ADME Flashcards
4 phases of pharmacokinetcs
absorption, distribution, metabolism, excretion
Absorption
The process by which the drug reaches the blood stream into the systemic circulation in the various forms of administration.
What for of administration does not go through absorption
IV route is the only process by which absorption into the blood stream does not take place as it is already absorbed.
3 main mechanisms of absorption
Passive diffusion – lipid soluble drugs diffusing across membranes as a result of a concentration gradient – high to low concentration.
Active transport – drugs that use carrier molecules within the membrane – can go against a concentration gradient e.g. Vit B12, thyroxine
Filtration through pores – particularly small water-soluble molecules – passive diffusion through the pore. E.g. glucose, ions such as sodium, potassium, calcium
Dissolution in relation to oral dosage absorption
‘Solid tablet must first disintegrate before the particles dissolve in the GI fluids before the process of absorption can begin.’
What is pKa
pKa refers to the pH point where the drugs is 50% ionized and 50% unionized (lipophilic)
What do you understand by the term ‘first-pass metabolism’? Give examples of drugs that undergo extensive first-pass metabolism.
All drugs absorbed through the GI system (except sublingual. Buccal and distal rectum) pass through the portal vein – passing through the liver before it reaches the systemic circulation.
Some of the drug can be metabolized (inactivated) in the liver before going into the systemic circulation. The first pass effect is a strong determinant of oral bioavailability.
E.g. GTN – very lipophilic, oral dose = 95% metabolized before it gets to the circulation for distribution, hence why it is given S/L.
People in liver failure will have lower or lack first pass metabolism – need to consider this with dosing.
What do you understand by the term ‘distribution’ in relation to drugs?
Reversible transfer of drugs from the bloodstream to other tissues and organs.
Distributed via passive diffusion. Follow similar pattern as drug absorption.
Drugs need to be lipid soluble to diffuse in and out of cells – following passive diffusion.
From blood stream to ECF to tissues and secreted back out as levels fall.
What is the significance of ‘protein-binding’ in relation to the distribution of drugs?
Drugs can reversibly bind to proteins in relation to the concentration of free drug. When it is protein bound it is unavailable. ‘Acts as depot for many drugs’ only free drugs can distribute and be metabolized and excreted. Albumin is the main plasma protein – therefore albumin levels can significantly affect the amount of free drug.
Why is adipose tissue sometimes described as a ‘depot’ for drug distribution?
As lipophilic drugs distribute into the adipose tissue which acts a reservoir, through passive diffusion the drug will diffuse back into the blood stream as systemic levels in the plasma decrease.
What other physiological barriers can limit the distribution of drugs?
Blood brain barrier Protein binding. Adipose tissue. Perfusion of the tissues – bones and finger nails – low perfusion – difficult to treat. CSF – impenetrable except when inflamed.
Factors affecting oral absorbtion
Formulation of drug
Physicochemical properties of drug
Environment adjacent to membrane
Membrane characteristics
Drugs with low pKa
Drugs with low pKa (e.g., aspirin, pKa 3.5) are more unionised (lipophilic) in acidic media (e.g., in stomach)
Drugs with low pKa
Drugs with low pKa (e.g., aspirin, pKa 3.5) are more unionised (lipophilic) in acidic media (e.g., in stomach)
Drugs with high pKa
Drugs with high pKa (e.g., paracetamol, pKa 9.5) are more unionised (lipophilic) in neutral/alkaline media (e.g., in small intestine)
What is the clinical significance of gastric stasis in absorbtion?
oral absorption of drugs such as paracetamol and morphine cannot occur as they cannot be absorbed in the stomach
Extent of distribution depends on …
- the physicochemical properties of the drug (lipid solubility)
- the extent to which it is bound to plasma proteins
- the perfusion of the tissue (circulation) (e.g., bone and nails difficult for drug to penetrate as not well perfused)
- the existence of any ‘special’ physiological barriers (e.g., blood-brain barrier, placenta)
drug distribution - protein binding
Only free (unbound) drug can distribute to tissues, cross biological membranes, and be metabolised and excreted. Plasma proteins can therefore act as a kind of ‘drug reservoir’
what is the main plasma protein
albumin
strongly binds to warfarin, sodium valporate, NSAIDs
What do you understand by the term ‘metabolism’ in relation to drugs?
Transforming the original chemical to one or more metabolites – to prepare the drugs for eventual excretion. ‘make it more water soluble’
Regulated by many tissues but mostly the liver.
What is Phase 1 metabolism and what is the enzyme system mostly involved in Phase 1?
Enzymatic conversion – through chemical reaction (hydrolysis, reduction, and oxidation) conversion to a metabolite occurs. Main enzyme system is Cytochrome P450 oxidase system.
Pro-drugs only become active after phase 1.
Phase one is enzyme driven.
What is Phase 2 metabolism and what are the compounds usually involved in Phase 2?
Addition of another chemical structure to the drug or metabolite by a process known as conjugation. (Glucuronic acid, glutathione, sulphate). Adding or joining of a molecule to increase the water solubility of the drug in preparation for excretion via the kidney.
Pro drug
inactive until it reaches the liver for metabolizing where it turns into an active
Active metabolite
Inactive Metabolite
Active metabolite – pharmacological effect on the body – codeine into morphine
Inactive metabolite – Water soluble, ready for excretion – not effect on the body.
Toxic metabolite
metabolite that has toxic effect on the body e.g. paracetamol overdose
What is ‘entero-hepatic’ circulation of drugs?
Where conjugated metabolites from the liver are excreted into the GI tract via the bile duct and excreted in the faeces. In the GI they can be unconjugated ‘become more lipophilic’ (by normal gut flora/bacteria) and a portion can be reabsorbed. Causing enterohepatic circulation – prolonging the drug effect.
e.g. NSAIDs, oestrogen.
What do you understand by the term ‘excretion’ in relation to drugs?
Generally following metabolism – a drug must be eliminated from the body. Main organ for excretion is the kidney. Also can be skin, feces, breath.
- What are the three possible phases involved in the excretion of drugs by the kidney?
3 phases – filtration at the glomerulus, active secretion into the proximal tubule, passive diffusion from filtrate back to blood along the length of the renal tubule (in order to be reabsorbed it must be in a lipid soluble un-ionized compound)
ionized = stay in water soluble
un-ionized = to be reabsorbed
what is the main metabolic enzyme in the liver in phase 1 metabolism
Cytochrome P450 oxidase system
In excretion what happens if a drug or metabolite is lipid soluble
, it is reabsorbed back into the bloodstream by passive diffusion
In excretion what happens if a drug or metabolite is lipid soluble
, it is reabsorbed back into the bloodstream by passive diffusion
In excretion what happens if a drug or metabolite is water soluble
if it is water soluble it is excreted in urine
