receptors receptor class mechanism/second site action...
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RECEPTORS
Receptor Class Mechanism/Second messenger
Site Action Effect Drug receptor selectivity
α α1 ↑DAG & IP3↑ IC Ca2+ Blood Vessel Smooth Muscle-TPR (skin) Pupil Radial muscle Intestine, Prostate, Bladder sphincter
Vasoconstriction-Blood vessels-TPR Mydriasis ↓GIT, Contraction-↓urinary
VASOCONSTRICTION ↑BP on stimulation/agonist Mydriasis-good in glaucoma
Epinephrine> Norepinephrine >>>>>>>>> Isoproterenol
α2 ↓cAMP↓Norepinephrine release
Presynaptic receptor↓Nor(auto)/Ach(hetero) INHIBITORY Pancreatic β cell↓insulin Fat, Platelet
↓Nor/Ach—Neuromodulation—inhibitory ↓insulin & lipolysis (DOMINANT) Platelet aggregation
↑blood sugar on stimulation↓ insulin release
β β1 Heart↑Ino, Chrono, AV nodal conduction velocity JG cells↑Renin
↑BP, ↑HR,↑conduction ↑Renin↑fluid retention↑venous return↑SVCO↑BP;↑Ang2↑TPR↑afterload↑heart work,↑BP GIT smooth muscle relaxation
↑BP on stimulation/agonist Isoproterenol> Epinephrine> Norepinephrine
β2 Blood Vessel SKELETAL, (coronary) Uterine Smooth muscle Respiratory Liver Pancreatic β cell Ciliary muscle
Vasodilation Relaxation (tocolysis) Bronchodilation Glycogenolysis ↑insulin (MILD) Relaxation-Mydriasis
↑blood flow to skeletal muscle/HEART ↑ air in lungs ↑ energy Good in glaucoma On stimulation/agonist
Isoproterenol> Epinephrine >>>>>>>>>> Norepinephrine
β3 Fat cell ↑lipolysis
Dopamine 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 cyclase Open K channel ↓Ca influx
Nerve terminal ↓Norepinephrine release Autoregulator
Cholinergic Nicotinic Agonist-small dose Nicotine Antagonist-Large dose nicotine Ach↓Norepinephrine at vasoconstrictor nerves AchM3NO/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, airway Endothelium Brain
Smooth Muscle Contraction Blood Vessel: (Short Lasting) Vasodilation-NO, PG release
capillary permeability, gap junction widening Smooth muscle: vasoconstriction-larger vessels Afferent Nerve Stimulation
Bronchoconstriction Allergies
Sensory Nerve Endings-stimulation-pain Waking Amine Triple response-ID injectionRed spot, edema & flare
BP(vasodilation), sense of warmth, Headache
H2 Gastric Parietal Cells Cardiac Muscle Smooth Muscle Brain
Gastric Gland-Gastric Acid Secretion Blood Vessels: (persistent) Vasodilation-smaller vessels
Heart: +ve Chronotropy & +ve Inotropy, HR
Peptic Ulcer
H3 Histaminergic Neurons Myenteric Plexus
Presynaptic H3 Receptors-release several transmitters
AGONISTS
Classification Drug Class Receptors Action Effect Uses ADR/Interactions
DIRECTLY ACTING
Epinephrine Catecholamines All α1=α2; β1=β2
Low dose-β action-vasodilation High dose-α action-vasoconstriction
β2-dilates coronaries & skeletal blood vessels-↑blood flow α1&2-consticts blood vessels of skin & mucosa
ANAPHYLACTIC SHOCK(α)(IM), local anaesthetic, GLAUCOMA(α1), local bleed (nose)(α 1&2) Physiological antagonist of Histamine Glauoma Heart block, cardiac arrest Local hemostasis(α1)
+COCAINE↑CVS effects
↑cardiac work-ischaemia, MI, heart failure ↑BP ↑HR Arrythmias Pulmonary edema
Norepinephrine α1=α2 β1>>>β2 α1,α2,β1 agonist
α1 –vasoconstriction-↓TPR-↑BP
↑BP Shock Dopamine preferred
↑BP*baroreceptor*VagusREFLEX BRADYCARDIA (α1)
Isoproterenol β1=β2>>>>α Mainly 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, viscera D2-presynaptic autoreceptor-↓Norepinephrine release Moderate dose: (D1) ↑contraction,conduction (heart) High dose: α-vasoconstriction
Inotrope Cardiogenic/Septic shock Inotrope-↑CO, xHR ↑perfusion kidney, viscera↑urine output Acute HF
Xylometazoline, Oxymetazoline, Naphazoline Pseudoephederine,
α Vasoconstriction of nasal mucosa Topical-long acting
Nasal decongestants
Initial sting ↑BP Prolong: Atrophic rhinitis
Selective Adrenergics Phenylephrine Selective α1 agonist
α1
Vasoconstriction Mydriasis
Nasal Decongestant Mydriasis-retinal exam GLAUCOMA
No cycloplegia ↑BP
Methoxamine Selective α1 agonist
Clonidine Selective α2 agonist
α2 Central sypatholytics
↓vasomotor sympathetic center↓BP, relax
Antihypertensive ↓TPR-relax peripheral blood
Antihypertensive GLAUCOMA-apraclonidie
Withdrawal reaction of Opiates, Benzodiazepines
αmethylDOPA Selective α2 agonist αmethyl analogue of DOPA (precursor of DA, NE)
peripheral blood vessels vessels Antihypertensive-synthetic-no ADR/interaction GLAUCOMA
No ADR/interaction therefore Coombs test/DAT globulin negative
Dobutamine Selective(relatively) β1 agonist
β1 >β2>>>α
↑intropy, conduction--↑CO No ↑ in O2 demand x HR, BP, TPR
Inotrope Cardiogenic/Septic/Renal shock CHF-inotrope Post MI shock/pump failure Cardiac 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 action Also indirect action
Release Norepinephrine + α&β stimulation
Long acting Less efficacy
Postural Hypostension Ma 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-Epilepsy Methyphenidate: ADHD
Drug of Abuse ↑CNS: tremors, anxiety, insomnia, convulsions, anorexia
Tyramine Indiectly acting adrenergic
↑Norepinephrine release
Present in fermented food- cheese, wine, sausages Metabolized: Liver-MAO enzyme
