1. apparent volume of distribution (vd)
    • vd= dose/c0; amount of drug in the body/ plasma drug concentration at zero time
    • vd low-- high % of drug bound to plasma proteins
    • vd high-- high % of drug sequestered in tissues-- raises the possiblility of displacement by other agents; ex- verapamil and quinidine can displace digosin form tissue binding sites enhancing digoxin toxicity
    • vd contributes to half life of a drug, vd change = t1/2 change
  2. Receptor definition
    • gives biological response when bound by a drug
    • plasma proteins: inert binding sites, not receptor
  3. Competition between drugs for the plasma protein binding sites may increase the free fraction, possibly enhancing the effects of the drug displaced. Examples?
    • Sulfonamides and bilirubin in neonates 
    • sulfonamides and warfarin: sulfonamides replace warfarin from protein binding sites causing higher plasma levels of free drug and thus bleeding
  4. Features of safer drug in pregnancy
    • water soluble
    • large molecule
    • protein bound
    • ex: PTU vs Methimazole: PTU is highly protein bound and DOC in hyperthyroidism in pregnancy-- methimazole causes cretinism
    • Phenobarbital: highly protein bound-- phenytoin, valproate, caebamazepine cross placental barrier and are teratogenic

    if a drug can cross BBB, it can easily cross placenta-- Lithium, ethanol
  5. vd values (wt=70 kg)
    • plasma volume= 3l
    • total blood volume= 5l
    • ECF= 12-14l
    • TBW= 40-42l
  6. Redistribution
    • Lipid soluble drugs redistribute into fat tissues prior to elimination
    • CV: thiopental-iv anesthetic; reaches brain <1min, short duration of action; has a half life: 9 hrs--- goes into brain, comes out of brain quickly, redistributed in the fat, no effect but longer half life.
    • repeated doses can saturate the fat and increase duration of action of drug
  7. Biotransformation definition
    • simply drug metabolisn
    • conversion from lipid soluble form to more water soluble forms that are readily excreted
  8. cyt p450
    inducers: Phenobarbital, phenytoin, carbamazepine, rifampicin, chronic alcohol

    inhibitors: Cimetidine, macrolides(esp erythromycin; excepting azithromycin), ketoconazole, protease inhibitors "navirs", acute alcohol, grapefruit juice

    POI: grapefruit juice also inhibits metabolism of statins (atorvastatin), thus increasing their serum levels and enhancing toxicity
  9. produrg
    • antimetabolites, inactive as given
    • need metabolism to convert to active form
  10. Non- microsomal metabolism
    hydrolysis: local anesthetics, genetic polymorphism exsists with pseudocholinesterase-- increases levels of SCh

    • monoamine oxidase: metabolize amine neurotransmitters;
    • endogeneous amines- dopamine, NE, serotonin;
    • exogenous amines- tyramines found in beer, red wine, cheese, fish

    alcohol metabolism: by dehydrogenases
  11. Phase II reactions
    involve trasferase enzymes for conjugation with endogenous compounds
  12. Glucuronidation
    • enzyme glucuronysyl transferase
    • reduced activity in neonates-- chloramphenicol toxicity--- Gray baby syndrome
    • Gilbert and Crigler-Najjar syndromes
  13. Acetylation
    • fast and slow metabolizers (people)
    • Drug induced SLE by slow acetylators; also possible with hydralazine, procainamide, isoniazide
    • Antihistone antibodies typical of drug induced SLE, also symptoms go away with stopping of drug
  14. Glutathione conjugation
    depletion in acetaminophen hepatotoxicity
  15. Pearmeation
    • solubility
    • concentration gradient
    • suface area and vascularity
    • ionization- 80% of drugs
  16. pKa
    • pH at which a drug is half ionized and half non-ionized
    • ionized form is water soluble-- excreted
    • non-ionized form is lipid soluble-- cross membranes, act on body
    • only 

