Clinical Pharmacokinetics and Pharmacodynamics

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Clinical Pharmacokinetics and Pharmacodynamics

• Janice E. Sullivan, M.D.
• Brian Yarberry, Pharm.D.

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Why Study Pharmacokinetics (PK) and
Pharmacodynamics (PD)?

• Individualize patient drug therapy
• Monitor medications with a narrow therapeutic
  index
• Decrease the risk of adverse effects while
  maximizing pharmacologic response of medications
• Evaluate PK/PD as a diagnostic tool for
  underlying disease states

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Clinical Pharmacokinetics

• The science of the rate of movement of drugs
  within biological systems, as affected by the
  absorption, distribution, metabolism, and
  elimination of medications

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Absorption

• Must be able to get medications into the
  patients body
• Drug characteristics that affect absorption
• Molecular weight, ionization, solubility,
  formulation
• Factors affecting drug absorption related to
  patients
• Route of administration, gastric pH, contents of
  GI tract

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Absorption in the Pediatric Patient

• Gastrointestinal pH changes
• Gastric emptying
• Gastric enzymes
• Bile acids biliary function
• Gastrointestinal flora
• Formula/food interaction

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Time to Peak Concentration
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Distribution

• Membrane permeability
• cross membranes to site of action
• Plasma protein binding
• bound drugs do not cross membranes
• malnutrition ?albumin ? free drug
• Lipophilicity of drug
• lipophilic drugs accumulate in adipose tissue
• Volume of distribution

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Pediatric Distribution

• Body Composition
• ? total body water extracellular fluid
• ? adipose tissue skeletal muscle
• Protein Binding
• albumin, bilirubin, ?1-acid glycoprotein
• Tissue Binding
• compositional changes

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Metabolism

• Drugs and toxins are seen as foreign to patients
  bodies
• Drugs can undergo metabolism in the lungs, blood,
  and liver
• Body works to convert drugs to less active forms
  and increase water solubility to enhance
  elimination

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Metabolism

• Liver - primary route of drug metabolism
• Liver may be used to convert pro-drugs (inactive)
  to an active state
• Types of reactions
• Phase I (Cytochrome P450 system)
• Phase II

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Phase I reactions

• Cytochrome P450 system
• Located within the endoplasmic reticulum of
  hepatocytes
• Through electron transport chain, a drug bound to
  the CYP450 system undergoes oxidation or
  reduction
• Enzyme induction
• Drug interactions

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Phase I reactions types

• Hydrolysis
• Oxidation
• Reduction
• Demethylation
• Methylation
• Alcohol dehydrogenase metabolism

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Phase II reactions

• Polar group is conjugated to the drug
• Results in increased polarity of the drug
• Types of reactions
• Glycine conjugation
• Glucuronide conjugation
• Sulfate conjugation

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Elimination

• Pulmonary expired in the air
• Bile excreted in feces
• enterohepatic circulation
• Renal
• glomerular filtration
• tubular reabsorption
• tubular secretion

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Pediatric Elimination

• Glomerular filtration matures in relation to age,
  adult values reached by 3 yrs of age
• Neonate decreased renal blood flow, glomerular
  filtration, tubular function yields prolonged
  elimination of medications
• Aminoglycosides, cephalosporins, penicillins
  longer dosing interval

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Pharmacokinetic Principles

• Steady State the amount of drug administered is
  equal to the amount of drug eliminated within one
  dosing interval resulting in a plateau or
  constant serum drug level
• Drugs with short half-life reach steady state
  rapidly drugs with long half-life take days to
  weeks to reach steady state

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Steady State Pharmacokinetics

• Half-life time required for serum plasma
  concentrations to decrease by one-half (50)
• 4-5 half-lives to reach steady state

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Loading Doses

• Loading doses allow rapid achievement of
  therapeutic serum levels
• Same loading dose used regardless of
  metabolism/elimination dysfunction