↓Reuptake Cocaine Indirectly acting adrenergic
↓Reuptake at noradrenergic synapses
Drug of Abuse: ↑Dopamine in brain neurons
ANTAGONISTS
Type Class Drug Uses/effect Action ADR/Interactions
α blocker Nonselective Phenoxybenzamine Ergotamine Dihydroergotamine Phentolamine Chlorpromazine
Phentolamine: Penile erection for impotence
α1 blockade↓TPR↓CO↓BP Secondary shock-reflex vasoconstriction-hypovolemic shock CHF-short term relief Peripheral vascular disease
Postural hypostension-dizziness & syncope Nasal stuffiness-dilated blood vessels-extravasation Miosis-cholinergic-pupillae constrictor Diarrhea: cholinergic dominance Inhibition of ejaculation
Selective
α1 blocker Prazosin Hypertension Pheochromocytoma
Tamsulosin BPH
Terazosine
α2 blocker Yohimbine
β blocker Propanolol Hypertension ↓vasodilation-β2 blockade ↓Renin-↓Ang2-↓TPR-↓BP-β1 blockade Heart 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 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, Promethazine-
tremor,rigidity(Anti Chloinergic) Pregnancy Nausea/Vomiting: Doxylamine, Promethazine Motion Sickness: Dipenhydramine/inate, Promethazine, Cyclizine, Meclizine Pomethazine: Vestibular Disturbances: Cinnarazine (AntiHistaminic, AntiCholinergic, Anti5HT)
AntiAllergic-(Histamine=type 1 S) Sedative Highly: Dipenhydramine/inate, Promethazine Moderately: Pheniramine, Cyproheptadine, Meclizine, Cinnarazine Anticholinergic: Dipenhydramine/inate, Promethazine AntiHistaminergic+AntiMuscarinic = AntiEmetic/AntiNausea- Doxylamine (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
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
Second generation Fexofenadine Loratidine, Desloratidine Cetrizine,
Narrow Spectrum of Uses: Allergic rhinitis (hay fever) Conjunctivitis Urticaria, atopic eczema
H1 Selectivity Rapid Acting No AntiCholinergic effects Absence of Sedation
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
Adrenaline
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
No role in Asthma: Asthma due to Leukotriene & PAF Low concentration at site of action No role in other humoral & cell mediated allergies
MYOCARDIAL INFARCTION/ANTI-ANGINAL
Class Drug Site/Mechanism Uses ADR Interaction
Nitrates Short acting: Glyceryl Dinitrate, isosrbide dinitrate ( sublingual) Long acting: oral, transdermal
Venodilationpreload Arteriolar
dilationTPRAfterload Coronary dilation
Angina Pectoris NSTEMI Hypertensive emergency LV failure Abdominal Colic Cyanide Poisoning
Throbbing headache Tolerance dependance
+sildenafil/Viagra=death
+other antihypertensives=BP
β blocker Anti-adrenergic
CO/cardiac work and myocardial O2 requirements
reninangiotensin
Classical & Unstable angina MI Mild CHF Hypertension Arrythmia Dissecting Aortic Aneurysm Hypertrophic obstructive cardiomyopathy Migraine, thyrotoxicosis, Anxiety, tremors, glaucoma
TG
quality of life Worsening Peripheral vascular disease CHF Heart block Tiredness & reduced exercise
+verapamil/diltiazem=SA & AV nodal depressioncardiac arrestdeath +insulin & oral antidiabeticsdelay recovery from hypoglycaemia Blocks warning symptoms of hypoglycaemia: tremors, seating, tachycardia +α agonists (cold remedies:
ephedirine/phenylephrine)=BP (unopposed action)
+NSAIDS=β blocker effect
Propanolol=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↓CO Block L type voltage channel
Cardiac arrhythmia Migraine, nocturnal leg cramp
+βblockercardiac depression-death
Dihydropyridine: Nifedipine, Amlodipine, Lercanidipine
SMOOTH & CARDIAC muscle
Angina pectoris Hypertension Premature labor Hypertrophic cardiomyopathy, Reynaud’s disease
Weak uterine contraction, foetal hypoxia, tachycardia, hypotension ↓placental perfusion
Nifedipine: tachycardia & death
Benzothiazepines: Diltiazem
Broad spectrum: nerve + muscle
Cardiac arrhythmia Angina pectoris Hypertension Hypertrophic cardiomyopathy
+βblockercardiac depression-death
K+ channel openers
Nicorandil Pinacidil
Visceral+vascular smooth muscle dilation Arterial+veno dilation Dilation of epicardial & deeper vessels ↑coronary blood flow
Hypertension MI-nicorandil-cardioprotective
Combinations β blocker + Long acting nitrate
Nitrate + CCB β blocker + nitrate + CCB
AVOID verapamil+ diltiazem
βblocker-x nitrate tachycardia
Nitrate - ↓ preload CCB - ↓ afterload
Nitrate - ↓preload CCB - ↓afterload +
Nitrate- x β blocker cardiac dilation & ↓blood flow
Vasospastic angina ↑coronary blood flow β blocker - ↓ cardiac work
Pre-hosptal/Emergency management
Aspirin: 162-325 mg-chewed &swallowed Nitroglycerine: sublingual-0.4mg/5min O2 Morphine
NSTEMI: Stabilize acute coronary lesion Rx residual ischemia Prophylaxis
Anti-thrombotic therapy: Antiplatelets: clopidogrel (ADP), abciximab (Gp 2b/3a), Apirin (COX) Anticoagulant: heparin/enoxaparin Anti-ischemic/Cadioprotective therapy: Cardioselective β blockers, ACE inhibitors, Nitrates
Prevention of Recurrence: Aspirin: lifelong β 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 β blockers: Atenolol, Metoprolol ↓cardiac work & O2 demand↓injury & 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)
In hospital management
