Pharmacokine Tics
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Transcript of 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. . .