NURS 8024:
Pharmacokinetics/Pharmacodynamics
Absorption - ANS-entry of pharmacologic agent into plasma
\Active transport - ANS-Type of drug transport
Energy dependent
Able to move drug from lower to higher concentration
\Additive effect - ANS-When 2 drugs w/similar actions are taken together and combined
effect is cumulative (1+1=2)
\ADME - ANS-Absorption, Distribution, Metabolism, Elimination (fundamental pathways of
drugs)
\Bioavailability - ANS-Fraction of chemically unchanged drug that reaches systemic
circulation; affected by first-pass metabolism, solubility, chemical instability, nature of the
drug formation (chemistry, molecule size, entering coatings, etc.)
\Bioavailability: Enteral/Parenteral administration - ANS-Bioavailability for IV drugs is high
right away; PO medication bioavailability is never quite as high d/t first-pass effect
\Bioequivalence - ANS-Similar drugs are bioequivalent if they have comparable
bioavailability and similar time to achieve peak plasma concentration
\Chemical antagonist (ionic binding) - ANS-making proteins unavailable for interactions
(protamine binds to heparin)
\Chronotherapy considerations - ANS-possible circadian or ultradian variations in
pharmacokinetics; ex. statin drugs work best in the evening according to research
\Clinical implications of plasma protein binding - ANS-Source of drug interactions
Class I drug (warfarin) is highly protein bound and very small fraction free in plasma; if class
II drug (sulfa) introduced, sulfa will displace the warfarin from albumin and cause rapid rise in
warfarin free drug concentration --> increased therapeutic effect --> toxicity
\Cockcroft-Gault equation - ANS-Estimates creatinine clearance (ml/min)
(140-age (yrs) x weight (kg) x [0.85 if female])/ (72xsCr (mg/dL)
\Competitive antagonist - ANS-When antagonist & agonist bind to same receptor site
Higher concentrations of agonist required to produce a given effect
\Cytochrome P450 system - ANS-Comprised of many families of isoenzymes
Found in most cells but much higher amounts in liver & GI tract
Various mutations in this group of isoenzymes cause increased or decreases ability to
metabolize certain drugs
Important in metabolism of many endogenous compounds (hormones) and
biotransformation of exogenous substances (drugs)
\Distribution - ANS-agent leaves bloodstream and distributes into interstitial and intracellular
fluids (where ever the target is)
\Down regulation - ANS-Constant stimulation of receptor leads to decreased responsiveness
(receptors move intracellularly)
\Drug combinations - ANS-Often utilized for therapeutic advantage when effects are additive
or synergistic
Utilization of submaximal doses of drugs together can achieve therapeutic effects w/fewer
drug-specific adverse effects
, Combination therapy optimal for many conditions (HF, HTN, cancer)
Pharmacologic interactions can also produce significant adverse effects (nitrate vasodilators
w/phosphodiesterase type 5 inhibitors causes severe hypotension)
\Drug delivery depends on... - ANS-Blood flow
Capillary permeability
Plasma protein binding
Drug structure
Hydrophobicity
\Drug displacement & volume of distribution - ANS-Large Vd: displaced drug may distribute
to periphery; insignificant change in free drug concentration
Small Vd: displaced drug less likely to distribute to tissues; more significant change in free
drug concentration
\Drug distribution - ANS-Process in which drug reversibly leaves bloodstream and enters
interstitium and/or cells
\Drug distribution: Blood flow - ANS-Wide variance d/t unequal distribution of cardiac output;
highest in organs (heart, brain, lungs, liver, kidney, guts), lower in skeletal muscles, lowest in
adipose tissue
\Drug distribution: Capillary permeability - ANS-Governed by capillary structure & chemical
nature of the drug
Large slit junctions between endothelial cells of spleen and liver allow passage of plasma
proteins & thus drug molecules
Slit junctions are absent in brain: "blood brain barrier"
Lipid soluble drugs penetrate the brain by going across membrane, but ionized or polar
drugs cannot enter brain d/t lack of slit junctions
\Drug distribution: Drug Structure - ANS-Chemical nature of the drug largely determines it's
ability to cross cell membranes
Hydrophobic/lipophillic drugs (no net charge, uniform electron distribution, easier to pass
through, able to dissolve in lipid cell membranes and permeate cell surface)
Hydrophillic/lipophobic drugs (positively or negatively charged, do not easily pass through
cell membranes, need slit junction for passage: liver, spleen)
\Drug distribution: Plasma protein binding - ANS-Plasma protein binding generally reversible
and non-selective; drugs bind where other compounds (such as bilirubin) would normally
attach
Plasma albumin: major drug binding protein
May act as "drug reservoir"- as free drug concentration decreases, protein bound drug
dissociates from protein to maintain a stable free-drug concentration in plasma
\Drug efficacy - ANS-Determined by the number of receptor-drug couplings formed and the
efficiency of these activations to produce a cellular response
More clinically important than potency
\Drug metabolism: Phase 2 - ANS-conjugation- reaction in which a large chemical group is
attached to the molecule to increase solubility and facilitate excretion of the metabolite from
the body
\Drug metabolism: Phase I - ANS-oxidation, reduction, hydrolosis to increase polarity and
water solubility of drug
Phase I reactions involve CYP450 system: serves to convert lipophillic molecules into more
polar molecules
Can increase, decrease, or leave drug pharmacologic activity unchanged
Pharmacokinetics/Pharmacodynamics
Absorption - ANS-entry of pharmacologic agent into plasma
\Active transport - ANS-Type of drug transport
Energy dependent
Able to move drug from lower to higher concentration
\Additive effect - ANS-When 2 drugs w/similar actions are taken together and combined
effect is cumulative (1+1=2)
\ADME - ANS-Absorption, Distribution, Metabolism, Elimination (fundamental pathways of
drugs)
\Bioavailability - ANS-Fraction of chemically unchanged drug that reaches systemic
circulation; affected by first-pass metabolism, solubility, chemical instability, nature of the
drug formation (chemistry, molecule size, entering coatings, etc.)
