Exam I: Pharmacokinetics Flashcards
Why is pharmacokinetics important?
PROPER DRUG THERAPY!
- Proper drug to be used
- Route of administration (IV v. oral v. solution)
- Dosing schedules
What are the 4 processes of pharmacokinetics?
ADME
Absorption (bioavailability)
Distribution
Metabolism (Biotransformation)
Excretion/Elimination
What is the difference between pharmacokinetic interaction and pharmacodynamic interactions?
Pharmacokinetic:
- The relationship between the DOSE and CONCENTRATION changes the outcome
- Pharmacologic effect has changed as a result in a change in DRUG CONCENTRATIONS
Pharmacodynamic:
- The relationship between the DRUG CONCENTRATION and EFFECT changes the outcome
- Pharmacologic effect has changed despite a lack of change in drug concentration
How is bioavailability determined?
Area Under Curve (AUC)
–> expressed as a percentage
What affects movement across cell membranes?
- Lipid solubility
- Passive/Active Transport
- Ionization
If a drug is lipid soluble does it move freely though cell membranes or not freely though membranes?
Lipid soluble substance can move freely though cell membranes
Referred to as “non polar” substances
Passive Transport
Diffusion from higher to lower concentration
Active Transport
Going against the concentration gradient
Requires energy
Ionization: Non-ionized v. ionized
Ionized: poor solubility
–> because it is polar
Non-Ionized: can move across membranes
–> because it is non polar
What is the only administration method that bypasses absorption?
Intravenous (IV)
AUC
serum concentration v. time
Factors that effect the extent to which an orally administered drug reaches systemic circulation?
- Absorption characteristics of drug and dose form
- Amount of metabolism that occurs prior to drug reaching systemic circulation
- Presence of interaction substances (drugs, food, type of food)
Hepatic First Pass Metabolism
Metabolism in the liver that occurs prior to drug reaching systemic circulation
Absolute Absorption
Comparing the AUC of a drug form to that in which there is “absolute” (100%) absorption
So you can compare it to IV dose form because it bypasses absorption
Relative Absorption
Comparing the AUC of two different drug forms of same compound
Ex: Tablet v. capsule
If comparing to a product with 100% (IV dose) then this would still be referred to as relative absorption
Can also use relative absorption to figure out bioavailability w/ and w/o food: AUC fasting/AUC food
How is Volume Distribution (Vd) determined?
After drug is administered, maximum concentration is measured and using the calculation:
Cp max = (Dose) / (Vd)
to get Volume Distribution
If a drug’s Vd is small (<0.25) where is it likely to distribute?
Extracellular fluid (interstitial fluid + plasma/blood)
Stays in systemic system…not peripheral
If a drug’s Vd is medium (0.55-0.7) where is it likely to distribute?
Extracellular fluid and intracellular fluid (both central and peripheral tissues)
Move freely in and out of central compartment
If a drug’s Vd is large ( >0.7) where is it likely to distribute?
Distributed throughout body (peripheral tissues) and is NOT allowed to reenter central component
What is the relationship between Vd and drug’s lipid solubility?
The higher the lipid solubility, the higher the Vd
What is the relationship between Vd and drug’s protein binding?
WHY?
The higher the Vd, the lower protein binding a drug has
WHY?
When drug binds to blood proteins, they don’t distribute as freely. They stay in central compartment
What is the relationship between Vd and drug’s tissue binding ability?
The higher the Vd, the higher tissue binding occurs
Is second distribution phase faster or slower than the first?
Slower
Where is drug usually delivered in second distribution phase?
Muscle, skin, fat
What happens when a drug is highly lipid soluble and binds to adipose tissue?
Since there is low blood flow in adipose tissue, it acts as a drug reservoir and prolongs effects of drugs
Examples:
- Benzodiazepines
- Barbiturates
- Phenothiazines
What is a metabolite?
byproduct of the reaction in which enzymes modify the chemical structure of drugs.
Usually has less/no pharmacologic activity
What is the typical location of biotransformation (metabolism)?
The Liver
What is a prodrug?
a parent drug that has no activity but its metabolite does
Hepatic Biotransformation: Phase I Reaction
Introduction of functional groups to prepare for phase II reaction
- OH
- COOH
- SH
- O-
- NH
Name the 3 reactions of Phase I (hepatic biotransformation)
- Oxidation (Most Common)
- Reduction
- Hydrolysis
Oxidation
Oxygen is added or removed
What are the enzymes that mediate oxidation?
Cytochrome P450 enzymes
CYP450 enzymes are sensitive to…
…substrates (drugs, alcohol, smoking)
…hepatic disease
…againg
Drugs, alcohol, smoking can act as _______, _______, or ________ of CYP metabolism.
Substrates
Inhibition
Induction
Enzyme Inhibition:
Decreases rate of metabolism of object drug by obstructing metabolizing enzymes
This leads to an INCREASE in drug concentration
INCREASED half-life, accumulation, and side effects/toxicities
Ex: Grapefruit juice, Tagamet
Enzyme Induction:
Stimulates the increase in CYP450 enzyme activity
INCREASE clearance of drug
DECREASE drug concentration
Ex: cigarette smoking, phenytoin
Prototype for enzyme inducers?
Phenobarbital
Define reduction
oxygen is removed or hydrogen is added
What occurs during phase II reactions?
Parent drug or metabolite is conjugated with:
- Glucuronic acid
- A methyl group
- An acetyl group
- Sulfate group
What type of enzymes conjugate metabolites during phase II reactions?
Transferases
What happens to metabolites after conjugated during phase II reactions?
Hint: polar, or non polar and what that means
Metabolite produced is more polar (less lipophilic)
This is likely to stay in blood stream (central compartment) and be available for excretion via kidneys
Location of excretion?
Kidneys
Describe the 4 steps (or processes) of excretion
- Filtration
At glomerulus - Reabsorption
Less polar substances reabsorbed from tubule
Reenter systemic circulation - Secretion
Into tubules via active transport - Excretion
Drugs may be unchanged
After biotransformation in liver
Enterohepatic Recirculation
When small intestine takes off conjugation from phase II so that drug is reabsorbed and re-enters systemic circulation
Systemic circulation –> Liver –> Gallbladder –> Bile –> Small Intestine –> Systemic circulation
(repeat circle)
Besides the kidney, what are other ways a drug can be excreted?
- Feces
- Lungs
- Skin
- Breast Milk
Substrates excreted in feces are :
- unabsorbed orally ingested drugs
- drug metabolites excreted either in bile or secreted directly into intestinal tract and not reabsorbed
Substrates excreted in lungs are primarily:
anesthetic gases
List factors that affect the pharmacokinetic principles (ADME):
- Age
- Sex
- Weight
- Disease States (COPD for example)
- Genetic factors (race for example)
Bound Drug v. Unbound (free) drug
Bound: drug is bound and inactive
Unbound (free): active drug
Factors that can affect absorption?
GI pH Chelatin bidning Increase or decrease in motility Changes in GI flora
