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PTCH 201 > 3. Pharmacokinetics > Flashcards

3. Pharmacokinetics Flashcards

1
Q

What are the 4 major phases influencing “free” (unbound) plasma [drug] as a function of time

A
  • 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.

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2
Q

Pharmacokinetics

A
  • 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

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3
Q

What is the absorption phase and what is it influenced by?

A
  • 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)
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4
Q

What is the Route of Administration (ROA) based on?

A
  • 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
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5
Q

What are Enteral and Parenteral ROAs? Tell the many ways of ROA examples.

A
  • 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
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6
Q

How do drugs cross membranes and why do we need it to cross? What are the requirements?

A
  • 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
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7
Q

Explain drugs as acids and bases

A

*please see slide 12 and 13

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8
Q

What happens after the drug gets absorbed?

A
  • 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
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9
Q

What is the distribution phase and what is it influenced by?

A
  • 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
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10
Q

Explain the binding in drugs and proteins.

A
  • 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

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11
Q

explain tissue perfusion

A
  • 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
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12
Q

What would happen to distribution in pathological states involving decreased circulation/tissue perfusion?
- since it take the most time to get drug

A
  • inc amount of [ ]
  • Muscle is an important site of accumulation (that can vary by individual based on gender, age, pathology and other considerations
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13
Q

What is metabolism

A

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

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14
Q

What are the 2 major enzyme-catalyzed processes

A
  • 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.

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15
Q

What is Phase I Metabolism and what does it do?

A
  • 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

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16
Q

Explain CYP450 Enzyme Induction

A
  • Inducers INCREASE enzyme activity
    • Rate of metabolism speeds up
    • Drug is removed from body faster
17
Q

Explain CYP450 Enzyme Inhibition

A
  • Inhibitors decrease enzyme activity
    • Rate of metabolism slows down
    • Drug stays in body for longer
18
Q

What is Phase II metabolism? What does it do to the drug?

A
  • 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
19
Q

What are the steps from parent drug to excretion? (metabolism)

A
  • 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

20
Q

What is Excretion?

A
  • 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
21
Q

refer to slide 27 and 28 for summary of the 4 major phases

A

other side!

22
Q

What are the 2 clinical applications of pharmacokinetics?

A
  1. Treating a drug overdose
  2. Designing drug dosing regimens
23
Q

Which form of weak acid is absorbed and which is excreted? What about for weak bases?

A
  • weak acid
    • (HA) <–> (A-) + (H+)
      • HA is absorbed
      • A- is excreted
  • weak base
    • (BH+) <–> (B) + (H+)
      • B is absorbed
      • BH+ is excreted
24
Q

What will happen to the equilibrium of a weak acid drug if the surrounding pH is increased?

A
  • (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
  • 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
25
Q

How could you treat a patient who has overdosed on a weak base drug (e.g. amphetamine)?

A
  • (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
26
Q

What do you have to consider when designing drugs?

A
  • 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)
27
Q

Refer to slides 34-37 to study about concentration time curves

A

other side!

PTCH 201 (7 decks)

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