    • only free unbound drugs, both ionized or non-ionized are filtered
    • but only non ionized forms undergo active secretion and passive reabsorption
  17. Weak acids and weak bases
    • Weak acids: aspirin, penicillins, cephalosporins, loop diuretics, thiaziddes
    • Weak bases: morphine, local anesthetics, amphetamine, PCP
  18. Body pHs
    • stomach- 1 to 2
    • sm int- 6
    • blood- 7.4
    • urine- 5 to 8
  19. To change urinary pH
    • Acidification: NH4CL, vitamin C, cranberry juice-- increases elimination of weak bases (amphetamine)
    • Alkalinization: NaHCO3, acetazolamide (historically)-- increases elimination of weak acids (aspirin)
  20. Lactulose in HE
    converted to Lactic acid by gut bacteria--  ammonia acidified to ammonium ion-- excreted
  21. Absorption
    • entry of a drug from site of administration to systemic circulation
    • iv route does not involve absorption-- 100 % bioavailability
  22. fastest route of absorption
  23. lag time
    time from first administration to first molecule appears in plasma
  24. MEC
    point at which pharmacologic effect of drug is first seen
  25. Bioavailability
    • f= AUC(po route)/ AUC(iv route)
    • auc- area under curve
    • f= fraction of dose that reaches systemic circulation
  26. factors affecting bioavailability
    first pass metabolism/effect- liver
  27. Elimination
    termination of action
  28. major modes of elimination
    • biotransformation into inactive metabolites
    • excretion via kidneys
  29. half life
    time to eliminate 50 % of a given amount or time to decrease to 50 % of former levels
  30. zero order elimination
    • constant amount of drug is eliminated per unit time
    • no fixed half life
    • ex: phenytoin, aspirin, ethanol
    • @Zero PEAs
    • P act as zero order at high therapeutic or toxic doses except ethanol
  31. first order elimination
    • constant fraction of drug is eliminated per unit time
    • t1/2 is a constant, inversely  related to elimination constant(k)
    • t1/2=0.7/k
  32. clearance
    • volume of drug cleared of drug per unit time
    • constant in first order kinetics
    • Cl= GFR (when no reabsorption or secretion and no plasma protein binding)
    • Cl= GFR* free fraction (non- protein bound drug)
  33. Steady state
    • rate in=rate out
    • when values associated with a dosing interval are the same as those in succeeding interval
    • to achieve SS is goal of maintenance dose equations
  34. plateau principle
    • time to reach steady state is dependent only on elimination half-life of a drug
    • it is independent of size of dose and frequency of administration
  35. time and steady state
    • 50% : 1 half life
    • 90% : 3.3 half lives
    • 95% : 4-5 half lives (clinical)
    • 100% : >7 half lives (mathematical)

    • 4-5 half lives to reach clinical steady state (clinical relevance)-- how long does it take a drug to reach steady state?
    • >7 half lives to reach mathematical steady state
  36. Goal of administering a drug is
    to keep concentrations between MEC and Minimal Toxic Concentration (MTC)
  37. Pharmacokinetic calculations
    • vd= dose/ c0
    • t1/2= 0.7* vd/cl

    • infusion rate(k0)= Cl* Css
    • LD= (Vd*Cp)/ f
    • MD= (Cl*Css*tau)/ f
    • tau: dosind interval; bd, tds, qid
    • Cp: target plasma concenteration
  38. Antiaahythmics classes
    • Class I: Na channel blockers
    • ClassII: Beta blockers
    • Class III: Potassium channel blockers
    • Class IV: Calcium channel blockers
    • Unclassified: Adenosine, Magnesium
  39. Class Ia
    • Drugs: Quinidine, Procainamide, Disopyramide
    • MOA: Block activated Na channel, Increase APD and ERP
  40. Quinidine
    • causes muscarinic receptor block-- increase HR and AV conduction
    • causes alpha receptor block-- hypotension and reflex tachycardia
    • use-- many arrhythmias, need initaial digitalization with atrial fibrillation
    • (DI: replaces digoxin from tissue binding sites enhancing digoxin toxicity)
    • Adverse effects-- cinchonism; hypotension, torsades
  41. Procainamide
    • less muscarinic receptor block
    • metabolized via acetylation with N-acetyltransferase to N-acetylprocainamide (active metabolite)
    • ADR-- SLE-like syndrome in slow acetylators, hematotoxicity (thrombocytopenia, agranulocytosis), torsades
  42. Class Ib
    • Drugs: Lidocaine, Mexiletene, Tocainide
    • MOA: Blocks inactivated sodim channels thus results in increased threshold for excitation and less excitability of hypoxic heart muscle. 
    • preference for tissues partly depolarized (slow conduction in hypoxic and ischemic tissues)
    • decreased APD d/t clock of "slow Na window current" but this increases diastole and extends time for recovery; also improves filling and thus CO in a failing heart
  43. Lidocaine and Mexiletene
    • Lidocaine
    • use-- Post-MI, digoxin-toxicity induced ventricular arrhythmias, open heart surgery
    • S/E-- CNS toxicity(seizures), least cardiotoxic of conventional antiarrhythmics
    • only IV use in arrhythmias, because of first pass metabolism