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Linear Pharmacokinetics

• Linear rate of elimination is proportional to
  amount of drug present
• Dosage increases result in proportional increase
  in plasma drug levels

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Nonlinear Pharmacokinetics

• Nonlinear rate of elimination is constant
  regardless of amount of drug present
• Dosage increases saturate binding sites and
  result in non- proportional increase/decrease in
  drug levels

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Michaelis-Menten Kinetics

• Follows linear kinetics until enzymes become
  saturated
• Enzymes responsible for metabolism /elimination
  become saturated resulting in non-proportional
  increase in drug levels

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Special Patient Populations

• Renal Disease same hepatic metabolism,
  same/increased volume of distribution and
  prolonged elimination ? ? dosing interval
• Hepatic Disease same renal elimination,
  same/increased volume of distribution, slower
  rate of enzyme metabolism ? ? dosage, ? dosing
  interval
• Cystic Fibrosis Patients increased metabolism/
  elimination, and larger volume of distribution ?
  ? dosage, ? dosage interval

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Pharmacogenetics

• Science of assessing genetically determined
  variations in patients and the resulting affect
  on drug pharmacokinetics and pharmacodynamics
• Useful to identify therapeutic failures and
  unanticipated toxicity

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Pharmacodynamics

• Study of the biochemical and physiologic
  processes underlying drug action
• Mechanism of drug action
• Drug-receptor interaction
• Efficacy
• Safety profile

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Pharmacodynamics

• What the drug does to the body
• Cellular level
• General

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Pharmacodynamics

• Cellular Level

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Drug Actions

• Most drugs bind to cellular receptors
• Initiate biochemical reactions
• Pharmacological effect is due to the alteration
  of an intrinsic physiologic process and not the
  creation of a new process

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Drug Receptors

• Proteins or glycoproteins
• Present on cell surface, on an organelle within
  the cell, or in the cytoplasm
• Finite number of receptors in a given cell
• Receptor mediated responses plateau upon
  saturation of all receptors

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Drug Receptors

• Action occurs when drug binds to receptor and
  this action may be
• Ion channel is opened or closed
• Second messenger is activated
• cAMP, cGMP, Ca, inositol phosphates, etc.
• Initiates a series of chemical reactions
• Normal cellular function is physically inhibited
• Cellular function is turned on

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Drug Receptor

• Affinity
• Refers to the strength of binding between a drug
  and receptor
• Number of occupied receptors is a function of a
  balance between bound and free drug

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Drug Receptor

• Dissociation constant (KD)
• Measure of a drugs affinity for a given receptor
• Defined as the concentration of drug required in
  solution to achieve 50 occupancy of its receptors

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Drug Receptors

• Agonist
• Drugs which alter the physiology of a cell by
  binding to plasma membrane or intracellular
  receptors
• Partial agonist
• A drug which does not produce maximal effect even
  when all of the receptors are occupied

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Drug Receptors

• Antagonists
• Inhibit or block responses caused by agonists
• Competitive antagonist
• Competes with an agonist for receptors
• High doses of an agonist can generally overcome
  antagonist

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Drug Receptors

• Noncompetitive antagonist
• Binds to a site other than the agonist-binding
  domain
• Induces a conformation change in the receptor
  such that the agonist no longer recognizes the
  agonist binding site.
• High doses of an agonist do not overcome the
  antagonist in this situation

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Drug Receptors

• Irreversible Antagonist
• Bind permanently to the receptor binding site
  therefore they can not be overcome with agonist

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Pharmacodynamics

• Definitions

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Definitions

• Efficacy
• Degree to which a drug is able to produce the
  desired response
• Potency
• Amount of drug required to produce 50 of the
  maximal response the drug is capable of inducing
• Used to compare compounds within classes of drugs

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Definitions

• Effective Concentration 50 (ED50)
• Concentration of the drug which induces a
  specified clinical effect in 50 of subjects
• Lethal Dose 50 (LD50)
• Concentration of the drug which induces death in
  50 of subjects

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Definitions

• Therapeutic Index
• Measure of the safety of a drug
• Calculation LD50/ED50
• Margin of Safety
• Margin between the therapeutic and lethal doses
  of a drug

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Dose-Response Relationship

• Drug induced responses are not an all or none
  phenomenon
• Increase in dose may
• Increase therapeutic response
• Increase risk of toxicity

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Clinical Practice

• What must one consider when one is prescribing
  drugs to a critically ill infant or child???

