytonadione

Toxicity: BP, Flushing Menodione: Kernicterus in NewbornsTreat by Phytonadione

Plasma Fractions

Factor 8 Anti-Hemophilic Factor Prothrombin Complex Concentrates Factor 9 Complex Factor 7a Cryoprecipitate Fibrinogen

Treat Hemophilia A

Treat Hemophilia B (Factor 7 deficiency)

Liver Disease, Blood Loss Factor 7 deficiency Hemophilia A Liver Disease DIC

Megaloblastic Anemia:

Hb: RBC: WBC: =/ Platelet: =/ Reticulocyte: Hct: MCV: MCH: =/ MCHC: = Serum LDH: Serum Bilirubin: B12 &/or Folate: B12<100pg/ml PBS: hypersegmented neutrophils, macroovalocytes BM: erythroid hyperplasia Penicious Anemia: Serum Ab to parietal cells Serum Ab to IF Achlorydia (HCl ve)

Aplastic anemia: Congenital: Fanconi Secondary: Radiation, Chemical, Drugs: Chloramphenicol, Infections: Parvovirus B19, HIV, Hep A, B, C DD: Severe Megaloblastic anemia w/ pancytopenia MDS Primary Myelofibrosis Marrow Fibrosis secondary to any other disease

Hb: RBC: WBC: Platelet: PBS BM: Trephine-dry tap w/ hypocellular imprints Fanconi: Kidney & Spleen hypoplasia Hypoplasia of bone: Thumbs/radii Short stature

PRCA: Congenital: Diamond Blackfan AcquiredPrimary-AI destruction of erythroid precursors Secondary: -Thymic tumorthymoma -Malignancy-CLL, lymphoma -drugs, pregnancy -AI-SLE -Virus: Parvovirus B19, EB

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

Anemia of Chronic Disease: Normocytic Normochromic/Mildly microcytic, hypochromic MCV: 77-82;rarely<75 Hb rarely<9 Reticulocytopenia Serum Fe TIBC Serum Ferritin: =/ BM Fe store: Perls stain: = Hepcidin: caused by IL1 & TNF

Iron Deficiency Anemia: Microcytic Hypochromic MCV: MCH: Hb: RBC: Serum Fe: TIBC:

Hereditary Spherocytosis: AD Hb: Reticulocytosis: 520% PBS: spherocytes DAT: normal Osmotic Fragility:

Plasmodium Falciparum Malariae Vivax Ovale

Malaria

Female Anopheles Mosquito

Infective: Sporozoites Diagnostic: Trophozoites, Schizonts, gametocytes

Sexual: Gametogony: Mosquito Sporogony: humans Asexual: Schizogony: humans Sporozoites liver schizonts (hypnozoites) blood RBC trophozoites Schizonts (merozoites) or gametocytes mosquito gut ookinete oocysts sporozoites Oocystcat ingests tachyzoitestissue bradyzoites/oocysts

Anemia, cyclic fevermerozoites lyse RBC & get released Cerebral Malaria: falciparum-aggregates of RBCs occlude capillaries Relapse: hypnozoites- Vivax Ovale

Toxoplasma gondii

Congenital Toxoplasmosis Toxoplasmosis Chagas Disease

Cat-definitive host Humans: intermediate host

Trypanosoma cruzii

Trypanosoma Brucie: African Gambiense & Tryposomniasis: Rhodensie Sleeping Sickness

Leishmania donovanii

Kala- Azar Visceral Leishmaniasis

Infective: Ocysts from cat feces/raw meat transplacental Reduviid Bug Infective: Trypomastigotes Diagnostic: Trypomastigotes/ Amastigotes Tsetse Fly-both sexes Infective: metacyclic trypiomastigotes Gambiense: west Diagnostic: Africa-Human trypomastigotes Rhodensie: east Africa-Animalantelope SandflyInfective: Phlebotomus, Promastigotes Lutzomyia Diagnostic: Amastigotes Animal: Dog, small carnivores, rodents Human: India Reservoir: Forest rodents

Trophozoites: Brain, eye, Liver Tissue Cysts-enlarge & cause symptoms Encephalitis in AIDS patients: impaired CMI Myocarditis: amastigotes kill myocytes Neuronal Damage: Megacolon, Megaoesophagus

Blood meal Trypomastigotes Reduviid Bug Midgut: Epimastigotes Hind gut: Trypomastigotes defecated human amastigotes trypomastigotes Blood meal Trypomastigotes Midgut: epimastigotes (procyclic) salivary glands: trypomastigotes (metacyclic) Blood stream

Trypomastigottes infect braindemyelinatin Encephalitis Cervical LNopathy winterbottoms sign

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

Kill RE cells Liver, Spleen, BM

Leishmania Tropicana & Mexicana Leishmania Brazilensis Wuchereria bancrofti

Cutaneous Leishmaniasis Mucocutaneous Leishmaniasis Filariasis

Female Anopheles & Culex Mosquito Definitiev host: Humans

Infective: Larvae (L3) Diagnostic: Microfilariae

Mosquito bites wound infective larvaelymphatics: Adultsblood: microfilariae

Adult worms block Lymphatics