- usually expressed as the dissociation constant (Kd) • KD=concentration of free drug at which half of the receptors are bound • Concentration of free drug (D) • Concentration of free receptors (R) • Concentration of bound drug-receptors (DR) • Expressed in molar units (µM, nM, pM)

Exam 3: Basic of Pharmacokinetics I Flashcards by Angelise Hicks

Histamine H2 receptor

-Type of receptor: This is a GPCR really only present significantly in the GI tract
• Stomach
• Small intestine

Its endogenous ligand is histamine
Histamine stimulates gastric acid production

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Famotidine H2 receptor

It is a competitive antagonist for histamine
• It blocks histamine from binding, hence less acid is
produced
• It is used to treat GERD

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H2 receptors are

transmembrane proteins
•A single peptide with seven membrane spanning regions.
•Ligand binding initiates release of GDP from G-protein subunits from the intracellular side and allows binding instead to GTP
•The result is an increase in activity of adenylyl cyclase.
•Response time: Slow with a duration of seconds to min

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GABAa receptor

This is a ligand-gated ion channel expressed in the brain•Its endogenous ligand is gamma-aminobutyric acid (GABA)
•GABA is an inhibitory neurotransmitter
•When GABA binds, it allows chloride ions to pass
•This inhibits neurotransmission
•Response time: Rapid with a duration of milliseconds

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Zolpidem is what

is a GABAa receptor agonist
- It binds allosterically to GABAA and helps GABA bind
•This inhibits neurotransmission above and beyond natural levels
•It is used to treat insomnia

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GABAs is a protein with

five subunits (a,B, y’s) that are combined to yield a functional receptor

It has two binding sites for its endogenous ligand GABA that effect Cl- passage through a central pore
It has one allosteric binding site for benzodiazepines

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Pharmacokinetics

What body does to drug
The relationship between dose and effect ( dose-concentration)

-ADME

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Pharmacodynamics

What drug does to the body
Concentration-effect
-Receptor-Drug interactions
- Cell signaling/2nd messenger
-Receptor expression/gene regulation
- Potency and Efficacy

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Affinity

usually expressed as the dissociation constant (Kd)
• KD=concentration of free drug at which half of the receptors are bound
• Concentration of free drug (D)
• Concentration of free receptors (R)
• Concentration of bound drug-receptors (DR)
• Expressed in molar units (µM, nM, pM)

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A small/low Kd indicates

high affinity

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Formula for finding Kd

Kd = [D][R] / [DR]

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As we increase the drug concentration,

we increase the amount of receptor binding

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More drug-bound receptor equates

to greater biological effect

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Increase in dose results in

increase in plasma conc. which increases the response/effect

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EC50

The drug conc. at which yields 50% maximal response

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If the receptor has lower affinity for a drug

it will require more of that drug to bind to the same number of receptors

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Potency

amount of drug (conc.) needed to produce a certain effect

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Efficacy

maximal effect a drug produces regardless of dose

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ED50

dose that is therapeutically effective in 50% of the population

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TD50

Dose that causes toxic effects in 50% of the population

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LD50

Dose that is lethal in 50% of the population (animal)

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Therapeutic Index

Ratio between toxic dose and effective dose

• Therapeutic Index (TI) = TD50/ED50

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Is it preferable to have:
A. a high therapeutic index or
B. a low therapeutic index?

A. a high therapeutic index

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Absorption

Dissolution/liberation of drug from formulation
• Gastric emptying
• Passive/facilitated/active transport through intestinal wall

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Metabolism

* Intestinal microbiota * Enterocyte enzymes * First pass effect

Distribution

* Highly perfused tissues - Blood, liver, kidney, heart, lungs * Poorly perfused tissues - Fat, muscle, CSF

Excretion

Filtration/secretion into urine | • Biliary excretion

Cmax

Max observed plasma drug conc.

Tmax

Time it takes to reach Cmax

MTC

Maximum Therapeutic Concentration

MEC

Minimum Effective Concentration

MTC-MEC

Therapeutic window/range

Latency/ Onset of effect

How long it takes to get to Minimum Effective Concentration (MEC)

Serum

soluble components of blood obtained after clotting and centrifugation

Plasma

soluble components of blood, clotting factors are inactivated (i.e.-fibrinogen)

Buffy coat

WBCs and platelets

Whole blood

Consists of: - WBCs - RBCs - platelets - plasma proteins - small molecules - ions - water

Concentration is

mass / volume mass of drug = amount of drug (mg) Volume (Units= L, mL and cc)

Blood volume

5 L

Plasma volume

Blood - cells = 2.5 L

Hemocrit

% of blood volume that cells take up

By what route of administration do we assume 100% absorption?

IV bolus

Soluble substances will partition more into

the plasma

Insoluble substances will partition/ go into

fat

Volume of distribution

Theoretical volume that the drug homogeneously distributes into - How large of a volume is needed to account for the observed plasma concentration given the introduced dose

Volume of distribution (Vd) formula

Vd = Amount of drug (mg) / [Conc] (mg/L) Amount of drug absorbed on top Plasma Conc. (C0, (mg/L)) - Assumes 100% absorption

Intravascular

within blood vessels

Plasma

fluid between RBCs and WBCs in the blood

Intracellular fluid

fluid within RBCs and WBCs

Extravascular

outside of blood vessels

Interstitial fluid

fluid between tissue cells in the extravascular space

Intracellular fluid

fluid within tissue cells

Body Composition

Fluids make up 60% of body weight - Of this ~ 35% is intracellular fluid Blood volume is 2x of plasma

Whole body has how many liters

40 L

If the drug is highly water soluble, it will be retained where?

- largely in the aqueous media of the body | - will have a higher plasma concentration and a low VD

If the drug is highly lipid soluble, it will partition into

tissues and fat, hence will have a lower plasma concentration and a high VD

A low Vd will have a

higher plasma conc.

A high Vd will have a

Low plasma conc. and will partition into the tissues and fats

• If the VD is very small, then the drug is largely present

in the intravascular fluid (plasma) only and doesn’t partition much into the intracellular fluids

If the VD is 18 L, then the drug is largely present

in the total extracellular fluids only and doesn’t | partition much into the intracellular fluids

If the VD is ~40 L, then the drug is largely present

in all body fluids and not in the tissues

Loading dose

Drug plasma conc. x Vd - dose needed if we have the desired plasma conc. and the Vd

Characteristics of drugs in the blood

Drug distribute to organs, but it also can distribute to cells within whole blood - A drug is twice as concentrated in the plasma

Drug conc. in the plasma

Plasma conc. may not be the same as Blood conc. Blood: Plasma ratio Ratio of conc. of drug in whole blood (cells + plasma) versus that in the plasma only Plasma proteins reside in the plasma – not in the cellular components

Chloroquine

its an anti-malarial - it partitions into and is sequestered by RBCs leaving less drug in the plasma - Yields a blood: plasma ratio greater than 1:1

Warfarin

- is an anti-coagulant agent • Prevents oxidized vitamin K from becoming reduced • Prevents formation of clotting proteins • Warfarin is highly plasma protein bound • It remains sequestered in the plasma • This would yield a blood:plasma ratio <1:1

Intracellular fluid has what volume

24.5L- volume | 35%

Extracellular fluid

18 L-volume | 25%

Interstitial fluid is what % of body

21%-volume

Plasma

4% | 2.5 L- Volume

Exam 3: Basic of Pharmacokinetics I Flashcards

(70 cards)