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Clinical Practice

• Select appropriate drug for clinical indication
• Select appropriate dose
• Consider pathophysiologic processes in patient
  such as hepatic or renal dysfunction
• Consider developmental and maturational changes
  in organ systems and the subsequent effect on PK
  and PD

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Clinical Practice

• Select appropriate formulation and route of
  administration
• Determine anticipated length of therapy
• Monitor for efficacy and toxicity
• Pharmacogenetics
• Will play a larger role in the future

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Clinical Practice

• Other factors
• Drug-drug interaction
• Altered absorption
• Inhibition of metabolism
• Enhanced metabolism
• Protein binding competition
• Altered excretion

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Clinical Practice

• Other factors (cont)
• Drug-food interaction
• NG or NJ feeds
• Continuous vs. intermittent
• Site of optimal drug absorption in GI tract must
  be considered

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Effect of Disease on Drug Disposition

• Absorption
• PO/NG administered drugs may have altered
  absorption due to
• Alterations in pH
• Edema of GI mucosa
• Delayed or enhanced gastric emptying
• Alterations in blood flow
• Presence of an ileus
• Coadministration with formulas (I.e. Phenytoin)

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Effect of Disease on Drug Disposition

• Drug distribution may be affected
• Altered organ perfusion due to hemodynamic
  changes
• May effect delivery to site of action, site of
  metabolism and site of elimination
• Inflammation and changes in capillary
  permeability may enhance delivery of drug to a
  site
• Hypoxemia affecting organ function
• Altered hepatic function and drug metabolism

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Effect of Disease on Drug Disposition

• Alterations in protein synthesis
• If serum albumin and other protein levels are
  low, there is altered Vd of free fraction of
  drugs that typically are highly protein bound
  therefore a higher free concentration of drug
• Substrate deficiencies
• Exhaustion of stores
• Metabolic stress

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Effect of Disease on PD

• Up regulation of receptors
• Down regulation of receptors
• Decreased number of drug receptors
• Altered endogenous production of a substance may
  affect the receptors

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Effect of Disease on PD

• Altered response due to
• Acid-base status
• Electrolyte abnormalities
• Altered intravascular volume
• Tolerance

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Management of Drug Therapy

• Target-effect strategy
• Pre-determined efficacy endpoint
• Titrate drug to desired effect
• Monitor for efficacy
• If plateau occurs, may need to add additional
  drug or choose alternative agent
• Monitor for toxicity
• May require decrease in dose or alternative agent

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Management of Drug Therapy

• Target-concentration strategy
• Pre-determined concentration goal
• Based on population-based PK
• Target concentration based on efficacy or
  toxicity
• Know the PK of the drug you are prescribing
• Presence of an active metabolite?
• Should the level of the active metabolite be
  measured?
• Zero-order or first-order kinetics?
• Does it change with increasing serum
  concentrations?

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Management of Drug Therapy

• Critical aspects of target-concentration
  therapy
• Know indications for monitoring serum
  concentrations
• AND when you do not need to monitor levels
• Know the appropriate time to measure the
  concentration
• If the serum concentration is low, know how to
  safely achieve the desired level
• Be sure the level is not drawn from the same line
  in which the drug is administered
• Be sure drug is administered over the appropriate
  time
• AND Treat the patient, not the drug level

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REMEMBER

• No drug produces a single effect!!!

