Drug Distribution COPY Flashcards by David Brennan

What must a drug do to be active

Leave the blood stream and enter the inter or intracellular spaces

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What is drug distribution

The Reversible Transfer of a Drug between the Blood and the Extra Vascular Fluids and Tissues of the body (e.g. fat, muscle, and brain tissue)

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What factors determine tissue distrubution

Plasma protein binding
Tissue perfusion
Membrane characteristics
Transport mechanisms
Diseases and other drugs (esp renal failure, liver disease, obesity)
Elimination

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What type of membrane characteristics are there

Blood-brain barrier

Blood-testes/ovary barrier

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Give examples of drugs which bind to proteins in plasma

Many drugs do this
Albumin
Alpha 1-glycoprotein (e.g. phenytoin)

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In what sate are drugs biologically active

Unbound

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Is plasma protein binding reversible

Yes

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How can the amount of bound drug be changed

By:
Renal failure
Hypoalbuminaemia
Pregnancy
Other drugs
Saturability of binding

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What parameters need to be characterised when considering therapeutic range

Volume of distribution
Clearance
Half-life

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What is Vd

Apparent volume of distribution

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What is volume of distribution

The volume of plasma that would be necessary to account for the total amount of drug in a patient’s body, if that drug were present throughout the body at the same concentration as found in the plasma (L/kg)

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What does it mean if the Vd is high

A high ability of the drug to diffuse into and through membranes

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What is Cl

Clearance

The theoretical volume from which a drug is completely removed over a period of time

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How is clearance measured

Measure of elimination in units of time (ml/min)

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What is renal clearance dependent on

Concentration and urine flow rate

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What is hepatic clearance dependent on

Metabolism and biliary excretion

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What is half life (t1/2)

The time taken for the drug concentration in the blood to decline to half of the current value

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Give an example of drug half life

If it takes 4 hours for the concentration of a drug in the blood stream to drop from 10mg/L to 5 mg/L then the half life is 4 hours

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What does half life depend on

The volume of distribution and rate of clearance

What does the prolongation of the half life of a drug do

Increase toxicity of a drug because of a:
Reduction in clearance
Large volume of distribution (e.g. amiodarone)

What does the formula, t1/2 = 0.693Vd/Cl link together

The chemical properties of the drug, i.e. lipophilicity, and the ability of the body to metabolise and excrete the drug

How does knowledge of the half life of a drug help us clinically

Helps us to work out how often a drug needs to be administered

How should drugs be administered to have a therapeutic benefit

Depends on the half life
Long half life = less doses required
Short half life = more doses required

What can chronic administration cause

The plasma levels of a drug to take many doses before they stabilise, usually 4-5 half-lives
This may necessitate a loading dose

What is drug elimination

The removal of active drug and matabolites from the body | It determines the length of action of the drug

What is drug elimination made up of

Drug Metabolism | Drug Excretion

Where does drug metabolism normally take place

Liver

Where does drug excretion normally take place

Mainly kidney but also biliary system/gut, lung and breast milk

What mechanisms are used for drug excretion

Glomerular filtration Passive tubular reabsorption Active tubular secretion

About how many liters of fluid does the glomerulus filter a day

190

What happens to all unbound drug

It's filtered at the glomerulus as long as their molecular size, charge or shape are not excessively large

What effect will the factors that affect the glomerular filtration rate have on the clearance of a drug

Reduce the clearance of a drug

Which system is important for eliminating protein bound cationic and anionic drugs

The active secretion of some drugs into the proximal tubule (acidic and basic compounds)

What does the active secretion into the proximal tubule eliminate

Protein bound cationic and anionic drugs

What does passive diffusion along the concentration gradient allow

The drug to move back through the renal tubule into the circulation

Describe the features of passive tubular reabsorption

Occurs in the distal tubule and collecting duct Only un-ionised drugs such as weak acids are reabsorbed Can also be affected by renal failure

How much bile is secreted a day

1 liter by the liver

In what ways can drugs be secreted into bile

Passively or actively

How much drug elimination does biliary secretion account for

5-95%

What happens to the drugs after they have been secreted into the bile

Many are then reabsorbed from the bile into the circulation | This is called entero-hepatic circulation

What is entero-hepatic circulation

Drugs being reabsorbed from the bile into the circulation

How long does entero-hepatic circulation last for

Continues until the drug is metabolised in the liver or excreted by the kidneys

What can metabolism of the drug in the liver lead to

Conjugation of the drug

What happens to conjugated drugs

They are not reabsorbed from the intestine

What can damage to the liver cause

May reduce the rates of conjugation and biliary secretion, so allow the build up or reabsorption of the drug with resultant toxicity

Name some drugs which undergo enterohepatic recirculation

Chlordecone Morphine Phenytoin Methadone