Complete bed rest Aspirin & Heparin: after fibrinolysis(x reocclusion) β blocker: w/in 24 hrs2 years ACE inhibitors: STEMI-w/in 24 hrs Antihyperlipidemic drugs
STEMI: Reperfusion therapy
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
ANTI-ARRHYTHMICS
Class Phase of action
Mechanism Drugs Effects Uses ADRs/Interactions/Contraindications
Class 1 Na channel blocker
Phase 0 Phase 4 (Phase 0 & 3)
↓rate of conduction in tissue w/ fast potential Ignores slow potential - SA, AV nodes
1a Quinidine Procainimide (phase 0 & 3)
↑AP duration & refractoriness ↓conduction through ventricle ↓Repolarization rate ↑ QRS & QT intervals
Atrial & Ventricular arrythmias ↓myocardial contractility, cardiac arrest +diureticshypokalemiatorsades de Pointes GIT side effects Hypersenstivity
1b Lidocaine Mexiletine (phase 3)
↓AP duration and refractoriness ↓conduction through ventricles ↓Repolarization rate ↓automaticity in ectopic foci
Ventricular arrythmias Ineffective in atrial arrythmias
Neurological: dizziness, drowsiness, nausea, blurred vision, paraesthesia, confusion, convulsion Bradycardia Hypotension
1c Flecainide (phase 0)
↓conduction in all cardiac tissues
Atrio-ventricular re-entrant tachycardia
GI symptoms, blurred vision, tremors Contraindicated-Sick sinus syndrome, heart failure, MI
Class 2 β blocker
Phase 4
β receptors-attached to Ca2+ channels β blocker: ↓ Ca2+ influx similar to class 4 (CCB)
Propanolol Esmolol (short acting)
Slow gradual Ca2+ influxautomaticity β blocker: ↓ Ca2+ influx ↑PR interval; no change in QRS
Supraventricular arrhythmias associated w/ exercise, emotion & stress Sinus tachycardia Extrasystoles
Severe bradycardia ↓cardiac contractility, cardiac arrest
Class 3 K+ channel blocker
Phase 3 ↓K+ effluxprolongs repolarization & ERP
Amiodarone ↓ K+ efflux ↑Repolarization & ERP ↑PR, QRS, QT interval
Supraventricular and Ventricular arrhythmia Resistant ventricular tachycardia Recurrent ventricular fibrillation Atrial fibrillation: maintain sinus rhythm
Bradycardia, Heart block Hypothyroidism: amiodarone has Iodine GI related Photosenstivity Skin & corneal pigmentation Peripheral neuropathy Pulmonary alveolitis & fibrosis (serious)
Class 4 Ca2+ channel blocker
Phase 2 (Phase 4)
Similar effect as β blocker
Verapamil Diltiazem
↓SA/AV automaticity ↑AV nodal conductivity ↑ERP ↑PR interval Breaks reentrant circuit
Paroxysmal Supraventricular Tachycardias (PSVT) Poor efficiency in ventricular arrythmia
Hypotension, Bradycardia Additive AV block Negative inotropic effect
Adenosine (α 1 agonist)
Very short acting purine nucleotide
Hyperpolarization of membrane ↓conduction velocity via slow potential/Ca2+ channels No effect on fast potential/Na+ channel ↑PR interval
Paroxysmal Supraventricular Tachycardias (PSVT) involving AV node-alternative to verapamil
Transient dyspnea, Chest pain ↓BP Ventricular standstill or fibrillation
Digoxin Na/K ATPase inhibitor
Inhibits Na/K ATPase of myocardial fibers ↑intracellular Na+ ↑intracellular Ca2+ (via
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 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
Myopathy
Hepatitis-↑serum
transaminase
GI disturbance
Rash, Insomnia,
Angioedema
Hypercholestrolemia
IIa, IIb
Anticoagulants &
Antidiabetics
95% PP binding
TERATOGENIC
Fibric Acid
Derivatives
Gemfibrozil
Bezafibrate
Clofibrate
Fenofibrate
PPAR-α
↑Lipopritien Lipase
Synthesis
↑clearance of VLDL
and Chylomicrons
↓TG
↑HDL
Rash, Nausea,
Dyspepsia, Diarrhea,
Myopathy
↓testosterone-
impotence
↑liver enzymes
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 activity-
↑clearance of VLDL
& chylomicrons
↓VLDL(hepatic
secretion)
↓LDL
↓TG
(synthesis)
↓FFA (from
adipose tissue)
↑HDL
Flushing & pruritus
GI disturbance
Hepatotoxicity
Hyperuricemia
Impaired glucose
tolerance
↑HDL
HyperTGemia
IIb, V
Exogenous Cholesterol
Uptake Inhibitors
Ezetimibe (oral) Interferes with
cholesterol transport
protein NPC1L1
(intestine) -
↓cholesterol
absorption
Diarrhea , Headache,
Myalgia
Hypercholestrolemia
Combined with
statins-synergistic
IIa
Bile Acid Binding
Resins
Cholestyramine
Colestipol
Colesevelam (no dug
interaction)
Bind to Bile acid-
interrupt
enterohepatic
circulation
↑excretion of bile in
feces
↑cholesterolbile
↓hepatic
cholesterol-↑LDL
receptor on
hepatocytes-
↑clearance of LDL
↓LDL
NE TG
Constipation,
Flatuence
Impaired fat soluble
vit absorption
↑gallstones
Hypercholesterolemia
Patients who cannot
tolerate other drugs
Delasy absorption
of Warfarin,
Digoxin,
Chlorothiazide
↑ LDL Statins
Fibrates
Ezetimibe
↑ TG Fibrates
Nicotinic Acid
ANTI-HYPERTENSIVES
Class Drugs Mechanism Features Effects Uses ADR Interactions/Contraindications
Renin inhibitors
β blockers Aliskrenin (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 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
ARB Losartan, Valsartan, Irbesartan
Competitive antagonist of AT-1 receptor
Inhibit angiotensin II No effect on bradykinin
No Cough (bradykinin metabolized)
Hypertension w/ cough (ACEI) Hypotension , Hyperkalemia, Teratogenic
Calcium Channel Blockers
