pharmacokine tics

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    Pharmacokine

    tics

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    Component Processes

    Absorption entry of a drug from its site ofadministration to the systemic circulation

    Distribution process by which a drug entersthe interstitium or tissues from the blood

    Metabolism / Biotransformation processes bywhich a drug is changed: to its active form or toits removable form

    Excretion removal of the drug from the body

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    Drug

    Absorption into Plasma

    Distribution to

    Tissues

    Bound Drug

    Free Drug

    Tissue

    StorageSites of

    Action

    Drug Metabolism: Liver, Lung,

    etc

    Drug Excretion: Renal, Biliary,

    etc.

    Drug Biodisposition

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    Permeation

    Permeation travel of a drug acrosscellular membranes, influencing itsbiodisposition; is dependent on:Solubility

    Ionization

    Concentration gradient

    Surface area

    Tissue vascularity

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    Solubility Lipid solubility - ability to diffuse through lipid

    bilayers

    Water solubility in aqueous phases Partition Coefficient: The ratio of lipid solubility to

    aqueous solubility. The higher the partitioncoefficient, the more membrane soluble is thesubstance.

    Ionization

    Drugs are weak acids or weak bases, & can exist innonionized or ionized forms in an equilibrium,depending on pH & pKa. The HendersonHasselbalch equationdetermines the percentageof ionization (ionized water-soluble; nonionized lipid-soluble) Ionization increases renal clearance of drugs

    Concentration gradient diffusion is down aconcentration gradient

    Surface area the larger the surface area, the betterthe permeation

    Tissue vascularity the better the vascularity, thebetter the permeation

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    AbsorptionPassive diffusion most commonAqueous diffusion: Ficks Law:

    Flux (J) = (C1 C2) x S.A. x P.coefficientThickness J = molecules per unit time C1= higher concentration C2 = lower concentration

    S.A. = surface area available for diffusion P. Coefficient = permeability coefficient / partition

    coefficient Thickness = length of the diffusion path

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    Absorption

    Lipid diffusion: the HendersonHasselbalch equation

    log (protonated / unprotonated) = pKa pH

    *for acids: pKa = pH + log x concentration [HA] unionizedconcentration [A]

    *if [A] = [HA], then pKa = pH + log (1); log (1) = 0, so

    pKa = pH

    *for bases: pKa = pH + log x concentration [BH+] ionizedconcentration [B]

    *if [B] = [BH+], then pKa = pH + log (1); log (1) = 0, sopKa = pH

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    weak Acids & weak Bases

    A weak acid is a neutral molecule that dissociatesinto an anion & a proton (H+) so that itsprotonated form is neutral, more lipid-soluble

    A weak base is a neutral molecule that can form a

    cation by combining with a proton so itsprotonated form is charged, water-soluble

    weak acids pKa weak bases pKa

    Phenobarbital 7.1 Cocaine 8.5

    Pentobarbital 8.1 Ephedrine 9.6

    Acetaminophen 9.5 Chlordiazepoxide 4.6

    Aspirin 3.5 Morphine 7.9

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    Diffusion

    Aqueous diffusionwithin large aqueous

    compartments

    across tight junctions

    across endothelium thru pores(MW20,000 - 30,000)

    molecules tend to move from anarea of higher to an area oflower concentration

    plasma protein-bound drugscannot permeate thru aqueouspores

    charged drugs will be influencedby electric fields

    Lipid diffusionhigher partition coefficient =

    easier for a drug to enter lipidphase from aqueous

    charged drugs difficulty indiffusing thru lipid

    uncharged lipid-soluble lower pH relative to pKa,

    greater fraction of protonateddrug (protonated form of anacid is neutral; protonatedform of a base is charged)

