drug distribution, metabolism and excretion

what is drug distribution?

the process by which a drug is transferred from the bloodstream and into the tissues

what does the rate, sequence and extent of distribution depend on?

1. blood flow

2. ability of the drug to pass biological membrane (based on the polarity and size of the drug)

3. binding of the drugs to plasma proteins

how is distribution affected by blood flow?

as blood flow increases, so does drug distribution. as it decreases, so does distribution

what organs are highly vascularized, facilitating rapid initial exposure to systemic drugs?

• lungs

• liver

• brain

what parts of the body have a low perfusion rate, making it difficult to distribute systemic drugs?

• adipose tissue

• skeletal muscle

what is an example of an organ that is highly permeable?

the liver, which has large fenestrations between the endothelial cells of the blood vessels, which allows the drug to exchange freely between blood and interstitium. as a result, most drugs can easily access liver cells for metabolism.

what is an example of an organ that is highly selective?

the brain, as the capillaries are continuous and the endothelial cells are tightly packed and connected by tight junctions, with virtually no gaps (slit junctions) between them, which forms the BBB, or the blood brain barrier

for drugs to cross the BBB, what is required?

they must be either highly lipid soluble or be actively transported to the brain

what can drugs bind to?

reversibly to plasma proteins

what are bound drugs considered to be?

pharmacologically inactive

what are free drugs considered to be?

pharmacologically active

what is the nature of bonding between drugs and plasma proteins?

a reversible and non-specific process

drug + plasma protein = ?

Drug–Protein Complex

what plasma protein do acidic drugs mainly bind to?

albumin

what plasma protein do acidic drugs mainly bind to?

α₁-acid glycoprotein and β-globulins

what type of relationship is there between bound and free drugs?

a dynamic one, as when the free drug concentration is decreased, some of the bound drug dissociates and becomes free, maintaining a relatively constant active drug level in the blood.

how can displacement by another drug increase free drug concentration?

a second drug with higher affinity for plasma proteins can displace the first drug, which increases the free (active) concentration of the displaced drug → may lead to toxicity.

what is an example of displacement of the free drug concentration by another drug?

aspirin displaces warfarin, an anticoagulant, due to high affinity to plasma proteins, increasing Warfarin toxicity and bleeding

how can a decrease in plasma proteins increase free drug concentration?

seen in conditions such as liver disease, malnutrition or severe illness, less protein available → less binding → more free drug → increased drug effect/toxicity.

what is the volume of distribution?

the apparent volume of fluid into which an administered drug is dispersed, following the formula Vd​ = Q/Cp

What does the formula Vd = Q / Cp represent?

total amount of drug in the body divided by plasma concentration of drug equals the volume of distribution of a drug

what does high Vd mean?

the drug has low affinity to binding to plasma protein. it means the drug is widely distributed into tissues and there is a low concentration in plasma

what does low Vd mean?

the drug has high affinity to binding to plasma protein. it means the drug remains mainly in the blood (plasma) and there is a high concentration in plasma

what is drug redistribution?

after administration, a drug first distributes to highly perfused organs (e.g., brain, liver, kidneys), then redistributes to less perfused tissues (e.g., muscle, fat).

what is an example of drug redistribution?

Thiopental is an ultra-short acting anesthetic. it rapidly enters the brain, causing anesthesia, before being quickly redistributed to the rest of the body, leaving the brain, leading to rapid loss of effect, even though the drug is still in the body

what is drug metabolism?

the biochemical transformation of the compound to another chemical form that is usually more polar (water-soluble) than the original molecule

for the most part, what do metabolic reactions generate?

more polar and inactive metabolites that are readily excreted from the body. in some cases, metabolites with potent activity or toxic effect are generated

what does hepatic metabolism consist of?

it takes places in the hepatic smooth ER. processes included are oxidation via cytochrome P450, reduction, hydrolysis, dehalogenation and conjugation by Glucuronidation (only / mainly)

what does non hepatic metabolism consist of?

it takes place in the lungs, kidneys, skin and plasma. processes included are oxidation, reduction, and all conjugations except for Glucuronidation

what occurs during phase I of drug metabolism?

reactions introduce or expose functional groups (e.g., –OH, –NH₂), making the drug more polar. they are:

1. oxidation

2. reduction

1. hydrolysis

2. dehalogenation

what is an example of an oxidation reaction?

phenacetin → acetaminophen

what is an example of an reduction reaction?

chloral hydrate → tri-chloroethanol

what is an example of an hydrolysis reaction?

acetylcholine → choline + acetic acid

what is an example of an dehalogenation reaction?

halothane → trifluoroacetyl chloride

what occurs during phase II of drug metabolism?

the reactions combine the drug with endogenous substances to increase water solubility and facilitate excretion. they include conjugation

what are some examples of conjugation?

1. acetylation with acetic acid, with an example of a drug undergoing this being isoniazid

2. methylation, with an example of a drug undergoing this being noradrenaline

3. glucuronidation (with glucuronic acid), with an example of a drug undergoing this being chloramphenicol

what are the outcomes of drug metabolism?