Verapamil Block L-type channels Arteriolar vasodilation ↓coronary tone ↓myocardial O2 requirements ↓LV wall stress ↓HR Smooth Muscle Relaxation: Bronchiole, Uterine, GIT ↓Afterload only
Cardiac>vascular smooth muscle
↓AV nodal conduction: in Supraventricular Reentry tachycardia Atrial fibrillation-↓ventricular response Sympathetic blockade Typical Angina Atrial tachycardia/flutter/fibrillation Migraine
↓Ca2+ influx in heart Cardiac depression/arrest/failure ↓HR AV block
AV conduction abnormalities Overt Heart Failure Verapamil/Diltiazem + β blockerAV block↓ventricular function
Diltiazem
Cardiac=vascular smooth muscle ↓inotropy vs Verapamil
↓AV nodal conduction: in Supraventricular Reentry tachycardia Atrial fibrillation-↓ventricular response Sympathetic blockade Typical Angina Variant Angina Atrial tachycardia/flutter/fibrillation
↓Ca2+ influx in heart Cardiac depression/arrest/failure ↓HR AV block Constipation
Dihydropyridine
Nifedipine 1 gen Short acting
Reflex Sympathetic Stimulation: Reflex Tachycardia, BP swing MORTALITY in CAD
Cardiac<vascular smooth muscle
Less effect on AV nodal conduction Typical Angina Variant Angina Hypertension Pregnancy induced Hypertension
Reflex Sympathetic Stimulation: Reflex Tachycardia, BP swing MORTALITY in CAD ↑MI risk in hypertensive Vasodilation: flushing, headache, ankle edema, ↓BP Elderly: Urine retention
Unstable Angina: ↑ risk of adverse cardiac events
Amlodipine 2 gen HR, CO not affected
Can be used in overt heart failure
Direct Vasodilators
Hyadralazine/dihydralazine ↓TPR↓BPReflex sympathetics↑contractility, HR, O2 consump↑MI, angina, Heart failure (counteract: β blocker) ↑Renin↑salt&H2O retention (counteract: diuretic)
↓TPR↓diastolic BP
Arteries & Arterioles Moderate Hypertension Pregnancy Induced Hypertension
Lupus Syndrome ↓BP Palpitation ↑HR, Angina Fluid retention Edema
Sodium Nitroprusside Forms NO
Forms NO IV: T1/2 is small (2-5 min) continuous infusion ↓TPR&CO↓sys & dias BP
Arteries & Veins ↓BP Reflex tachycardia ↓Preload & Afterload
Hypertensive Emergencies
MetabolismCN_ ion Large dose: Toxicity+thiosulphateThiocynatekidneys excrete Light sensitive: protect from light
Dizoxide K channel opener
K channel opener IV Long 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 FAILURE
Class Drugs Source/Comment Mechanism Effects Uses ADRs & Antidote Interactions
Positive Inotrope
Cardiac Glycosides
Digoxin: Fast acting (15-30 mins) Commonly used ↓protein binding T1/2: 40 hrs Digitoxin: Slow onset Not commonly used ↑protein bound T1/2: 5-7 days
Foxgrove Plant Sugar Steroid Lactone 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:↓rate Atria:↓refractory period AV:↓conduction velocity ↑ refractory period Purkinje/Ventricle: ↓refractory period (slight) ECG: ↑PR,↓QT interval ↑venous tone Kidney: diuresis
Heart failure CHF + Atrial fibrillation Severe/Chronic CHF + LV systolic dysfunction Atrial flutter/fibrillation: ↓Av node conduction ↑AV node ERP
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
+ 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 receptor↑cAMPactivation of PK-Aphosphorylation of Ca channel↑Ca2+ flow into
↑CO ↓ventricular filling pressure
Acute Heart Failure Arrythmias Tachycardia
Less arrythmogenic & less tachycardia vs
cellmyofibrils↑contraction force
dopamine
Dopamine ↑BP Acute Heart Failure, raise BP
Phosphodiesterase Inhibitors
Amrinone Milrinone
PDE are enzymes that inactivate cAMP & cGMP PDE inhibitors: X PDE↑cAMP & ↑cGMP
Inotropic agent Vasodilation
Severe Heart Failure ↑Mortality Nausea, Vomiting Arrhythmias ↑Liver enzyme Thrombocytopenia
Vasodilators ACE inhibitors Enalapril Lisinopril
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 & morbidity Asymptomatic patients w/ LV dysfunction + no edema Symptomatic patients: ↓preload and afterload Hypertension MI Diabetic Nephropathy
First dose hypotension (post diuretics) Cough (↑bradykinin) Hyperkalemia Dysguesia, rashes, urticarial Acute Renal Failure; angioedema TERATOGENIC
Angiotensin Receptor Blocker
Losartan Valsartan Irbesartan Candesartan
No cough Block AT-1 receptor (angiotensin-2 receptor) No effect on ACEBradykinin metabolized
ACEI intoleration due to cough CHF: all stages Hypertension
Hypotension ↑K+ Angioedema TERATOGENIC: fetal damage
Nitrate Isosorbide Dinitrate
Venodilator Venodilator ↓preload
Dyspnea NOT FIRST LINE DRUGS Isosorbide dinitrate + hydralazine↓remodelling (africans)
Hydralazine Arteriole dilator Dilates arteriole↑CO ↑cGMP-smooth muscle
Arteriole dilator Patients w/ increased fatigue Antihypertensive-pregnancy + α methyl DOPA
Sodium Nitroprusside
Arteriole + Veno dilator
↑NO↑cGMP Arteriole + Veno dilator ↓afterload & ↓preload
CHF Hypertensive emergency
Diuretics Loop diuretics Furosemide Bumetanide Torsemide
↓venous pressure↓preload↓systemic pulmonary edema ↓cardiac size↑pump efficiency↑CO
CHF: FIRST LINE Furosemide/loop diuretic: Acute pulmonary edema, severe chronic failure Spirinolactone: Severe chronic heart failure, ↓morbidity &↓mortality
Hypokalemia: leads to digoxin interaction Hypervolemia Ototoxicity Hyperuricemia: Gout Metabolic alkalosis Hyperlipidemia
Thiazide diuretics