    A weak acid at acid pH & a

    weak base at alkaline pH willbe more lipid-soluble

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    Special Carriers

    Facilitated diffusion passive (no E expended)carrier-mediated transport.saturable;subject to competitive & non-competitive inhibition

    used by peptides, amino acids, glucose

    Active (uses E) carrier-mediated transportsaturablesubject to competitive & non-competitive inhibitionagainst a concentration gradient e.g. Na K pump

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    Endocytosis & Exocytosis

    ENDOCYTOSIS

    entry into cells by very large substances (uses E)

    e.g. Iron & vit B12 complexed with their bindingproteins into intestinal mucosal cells

    EXOCYTOSIS

    expulsion of substances from the cellsinto the ECF (uses E)

    e.g. Neurotransmitters at the synapticjunction

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    Ion Trapping

    Ion trapping or reabsorption delays excretionKidneys:

    nearly all drugs are filtered at the glomerulus most drugs in a lipid-soluble form will be reabsorbed

    by passive diffusion to increase excretion: change urinary pH to favor the

    charged form of the drug (not readily absorbed) weak acids are excreted faster in alkaline pH (anion form

    favored) weak bases are excreted faster in acidic pH (cation form

    favored)

    Other sites: body fluids where pH differs from blood pH,

    favoring trapping or reabsorption stomach contents aqueous humor small intestines vaginal secretions

    breast milk prostatic secretions

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    Distribution

    First pass effect decreased bioavailabilityof drugs administered orally because ofinitial absorption into the portal circulation& distribution in the liver where they may

    undergo metabolism or excretion into bileExtraction Ratio magnitude of the first

    pass effect.ER = cl Liver / q (hepatic blood flow)

    Systemic drug bioavailability determinedfrom extent of absorption & ER.F = f x (1 ER)

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    Distribution

    Volume of Distribution ratio between theamount of drug in the body (dose given) &the concentration of the drug in bloodplasma. Vd = drug in body / drug in blood

    Factors influencing Vd:drug pKa (permeation)

    extent of drug-plasma protein binding

    lipid solubility (partition coefficient)

    patient age, gender, disease states, bodycomposition

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    Drug Plasma ProteinBinding

    Most drugs are bound to some extent to plasmaproteins Albumin, Lipoproteins, alpha 1 acidglycoprotein

    Extent of protein binding parallels drug lipidsolubility

    Binding of drug to Albumin is often non-selective,Acidophilic drugs bind to Albumin, basophilic drugs

    bind to Globulinsdrugs with similar chemical/physical properties may

    compete for the same binding sites

    Volume of distribution is inversely proportional toprotein binding

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    Distribution

    Non-ionized (hydrophobic) drugs cross biomembraneseasily

    Binding to plasma proteins accelerates absorption intoplasma but slows diffusion into tissues

    Unbound / free drug crosses biomembranes

    Competition between drugs may lead to displacement ofa previously bound drug higher levels of free/unbounddrug better distribution

    Distribution occurs more rapidly with high blood flow &high vessel permeability

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    Distribution

    Special barriers to distribution:placentablood-brain barrier

    Many disease states alter distribution:Edematous states cirrhosis, heart failure, nephrotic

    syndrome prolong distribution & delay ClearanceObesity allows for greater accumulation of lipophilic

    agents within fat cells, increasing distribution &prolonging half-life

    Pregnancy increases intravascular volume, thus

    increasing distributionhypoAlbuminemia allows drugs that normally bind toit to have increased bioavailability

    Renal failure may decrease drug bound fraction(metabolite competes for protein binding sites) &thus free drug levels

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    Blood Brain Barrier (BBB):

    Only lipid-soluble compounds get through the BBB.

    Four components to the blood-brain barrier:Tight Junctions in brain capillaries

    Glial cell foot processes wrap around the capillaries

    Low CSF protein concentration ------> no oncotic pressure forreabsorbing protein out of the plasma.

    Endothelial cells in the brain contain enzymes that

    metabolize, neutralize, many drugs before they access theCSF.