\Bioavailability: Enteral/Parenteral administration - ANS-Bioavailability for IV drugs is high
right away; PO medication bioavailability is never quite as high d/t first-pass effect
\Bioequivalence - ANS-Similar drugs are bioequivalent if they have comparable
bioavailability and similar time to achieve peak plasma concentration
\Chemical antagonist (ionic binding) - ANS-making proteins unavailable for interactions
(protamine binds to heparin)
\Chronotherapy considerations - ANS-possible circadian or ultradian variations in
pharmacokinetics; ex. statin drugs work best in the evening according to research
\Clinical implications of plasma protein binding - ANS-Source of drug interactions
Class I drug (warfarin) is highly protein bound and very small fraction free in plasma; if class
II drug (sulfa) introduced, sulfa will displace the warfarin from albumin and cause rapid rise in
warfarin free drug concentration --> increased therapeutic effect --> toxicity
\Cockcroft-Gault equation - ANS-Estimates creatinine clearance (ml/min)
(140-age (yrs) x weight (kg) x [0.85 if female])/ (72xsCr (mg/dL)
\Competitive antagonist - ANS-When antagonist & agonist bind to same receptor site
Higher concentrations of agonist required to produce a given effect
\Cytochrome P450 system - ANS-Comprised of many families of isoenzymes
Found in most cells but much higher amounts in liver & GI tract
Various mutations in this group of isoenzymes cause increased or decreases ability to
metabolize certain drugs
Important in metabolism of many endogenous compounds (hormones) and
biotransformation of exogenous substances (drugs)
\Distribution - ANS-agent leaves bloodstream and distributes into interstitial and intracellular
fluids (where ever the target is)
\Down regulation - ANS-Constant stimulation of receptor leads to decreased responsiveness
(receptors move intracellularly)
\Drug combinations - ANS-Often utilized for therapeutic advantage when effects are additive
or synergistic
Utilization of submaximal doses of drugs together can achieve therapeutic effects w/fewer
drug-specific adverse effects
, Combination therapy optimal for many conditions (HF, HTN, cancer)
Pharmacologic interactions can also produce significant adverse effects (nitrate vasodilators
w/phosphodiesterase type 5 inhibitors causes severe hypotension)
\Drug delivery depends on... - ANS-Blood flow
Capillary permeability
Plasma protein binding
Drug structure
Hydrophobicity
\Drug displacement & volume of distribution - ANS-Large Vd: displaced drug may distribute
to periphery; insignificant change in free drug concentration
Small Vd: displaced drug less likely to distribute to tissues; more significant change in free
drug concentration
\Drug distribution - ANS-Process in which drug reversibly leaves bloodstream and enters
interstitium and/or cells
\Drug distribution: Blood flow - ANS-Wide variance d/t unequal distribution of cardiac output;
highest in organs (heart, brain, lungs, liver, kidney, guts), lower in skeletal muscles, lowest in
adipose tissue
\Drug distribution: Capillary permeability - ANS-Governed by capillary structure & chemical
nature of the drug
Large slit junctions between endothelial cells of spleen and liver allow passage of plasma
proteins & thus drug molecules
Slit junctions are absent in brain: "blood brain barrier"
Lipid soluble drugs penetrate the brain by going across membrane, but ionized or polar
drugs cannot enter brain d/t lack of slit junctions
\Drug distribution: Drug Structure - ANS-Chemical nature of the drug largely determines it's
ability to cross cell membranes
Hydrophobic/lipophillic drugs (no net charge, uniform electron distribution, easier to pass
through, able to dissolve in lipid cell membranes and permeate cell surface)
Hydrophillic/lipophobic drugs (positively or negatively charged, do not easily pass through
cell membranes, need slit junction for passage: liver, spleen)
\Drug distribution: Plasma protein binding - ANS-Plasma protein binding generally reversible
and non-selective; drugs bind where other compounds (such as bilirubin) would normally
attach
Plasma albumin: major drug binding protein
May act as "drug reservoir"- as free drug concentration decreases, protein bound drug
dissociates from protein to maintain a stable free-drug concentration in plasma
\Drug efficacy - ANS-Determined by the number of receptor-drug couplings formed and the
efficiency of these activations to produce a cellular response
More clinically important than potency
\Drug metabolism: Phase 2 - ANS-conjugation- reaction in which a large chemical group is
attached to the molecule to increase solubility and facilitate excretion of the metabolite from
the body
\Drug metabolism: Phase I - ANS-oxidation, reduction, hydrolosis to increase polarity and
water solubility of drug
Phase I reactions involve CYP450 system: serves to convert lipophillic molecules into more
polar molecules
Can increase, decrease, or leave drug pharmacologic activity unchanged