Chlorothiazide Hydrochlorothiazide
Aldosterone antagonist
Spirinolactone Eplerenone
β blockers Bisprolol Carvedilol Metoprolol
↓catecholamines: ↓HR↓symptoms ↓Myocyte apoptosis↓remodelling
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 BNP, IV continuous infusion Acute Heart Failure
Bosentan Endothelin receptor antagonist
Severe Pulmonary Hypertension
↑survival in CHF
ACEI, ARB, β blockers, spirinoloactone, hydralazine+nitrate
Stage A: High risk, No symptoms ↓Risk factors Treat: hypertension, hyperlipidemia, diabetes, obesity (ACEI/ARB for vascular disease)
Stage C: Structural disease, Symptoms ↓ Na, H20, Work Diuretics, ACEI, ARB Digitalis: systolic dysfunction + 3 HS/atrial fibrillation β blockers ( in stable class 2-4) Spirinolactone
Drugs causing CHF NSAID CCB Anti arrhythmic (some) Alcohol
Chronic Heart Failure
↓work, ↓Na & H20 ACEI or ARB Thiazide diuretic β blocker (in stable class 2-4) Digitalis (if systolic dysfunction/atrial fibrillation) Nitrate/hydralazine (vasodilator) Cardiac resynchronization (if wide QRS)
Acute Heart Failure Can be due to AMI Anemia, fever↑metabolic 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, β blockers)
Stage D: Refractory Symptoms ↓ Na, H20, Work Diuretics, ACEI, ARB Digitalis: systolic dysfunction + 3 HS/atrial fibrillation β blockers ( in stable class 2-4) Spirinolactone Cardiac resynchronization Cardiac transplant
SHOCK
Type of Shock Mechanism Treatment
Hypovolemic/Oligemic shock Low Volume
Internal & external fluid loss↓preload Hemorrhagic/Non Hemorrhagic Trauma Non traumatic: Vaginal, GI, GU Burns, Diarrhea Vomiting Diuresis, Sweating Third Space Loss: Pancreatic, peritonitis, bowel obstruction
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
Neurogenic shock Low 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↑MAP IV fluids for relative hypovolemia
Cardiogenic shock Pump Failure
Severe LV dysfunctionsystemic hypoperfusion MI, acute myocarditis
MI: Morphine,O2, nitroglycerine, aspirin, alteplase (fibrinolytic), metoprolol (β 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
Septic/Bacteremic/Endotoxic shock
Severe infection & tissue hypoperfusion GN (E coli)>GP (staph)
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)
Anaphylactic shock Histamine release & other mediators 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
Dopamine D1, D2, α1, β1 Low dose: 2 µg/Kg/minD1dilates renal vascular bed Moderate dose: 2-10 µg/Kg/minD1,β1+ve chronotropic & inotropic effect
Dobutamine β1 selective inotropic w/ afterload reduction(peripheral vasodilator)minimize cardiac O2 consumption Cardiogenic shock-pump failure due to MI
Norepinephrine α1, α2, β1 Strong vasoconstriction↑BP Shock w/ severe hypotension
Phenylephrine α1 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
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
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
Parenteral Fe
Iron Dextran IV/IM
Iron Sorbitiol-Citrate IM
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
ADRs Local: Pain Skin Pigmentation Sterile abscess Systemic: Fever, headache, joint pain, flushing Palpitation, chest pain, dyspnea LN enlargement Anaphylaxis Renal Disease- X Fe sorbitol
USES Fe deficiency anemia (treatment & prophylaxis) Megaloblastic anemia FeCl3-astringent in throat pain
↑MW IM(locally bound)/IV Not excreted Absorbed through Lymphatics Not transferrin bound Taken up by macrophagesslowly available to erythron
↓MW IM-Not locally bound 30 % excreted Absorbed through Circulation Transferrin bound Directly available
Fe overload
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
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
Hemopoetic GF Erythropoetin: peritubular cells of kidney↑RBC MCSF, GCSF↑WBC Thrombopoetin↑platelets Stem cell factor IL
Megaloblastic state
B12/Cobalamin deficiency: Gastric failure: Pernicious anemia Total gasterectomy Ileal failure: Crohn’s 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
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
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
DRUGS AFFECTING BLOOD ELEMENTS
Disease/Condition Causative Drugs/Causes Treatment/Therapeutic Drugs Adverse effects
G6PD-Hemolytic anemia
Antimalarials: Primaquine Chloroquine Fansidar Maloprim
Stop drug Treat underlying infections Severe anemiablood transfusion Hemoglobinuriamaintain good renal flowavert renal damage Neonatal jaundicephototherapy
Sulfonamides: Sulfacetamide Co-trimexazole Dapsone
Antibiotics: Chloramphenicol Furazolidone Niridazole Nalidixic acid Nitrofurantoin
Antidiabetics: Glibenclamide
Analgesics; High dose ASPIRIN
Vitamin K analogues Naphthalene
Immune Hemolytic Anemia
Penicillin-High Dose: Ab against drug-RBC complex
Stop Drug CORTICOSTEROIDS: PrednisoneFIRST LINE Azathioprine, Cyclosporin, Cyclophosphamideused when other measures fail Splenectomy Severe Cases: Blood Transfusions Folate
Quinidine Rifampin: Drug-ag-ab deposits complement on RBC surface
Methyldopa Fludarabine
Chemical AgentsHemolysis
Dapsone-High Dose Stop Drug Severe Anemia: Blood Transfusion
