- process where the absorbed chemical moves away from the site of absorption to other areas of the body - process by which a drug is transferred from the blood stream (plasma) to tissues (interstitial fluid and cells)

Pharmacokinetics- Distribution Flashcards by Patricia Singh

Define Distribution

process where the absorbed chemical moves away from the site of absorption to other areas of the body
process by which a drug is transferred from the blood stream (plasma) to tissues (interstitial fluid and cells)

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What do the rate and degree of drug distribution depend on?

Hint: CAMP B

C: capillary permeability
A: accumulation in and redistribution to other sites
M: miscellaneous factors (i.e. age, obesity, diet, etc.)
P: protein binding (i.e. to albumin)

B: blood flow

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What is Re-distribution?

when well-perfused organs initially receive most of the drug before being received by lesser perfused organs
results in the termination of drug action

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What are the well-perfused organs?

Hint: BLacK

B: brain
L: liver
K: kidney

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What are the lesser-perfused organs?

Hint: MS VF

M: muscle
S: skin

V: (most) viscera
F: fat

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Where would the drug likely be found if there are very large drug molecules?

drug confined to circulation

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Where would the drug be if drug molecules are very polar?

drug excluded by cell membrane

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Where would the drug be if drug is lipophilic?

in fat within the cells

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Why is drug distribution not uniform throughout the body?

because different tissues receive the drug from the plasma at different rates and to different extents

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Define Volume of Distribution (Vd)

apparent volume of distribution
theoretical volume that would be necessary to contain the total administered drug at the same concentration as seen in the plasma
predicts whether drug will reside in blood or tissue

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Where will water soluble drugs reside?

the blood

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Where will lipid soluble drugs reside?

Hint: CAFe

C: cell membrane
A: adipose tissues
F: fat-rich areas

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What is the Vd for drugs that are charged?

tend to bind to serum proteins -> increase in molecular size -> does not pass through cell membrane easily -> confined to circulation

low Vd

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What is the Vd of hydrophilic or charged drugs?

low Vd

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What is the Vd if there is an underlying disease of renal failure?

increased Vd

- due to fluid retention

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What is the Vd if there is an underlying disease of liver failure?

increased Vd

- due to altered body fluid and plasma protein binding

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What are factors that affect Vd?

Hint: MALT PWP

M: molecular weight of drug
A: acidity
L: lipid solubility
T: tissue perfusion

P: pathological condition
W: water solubility
P: plasma protein binding

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Explain how the molecular weight of a drug affects Vd

low molecular weight of drugs -> high Vd (can pass through pores)
high molecular weight -> low Vd

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Explain how the acidity of a drug affects Vd

acidic drugs have low Vd (high affinity for albumin)

- basic drugs have high Vd (high affinity for alpha-1 acid glycoprotein / free drug)

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Examples of acidic drugs

Hint: Basic drugs don’t Bind To Plasma Very Fast

Basic: bilirubin
Bind: bile acids
To: tetracycline
Plasma: penicillin
Very: Vitamin C
Fast: fatty acids

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What do acidic drugs have high affinity for (blood binding)?

plasma albumin

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What do basic drugs have high affinity for (blood binding)?

alpha-1 acid glycoproteins

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Explain how lipid solubility of a drug affects Vd

lipid soluble drugs have high Vd

- can move through the plasma membrane freely

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Explain how tissue perfusion of a drug affects Vd

low tissue perfusion means low Vd

- high tissue perfusion means high Vd

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Explain how pathological conditions may affect Vd

e.g. in edematous conditions, water soluble drugs have high Vd

Explain how water solubility of a drug affects Vd

- water soluble drugs have low Vd | - due to the inability to cross the plasma membrane on its own

Explain how plasma protein binding (PPB) of a drug affects Vd

- high PPB of a drug means low Vd (increases the molecular size -> cannot pass through pores) - low PPB of a drug means high Vd

What is the affect of lipid solubility of a drug on redistribution?