    • Mexiletene
    • Same as lidocaine 
    • oral formulations available
  44. Class Ic
    • Drugs: Flecainide
    • MOA:Blocks all types of sodium channel
    • Lethal drug, only used as last resort when all drugs have faile to control arrhythmias
    • No effect on APD, No ANS effects
    • S/E-- proarrhythmogenic, increased sudden death post-MI when used prophylactically in VT.
  45. Class II
    • Drugs: Propanolol (non-selective), Acebutolol and Esmolol (selective)
    • MOA: prevent beta receptor activation, decrease SA and AV nodal activity (PANS predominant), decrease slope of phase 4 (pacemaker potential), thus prolong APD and ERP in slow fibers
    • Use-- Post-MI--propranolol used prophylactically  d/t its negative ionotropic effect (decrease O2 demand), all three in supraventricular tachycardias
  46. Class III
    • Drugs: Amiodarone, Sotalol
    • MOA: Decrease delayed rectifier potasiium current in both fast and slow fibers, slowing phase 3 of AP (repolarization, thus increase APD and ERP esp in His-Purkinje and ventricular fibers
  47. Amiodarone
    • mimics classes I, II, IV
    • increased APD and ERP in all cardiac tissues
    • Use: any arrhythmia
    • t 1/2: >80 days
    • binks excessively to tissues, large Vd and multiple effects
    • S/E: pulmonary fibrosis (acts as hapten- 45 % cases), phototoxicity, corneal deposits, hepatic necrosis, thyroid dysfunction (hypo /hyper depending on iodine-5 % cases), torsades
  48. Sotalol
    • Non-selective beta blocker, beta 1 blockade leads to decreased HR and AV conduction
    • also decreases I(K), slowing phase 3 of AP
    • Use--life threatening ventricular arrhythmias
    • s/e-- torsades
  49. Class IV
    • Drugs: Verapamil and diltiazem, NOT --dipines
    • MOA: block Ca++ channels in slow fibers, decrease phase 0 and phasse 4, decrease SA and AV nodal activity
    • Use-- supraventricular tachycardias
    • S/E-- constipation with verapamil, potential AV block
    • D/I: additive with beta blockers, digoxin-- increases risk of AV block
    • verapamil displaces digoxin from tissue binding sites enhancing digoxin toxicity
  50. Unclassified drug--Adenosine
    • MOA: activates adenosine receptors -- causes Gi coupled decrease in cAMP-- decreases SA and AV nodal activity
    • Uses: DOC for PSVT and AV nodal arrhythmias
    • IV administration
    • t 1/2: <10 seconds
    • S/E: dyspnea (Gq coupled receptor for adenosine in bronchioles cause profound bronchoconstriction--no risk d/t very very short half life), maycause sedation, flushing
    • D/I: antagonized by theophylline and caffeine 

    note: Theophylline is used in COPD. it antagonizes adenosine in decresing nodala ctivity and may precipitate VT by increasing AV nodal activity.
  51. Drugs that cause torsades:
    • Any drug that decreases potassium efflux from cell causing prolonged depolarization may precipitate torsades.
    • ECG: widened QRS complex and prolonged QT interval
    • Drugs:
    • Potassium channel blockers- amiodarone, sotalol
    • Muscarinic blockers like
    • Atropine
    • Quinidine
    • Meperidine
    • Amantadine
    • Antipsychotics-Thiaridazone
    • Tricyclic antidepressants
    • Antihistamines
  52. Long QT syndrome
    • familial condition that may result from a mutation in the gene encoding cardiac potassium channels
    • in such patients class iA and class III drugs increase the risk of torsades, along with all other that are potential of torsades.
  53. T/t of torsades
    • correct hypokalemia
    • correct hypomagnesemia
    • discontinue drugs that prolong QT interval
  54. Commonest arrhythmia
    • Atrial fibrillation
    • t/t: 2 primary goals
    • ventricular rate control-- beta blockers, CCBs, digoxin
    • Anticoagulation

    A fib threats: Embolism, may lead to VT
  55. Wolff- Parkinson-White Syndrome
    • Do: block accessory pathway with class Ia or III
    • Do not: slow AV condition-- avoid digoxin, beta blockers, CCBs, adenosine
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