what happens after you take a medicine - week 6

what happens after you take a medicine

what happens after you take a medicine?

ADME: four connected processes

intravenous

• IV enters blood directly

oral administration

• extracellular route requires absorption

ABSORPTION: reaching the bloodstream

Passive Diffusion

• Many drugs cross biological membranes by passive diffusion.

• Drugs move from high to low concentration.

• Movement occurs down a concentration gradient.

• No cellular energy (ATP) is required.

what is a biological membrane?

hydrophilic and lipophilic

drug properties and membrane passage

what is LogP?

1. How is it measured?

• Mix the drug with octanol and water.

• Allow the two layers to separate at equilibrium.

• Measure the drug concentration in each layer.

2. How do we interpret it?

• Higher LogP: Greater preference for octanol.

• Lower LogP: Greater preference for water.

Calculating LogP
Formula:
LogP = log₁₀(Cₒctanol / Cwater)

weak acids and weak bases

Key idea: Many drugs exist in both ionised (charged) and unionised (uncharged) forms. Their proportions depend on pH and pKa.

what do pH and pKa tell us?

pH: Indicates how acidic or alkaline the surrounding environment is.
pKa: The pH at which 50% of a weak acid or base is ionised and 50% is unionized

what is LogD?

LogD measures how a drug distributes between octanol and water at a specific pH, considering both ionised and unionised forms

what does LogP/LogD tell us about drug absorption?

Kep point: Higher lipophilicity does not always mean better oral absorption

dissolution

A drug generally needs to dissolve before it can be absorbed

surface area

the small intestine provides a large surface area for absorption (villi and microvilli)

blood supply

good blood flow helps carry absorbed drug away and maintain concentration gradients

GI pH

influence drug ionization, solubility and membrane permeability

transporters

specialized proteins help certain drugs cross biological membranes (eg. glucose, amino acids)

pH of stomach

• pH 1-3

• highly acidic environment

pH of duodenum

• pH ~5-6

• pH increases after the stomach

pH of jejunum/ileum

• pH ~6-8

• major site of absorption for many oral drugs

pH of colon

• pH ~5.5-8

• usually less absorption than the small intestine

DISTRIBUTION: where the drug travels

• drug distribution is the reversible movement of a drug from the bloodstream into the tissues and organs of the body

• blood carries the drug to different organs and tissues

• some drug molecules lave the bloodstream and enter tissues

• the drug may then reach its site of action

for example, Paracetamol is absorbed into the bloodstream after oral administration and then distributed to different tissues throughout the body.

factors that affect distribution

affect of blood flow on distribution

Highly perfused organs (e.g., brain, liver and kidneys) generally receive drugs more rapidly than poorly perfused tissues.

free drug

• Not bound to plasma proteins

• Generally available to enter tissues and interact with receptors

protein-bound drug

• Temporarily attached to proteins such as albumin

• Generally unable to cross lipid membranes while bound

reversible binding

Bound drug can detach from proteins and replenish the free drug fraction

fraction unbound (fᵤ)

albumin and acidic drugs

• albumin is a major plasma binding protein for many acidic drugs

ALPHA-1-ACID GLYCOPROTEIN (AAG)

• Binds many basic drugs

• Example: Lidocaine

ALBUMIN

• Binds many acidic drugs

• Example: Warfarin (approximately 99% protein-bound)

KEY POINT: Protein binding is reversible, and unbound drug is generally available for pharmacological activity.

CLINICAL SIGNIFICANCE
Changes in protein binding may alter the free drug concentration and influence drug effects.

blood-brain barrier (BBB)

What is the BBB?

A selective barrier formed mainly by tightly joined endothelial cells lining the brain capillaries. It controls which substances can enter the brain from the blood.

What determines drug entry?

• Tight junctions: Seal the gaps between endothelial cells, restricting substances from passing between them.

• Lipid solubility: Small, lipid-soluble drugs can cross the BBB more easily.

• Transporters: Allow certain substances to enter the brain and can pump some drugs back into the blood.

Examples

• Diazepam: Lipid-soluble, so it crosses the BBB easily and produces effects in the central nervous system (CNS).

• Loperamide: Normally has limited entry into the brain because P-glycoprotein pumps it back into the blood.

Glossary – difficult terms

• Endothelial cells: Cells that line the inside of blood vessels.

• Tight junctions: Connections that seal the gaps between neighbouring cells.

• Lipid-soluble: Able to dissolve in fats and oils.

• Transporters: Proteins that move substances across cell membranes.