    MAO and COMT are found in brain endothelial cells. Theymetabolize Dopamine before it reaches the CSF, thus wemust give L-DOPA in order to get dopamine to the CSF.

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    Exceptions to the BBB. Certain parts of the brain arenot protected by the BBB:

    Pituitary, Median Eminence Supraventricular areas

    Parts of hypothalamus

    Meningitis: It opens up the blood brain barrier dueto edema. Thus Penicillin-G can be used to treat

    meningitis (caused by Neisseria meningitides),despite the fact that it doesn't normally cross theBBB. Penicillin-G is also actively pumped back outof the brain once it has crossed the BBB.

    Sites of Concentration: can affect the VdFat, Bone, any Tissue, Transcellular sites: drug

    concentrates in Fat / Bone / non-Plasma locations lower concentration of drug in Plasma higher Vd

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    page break . . . .

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    Metabolism

    Biotransformation of drugs (usually in the Liver; alsoin the Lungs, Skin, Kidney, GIT)) to more polar,hydrophilic, biologically inactive molecules; requiredfor elimination from the body.

    Phase I reactions alteration of the parent drug by

    exposing a functional group; active drug transformedby phase I reactions usually lose pharmacologicactivity, while inactive prodrugs are converted tobiologically active metabolites

    Phase II reactions parent drug undergoes

    conjugation reactions (to make them more soluble)that form covalent linkages with a functional group:glucuronic acid, acetyl coA, sulfate, glutathione, aminoacids, acetate, S-adenosyl-methionine

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    Metabolism

    Phase I reaction products may be directly excreted in urineor react with endogenous compounds to form water-soluble conjugates

    mixed function oxidase system (cytochromeP450 enzymecomplex: Cyt P450 enzyme, CytP450 reductase) requires NADPH (not ATP) as Esource, & molecular O2; [drug metabolizingenzymes are located in hepatic microsomes:lipophilic, endoplasmic reticulum membranes (SER)]

    Phase I enzymes perform multiple types of

    reactions: OXIDATIVE REACTIONS REDUCTIVE REACTIONS HYDROLYTIC REACTIONS

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    CYTOCHROME-P450 COMPLEX:

    There are multiple isotypes. CYT-P450-2,CYT-P450-3A are responsible for the metabolism of most

    drugs.

    CYT-P450-3A4 metabolizes many drugs in the GIT, decreasing thebioavailabilityof many orally absorbed drugs.

    INDUCERS of CYT-P450 COMPLEX: Drugs that increase theproduction or degradation of Cyt-P450 enzymes. Phenobarbital, Phenytoin, Carbamazepine induce CYT-P450-3A4

    Phenobarbital, Phenytoin also induce CYT-P450-2B1 Polycyclic Aromatics (PAH): Induce CYT-P450-1A1

    Glucocorticoids induce CYT-P450-3A4

    Chronic Alcoholism, Isoniazid induce CYT-P450-2E1. important! thisdrug activates some carcinogens e.g. Nitrosamines.

    *Chronic alcoholics have up-regulated many of their CYT-P450 enzymes.

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    INHIBITORS of CYT-P450 COMPLEX

    Inhibit production: Ethanol suppresses many of the CYT-P450 enzymes, explaining some of the drug-interactions ofacute alcohol use.

    Noncompetitive inhibition:Chloramphenicol is metabolizedby Cyt P450 to an alkylating metabolite that inactivates CytP450

    Competitive inhibition: Erythromycin inhibits CYT-P450-

    3A4. Terfenadine (Seldane) is metabolized by CYT-P450-3A4, so the toxic unmetabolized form builds up inthe presence of Erythromycin. The unmetabolized form istoxic and causes lethal arrhythmias. This is why Seldanewas taken off the market;

    Cimetidine, Ketoconazole bind to the heme in Cyt P450,

    decreasing metabolism of Testosterone & other drugsSteroids: Ethinyl estradiol, Norethindrone; Spironolactone;Propylthiouracil (PTU): inactivate Cyt P450 by binding theheme

