pharmacokine tics

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  • 8/14/2019 Pharmacokine Tics




  • 8/14/2019 Pharmacokine Tics


    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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    Absorption into Plasma

    Distribution to


    Bound Drug

    Free Drug


    StorageSites of


    Drug Metabolism: Liver, Lung,


    Drug Excretion: Renal, Biliary,


    Drug Biodisposition

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


    Concentration gradient

    Surface area

    Tissue vascularity

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    Solubility Lipid solubility - ability to diffuse through lipid


    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.


    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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    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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    Aqueous diffusionwithin large aqueous


    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


    entry into cells by very large substances (uses E)

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


    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


    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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    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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    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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    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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    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, Transcellu