4. Pharmacokinetics 2 Flashcards
What is the definition of Absorption, Distribution, Metabolism and Excretion?
Absorption, Distribution, Metabolism and Excretion
- A - absorption (movement of a drug from its site of administration into the blood)
- D - distribution (movement of drug out of the blood into the tissues and site of action)
- M - metabolism or breakdown of drug (mainly in the liver, but also in other tissues)
- E - excretion of drug and metabolites (mainly via the kidney, but also through other routes)
What are 5 factors which may affect distribution of a drug?
Factors that Affect Drug Distribution
- In order to be distributed into the tissues/site of action a drug must pass through cell membranes
- Factors which may affect distribution include
- lipid solubility of the drug
- molecular size of water soluble drugs
- whether the drug is carried by transporters
- protein binding
- specialised barriers within the body e.g. blood brain barrier
- Most drugs are distributed by passive diffusion
What are 3 proteins involved in the binding of drugs?
Protein Binding
- After absorption some drugs are bound to proteins in the blood (plasma)
- Proteins involved in the binding of drugs include
- Albumin
- alpha1 glycoprotein
- some lipoproteins
What is the significance of protein binding on drug distribution?
What are 3 examples of highly protein bound drugs?
Protein Binding - Distribution
- The forces involved in protein binding are not strong, and the free drug and bound drug exist in equilibrium
- It is only the free drug which can be distributed into the tissues (drugs bound to protein cannot cross the cell membrane)
- Some drugs are highly protein bound
- naproxen 99%
- diazepam 98%
- propranolol 93%
What is the Blood Brain Barrier?
Structure?
Blood Brain Barrier
- The blood brain barrier (BBB) is the barrier drugs must pass through in order to be distributed into the brain
- The blood brain barrier (BBB)
- the endothelial cells of the capillaries supplying the brain are packed very tightly (tight junctions)
- the basement membrane is continuous
- specialised cells e.g. astrocytes and pericytes
- limited number of small, aqueous pores
- specific transport proteins for some substances e.g. glucose (GLUT 1)
- The blood brain barrier (BBB) is basically a lipid barrier
Which drugs can enter the brain and which can’t?
Blood Brain Barrier
- Lipid soluble drugs can dissolve in the membrane and enter the brain by passive diffusion
- Water soluble drugs have greater difficulty in entering, or cannot enter the brain
- Also has influx transporters (e.g. GLUT1) and efflux transporters (e.g. P-glycoprotein)
What is P-glycoprotein?
Which tissues contain this? (3 examples)
P-glycoprotein
- Is a carrier molecule (pump) which plays an important part in the absorption, distribution and elimination of some drugs
- It is an ATP-binding cassette (ABC) transporter (requires energy)
- It moves compounds out of cells (efflux transporter)
- It is located in several tissues including the kidneys, gastrointestinal tract and brain
How can drugs be distributed into breast milk?
Clinical significance?
Breast Milk
- Medications taken by the mother may distribute into breast milk (passive diffusion) - oral dose for the baby
- For some commonly used drugs the dose received via milk is generally much less than the known safe dose of the same drug given directly to neonates and infants
- If a mother is breast feeding and takes paracetamol the amount available for ingestion by the infant has been reported variously as less than 0.1% of a single 500 mg dose
- However, it is important to note some drugs are contraindicated - always check references, Product Information etc
What is the 1 major organ and 3 other organs that are involved in drug metabolism?
Metabolism
The major organ involved in drug metabolism is the liver although other organs can also be involved e.g. kidney, lung, gastrointestinal wall
What are the 2 types of reactions involved in drug metabolism?
Drug Metabolism
- Drug metabolism basically involves two types of reaction
- phase 1 reactions which involve oxidation, reduction and hydrolysis
- phase 2 reactions which are conjugation reactions and involve the attachment of a chemical group to the drug e.g. glucuronidation, sulphation
Where do most Phase 1 Reactions occur?
Which enzymes are involved in Phase 1 reactions?
Phase 1 Reactions
- Phase 1 reactions occur mainly in the liver, although some can occur elsewhere e.g. in the wall of the gastrointestinal tract
- Phase 1 reactions often involve enzymes which are part of the cytochrome P450 system
- Cytochrome P450 enzymes are the most important enzymes in the body for metabolising drugs
What do Phase 2 Reactions involve?
Where do they mostly occur?
What is the most common phase 2 reaction?
Phase 2 Reactions
- Phase 2 reactions are conjugation reactions which occur mainly in the liver
- A polar group is attached to the drug by a “handle” that is either already on the drug, or has been placed there by a Phase 1 reaction e.g. a hydroxyl group
- The resulting conjugate is more polar, has increased water solubility and is more likely to be excreted in the urine
- The resulting conjugates are usually inactive
- Glucuronic acid conjugation is the most common phase 2 reaction, but others can also occur e.g. sulphation
What are 4 examples of drugs which are subject to phase 2 reactions, and which are conjugated with glucuronic acid and/or sulphate include?
Phase 2 reactions - Drug examples
Drugs which are subject to phase 2 reactions, and which are conjugated with glucuronic acid and/or sulphate include
- Paracetamol
- Oestrogen
- Lorazepam, oxazepam and temazepam
- Sertraline
Why are Cytochrome P450 System enzymes named as such?
Cytochrome P450 System - Naming
- Enzymes of the cytochrome P450 system contain haem and iron (haemoproteins)
- When the reduced forms of the enzymes combine with carbon monoxide they form a pink (pigmented) compound which has absorption peaks near 450nm (447-452nm)
- Cytochromes are structures with haem bound to a protein (also located in cells (cyto) and the haem moiety absorbs coloured (chrome) light)
- Hence the enzymes are collectively known as the cytochrome P450 system
Where are the enzymes of the Cytochrome P450 System mostly located?
Cytochrome P450 System
Enzymes of the cytochrome P450 system are located mainly in the liver (some in gut wall)
