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Pharmacology 1 > ADME > Flashcards

ADME Flashcards

1
Q

First order kinetic processes

A

Remove a constant proportion (percentage) of drug

  • applies to most oral and extra-vascular administrations
  • elimination rate constant primarily determines terminal drug concentrations
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2
Q

Drug disposition is composed of

A

Absorption
Distribution
Metabolism
Excretion

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3
Q

Biotransport

A

Movement of drug across biological membranes

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4
Q

Filtration

A

Open channels allow small molecules to move

  • bulk flow
  • ex: filtration of drugs at the glomerulus
  • water flows freely thru pores
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5
Q

Facilitated diffusion

A

Passive diffusion that utilizes carrier protein for the solute to cross the membrane (carries substances that would not normally cross)

  • uses no energy
  • follows concentration gradient
  • can become saturated
  • ex: glucose
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6
Q

Active transport

A

Uses carrier protein to move drug against a concentration gradient
- relies on direct expenditure of ATP as energy source

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7
Q

Pinocytosis

A

Type of endocytosis (cell drinking) used to move very large molecules in a solution inside the cell
- takes in dissolved water soluble molecules that would not normally enter the cell

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8
Q

Passive diffusion

A

Most common method of biotransport, drugs must pass 3 interfaces (phospholipid bilayer)

  • outer water-lipid interface
  • lipid membrane
  • inner water-lipid interface
  • drugs must be water soluble enough to enter aqueous solutions, but lipid soluble enough to traverse lipid membrane*
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9
Q

What allows a substance to cross the lipid membrane?

A

Lipid solubility

all drugs are water soluble

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10
Q

What attributes must a drug have for biotransport by passive diffusion?

A
  • small: diffusion coefficient inversely related to sq root of MW
  • unbound (free) drugs
  • lipid solubility
  • unionized
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11
Q

What effect does protein binding of a drug have on its ability to passively diffuse?

A

Most drugs are nonspecifically bound to proteins (acidic drugs bind to albumin, basic drugs bind to glyco/lipoproteins)

  • weak (reversible) binding via electrostatic interactions, van der Waals, hydrogen binding
  • drug-protein complex is too large to allow for passive diffusion
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12
Q

Regarding drug binding, is bound, unbound (free), or both in an active state to interact with receptors?

A

Unbound*

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13
Q

Fick’s Law of diffusion

A 
dQ/dt = rate of diffusion
A = surface area of membrane
h = membrane thickness
D = diffusion coefficient
Characteristics of solute (drug): 
Kp = partition coefficient
C1-C2 = concentration difference for solute
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14
Q

Rate of diffusion characteristics

A
  • larger the surface area = greater rate of diffusion
  • thicker the membrane = slower rate of diffusion
  • diffusion coefficient = characteristics of membrane
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15
Q

Lipid-solubility

A

Oil:water partition coefficient

- greater partition coefficient, higher the lipid-solubility of the drug, and the greater its diffusion across membranes

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16
Q

Most drugs are ______

A

Weak acids or weak bases

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17
Q

Unionized characteristic

A

Ionized particles attract water –> cannot pass thru lipid bilayer
- fraction of drug that is unionized depends on chemical nature, pKa, and local pH

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18
Q

Brodie pH partition hypothesis

A

Uses Henderson-Hasselback equation to predict drug concentration across a membrane

  • acidic drugs concentrate on more basic side of membrane (outside cell)
  • basic drugs concentrate on more acidic side of membrane (inside cell)
  • need to know the pKa and the pH)
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19
Q

Clinical application of Brodie pH partition hypothesis

A

Basic drugs penetrate intracellularly better than acidic drugs
- ion trapping can be used to enhance renal elimination of a drug or toxin

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20
Q

pKa

A

pH at which half of a molecule is in its ionized form

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21
Q

Bioavailability versus bioequivalence

A

Bioavailability: fraction of drug absorbed (F)
Bioequivalence: refers to extent of absorption (bioavailability) and rate of absorption

22
Q

A drug is considered to be absorbed when it enters _________

A

Central circulation

23
Q

Generic formulations must show _______ to pioneer product in order to be approved

A

Bioequivalence

24
Q

First pass effect

A

Removal of the drug by the liver before it enters the central circulation after oral dosing

25
Q

____ and _____ administration may bypass the first effect

A

Rectal and buccal

26
Q

What is enterohepatic recirculation and how does it affect bioavailability?

