Exam 1: Pharmacokinetics/Pharmacodynamics Flashcards
Pharmacokinetics vs. pharmacodynamics:
Pharmacokinetics = “what the body does to a drug”
Pharmacodynamics = “what a drug does to the body”
Four components of pharmacokinetics:
Absorption
Distribution
Metabolism
Excretion
Three components of pharmacodynamics:
Mechanism of effect
Sensitivity
Responsiveness
Four commonly measured pharmacokinetic parameters of IV drugs:
- Elimination half-time
- Bioavailability
- Clearance
- Volume of distribution
Define bioavailability
How much of the drug administered is available at the site of action
Define volume of distribution
The volume that the drug is able to distribute into
Compartments in the two compartment model:
Central
Peripheral
Define central compartment:
Highly perfused tissues: kidney, liver, lungs, heart, brain, vessels
What pathway does a drug take between the two compartments?
Introduced into central
Distributes into peripheral
Returns to central for clearance
What % of CO does the central compartment receive? What % of body mass does it represent?
75% of CO
10% of mass
What is the peripheral compartment?
The not highly perfused organs/tissues
What are the characteristics of the peripheral compartment?
Large volume
Extensive uptake of drug
What type of drugs will transfer easily between plasma and tissues?
Highly lipid soluble
How does aging affect the rate of transfer between compartments?
Decreases it, leading to greater plasma concentration
What causes a drug to leave the peripheral compartment?
Drop in plasma concentration below peripheral compartment concentration due to clearance
How are the duration of effect and elimination half-time related in lipophilic drugs?
Duration of effect much shorter than elimination half-time
Plasma concentration drops rapidly but drug is slow to leave tissues and get cleared
Why do large/repeat doses of a drug prolong duration of action?
Tissues become saturated so clearance depends on metabolism, not redistribution
What are the 3 and 4 compartment models?
3: vessel rich, muscle, fat & vessel-poor
4: vessel rich, muscle, fat, vessel-poor
Body mass and flood flow % for each compartment (vessel rich to vessel poor):
Body mass: 10%, 50%, 20%, 20%
Blood flow: 75%, 19%, 6%, <1%
Special function of lungs r/t drugs:
Serve as a reservoir for basic lipophilic drugs
Why does Fentanyl have two peaks?
Lungs sequester initially and then release
What type of drugs does the blood-brain barrier block?
Ionized, water-soluble drugs
Under what conditions can the blood-brain barrier be overcome?
Large doses of drug in patients with head injury or hypoxemia
What populations have weaker blood brain barriers?
Neonates
Elderly
Define biophase:
Site of action of drug, aka “effect site”
What is the rate constant of drug elimination from effect site?
ke0
How do we calculate Vd?
Vd = dose of IV drug / plasma concentration of drug
How does lipid solubility affect Vd? Why?
More lipid soluble = higher Vd
Lipid soluble drugs easily cross membranes to enter the peripheral compartment
How does protein binding affect Vd? Why?
More protein bound = lower Vd
If drug is bound to proteins, it cannot cross membranes and enter tissues
Why does coumadin have such a small therapeutic index?
High protein binding affinity; small changes in [plasma protein] lead to large changes in plasma levels
How does molecular size relate to Vd? Why?
Greater molecular size = smaller Vd
Larger molecules have a harder time crossing the membrane and stay in the plasma more
Elimination half-time
The time for the plasma concentration of the drug to decrease to 50% during the elimination phase (NOT the total amount of drug in the body)
How are elimination half-time and Vd related?
Directly proportional
How are elimination half-time and clearance related?
Inversely proportional
How are elimination half-time and drug dose related?
They are independent of each other
Define elimination half-life:
How long it takes for drug to leave the body by 50%
What occurs if dosing intervals are less than elimination half-time?
Drug accumulation
% of initial drug eliminated at each of the first 6 half-times:
50%
75%
- 5%
- 8%
- 9%
- 4%
Advantages of oral administration:
Convenient and economic
Disadvantages of oral administration:
Emesis
Destruction by gastric enzymes/acid
Irregular absorption with food/other drugs
What is the first-pass effect?
Drugs absorbed via GI system have to pass through the portal system/liver before systemic circulation and get metabolized
What is the advantage of sublingual/transmucosal administration?
Bypasses the liver and the first-pass effect
What are the advantages of transdermal administration?
Sustained therapeutic plasma concentration of drug
How does absorption occur for transdermal drugs?
Along sweat ducts and hair follicles
What is the rate-limiting step for transdermal absorption?
Diffusion across stratum corneum
Differences in proximal vs. distal rectal administration:
Proximal: portal system
Distal: caval system
What is the advantage of IV administration?
Achieve therapeutic plasma levels precisely and rapidly
How acidic/basic are most drugs?
Weak acids and bases
Non-ionized drugs are usually (lipid soluble/non lipid soluble):
Lipid soluble
Is the ionized or non-ionized fraction of a drug the active part?
Non-ionized
How is the ionized fraction of a drug cleared?
By the kidneys, u nchanged
Why are drugs with a high ionized fraction a bad idea for renal patients?
Ionized fraction of drugs passes out unchanged via kidneys
What two factors determine the degree of ionization?
- Dissociation constant (pK)
* pH of surrounding fluid
Acidic drugs are highly ionized at an _______ pH.