Wilson’s 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
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
Drugs: Anticancer: Busulphan Cyclophosphamide Anthracyclines Nitrosoureas
Idiosyncratic: Chloramphenicol Sulphonamide Gold
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
Neutropenia Anticancer Drugs: Alkylating agents-non selective neutropenia
General Treatment: Stop Drug Prevent & Treat infections: Bacterial Usually Can also be: Viral, Fungal, Protozoal
Antibiotics: Chloramphenicols Sulfonamides Co-trimexazole Cephalosporins
Antipsychotics: Chlozapine Chlorpromazine
Specific Treatment: GCSF GM-CSF Autoimmune Neutropenia: Corticosteroids & Splenectomy Rituximab: Anti CD-20 (Monoclonal Antibody)
Antithyroids: Carbimazole
Anti-Inflammatory: Phenylbutazone Gold Salts
Anti-Epileptic: Phenytoin Carbamazepine
Penicillamine Ticlopidine
Thrombocytopenia Bone Marrow Suppression: Anticancer, Ethanol Chloramphenicol, Co-trimoxozole, Arsenic
General Treatment: Blood Transfusion/Platelet Concentrates
Immune: Analgesics, Anti-inflammatory: Gold Salts Antibiotics: penicillin, trimethopterin, sulfonamides Antiepileptic: Diazepam, Carbamazepine Diuretics: Acetazolamide, Furosemide Antidiabetics: Chlorpropamide Digoxin, Heparin, Methyldopa, Quinidine
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)
Platelet Aggregation: Heparin
Erythropoetin:
Hb, Erythropoesis,
circulatory reticulocytes EPOETIN α, DARBOPOETIN α: IV, SC Uses: Anemia due to CRF/AIDS, cancer/drugs Anemia in premature babies Pre-Operationto
blood transfusions Adverse: Thrombosis,
BP
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
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 Class Drug Mechanism Uses Adverse Effects
Antimalarial Erythrocitic Schizonticide Chloroquine Degradation of RBC HB Fast & Long Acting
Prophylaxis & Cure of ALL types of Malaria Infectious Mononucleosis Rheumatoid Arthritis
toxicity; side effects GIT-A/N/V, epigastric pain
CVS: IV; BP; arrhythmia CNS: toxicity Eye: retinal damage Ear: Hearing Defects
Mefloquine Intermediate & Long Acting
Multidrug Resistant Plasmodium falciparum malaria
Not Parenteral Avoid in cerebral/complicate malaria Resistance
Quinine Multidrug Resistant malaria Cerebral malaria
+ Tetracycline=effect Nocturnal muscle cramps, varicose veins, myasthenia gravis
effective, toxicity than chloroquine Highly toxic8-10 g-fatal Cinchonism: CTZ damage, vomiting, tinnitus Hemolysis PregnancyAbortion
Sulfonamide (sulfamethopyrazine/sulfadoxine)+Pyremethamine (S/P)
Slow and Long acting Erythrocytic phase of P. falciparum Antifolate (like Cotrimoxazole)
P. falciparumcurative Toxoplasmosisfirst choice
SulfonamideSerious toxicityExfoliative dermatitis, Steven Johnson syndrome Not prophylactic Single Dose
Tetracyclines Weak & Slow acting
All Plasmodium species +Quinine or S/PChloroquine resistant Falciparum Doxycycline (100 mg/day): Second Line Prophylactic-Chloroquine resistant Falciparum malaria
X Pregnant, Lactating X Children <7 years NEVER USED ALONE
Blood Schizonticide Halofantrine Mefloquine like activity
Multidrug Resistant P. falciparum P. vivax Used when other drugs not working
GIT Ventricular Arrhythmia
Artemesinin Derivatives Artisunate: Water SolubleOral, IV, IM Artemether: Lipid Soluble Arteether: IM
Fastest and Short acting Prodrugs Damage ER & Protein synthesis in parasites Kills falciparum gametes
Multidrug Resistant Falciparum malaria treatment
+ enzyme inhibitors/anti-arrhythmic/anti-psychotic/anti-depressants arrhythmias Not useful in prophylaxis
Tissue/Liver Phase acting/Exoxryhtrocytic
Primaquine Effective against Gametocytes & Hypnozoites
Prevent & Cure malaria relapse
GIT G6PD: hemolysis
Filariasis Diethyl Carbamazine Selectively Filariasis GIT
sensitize microfilariae for phagocytosis
Tropic Pulmonary Eosinophilia
Fever, Rash LN enlargement
Leishmaniasis Sodium Stibogluconate Inhibits –SH dependant enzymes of parasite
Kala Azar (L. donovanii) N/V, abdominal pain Pancreatitis Kidney & Liver Damage
Trypanosomiasis Pentamidine Inhibits topoisomerase 2 & aerobic glycolysis
Trypanosomiasis Leishmaniasis AIDS patients: Pneumocystis jiroveci pneumonia
Highly Toxic Strong alkaline naturereleases Histamineanaphylaxis Heart, Liver, Kidney damage
Trypanosoma cruzi Nifurtimox/Benznidazole-Acute disease Chaga’s disease
Trypanosom gambiense/rhodensiense
Early disease: IV suramin Late 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 malaria Prevent clinical attacks Proguanil: P. falciparum Primaquine: all malarial species
Suppressive Prophylaxis: Erythrocytic Phase suppressionprevents malarial fever Clinical symptoms suppressed; exoerythrocytic phase not affected Chloroquine: 300mgx2tabs/wk; 1wk before & 1 month after endemic area return Resistant cases: Proguanil 200 mg daily + Chloroquine 300 mg weekly Mefloquine 250 mg weekly-4wks after endemic area return Doxycycline 100 mg 1day before to 4 weeks after endemic area return