• P-glycoprotein: A transporter that pumps certain drugs out of cells, limiting their entry into the brain.

• CNS (central nervous system): The brain and spinal cord.

membrane transporters - how drugs enter and leave cells

Membrane transporters are proteins embedded in cell membranes that help substances, including drugs, move into or out of cells.

Key terms:

ABC transporters: use energy from ATP hydrolysis to move various molecules across cellular membranes.

SLC transporters: family of membrane-bound proteins that control the movement of nutrients, ions, drugs, and other molecules across cell membranes

METABOLISM: changing drug molecules

The chemical transformation of drugs by enzymes, mainly in the liver.

Key points

• The liver is the principal organ responsible for the metabolism of most drugs.

• Metabolism often makes drugs more water-soluble, so they can be eliminated from the body more easily.

• Metabolism can:

  • Inactivate drugs: Make them inactive.

  • Activate prodrugs: Convert inactive drugs into their active form.

  • Produce active metabolites: Create breakdown products that still have a drug effect.

The two phases of metabolism

• Phase I: Oxidation, reduction and hydrolysis.

• Phase II: Conjugation reactions.

Glossary – difficult terms

• Enzymes: Proteins that speed up chemical reactions.

• Water-soluble: Able to dissolve in water, making elimination easier.

• Prodrug: An inactive or less active drug that is converted into an active form.

• Active metabolite: A drug breakdown product that still has an effect.

• Oxidation: A chemical reaction that often involves adding oxygen or removing hydrogen.

• Reduction: A chemical reaction that often involves adding hydrogen or removing oxygen.

• Hydrolysis: Breaking a chemical bond using water.

• Conjugation: Attaching another chemical group to a drug or its metabolite, often making it easier to eliminate.

Cytochrome P450 (CYP) enzymes – drug metabolism

What are CYP enzymes?

A family of drug-metabolising enzymes found mainly in the liver.

Key points

• Commonly involved in Phase I oxidation reactions.

• Can produce:

  • Active metabolites: Still have a drug effect.

  • Inactive metabolites: No longer have a drug effect.

  • Toxic metabolites: Can cause harmful effects.

• Changes in CYP enzyme activity can affect drug concentrations in the body and how patients respond to medicines.

Clinical example:

Codeine → CYP2D6 → Morphine (active metabolite)

CYP2D6 converts codeine into morphine, which produces the pain-relieving effect.

Key takeaway:

CYP enzymes influence how medicines are metabolised and how patients respond to them.

Glossary – difficult terms

• Cytochrome P450 (CYP): A family of enzymes involved in breaking down drugs.

• Phase I oxidation: A chemical reaction that modifies a drug, often making it easier to process further.

• Metabolite: A substance produced when the body breaks down a drug.

• CYP2D6: A specific CYP enzyme responsible for converting codeine into morphine.

• Drug concentration: The amount of a drug present in the body.

EXCRETION: leaving the body

Kidney - urine

• major route of excretion for many drugs and metabolites

liver/bile - faeces

• some drugs and metabolites are secreted into bile and subsequently eliminated in faeces

lungs - exhaled air

• eliminate volatile substances, such as some inhaled anaesthetics

how the kidney handles drugs?

enterohepatic recycling

cyclical pathway where substances travel from the liver, into the bile and small intestine, get reabsorbed across the intestinal wall, and return to the liver via the portal vein

following a drug orally

drug concentrations over time

pharmacokinetics helps us understand:

• how much drug reached the bloodstream

• how drug concentrations change over time

• how long a drug remains in the body

• how quickly the body eliminates a drug

overall, it helps guide safe and effective dosing

therapeutic window

What Is Elimination Half-Life (t½)?

Elimination half-life is the time required for plasma drug concentration to decrease by 50% during the elimination phase.

Key takeaway: With first-order elimination, the same fraction (50%) is removed during each half- life.

Glossary – difficult terms

• Elimination: Removal of a drug from the body.

• Half-life (t½): Time taken for the drug concentration to decrease by half.

• Plasma drug concentration: Amount of drug present in the blood plasma.

• First-order elimination: A process where a constant fraction of the drug is eliminated per unit of time.

• Elimination phase: The stage when drug concentration decreases as the body removes the drug.

mathematics of drug half-life

why does pharmacokinetics matter clinically?

renal impairment

• reduced kidney function may decrease drug elimination and increase drug exposure

drug interaction

• enzyme inhibition may slow metabolism and increase drug concentrations

repeated dosing

• drug accumulation can occur when doses are repeated before the previous dose is fully eliminated