Alkaline
Describe ion trapping and an example:
Drug ends up in an acid/basic environment where it becomes ionized and unable to cross back over to equilibrate
Ex. LA accumulating in placenta
Main three plasma proteins:
- Albumin-acids
- α 1 acid glycoprotein bases
- Lipoproteins
Which fraction of the drug (r/t protein binding) can cross membranes?
The free/unbound fraction
How does protein binding affect Vd and effect?
Lower Vd
Lesser effect
Name four drugs that are highly protein bound:
Warfarin
Propranolol
Phenytoin
Diazepam
Define clearance:
Volume of plasma cleared of drug by metabolism and excretion
Define first-order kinetics:
Rate of elimination increases with more of the drug
A constant fraction per unit of time is eliminated
Most drugs display ______-order kinetics:
First-order
Define zero order kinetics:
A constant amount of drug is eliminated per unit time
What are three common drugs that exhibit zero order kinetics?
ETOH
ASA
Dilantin
Define hepatic clearance:
Ratio of hepatic blood flow to hepatic extraction of drug
What is perfusion-dependent elimination?
Hepatic extraction ratio > 0.7
Clearance of drug depends on hepatic blood flow
Relationship between blood pressure and hepatic extraction ratio:
If ratio is > 0.7, drug is perfusion dependent; low BP means slower clearance
Define capacity-dependent elimination:
Hepatic extraction ratio is will not change clearance
Decrease in protein binding -or- increase in enzyme activity will increase hepatic clearance
Most important organ for elimination of unchanged drugs or metabolites:
Kidneys
Which type of drugs are most efficiently excreted by kidneys?
Water soluble compounds
Highly lipid soluble drugs in the kidney:
Get reabsorbed so little to no unchanged drug is excreted
Define drug metabolism:
Biotransformation to convert pharmacologically active, lipid soluble drugs into water soluble and often inactive drugs
Increased water solubility _____ the Vd for a drug and _____ its renal excretion.
Decreases; increases
Four pathways of metabolism:
- Oxidation
- Reduction
- Hydrolysis
- Conjugation
What occurs during phase I of metabolism?
Oxidation, reduction, or hydrolysis
What occurs during phase II of metabolism?
Conjugation of drug or metabolite with endogenous substance to form water-soluble compound
Sites of drug metabolism in the body (5):
Plasma
Kidneys
Lungs
GI Tract
Liver
What is the primary site for drug metabolism? What substance is responsible for metabolism there?
Liver; hepatic microsomal enzymes
What is an example of a drug metabolized in the plasma?
Succinylcholine (by plasma esterases)
Where are hepatic microsomal enzymes located?
In the hepatic smooth ER
What are the protein enzymes that frequently metabolize drugs collectively called?
Cytochrome P-450
What are the six CYP isozymes in the Cytochrome P-450 system?
CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP2E1
CYP3A
Define enzyme induction:
Increased enzymatic activity or enzyme concentration, resulting in increased elimination of a drug
What class of drugs were mentioned as huge enzyme inducers?
Barbiturates
How do nonmicrosomal enzymes typically work?
By conjugation and hydrolysis
Lesser extent via redox
Where are nonmicrosomal enzymes located?
Liver (mostly)
Plasma
GI tract
Which enzymes hydrolize drugs with ester bonds? What are two examples of these drugs?
Nonmicrosomal enzymes
Succinylcholine, esmolol
Which type of enzymes can be induced?
Hepatic microsomal enzymes
By what mechanism do most drugs exert their effect?
Interaction with cell membrane receptors
How do pts on beta-blockers adapt?
Upregulate (increase) the number of beta receptors
Define the state of receptor activation theory:
Non-activated receptors are converted to active by the drug
What is the receptor occupancy theory?
The more receptors occupied by the drug, the greater the effect
Ex. of a nonreceptor drug action:
Antacids neutralize gastric acid by direct action
Chelating drugs form bonds with metallic cations
Agonist drugs work by:
Mimicking cell signalling molecules and activating the same receptors
Antagonist drugs work by:
Binding to same receptors as cell signals WITHOUT activating the receptor, therefore blocking the signaling molecules
How much does the chemical structure of a drug affect its affinity for a receptor?
Small changes in structure can dramatically change effect
Define racemic:
1/2 R isomer, 1/2 L isomer
Enantomerism can be produced by:
sp3 hybridized carbon atoms
Define efficacy:
The ability of a drug to produce the desired therapeutic effect
Define potency:
The relationship between the effect of a drug and the dose necessary to achieve that effect
Quickness to effect and amount needed to effect: which is efficacy? Which is potency?
Efficacy: quickness
Potency: amount
Define ED50 and LD50:
ED50 is the dose effective in 50% of people
LD50 is the dose lethal in 50% of people
Define therapeutic index:
The ratio of LD50 to ED50
Define hyperreactivity:
An unusually low dose of drug produces the expected effect
Define hypersensitivity:
Allergy
Define additive effect:
A second drug acting with the first will produce effect equal to the sum of both
1+1=2
Define synergistic effect:
Two drugs interact to produce an effect greater than their sum
1+1=3
What type of combined effect do Fentanyl and Versed have?
Synergistic, esp. on respiratory rate