Clinical cure: terminate episode of malarial fever Erythrocytic Schizonticides Fast acting High efficacy: used alone Chloroquine, Mefloquine, Quinine, Amodiaquine, Halofantrine, Lumefantrine, Artemesinine, Atovaquone. Slow acting Low efficacy: used in combination Proguanil, Sulfonamides, Pyrimethamine, Tetracycline
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
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
Radical Cure: total eradication of parasite from body Exo-Erythrocytic drugs + Erythrocytic drugs = total cure P. falciparum & P. malariae: clinical cure=erythrocytic schizonticides=erythrocytic parasite elimination is enough. No exoerythrocytic phase P. vivax & P. ovale: Relapsing malariaerythrocytic & exoerythrocytic/hypnotic parasite elimination Exo-Erythrocytic drugs + Erythrocytic drugs
Falciparum Malaria: Chloroquine sensitive: Chloroquine + Primaquine (gametocidal) Chloroquine resistant: -Artesunate +Sulfadoxine+pyrimethamine (S/P)+Primaquine -Artesunate + Mefloquine
Multi Drug Resistant Falciparum Malaria: Uncomplicated Acute Multidrug Resistant Falciparum Malaria: ACT-Artemesinine based Combination Therapy Artemesinine + Erythrocytic
Vivax Malaria: Chloroquine sensitive: Chloroquine + Primaquine Chloroquine 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 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
ANTIRETROVIRALS
Class Drugs Mechanism Uses Adverse Effects Resistance
Nucleoside & Nucleotide Reverse Transcriptase Inhibitor
Zidovudine (AZT) Deoxythymidine Analog AZTThymidine KinaseTriphosphate form Competitive Inhibition of dTTP for Reverse Transcriptase Enzyme Causes Chain Termination
IV & Oral HIV 1, HIV 2, HTLV
HIV treatment: progression &
survival Prevents Mother to Child HIV transmission
Myelosuppression: Neutropenia, Anemia GI intolerance: N/V Headaches, Insomnia Crosses BBB Metabolite in urine
Mutations in reverse transcriptase gene Prolong therapy & Monotherapy
Stavudine Thymidine Analog Peripheral Neuropathy Lipidystrophy
Didanosine Synthetic Deoxyadenosine Analog
Pancreatitis Peripheral Neuropathy D/N/V Abdominal Pain
Zalcitabine Cytosine Analog Peripheral Neuropathy N/V Headache
Lamivudine Cytosine Analog
Abcavir Guanosine Analog More effective
Fatal Hypersensitivity
Non-Nucleoside Reverse Transcriptase Inhibitors
Nevirapine Binds to Viral Reverse TranscriptaseRNA & DNA dependent DNA polymerase blockade Substrate & Inhibitors of CYP3A4 Do not compete w/ nucleoside triphosphates Do not require Phosphorylation
Prevents HIV transmission from mother to neonate at labor/delivery
Delavirdine
Efavirenz TERATOGENIC
Protease Inhibitors Indinavir Protease: Cleaves large precursor polyprotein moleculefunctional componenets Inhibit Protease (late step in replication) prevent spread of infection
Nephrolithiasis Lipidystrophy: Abdominal Obesity, Buffalo Hump, Limb & Face wasting Dyslipidemia GI intolerance Dizziness Numbness Rashes Headache Limb & Facial tingling Asthenia Hyperlipidemia Insulin resistance
Ritonavir Fatigue Inhibits CYP3A4
Squavinavir Photosensitivity
Nelfinavir
Amprenavir
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
THROBOLYTICS, ANTITHROMBOTICS AND COAGULANTS
Class Drug Description Action Uses ADR Contraindications
Thrombolytics / Fibrinolytics Streptokinase Non enzymatic protein β hemolytic streptococci Proactivator plasminogen complexcatalyzes formation of plasmin
AMI: Thrombolytic Therapy-w/in 6 hrs of symptoms Peripheral Arterial Thrombosis Catheter & Shunt patency PE + Hemodynamic Instability Severe DVT Acute Ischaemic Stroke: rTPA w/in 3 hrs of symptoms Peripheral 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 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 Enzyme-Human urine Cultured Human Renal CellsNon-Antigenic Potent Direct Plasminogen Activator
Non Antigenic
Recombinant Tissue Plasminogen Activator: Alteplase Duteplase Reteplase
rDNA technology Expensive
Better than streptokinase & urokinase in dissolving older clots Does not act on circulating plasminogen Non 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 plasminogen
Thrombolytic Activity
Allergies
Bleeding Hypotension-Kinins
Anti-Coagulant (AntiThrombotic)
Parenteral Anticoagulant
Indirect Thrombin Inhibitor
Unfractionated Heparin (UFH) MW: 5000-30,000
Sulfated Mucopolysaccharide IV/SC Not given IMhematoma formation Immediate onset 4-6hrs Monitor: aPTT = 2-2.5 control
HeparinActivates Anti Thrombin 3 (AT-3)Inhibits Factors 2a (Thrombin), 9a, 10a
Bleeding time
Clotting time
aPTT Inhibits Coagulation InVivo & InVitro Inhibits Aldosterone Secretion
DVT & PE:
Prophylaxis-for bed rest, high risk surgeries, Cancer- Low 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 Surgery-CNS, 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
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
Prevention of DVT, PE Cannula patency in Dialysis patients
Fondaparinaux Anti Thrombin 3 mediated selective inhibition of Factor 10a No effect on Thrombin (2a) SC Long T1/2: 15 hrs
PE, DVT HIT AMI
Direct Thrombin Inhibitor
Hirudin/Lepirudin (Bivalent DTI) Specific irreversible Thrombin Inhibitor
Hirudin: Leech Saliva Lepirudin: recombinant form
Directly bind to active site of Thrombin
HIT Anaphylaxis
