1. Clinical Pharmacokinetics and Pharmacodynamics
Janice E. Sullivan, M.D.
Brian Yarberry, Pharm.D.

2. 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

3. 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

4. Absorption Must be able to get medications into the patient’s 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

5. Absorption in the Pediatric Patient
Gastrointestinal pH changes
Gastric emptying
Gastric enzymes
Bile acids & biliary function
Gastrointestinal flora
Formula/food interaction

6. Time to Peak Concentration

7. Distribution Membrane permeability Plasma protein binding
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

8. Pediatric Distribution
Body Composition
 total body water & extracellular fluid
 adipose tissue & skeletal muscle
Protein Binding
albumin, bilirubin, 1-acid glycoprotein
Tissue Binding
compositional changes

9. 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

10. 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

11. 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

12. Phase I reactions types
Hydrolysis
Oxidation
Reduction
Demethylation
Methylation
Alcohol dehydrogenase metabolism

13. 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

14. Elimination Pulmonary = expired in the air Bile = excreted in feces
enterohepatic circulation
Renal
glomerular filtration
tubular reabsorption
tubular secretion

15. 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

16. 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

17. 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

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

19. Linear Pharmacokinetics
Linear = rate of elimination is proportional to amount of drug present
Dosage increases result in proportional increase in plasma drug levels

20. 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

21. 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

22. 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

23. 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

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

25. Pharmacodynamics “What the drug does to the body” Cellular level
General

26. Pharmacodynamics
Cellular Level

27. 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

28. 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

29. 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”

30. 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

31. Drug Receptor Dissociation constant (KD)
Measure of a drug’s affinity for a given receptor
Defined as the concentration of drug required in solution to achieve 50% occupancy of its receptors

32. Drug Receptors Agonist Partial 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

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

34. 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

35. Drug Receptors Irreversible Antagonist
Bind permanently to the receptor binding site therefore they can not be overcome with agonist

36. Pharmacodynamics
Definitions

37. Definitions Efficacy Potency
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

38. Definitions Effective Concentration 50% (ED50) Lethal Dose 50% (LD50)
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

39. Definitions Therapeutic Index Margin of Safety
Measure of the safety of a drug
Calculation: LD50/ED50
Margin of Safety
Margin between the therapeutic and lethal doses of a drug

40. Dose-Response Relationship
Drug induced responses are not an “all or none” phenomenon
Increase in dose may:
Increase therapeutic response
Increase risk of toxicity

41. Clinical Practice
What must one consider when one is prescribing drugs to a critically ill infant or child???

42. 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

43. 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

44. Clinical Practice Other factors Drug-drug interaction
Altered absorption
Inhibition of metabolism
Enhanced metabolism
Protein binding competition
Altered excretion

45. Clinical Practice Other factors (con’t) Drug-food interaction
NG or NJ feeds
Continuous vs. intermittent
Site of optimal drug absorption in GI tract must be considered

46. 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)

47. 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

48. 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

49. 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

50. Effect of Disease on PD Altered response due to: Acid-base status
Electrolyte abnormalities
Altered intravascular volume
Tolerance

51. 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

52. 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?

53. 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

54. No drug produces a single effect!!!
REMEMBER
No drug produces a single effect!!!

55. 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

56. 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

57. 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

58. 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

59. 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

60. 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

61. 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