1. inactivation

2. activation

3. maintain activation

4. toxification

inactivation of a drug during metabolism

an active drug is turned into an inactive metabolite. example:

• acetylcholine → choline + acetic acid

activation of a drug during metabolism

an inactive / less active drug is activated into an active metabolite. example:

• imipramine → desipramine

maintaining activation of a drug during metabolism

an active drug is maintained as an active metabolite. example:

• phenacetin → acetaminophen

toxification of a drug during drug metabolism

a non-toxic drug produces a toxic metabolite during metabolism. example:

• methanol → formaldehyde

what is the mechanism of phase I?

the reactions that occur during this phase introduce a functional group to the drug molecule, leading to (in most cases) a more polar form, and it generally results in the loss of pharmacological activity, however, there are some drugs that have enhanced activity where the metabolite is more reactive and sometimes more toxic than the parent drug

what are the enzymes responsible for phase I metabolic reactions and where are they present?

they are mostly present in the endoplasmic reticulum (microsomes) of the liver and are known as microsomal enzymes

what is the main system of microsomal enzymes?

• cytochrome P450 (CYP450)

• also called mixed-function oxidases (MFO)

where are non-microsomal enzymes located and what is their function?

they are present in the cytoplasm, mitochondria, plasma and intestine and are involved in phase I and phase II reactions

are microsomal enzymes induced or inhibited by drugs?

yes:

• if the enzymes are induced, metabolism is increased

• if the enzymes are inhibited, metabolism is decreased

are non-microsomal enzymes induced by drugs?

they are not induced

what occurs when enzyme induction of microsomal enzymes (CYP450) occurs?

some drugs increase (induce) the activity of liver enzymes (especially CYP450), leading to faster metabolism of drugs.

what are some common enzyme inducers?

1. phenytoin

2. rifampicin

3. barbiturates (e.g., phenobarbital)

4. carbamazepine

what is auto-induction?

some drugs may induce their own metabolism (metabolic tolerance) and/or the metabolism of other drugs leading to reduced activity of those drugs

what occurs when enzyme inhibition of microsomal enzymes (CYP450) occurs?

some drugs inhibit liver enzymes (CYP450) → leading to reduced metabolism of other drugs or endogenous substances.

what are some common enzyme inhibitors?

1. omeprazole

2. erythromycin

3. chloramphenicol

4. isoniazid

5. cimetidine

what can inhibition of enzymes lead to?

reduced metabolism of other drugs or endogenous substrates (ex: testosterone) leading to enhancement of the activity or even toxicity of some drugs

what is phase II of drug metabolism?

conjugation reactions, where the drug (or its Phase I metabolite) is combined with an endogenous substance (e.g., glucuronic acid, sulfate, acetyl group).

what is the relationship between phase I and phase II of drug metabolism?

if the metabolite produced in phase I is sufficiently polar (water-soluble), it can be directly excreted by the kidneys, however, if it is still lipophilic (not water-soluble enough), it undergoes phase II

so what is the purpose of phase II reactions?

convert drugs into highly water-soluble (polar) compounds and facilitate renal excretion

in phase II, what are drugs or their phase I metabolites conjugated with?

endogenous substrates such as glucuronic acid, sulfuric acid or amino acid, as they will result in polar, usually more water-soluble, pharmacologically inactive and readily excretable molecules of the drugs

what is the most common conjugation reaction?

glucuronidation

who are deficient or immature conjugating systems?

neonates

due to neonates deficient / lacking in conjugating systems, what does that cause?

reduced drug metabolism, making them at high risk of toxicity

what does chloramphenicol cause in neonates?

since it cannot be properly conjugated, it accumulates and causes Gray baby syndrome when given to neonate

what are some routes of drug elimination?

1. the kidneys via urine, which is the most common and important route

2. biliary, with drugs being secreted into bile and eliminated in feces

3. sweat

4. saliva

5. exhalation (lungs)

6. tears

7. breast milk

what is an example of a drug excreted via feces?

morphine

what is an example of a drug excreted via exhalation?

1. nitrous oxide

2. halothane

what is an example of a drug excreted via breast milk?

1. nicotine

2. morphine

what is an example of a drug excreted via sweat?

rifampicin

what form are drugs eliminated as?

either unchanged or as their metabolites.

what type of compounds are readily excreted?

polar compounds, while non-polar compounds are not excreted until metabolized to more polar compounds

how does renal excretion in the kidneys occur?

by 3 main processes:

1. glomerular filtration

2. proximal active tubular secretion

3. distal passive tubular reabsorption

glomerular filtration

for water soluble non bound drugs

proximal Tubular Secretion (Active)

occurs in the proximal tubule and is an active transport system (energy-dependent). can eliminate even protein-bound drugs. an example of a drug excreted at this stage is penicillin

distal Tubular Reabsorption (Passive)

occurs in the distal tubule and is the passive diffusion back into blood and it mainly affects lipid soluble drugs

when does tubular reabsorption occur?

in the proximal and distal tubules, and it is a passive process and only unionized (lipid-soluble) drugs can diffuse back into blood

what happens to ionized drugs?

they are trapped in the urine and excreted

what happens to weak acids in alkaline urine?

they are ionized and readily excreted, so for example, aspirin is better excreted in alkaline urine

what happens to weak bases in acidic urine?

weak bases become ionized and ionized drugs are more readily excreted

why is Sodium bicarbonate (NaHCO₃) given in aspirin overdose?

it alkalinizes urine, allowing the aspirin to be excreted

what occurs during biliary excretion?

many drugs that are formed in the liver are excreted into the intestinal tract through bile

how are drugs excreted into the bile?

via active carrier systems which are specific and many drugs may compete for the same transport system, giving rise to drug interactions

what is enterohepatic circulation?

many hydrophilic drug conjugates, especially glucuronide, are concentrated in bile and excreted in the intestine, where the glucuronide is hydrolyzed, releasing the free drug once more, which can be reabsorbed and the cycle is repeated