First pass metabolisim
•Metabolism of drug prior to reaching systemic circulation
•Can be a limit on oral route for some drugs. Oral route not useable for insulin
•Gut lumen (acid, enzymes)
•Gut wall (metabolic enzymes)
•Liver (hepatic enzymes)
•These factors can be changed by drugs and disease
4 Factors determining drug pharmacokinetics
8 Mode of absorption
•Subcutaneous (under skin)
•Transdermal (through skin e.g adhesive patch)
•Other GI - Sublingual (under tongue), rectal
•Absorption is defined as the process of movement of unchanged drug from the site of administration to the systemic circulation.
Note: There is always a correlation between plasma concentration of a drug and the therapeutic response.
Oral absorption graph
•The time to peak plasma concentration (Tmax)
•The peak plasma concentration (Cmax)
•The area under the drug concentration-time curve (AUC)
Oral absorption explained
•The more rapid the rate of absorption, the earlier the drug concentration peak (Tmax)
•Increasing dose does not affect the time at which peak concentration is reached but does increase the peak concentration (Cmax)
•The area under the drug concentration-time curve represents the amount of drug which reaches the systemic circulation. AUC (area under curve)
•A drug is active over a range of concentrations: Therapeutic Range
•Below this there will be insufficient or no pharmacological action.
•Above this toxicity occurs
•The therapeutic index is a measure of the range at which a drug is safe and active.
•The proportion of a drug which enters the circulation when introduced into the body and so is able to have an active effect.
•A drug given intravenously has 100% bioavailability.
•The AUC allows us to estimate the amount of drug which reaches the circulation and which is available for action
Factors affecting bioavailability►
Ability of drug to pass physiological barriers
-pH and ionisation
First pass metabolism
Transport across membranes
•Most drugs do not completely ionise in water.
•As most drugs are weak acids/bases the degree of ionisation depends on the pH of the environment.
•Both ionised and un-ionised forms will be present. The ionised drug does not cross the membrane.
•The un-ionised form should distribute across the membrane until equilibrium is reached – an equal concentration at each side.
Diffusion - Ionisation 2
•An acidic drug will be more concentrated in the compartment with high pH (‘ion trapping’ ?)►
•The relationship between the local pH and the degree of ionisation is described by Henderson-Hasselbalch equation.
•The result is that small changes in pH may significantly influence the ionisation of a drug and so the rate of absorption or diffusion.
•Proton pump inhibitors and antacids
Diffusion- lipid solubility
•To pass across a lipid layer a drug must be in solution and be lipid soluble.
•The ability of a drug to diffuse across a lipid barrier is expressed as a lipid-water partition coefficient.
•This is the ratio of the amount of drug which dissolves in the lipid and water phase when they are in contact.
•A drug that is highly lipid soluble will rapidly diffuse across a cell membrane.
•Reach the brain, ovaries, testes and liver
•A drug that is not lipid soluble may not be absorbed at all, for example gentamicin.
Passive transport vs active transport pic
•Filtration normally occurs through channels in the cell membrane.
•Low molecular size (smaller than the diameter of the pore) with a molecular weight of 100 or less.
•The driving force for the passage of the drugs is the hydrostatic or the osmotic pressure difference across the membrane.
•Generally water-soluble drugs e.g. urea, water & sugars, renal excretion, removal of drug from CSF & entry of drug into the liver
•Speed of gastric absorption will affect speed at which drug reaches site of absorption (most drugs are absorbed in small intestine).
•Can be affected by other drugs, food/drink and illnesses (esp pain).
•Can enhance or impair rate of absorption.
•Malabsorption (eg Coeliac disease) can increase or decrease rate of absorption
•Migraine reduces rate of stomach emptying and therefore rate of absorption of analgesic drugs (pain killers)
Factors when considering mode of administration
•Purpose and site of drug action: Local absorption
•Avoid first pass metabolism
•Patients ability to take medicine
•Speed of action
•Depends on type of delivery system, particle size, patient technique.
•Better for volatile agents.
•Can be metabolism in lungs.
•Relatively rapid action.
•About 5-10% absorbed.
•Usually used for topical effect or to avoid problems of oral absorption (eg nausea).
•Drugs given via the rectum bypass first pass metabolism.
•Absorption tends to be slow.
•The rectum is often used for drugs which cause irritation of the stomach.
Sublingual and Buccal Mucosa (inside of cheeks lining)
•Sublingual absorption from the buccal mucosa bypasses first pass metabolism which will inactivate the drug.
•Drugs given this way enter the circulation directly i.e. GTN for angina-chest pain
Subcutaneous / Intra-muscular
•Can change the rate of absorption from these sites with different physical properties of formulation.
•Depends on blood flow to site.
•Needs small volume.
•Avoids first pass metabolism.
•Some drugs not well absorbed from this route (water soluble better).
•Avoids first pass metabolism.
•Can provide controlled release.
•Few substances well absorbed.
•Need to be non-irritant.