Total clearance ClTotal ClRenal ClLiver Metabolism Clother

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• Total clearance ClTotal ClRenal ClLiver
  Metabolism Cl(other)
• 1. For most drugs, last term is small and
  thus total clearance
• is a function of ability of liver and
  kidney to eliminate the
• drug.
• 2. In general, clearance is not affected by
  amount of drug
• present, but exception is drugs with
  dose-dependent or
• capacity limited metabolism (e.g.,
  ethanol, phenytoin)
• --------------------------------------------------
  ----------------------------------
• Organ clearance Cloverall Q x Clint
• Q Clint
• This equation deconstructs clearance into its
  two components. When QgtgtClint, CloverallClint.
  Where CintgtgtQ CloverallQ. (Note that clearance
  and flow have the same units.)

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• Sources of variability in clearance
• 1. Genetic differences Enzymes and transporters
• 2) Diseases or altered clinical states, CHF
  hepatic failure (no good marker akin to
  creatinine), renal failure (alter blood flow,
  GFR, metabolic activity, transport)
• 3) Protein binding changes for drugs with low ER
• 4) Drug/drug or drug/dietary substance
  interactions

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• Detailed analysis of pharmacokinetic variables
  indicates that between subject variability is
  most frequently determined by
• oral bioavailability gt clearance gt Vd
• Area under the curve (AUC) dictates
  bioavailability. If the curves are compared by
  weighing or inspection, the curve must be a
  rectilinear and not a log curve, since the
  concentration values must be equally spaced. See
  following graph which should not be used for a
  AUC comparison without conversion to a
  rectilinear plot..

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• Clinical use of plasma drug concentrations
• 1. Target Concentration Strategy Choose target
  concentration
• Predict Vd and Cl from population
  data with adjustments for weight,
• renal function give loading or
  maintenance dose calculated for
• target concentration, Vd and Cl
  check response and Cp revise Vd
• and/or Cl based on measurements and
  then revise dosing.
• 2. Plasma concentrations do not diagnose
  toxicity or efficacy -- these
• are clinical decisions -- DON'T
  TREAT DRUG LEVELS
• 3. Sampling time best is at trough, i.e.,
  before next dose eliminates
• equilibration time as variable
  between tissue and Cp.
• a. First 15-30 minute variable results due
  to
• absorption/distribution (see
  following slide-extrapolate the
• elimination curve to zero
  time)
• b. Drugs with narrow therapeutic indices,
  short t½ may need

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• Problems in interpretation of Cp's include
• a. Therapeutic effect may be longer than t1/2
  (e.g., active
• metabolites or "effective" drug
  concentration may be
• much lower than measured Cp-tissue
  concentrations
• lag behind plasma concentrations and
  the swings in
• concentration are buffered.
• b. Timing last dose
• c. Disease state/other drugs
• d. Changes in protein binding
• e. Tolerance
• f. Steady state requires gt3-4 t½'s (see
  following slide)
• g. Delay time from required for turnover at the
  physiologic target.

