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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
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Receptor definition
- gives biological response when bound by a drug
- plasma proteins: inert binding sites, not receptor
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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
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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
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vd values (wt=70 kg)
- plasma volume= 3l
- total blood volume= 5l
- ECF= 12-14l
- TBW= 40-42l
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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
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Biotransformation definition
- simply drug metabolisn
- conversion from lipid soluble form to more water soluble forms that are readily excreted
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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
-
produrg
- antimetabolites, inactive as given
- need metabolism to convert to active form
-
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
-
Phase II reactions
involve trasferase enzymes for conjugation with endogenous compounds
-
Glucuronidation
- enzyme glucuronysyl transferase
- reduced activity in neonates-- chloramphenicol toxicity--- Gray baby syndrome
- Gilbert and Crigler-Najjar syndromes
-
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
-
Glutathione conjugation
depletion in acetaminophen hepatotoxicity
-
Pearmeation
- solubility
- concentration gradient
- suface area and vascularity
- ionization- 80% of drugs
-
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
-
Weak acids and weak bases
- Weak acids: aspirin, penicillins, cephalosporins, loop diuretics, thiaziddes
- Weak bases: morphine, local anesthetics, amphetamine, PCP
-
Body pHs
- stomach- 1 to 2
- sm int- 6
- blood- 7.4
- urine- 5 to 8
-
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)
-
Lactulose in HE
converted to Lactic acid by gut bacteria-- ammonia acidified to ammonium ion-- excreted
-
Absorption
- entry of a drug from site of administration to systemic circulation
- iv route does not involve absorption-- 100 % bioavailability
-
fastest route of absorption
inhalation
-
lag time
time from first administration to first molecule appears in plasma
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MEC
point at which pharmacologic effect of drug is first seen
-
Bioavailability
- f= AUC(po route)/ AUC(iv route)
- auc- area under curve
- f= fraction of dose that reaches systemic circulation
-
factors affecting bioavailability
first pass metabolism/effect- liver
-
Elimination
termination of action
-
major modes of elimination
- biotransformation into inactive metabolites
- excretion via kidneys
-
half life
time to eliminate 50 % of a given amount or time to decrease to 50 % of former levels
-
zero order elimination
- constant amount of drug is eliminated per unit time
- no fixed half life
- ex: phenytoin, aspirin, ethanol
- @Zero PEAsP act as zero order at high therapeutic or A toxic doses except ethanol
-
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
-
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)
-
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
-
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
-
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
-
Goal of administering a drug is
to keep concentrations between MEC and Minimal Toxic Concentration (MTC)
-
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
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Antiaahythmics classes
- Class I: Na channel blockers
- ClassII: Beta blockers
- Class III: Potassium channel blockers
- Class IV: Calcium channel blockers
- Unclassified: Adenosine, Magnesium
-
Class Ia
- Drugs: Quinidine, Procainamide, Disopyramide
- MOA: Block activated Na channel, Increase APD and ERP
-
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
-
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
-
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
-
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
-
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.
-
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
-
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
-
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
-
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
-
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
-
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.
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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
-
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.
-
T/t of torsades
- correct hypokalemia
- correct hypomagnesemia
- discontinue drugs that prolong QT interval
-
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
-
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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