A

Drug already in the central circulation is removed by the liver but then reenters the circulation

  • falsely increases value of F to greater than 100%
  • give activated charcoal to prevent drugs/toxins from being reabsorbed
27
Q

Diffusion limited distribution

A

Distribution is diffusion (permeability) rate limited when:

  • drug is ionized and polar (water soluble), such that physiological barriers restrict the diffusion of such drugs into the cell
  • most drugs
28
Q

Perfusion limited distribution

A

Perfusion rate is the volume of blood that flows per unit time per unit volume of the tissue (ml/min per kg of tissue)

  • greater blood flow = faster distribution
  • extent to which a drug is distributed in a particular tissue depends on the size of the tissue and the tissue blood partition coefficient of the drug
29
Q

Distribution is perfusion rate limited when

A
  • drug is highly lipophilic

- drug is easily diffused through highly permeable membrane (capillaries, muscles)

30
Q

Restricted vascular space (category 1)

A

Most restrictive

  • can not pass thru endothelium
  • drugs bound to blood constituents (ex: protein bound portion of drug)
  • rare (ex: hetastarch)
31
Q

Restricted to extracellular space (category 2)

A

Free portion of drug with moderate protein binding able to pass thru endothelium

  • limited lipid solubility (primarily water soluble)
  • highly ionized
  • ex: penicillin, does not cross inside cell, but can move into extracellular fluid
32
Q

Category 3

A

Crosses most cell membranes and tissue barriers

  • moves into WBC, overcomes blood-placenta, blood-milk, blood-prostate barriers
  • free portion of drugs with moderate protein binding
  • moderate lipid solubility
  • unionized drug (ion trapped, as tissue pH is acidic vs plasma)
33
Q

Category 4

A

Crosses all barriers

  • blood brain, blood aqueous humor, blood testicular barriers
  • highly lipid soluble, low protein binding, non ionized
34
Q

How do neonates differ from adults relative to percentage of body water and how might this affect the dose of a water-soluble drug given to a neonate

A

Neonates have a larger percentage of body water

  • larger Vd for drugs that distribute primarily to extracellular space (cat 2 distribution)
  • lower albumin –> lower protein binding and greater distribution with greater excretion (unbound drug)
35
Q

How effective is the blood-placental barrier against penetration of most drugs?

A

No barrier!

- exception: heparin

36
Q

Storage sites for drugs

A
  • fat
  • bone: chelation to calcium, or active transport using calcium transporter
  • stored drug is biologically inactive until mobilized
37
Q

How do lipid soluble drugs differ from water soluble drugs regarding absorption and excretion?

A

Lipophilic: readily absorbed/stored
Hydrophilic: readily excreted

38
Q

Major routes of elimination

A 
Kidney
- filtration, secretion, reabsorption
- pH influence
Liver
- digestive tract (feces)
39
Q

Urine and feces are ________

A

Aqueous media

- lipophilic agents cannot partition into urine or feces and cannot be excreted (bioaccumulation)

40
Q

____ has a large influence on reabsorption

A

pH

41
Q

Minor routes of elimination

A
  • respiratory tract (major route for volatile anesthetics)

- tears, sweat, milk

42
Q

Which domestic animals are born with renal function near adult levels?

A

Foals and ruminants

- GFR adult at 2 days, secretion adult at 2-4 days

43
Q

Which domestic animals are born with hepatic function near adult levels?

A

Foals

- rapid hepatic metabolic development occurs in the first 3 days of life

44
Q

What is biotransformation

A

Metabolism

  • chemical alteration of molecule
  • tissues: liver most active, kidney, skin, intestine, adrenal are moderately active
  • enzyme-mediated (protein, chemical catalyst, lowers activation energy for rxn)
45
Q

Cytochrome P450

A

Enzyme family with broad substrate specificities

  • most significant of all drug oxidation reactions
  • important in detoxification of many compounds
  • can cause bioactivation
46
Q

In what organ does biotransformation primarily occur?

A

Liver

47
Q

Does biotransformation always inactivate a drug?

A

No, could result in no change in toxicity or result in greater toxicity

48
Q

Phase 1 of biotransformation rxn

A

Nonsynthetic reaction

  • adds or uncovers a reactive group
  • makes molecule more chemically reactive, metabolite can be same, less, or more active
  • more likely to undergo phase 2 metabolism
  • oxidation or hydrolysis
49
Q

Phase 2 of biotransformation rxn

A

Synthetic reaction

  • adds an endogenous ligand
  • makes more polar and water soluble, and usually detoxifies
  • ligand interacts with reactive group and metabolite is inactive (rare exceptions)
  • conjugation reactions
50
Q

Cats are deficient in what enzyme system involved in biotransformation? State an example where this deficit makes cats more susceptible to drug toxicity

A

Glucuronyl transferase

  • metabolism of many drugs altered, leading to toxicity
  • ex: acetaminophen toxicity, if body has enough glutathione then body is safe, if not intermediates build up and covalently bind leading to cell death
51
Q

Enzyme inhibitor

A

Decreases activity of metabolic enzymes, thereby decreasing the rate of metabolism of other drugs
- immediate onset due to chemical reaction

52
Q

Enzyme inducer

A

Increases the amount of enzymes available for metabolism, thereby increasing the rate of metabolism of itself (autoinduction) or other drugs (induction)
- requires several weeks

Pharmacology 1 (15 decks)

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