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Pharmacokinetic Drug Interactions
Absorption Alter pH, stomach emptying time,
physical adsorption in the g.I. tract. a.
First Pass Effect-prevents system
absorption-metabolism by the liver, intestinal
mucosa Disposition-Plasma protein binding
displacement from plasma protein sites,
transport deficiences a. bilirubin and
kernicterus Metabolism-Inhibition by
competition
Induction of activity
Elimination-compromised renal or hepatic
function cardiac
output compromised
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DRUG INTERACTIONS 1. Regulation of free drug
concentration and receptor response by multiple
factors that can be influenced by other
drugs a. Not all "interactions" are adverse
(e.g., antihypertensive meds., antacids,
antibiotics, etc.) b. Direct chemical/physical
interactions Heparin (acid mucopolysaccharide)
with protamine (a base) tetracycline - chelates
Ca c. Drug absorption few good studies on
clinical importance of these often complex
interactions. Interactions include agents that
provide large surface area to adsorb, bind or
chelate, alter gastric pH, alter GI motility,
affect transport proteins (e.g.,
P-glycoprotein), perturb GI wall metabolism.
Impact on extent, not rate, of absorption is
most important. d. Protein binding esp. for
drugs gt 90 bound transient ? free drug
followed by increased drug disposition so
re-equilibration at steady state altered tissue
binding e. Drug metabolism, especially in liver
are most important pharmacokinetic
interactions 1) Accelerated metabolism
enzyme induction may enhance drug effect if
active metabolites (e.g., acetaminophen and
EtOH) usually decreased effect (inducers
include barbiturates, rifampin, ethanol) 2)
Decreased metabolism especially of
anticonvulsants, anticoagulants, oral
hypoglycemics number of drugs do this
especially on CYP3A metronidazole
on alcohol. dehydrogenase 3) Altered renal
excretion via effects on renal blood flow, GFR or
excretion of weak acids or bases.
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• 2. Pharmacodynamic interactions can occur via
  drugs that act at multiple classes of receptors
  to sensitize or block receptors or produce
  postreceptor/pharmacodynamic change by functional
  antagonism of biochemical or physiologic
  pathways. Also, combined toxicity on same organ
  (e.g., nephrotoxic, ototoxic, or hepatotoxic
  drugs)
• Remember foods (grapefruit juice), OTC drugs, RX
  by other doctors, environmental exposures,
  neutriceuticals in health food stores (St. Johns
  wart)
• a. Some key pharmacodynamic interactions to
  remember
• 1) Diuretics digoxin arrhythmias
• 2) Monoamine oxidase inhibitors tyramine
  hypertensive crisis
• 3) Warfarin antibiotic, aspirin increased
  bleeding
• 4) NSAIDs antihypertensives increase in BP
  NSAIDs diuretics decreased diuresis

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• INDIVIDUALIZE THERAPY
• Particular classes of drugs that cause problems
  Katzung, 8th ed., Appendix has good list
• a. Steroids Adrenal and sex, esp. oral
  contraceptives
• b. Psychoactive drugs sedatives, hypnotics,
  antidepressants, ETHANOL
• c. Drugs requiring titration Anticoagulants,
  anticonvulsants, digitalis, quinidine, oral
  hypoglycemics
• d. Highly protein bound drugs nonsteroidal
  anti-inflammatory, anticoagulants, sulfas

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Non-nutrient Dietary Substances

• Ginseng
• Ginkgo-
• Garlic-
• Glucosamine
• St. Johns wort-best documented interactions with
  a variety of
• studies
• 6. Echinacea
• 7. Lecithin
• 8. Chondroitin
• 9. Creatinine
• Saw palmetto
• __________________________________________________
  ____________
• Reports to date have largely been anecdotal
  but caution should be registered for
  anticoagulants with ginseng and ginkgo

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Drug-Nutriceutical Interactions

• St. Johns Wort- the main component hypericum
  extract and perhaps
• some of the minor components, significantly
• reduces the concentration of several drugs.
  Induction of CYP3A4 and
• P-glycoprotein-(intestinal transport into the
  lumen). Reduces effective
• concentration of other drugs. The categories
  a, b and c reflect the
• relative importance and documented toicity of
  the interactions.
• antiviral-protease inhibitors indinavir,
  ritonavir, saquinavir, nelfinavir
• Irinotecan-antitumor agent
• b. cyclosporin, tacrolimus
• c. warfarin, digoxin, nifedipine, methadone

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Grapefruit Juice

• Active ingredients are the furanocoumarinsthey
  are unique to grapefruit and not found in other
  citrus species in appreciable concentrations.
• Inhibits CYP 3A4, particularly in the intestine
  and not the liver. This means that grapefruit
  will increase availability of those drugs that
  are partially cleared by the intestinal mucosa.
  Also, the influence is small if the drugs are
  given intravenously-again showing the smaller
  influence of hepatic metabolism (see following
  slide)
• Also there may be an inhibitory effect on the
  P-glycoprotein that will reinforce the enzyme
  inhibition.
• Drugs where dose should be adjusted include the
  Ca channel blockers (felodipine, nifedipine,
  nimodipine, nisoldipine) the statins
• (lovastatin, simvastatin), and triazolam-a
  benzodiazepine (Halcion)

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• Because the grapefruit ingredients are higher in
  the apical enterocyte of the small intestine,
  inhibition primarily occurs at this site and not
  at the liver. Hence in the presence of grapefruit
  juice, more drug is absorbed systemically.