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Case 1

• JB is a 5 y.o. male with pneumonia. He has a
  history of renal insufficiency and is followed by
  the nephrology service. His sputum gram stain
  from an ETT shows gram negative rods. He needs
  to be started on an aminoglycoside. Currently,
  his BUN/SCr are 39/1.5 mg/dL with a urine output
  of 0.4 cc/kg/hr. You should
• a) Start with a normal dose and interval for age
• b) Give a normal dose with an extended interval
• c) Give a lower dose and keep the interval
  normal for age
• d) Aminoglycosides are contraindicated in renal
  insufficiency

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Case 2

• MJ is a 3 y.o. female with a history of
  congenital heart disease. She is maintained on
  digoxin 10 mcg/kg/day divided bid. She has a
  dysrhythmia and is started on amiodarone. You
  should
• a) Continue digoxin at the current dose
• b) Decrease the digoxin dose by 50 and monitor
  levels
• c) Increase the digoxin dose by 50 and monitor
  levels
• d) Discontinue the digoxin

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Case 3

• AC is a 4 y.o male on a midazolam infusion for
  sedation in the PICU. He is currently maintained
  on 0.4 mg/kg/hr. You evaluate the child and
  notice that he is increasingly agitated. You
  should
• a) Increase the infusion to 0.5 mg/kg/hr
• b) Bolus with 0.1 mg/kg and increase the
  infusion to 0.5 mg/kg/hr
• c) Bolus with 0.4 mg/kg and increase the
  infusion to 0.5 mg/kg/hr
• d) Bolus with 0.1 mg/kg and maintain the
  infusion at 0.4 mg/kg/hr

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Case 4

• JD is a 10 y.o. child on phenytoin NG bid (10
  mg/kg/day) for post-traumatic seizures but
  continues to have seizures. He is on continuous
  NG feeds. His phenytoin level is 6 mcg/ml. You
  should
• a) Increase his phenytoin dose to 12 mg/kg/day
  divided bid
• b) Load him with phenytoin 5 mg/kg and increase
  his dose to 12 mg/kg/day
• c) Change his feeds so they are held 1 hr before
  and 2 hrs after each dose, give him a loading
  dose of 10 mg/kg, continue his current dose of
  10 mg/kg/day and recheck a level in 2 days
  (sooner if seizures persist).
• d) Add another anticonvulsant

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Case 5

• LF is a 12 y.o. with sepsis and a serum albumin
  of 1.2 mg/dL. She has a seizure disorder which
  has been well controlled with phenytoin (serum
  concentration on admission was 19 mcg/ml). You
  notice she is having clonus and seizure-like
  activity. You should
• a) Administer phenytoin 5 mg/kg IV now
• b) Order a serum phenytoin level now
• c) Obtain an EEG now
• d) Order a total and free serum phenytoin level
  now

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Case 6

• KD is a 12 y.o. child admitted with status
  asthmaticus who is treated by her primary
  physician with theophylline (serum concentration
  is 18 mcg/ml). Based on her CXR and clinical
  findings, you treat her with erythromycin for
  presumed Mycoplasma pneumoniae. You should
• a) Continue her current dose of theophylline.
  There is no need to monitor serum
  concentrations.
• b) Lower her dose of theophylline and monitor
  daily serum concentrations
• c) Increase her dose of theophylline by 10 and
  monitor daily serum concentration
• d) Continue her current dose of theophylline and
  monitor daily serum concentrations

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Case 7

• BJ is a 13 y.o. S/P BMT for ALL. She is
  admitted to the PICU in septic shock. She has
  renal insufficiency with a BUN/SCr of 45/2.1
  mg/dL and is on fluconazole, cyclosporine,
  solumedrol, vancomycin, cefepime and acyclovir in
  addition to vasopressors.
• a) Identify the drugs which may worsen her renal
  function
• b) Identify the drugs which require dosage
  adjustment due to her renal dysfunction
• c) Identify the drugs which require serum
  concentrations to be monitored and project when
  you would obtain these levels