3. Pharmacokinetics Flashcards
What are the 4 major phases influencing “free” (unbound) plasma [drug] as a function of time
- Absorption
- How does drug get into blood?
- Distribution
- Where does drug go?
- Metabolism
- What happens to the drug?
- Excretion
- How does the drug exit the body?
*Plasma concentration directly relates to the concentrations at the site of anticipated action, toxicities, etc.
Pharmacokinetics
- Resulting [ ] will produce a response (or not) and toxicities (or not) in a manner dependent on the pharmacodynamic profile of the drug
- Pharmacokinetic processes dictate effect magnitude and duration
*please refer to figure in slide 6
What is the absorption phase and what is it influenced by?
- Movement from site of administration to blood
- Influenced by
- Physicochemical factors of drug
- size
- lipophilicity
- charge/ionization
- drug stability
- Barriers of body to traverse
- Dependent on Route of Administration
- ex. orally –> absorbed a bit as it has to go through many layers to get absorbed (stomach)
- Dependent on Route of Administration
- Physicochemical factors of drug
What is the Route of Administration (ROA) based on?
- Drug characteristics
- Patient characteristics
- age
- willingness
- ability to follow instrutions
- Therapeutic objectives
- emergency? need drug right away?
- location
- May influence rate and extent of absorption into blood
What are Enteral and Parenteral ROAs? Tell the many ways of ROA examples.
- Enteral ROAs - Involve the gastrointestinal (GI) tract
- Oral (by far the most common ROA)
- Sublingual
- Rectal
- Parenteral ROAs - DOES NOT involve the gastrointestinal (GI) tract
-Injections
- ex. vaccines, insulin- Slow-release (drug eluting) devices
- ex. progesterone intrauterine devices
- Inhalation medicines
- ex. bronchodilators for asthma –> local effect
- ex. general anesthetics –> systemic effect
- Topical creams/ointments (ex. steroid creams, anti-fungal medicines)
- Generally intended for local effects
- Transdermal (ex. fentanyl or nicotine patches)
- Generally intended for systemic effects
- Slow-release (drug eluting) devices
How do drugs cross membranes and why do we need it to cross? What are the requirements?
- Required for absorption for MOST routes of administration
- Required for distribution as well
- Drug charge affects lipid solubility and membrane permeability!
- Uncharged drug is hydrophobic –> can passively diffuse across membranes
- Charged drug is hydrophilic –> passive diffusion very unlikely
- Characteristics that doesn’t allow to cross cell membrane
- charged
- ionized
- polar
- hydrophillic
- water soluble
- Characteristics that allows to cross cell membrane
- uncharged
- unionized
- non-polar
- hydrophobic
- lipid soluble
- lipophilic
- levels to cross membrane (from easiest to hardest)
- hydrophobic molecules and gases
- small uncharged molecules
- large uncharge molecules
- charged molecules and ions
Explain drugs as acids and bases
*please see slide 12 and 13
What happens after the drug gets absorbed?
- Drug circulates through body, going anywhere it can based on its physicochemical properties and tissue perfusion,
- If it encounters a receptor for which it has an affinity…
- it binds to the receptor and a pharmacological response is produced
What is the distribution phase and what is it influenced by?
- Process of drug reversibly leaving blood, and establishing equilibration throughout body
- Moving between body compartments
- Some drug reaching site(s) of action (i.e. receptors)
- Extent and efficiency dictated by
- Drug properties
- Concentration gradient
- Size
- Lipid solubility
- Organism properties
- Plasma protein binding
- Blood flow
- Drug properties
Explain the binding in drugs and proteins.
- Drug in any compartment will exist in dynamic (reversible) equilibria between free drug and protein-bound forms
- e.g. [plasma] = [free] + [protein-bound]
- At any point in time, only free (unbound) drug is
available for…- Crossing physiological membranes
- Pharmacological activity
- Protein-bound fraction will vary between different drugs,
- Typically higher with more lipophilic drugs
*refer to slide 17 for example
explain tissue perfusion
- Drug cannot pass through membranes if it’s not delivered
- Highly perfused tissue accumulates drug to greater extent than poorly perfused tissue ex. brain and heart accumulates drug greater than muscle and skin
What would happen to distribution in pathological states involving decreased circulation/tissue perfusion?
- since it take the most time to get drug
- inc amount of [ ]
- Muscle is an important site of accumulation (that can vary by individual based on gender, age, pathology and other considerations
What is metabolism
Conversion of parent (original) drug to metabolite(s)
- Increased polarity –> enhanced excretion
- inc polarity makes it difficult to passively cross membranes = trapped in blood = excreted through kidneys
- Decreased activity –> Does not always occur; some drugs have receptor activity before and after metabolism. Others (termed prodrugs) are inactive when given and become active after metabolism; an example of this is codeine, which is metabolized to morphine for its pain relieving effect
What are the 2 major enzyme-catalyzed processes
- Phase I Metabolism
- oxidation/reduction/hydrolysis
- Phase II
- conjugation
*these enzymes exist in other areas of the body (e.g. stomach, lung, blood plasma), but not nearly as concentrated as in the liver; still, these sites may provide some contribution to drug metabolism under specific circumstances.
