Lecture 1. Pharmacokinetics 1 Flashcards
What are the four routes of administration?
Absorption
Distribution
Metabolism
Elimination
What is the clinical aim of a drug?
To achieve an effective drug concentration at the site of action long enough to produce a therapeutic action
How do you calculate the therapeutic window/index?
Maximum non-toxic dose / minimum effective dose
What is bioavailability?
Proportion of dose of unchanged drug that reaches the site of action
What does 100% bioavailability mean?
All the drug reaches the site of action
What does the site of action equal?
Systemic circulation
What are the advantages of intravenous injection as a route of administration?
100% bioavailability
Rapid action
What are the disadvantages of intravenous injection as a route of administration?
Sterile equipment needed
Trained personnel needed
Expensive
Potentially painful
What are the advantages of the oral route as a route of administration?
Safest, most convenient and economical route
What are the disadvantages of the oral route as a route of administration?
Nearly always less than 100% bioavailability
Destruction by enzymes, pH and/or bacteria
Drug can complex with food
Absorption depends on rates of passage
Where does drug the drug have to be absorbed from?
GI tract to circulation
What process does most drug absorption follow?
Passive diffusion
What does the permeability of a drug depend on?
The lipid solubility of the drug
What are most drugs?
Either weak acids or bases
Is an ionised or an unionised drug better absorbed?
Unionised
Where does most absorption of the drug take place?
Small intestine
Outside of passive diffusion, what are the other methods of absorption?
Active transport (including drugs e.g L-DOPA in the gut lumen)
Ion-pair absorption (still absorbed despite being charged)
Pinocytosis (piece of membrane that engulfs material and removes it by endocytosis)
Solvent drag (Drug dissolved in solvent is absorbed easier than drug dissolved in water)
Properties of the small intestine
Very large surface area (200m²)
Alkaline pH (6.6-7.5)
Blood flow: 1lmin⁻¹
Where does little drug absorption take place?
Stomach and colon
When does most dissolution of a drug occur?
When the drug is fine particles (not tablets or granules)
What is GI absorption dependent on?
Formation
What is the rate of absorption dependent on?
Gut motility
Splanchnic blood flow
What modulates gastric emptying?
Meal size
Meal composition (fat)
Drugs (opioids, anticholinergics)
Physiological state (position)
Migraine (gastric stasis)
What problem can phenoxymethylpenicillin (pen V) cause?
Adsorbed by food, reduces bioavailability therefore take on an empty stomach
What problem can tetracyclines cause?
Chelate metals so absorption reduced by milk, antacids and iron preparations
What problem can aspirin (NSAIDS) cause?
Irritate the stomach: dyspepsia, nausea vomiting, diarrhoea
1in 5 chronic users will have gastric damage
What is the major site where drugs are metabolised?
Liver
What does the hepatic portal vein do?
Takes blood to the liver
What occurs to some drugs during first-pass metabolism?
Some drugs are rapidly metabolised by liver and gut wall
What are the other routes of administration?
Inhalation
Transdermal (through skin)
Buccal and Sublingual (under gums and under tongue)
Internasal
Rectal
What does subcutaneous mean?
Under the dermis (not in muscle)
How do drugs exist in the plasma?
Bound to proteins: equilibrium between bound and free drug
What do weak acids bind to?
Albumin
What do weak bases bind to?
Glycoprotein
What is the relation between dose and free (active) concentration?
Non-linear
What change does a small increase in drug concentration cause to the free drug concentration?
Small increase in drug concentration causes large increase in free drug concentration
How do lipid soluble drugs pass through the blood brain barrier?
Passive diffusion
How do water soluble drugs pass through the blood brain barrier?
Carrier mechanisma
How are drugs metabolised in the liver?
By hepatocytes
What happens to drugs metabolised in the liver?
Some drugs converted to inactive metabolites
Some drugs converted to active metabolites (i.e. benzodiazepines)
Some drugs are excreted unchanged
What happens in phase 1 of drug metabolism?
Transforms molecular structure of the drug
For example: oxidation, hydrolysis, reduction etc
Can introduce polar group/Increase water solubility Can abolish activity Can produce toxic or non-toxic metabolites
What usually carries out phase 1 of drug metabolism?
One of the cytochrome P450 enzymes (CYP450) of which there are many
What happens in phase 2 of drug metabolism?
Conjugation
Attaches an endogenous substance (eg sulphate/glucoronide etc) to parent drug or phase 1 metabolite
What enzymes carry out phase 2 of drug metabolism?
Transferases
What drug is excreted out of the body through the major renal route?
Only unbound drug
Apart from the renal route, what are the other possible routes of excretion of drug?
Biliary into intestine
Saliva, sweat, tears, expired air (minor routes)
Breast milk