- the greater the lipid solubility of the drug, the faster its redistribution

Define Bioavailability

fraction of the administered drug that reaches the systemic circulation

Define Absolute Bioavailability

compares the bioavailability of the active drug in systemic circulation following non-IV administration vs the same drug with IV administration

When will the bioavailability of a drug be 100%?

when the drug is administered intravenously

What is the purpose of absolute bioavailability?

to determine the best route of administration

Define Relative Bioavailability

compares the bioavailability of formulation A of a certain drug compared with another formulation B (of the same drug)

What is the difference between Absolute Bioavailability and Relative Bioavailability?

- absolute bioavailability: compares bio-availabilities of (the same) active drug administered via non-IV vs IV - relative bioavailability: compares bio-availabilities of formulations of the same drug

Define Bioequivalence

when two related drugs show comparable - bioavailability - similar times to achieve peak blood concentrations

Define Therapeutic Bioequivalence

when two similar drugs show comparable - efficacy - safety

What are factors that influence bioavailability? Hint: FSCN (like fasten)

F: first-pass hepatic effect S: solubility C: chemical instability N: nature of the drug formulation

How does the first-pass effect influence bioavailability?

- drug absorbed from the GI tract is first delivered to the liver before entering the systemic circulation - liver is where metabolism occurs -> if the drug is rapidly metabolised, the amount of unchanged drug that enters the system circulation is decreased - > greater the first-pass effect = less drug to reach systemic circulation

Under what circumstances does hepatic first-pass effect take place?

when drug is administered orally

When does the drug bypass first-pass effect?

when administered via: - IV - IM rectal - sublingual

How does the solubility of the drug influence bioavailability?

- hydrophobic drugs (increase bioavailability) | - hydrophilic drugs (decrease bioavailability)

How does chemical instability influence bioavailability?

instability decreases bioavailability i. e. - penicillin G is unstable in pH of gastric contents - insulin is destroyed in the GI tract by degradative enzymes

How does the nature of the drug formulation influence bioavailability? Hint: PEE

nature of drug formulation includes- P: particle size E: enteric coatings E: excipients - can influence ease of dissolution -> therefore altering the rate of absorption

How are drugs transported in the blood?

- free form | - bound form

What is the free form of a drug? Hint: DAA

- diffusible - active - available for metabolism and excretion

What is the bound form of a drug?

- bound to plasma albumin - inactive - neither metabolised nor excreted

What can protein binding be divided into?

- intracellular binding | - extracellular binding

What is the significance of plasma-protein binding?

- affects distribution (cannot pass through capillaries and cell membranes due to large molecular size) - inactive - non-diffusible - not available for metabolism nor excretion - reservoir (supplies free drug when required- stays within circulation longer)

True or False: | The plasma-protein binding of drugs can be irreversible.

True | - binding of drugs to proteins is generally reversible & irreversible

What constitutes for an irreversible plasma-protein binding of a drug?

- when there is a covalent binding (rare)

What constitutes for a reversible plasma-protein binding of a drug?

weak chemical bonds - hydrogen bonds - hydrophobic bonds - ionic bonds - Van der waal's forces

What happens when a irreversible plasma-protein binding occurs with a drug?

- carcinogenicity or tissue toxicity

What drug can bind to both primary and secondary site of albumin?

flucoxacillin

What drug has three different binding sites on albumin?

indomethacin

Example of basic drugs Hint: LIP

L: lidocaine I: imipramine P: propranolol

How do drugs bind to lipoproteins?

via hydrophobic bonds

What does alpha-1 globulin bind to?

steroidal drugs

What does alpha-2 globulin bind to?

Vitamins K, A, D, E

What does Beta-1 globulin bind to?

ferrous ions

What does Beta-2 globulin bind to?

carotinoids

What does gamma-globulin bind to?

antigens

How are some drugs displaced by other drugs?

drugs with high affinity for plasma proteins can displace other drugs/endogenous compounds that have lower affinity