Bivalirudin (Bivalent DTI)
Coronary Angioplasty
Argatroban (Univalent DTI)
HIT Coronary Angioplasty in HIT patients
Oral Anticoagulant
Vitamin K Antagonist
Warfarin Inhibits Vit K EpoxideVit K Hydroquinone (active form) Inhibits synthesis of Vit K dependent Factors 2,7,9,10 (TENS)
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
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: Synergism-impaired
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
Phenindione Hypersenstivity
Direct Thrombin Inhibitor
Dabigtaran No routine INR monitoring required Fewer 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 Heparin
AntiPlatelet Prostaglandin Synthesis Inhibitors
Aspirin Inhibits COX & Thromboxane Synthase Irreversibly
TXA2 synthesis in Platelets
Bleeding Time in
MI Prophylaxis Unstable Angina Cerebrovascular Disease
Arterial Thrombus-White Thrombus Prevent Reinfarction in
vivo Low Dose: 75-100 mg Platelets exposed to aspirincannot synthesize new enzyme
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 Clopidogrel Ticlopidine
Inhibits Platelet Aggregation (ADPCa2+ (2nd messenger)Gp 2b/3a active)
Blocks ADP Receptor (P2Y12) ADPplatelet aggregation ADP-RBinhibits aggregation
Aspirin Intolerant Patient Transient Ischemic Attacks Stroke, Unstable Angina Coronary Stent
Nausea, Diarrhea, Leukopenia Thrombocytopenic Purpura Clopidogrel: Less ADR, Safer
Glycoprotien 2b/3a Receptor Inhibitor
Abciximab Chimeric Monoclonal Antibody
Chimeric Monoclonal Antibody against Gp 2b/3a receptor
PCI AMI/Acute Coronary Syndromes
Eptifibatide Tirofiban
Parenteral Occupies ReceptorInhibits Ligand Binding
PDE Enzyme inhibitor Dipyridamole Weak effect on Platelet Aggregation
Inhibits Platelet PDE enzyme
cAMPPGI2 Weak effect on Platelet Aggregation
+Aspirincerebrovascular ischemia +WarfarinArtificial Heart Valves
Prasugrel Platelet Inhibition Platelet Inhibition Better Than Clopidogrel Platelet Inhibition
ischemic events Thrombolysis in AMI
Ticagrelor Oral, reversible Direct Inhibitor of ADP Receptor (P2Y12) Reversible
Fibinolytic Inhibitors / Antifibrinolytics
Amino Caproic Acid Treat Overdosage of Fibrinolytics Hemophilics: Limit excessive bleeding after Surgery Prevent recurrence of SubArachinoid Hemorrhage Abruptio Placenta, Post-Partum hemorrhage, Menorrhagia
Tranexaemic Acid Oral
7 x more potent than ACA
Aprotinin CABG Surgery: Blood Loss
Protamine Sulphate 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
Coagulants Vitamin K K1-Phytonadione-Fat soluble-Plants K2-Menaquinone-Bacteria K3-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 Factors Newborn Warfarin Overdose: Phytonadione
Toxicity: BP, Flushing Menodione: Kernicterus in Newborns-Treat by Phytonadione
Plasma Fractions Factor 8 Anti-Hemophilic Factor
Treat Hemophilia A
Prothrombin Complex Concentrates Factor 9 Complex
Treat Hemophilia B (Factor 7 deficiency)
Factor 7a Liver Disease, Blood Loss Factor 7 deficiency
Cryoprecipitate Fibrinogen
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 Acquired- Primary-AI destruction of erythroid precursors Secondary: -Thymic tumor-thymoma -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: Perl’s stain: =
Hepcidin: caused by IL1 & TNF
Iron Deficiency Anemia: Microcytic Hypochromic
MCV:
MCH:
Hb:
RBC:
Serum Fe:
TIBC:
Hereditary Spherocytosis: AD
Hb: Reticulocytosis: 5-20% 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
Anemia, cyclic fevermerozoites lyse RBC & get released Cerebral Malaria: falciparum-aggregates of RBCs occlude capillaries Relapse: hypnozoites- Vivax Ovale
Toxoplasma gondii Congenital Toxoplasmosis Toxoplasmosis
Cat-definitive host Humans: intermediate host
Infective: Ocysts from cat feces/raw meat transplacental
Oocystcat ingests tachyzoitestissue bradyzoites/oocysts
Trophozoites: Brain, eye, Liver Tissue Cysts-enlarge & cause symptoms Encephalitis in AIDS patients: impaired CMI
Trypanosoma cruzii Chaga’s Disease Reduviid Bug Infective: Trypomastigotes Diagnostic: Trypomastigotes/ Amastigotes
Blood meal Trypomastigotes Reduviid Bug Midgut: Epimastigotes Hind gut: Trypomastigotes defecated –human amastigotes trypomastigotes
Myocarditis: amastigotes kill myocytes Neuronal Damage: Megacolon, Megaoesophagus
Trypanosoma Brucie: Gambiense & Rhodensie
African Tryposomniasis: Sleeping Sickness
Tsetse Fly-both sexes Gambiense: west Africa-Human Rhodensie: east Africa-Animal-antelope
Infective: metacyclic trypiomastigotes Diagnostic: trypomastigotes
Blood meal Trypomastigotes Midgut: epimastigotes (procyclic) salivary glands: trypomastigotes (metacyclic) Blood stream
Trypomastigottes infect braindemyelinatin Encephalitis Cervical LN’opathy winterbottom’s sign
Leishmania donovanii
Kala- Azar Visceral Leishmaniasis
Sandfly- Phlebotomus, Lutzomyia Animal: Dog, small carnivores, rodents Human: India
Infective: Promastigotes Diagnostic: Amastigotes
Blood Meal Amastigotes Midgut: promastigotes Migrate to pharynx/proboscis human: macrophages Amastigotes
Kill RE cells Liver, 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
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