What is Phase I Metabolism and what does it do?
- Cytochrome P450 (CYP) enzyme family
- Different isozymes (family members) metabolize
specific drugs- Sometimes a single CYP 450 isozyme, but often multiple enzymes are capable of metabolizing a single drug
- Examples:
- Caffeine: CYP1A2
- Codeine: CYP3A4, CYP2D6
-CYP450 enzymes increase the polarity of the drug to increase water solubility
- Add new polar group
- Uncover existing polar group
–> common polar groups: -OH, -COOH, -NH2, -SH
- Enzyme activity can be induced or inhibited, resulting in changes in metabolism rate. The following influence enzyme activity:
- Other drugs
- Food
- Environmental changes
- Pregnancy
- Disease
Explain CYP450 Enzyme Induction
- Inducers INCREASE enzyme activity
- Rate of metabolism speeds up
- Drug is removed from body faster
Explain CYP450 Enzyme Inhibition
- Inhibitors decrease enzyme activity
- Rate of metabolism slows down
- Drug stays in body for longer
What is Phase II metabolism? What does it do to the drug?
- Various, non-P450 liver enzymes involved
- Covalently link parent drug or Phase I metabolite to a bulky, endogenous conjugate,
- e.g. glucuronic acid, sulfates, glutathione
- Metabolite is usually inactive –> ensures metabolite is too large to distribute effectively, preventing pharmacological activity at peripheral receptors AND keeping it in blood for renal excretion
- because it is too big = less likely to leave blood
What are the steps from parent drug to excretion? (metabolism)
- Parent drug
- Phase I (creates Parent drug+ from Parent drug)
- Parent drug+ (phase I metabolite)
- (may or may not be pharmacologically active)
- Phase II (creates Parent drug+conjugate from Parent drug+)
- Parent drug+conjugate (phase II metabolite)
- excretion
*some drugs enter Phase II directly from Parent drug
*some drugs skip metabolism altogether and go from Parent drug to excretion
*refer to slide 26 if you want a visual
What is Excretion?
- Irreversible loss of drug from the body (parent and/or metabolites)
- Primarily through the urine (most drugs), but also feces (some drugs)
- Combination of active and passive transport processes
Dependent on drug, and subject to pathological alteration
refer to slide 27 and 28 for summary of the 4 major phases
other side!
What are the 2 clinical applications of pharmacokinetics?
- Treating a drug overdose
- Designing drug dosing regimens
Which form of weak acid is absorbed and which is excreted? What about for weak bases?
- weak acid
- (HA) <–> (A-) + (H+)
- HA is absorbed
- A- is excreted
- (HA) <–> (A-) + (H+)
- weak base
- (BH+) <–> (B) + (H+)
- B is absorbed
- BH+ is excreted
- (BH+) <–> (B) + (H+)
What will happen to the equilibrium of a weak acid drug if the surrounding pH is increased?
- (HA)⇌(A-) + (H+)
- inc pH = dec H+ = equilibrium shifts to the right = inc (A-)
- can enhance excretion of drugs by trapping it in the kidney in its (A-) form
- inc pH = dec H+ = equilibrium shifts to the right = inc (A-)
- Clinical relevance?
- Intravenous (IV) sodium bicarbonate can be used to raise urine pH (e.g. from 6 to 8) and can help treat overdose of weak acid drugs (e.g. aspirin) by increasing renal drug excretion
How could you treat a patient who has overdosed on a weak base drug (e.g. amphetamine)?
- (BH+) ⇌ (B) + (H+)
- dec pH = inc H+ = equilibrium shifts to the left = inc (BH+)
- can enhance excretion of drugs by trapping it in the kidney in its (BH+) form
- dec pH = inc H+ = equilibrium shifts to the left = inc (BH+)
What do you have to consider when designing drugs?
- How much drug? (PK)
- (Where does the drug go in the body?)
- Magnitude of therapeutic and toxic effects depends on local concentration (Pharmacodynamics!), which is proportional to drug dose
- How often should drug be given? (PK)
- (How long does it last in the body?)
- Effect declines over time as drug levels decrease
- Most common measure Half-life (time for half the drug to be removed from body)
- How long should the drug be given? (Therapeutics, Influenced by PD and PK)
- (1 week? 1 month? 10 years? Rest of life?)
- Continuous drug use has associated costs (economic, side effects, toxicity)
Refer to slides 34-37 to study about concentration time curves
other side!
