Pharmacology

• 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

• gives biological response when bound by a drug
• plasma proteins: inert binding sites, not receptor

• 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

• 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

• plasma volume= 3l
• total blood volume= 5l
• ECF= 12-14l
• TBW= 40-42l

• 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

• simply drug metabolisn
• conversion from lipid soluble form to more water soluble forms that are readily excreted

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

• antimetabolites, inactive as given
• need metabolism to convert to active form

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

involve trasferase enzymes for conjugation with endogenous compounds

• enzyme glucuronysyl transferase
• reduced activity in neonates-- chloramphenicol toxicity--- Gray baby syndrome
• Gilbert and Crigler-Najjar syndromes

• 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

depletion in acetaminophen hepatotoxicity

• solubility
• concentration gradient
• suface area and vascularity
• ionization- 80% of drugs

• 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: aspirin, penicillins, cephalosporins, loop diuretics, thiaziddes
• Weak bases: morphine, local anesthetics, amphetamine, PCP

• stomach- 1 to 2
• sm int- 6
• blood- 7.4
• urine- 5 to 8

• Acidification: NH4CL, vitamin C, cranberry juice-- increases elimination of weak bases (amphetamine)
• Alkalinization: NaHCO3, acetazolamide (historically)-- increases elimination of weak acids (aspirin)

converted to Lactic acid by gut bacteria--  ammonia acidified to ammonium ion-- excreted

• entry of a drug from site of administration to systemic circulation
• iv route does not involve absorption-- 100 % bioavailability

inhalation

time from first administration to first molecule appears in plasma

point at which pharmacologic effect of drug is first seen

• f= AUC(po route)/ AUC(iv route)
• auc- area under curve
• f= fraction of dose that reaches systemic circulation

first pass metabolism/effect- liver

termination of action

• biotransformation into inactive metabolites
• excretion via kidneys

time to eliminate 50 % of a given amount or time to decrease to 50 % of former levels

• 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 A toxic doses except ethanol

• 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

• 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)

• 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

• 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

• 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

to keep concentrations between MEC and Minimal Toxic Concentration (MTC)

• 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

• Class I: Na channel blockers
• ClassII: Beta blockers
• Class III: Potassium channel blockers
• Class IV: Calcium channel blockers
• Unclassified: Adenosine, Magnesium

• Drugs: Quinidine, Procainamide, Disopyramide
• MOA: Block activated Na channel, Increase APD and ERP

• 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

• 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

• 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
• 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

• 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.

• 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

• 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

• 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

• 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

• 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

• 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.

• 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

• 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.

• correct hypokalemia
• correct hypomagnesemia
• discontinue drugs that prolong QT interval

• Atrial fibrillation
• t/t: 2 primary goals
• ventricular rate control-- beta blockers, CCBs, digoxin
• Anticoagulation

A fib threats: Embolism, may lead to VT

• Do: block accessory pathway with class Ia or III
• Do not: slow AV condition-- avoid digoxin, beta blockers, CCBs, adenosine