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    MetabolismPhase IIDrug Conjugation reactions: detoxification rxns:

    non-microsomal, primarily in the liver; also in plasma & GIT usually to glucuronides, making the drug more soluble.

    conjugates are highly polar, generally biologicallyinactive (exception: morphine glucuronide more potentanalgesic than the parent compound) & tend to be rapidly

    excreted in urine or bile Enterohepatic recirculation: high molecular weight

    conjugates are more likely to be excreted in bileintestines, where N flora cleave the conjugate bonds,releasing the parent compound into the systemiccirculation delayed parent drug elimination &

    prolongation of drug effects conjugation, hydrolysis, oxidation, reduction

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    Reaction Reactant transferase

    substrate Example

    Glucuron-idation

    Glucuronic acid

    Glucuronyltransferase

    Phenols,alcohols,carbolicacids,hydroxylamines,sulfonamides

    Morphineacetaminophendiazepamdigitoxinmeprobamate

    Acetylation

    AcetylCoA

    N-Acetyl-transferase

    Amines Sulfonamides isoniazidclonazepamdapsonemescaline

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    Reaction Reactant transfera

    se

    substrate Example

    Sulfateconjugation

    Phospho-adenosylphospho-

    sulfate

    Sulfo-transferase

    Phenols,alcohols,aromatic

    amines

    Estronewarfarinacetaminop

    henmethyldopa

    methylati

    on

    S-

    adenosylmethionine

    Trans-

    methylases

    Catecholami

    nesphenols,amines

    Dopamine

    epinephrinehistaminethiouracil,pyridine

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    Toxicity

    drugs are metabolized to toxic products

    hepatotoxicity exhibited by

    acyl glucuronidation of NSAIDS

    N-acetylation of Isoniazid

    Acetaminophen in high doses glucuronidation &sulfation are usual conjugation reactions in therapeuticdoses, but in high doses, these get saturated so CytP450 metabolizes the drug, forming hepatotoxicreactive electrophilic metabolites fulminant

    hepatotoxicity & death (antidote: N-acetylcysteine)

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    Reduction in Bioavailability

    First pass effect

    Intestinal flora metabolize the drug

    Drug is unstable in gastric acid e.g.Penicillin

    Drug is metabolized by digestiveenzymes e.g. Insulin

    Drug is metabolized by intestinal wallenzymes e.g. sympathomimetic drugs /catecholamines

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    Excretion

    Clearance CL removal of drug from the blood, or the amountof blood/plasma that is completely freed of drug per unit timeover the plasma concentration of the drugCL = rate of elimination of drug

    plasma drug concentrationespecially important for ensuring appropriate long-term dosing, or

    maintaining correct steady state drug concentrationsRenal clearance - unchanged drug, water-soluble metabolites

    glomerular filtration, active tubular secretion, passive tubularreabsorption of lipid-soluble agents

    Hepatic clearance extraction of drugs after GIT absorption

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    Excretion

    Half life (t ) time required to decrease the amount ofdrug in the body by 50% during elimination or during aconstant infusion; useful in

    estimating time to steady-state: approximately 4 half-lives toreach 94%

    Estimation of time required for drug removal from the bodyEstimation of appropriate dosing interval: drug accumulation

    occurs when dosing interval is less than 4 half-lives

    Affected by

    Chronic renal failure decreases clearance, prolongs half-life

    increasing Age Vd changes, prolongs half-life

    Decreased plasma protein binding shortens half-life

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    Drug Elimination

    Zero order kinetics rate of elimination of thedrug is constant regardless of concentrationi.e. constant amount of drug eliminated perunit time so that concentration decreaseslinearly with time

    examples: ethanol, phenytoin, aspirin

    First order kinetics rate of elimination of the

    drug proportional to concentration i.e.constant fraction of the drug eliminated perunit time so that concentration decreasesexponentially over time

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    thats all for now. . .