ADME Flashcards
What is pharmacokinetics?
Movement of drugs or what the body does to the drug
What are the four phases of pharmacokinetics?
Absorption, distribution, metabolism and excretion
What are plasma concentrations?
Proxy measure of how much drug is in the body. Principle foundation of pharmacokinetics. Used to determine dosages, distribution and duration of action of drugs
What route does not require absorption?
Other than IV or for local effect, all drugs must be absorbed into the blood stream (systematic circulation) before they can produce an effect
What is absorption?
Refers to the processes whereby the drug reaches the bloodstream (systematic circulation)
What is the barriers to absorption?
Absorption requires the drug to pass through cells and cell membranes to reach the blood steam. Cell membranes are comprised of phospholipids.
For drugs to be absorbed drugs need to be…?
Lipid-soluble (lipophilic). Cell membranes are semi-permeable
What are the mechanisms of action of drug absorption?
Passive diffusion, active transport, filtration
What is passive diffusion?
Lipid-soluble drugs will passively diffuse across membranes following a concentration gradient (moving from higher to lower concentration)
What is active transport?
for a small number of drugs/biochemicals using carrier molecules in the membrane - can work against a concentration gradient e.g. Vitamin B12, L-thyroxine
What is filtration?
Passive diffusion along a concentration gradient through pores - especially for small water-soluble molecules such as glucose, sodium, potassium calcium
What are the four main considerations in oral absorption?
Formulation of drug, physiochemical properties of drug, environmental adjacent to membrane, membrane characteristics
What are Formulation Factors?
Whether they are solid or liquid. Solids e.g. tablets must first disintegrate before particles of drug dissolve in GI fluids (dissolution). Amount/type of disintegrates in the formulation affect this
What is enteric coating?
Acid-resistant - does not disintegrate in the stomach
What is extended release/sustained release?
Allow extended or sustained release of active ingredients dependent on its formulation. Often used in drugs with a short half-life. Drugs can be released in a controlled way as it transverses through the whole GI tract and this reduces dosing frequency
What two stages do oral solid drugs need to go through before being absorbed?
Must first disintegrate and then dissolve
What is a weak acid drug?
Most drugs are weak acids or weak bases. A fraction of a weak acid or weak base is ‘ionised’ and a fraction is ‘unionised. It is the unionised portion which is lipid soluble and therefore absorbed.
Key Principle:
The degree of ionisation of a drug (weak acid or weak base) depends on the pH of the environment.
Chemically, acids are able to release (donate) hydrogen ions (protons) in solution, whereas bases are able to accept hydrogen ions)
In descending order how acidic is the GI tract?
Stomach strongly acidic (pH 1-2.5 - 5 when fed)
Neural to mildly alkaline - proximal small intestine pH 6.15-7.35
Mildly alkaline - distal small intestine pH 6.80-7.88
What is pKa?
Is the pH at which 50% of the drug is ionised form and 50% n unionised form
What are drugs with a low pKa?
Aspirin - are more unionised (lipophilic) in acidic media (e.g. stomach)
What are drugs with high pKa?
Paracetamol are more unionised (lipophilic) in neutral/alkaline media (e.g. small intestine)
What occurs if someone has gastric stasis?
oral absorption of drugs such as paracetamol that are absorbed in small intestine cannot occur
What are some considerations of environment for absorption?
Surface area - stomach small, small intestine large
pH in different parts of GI tract
Presence of enzymes in gut wall or lumen that might inactive drug before absorption - this is part of what is known as pre-systematic metabolism
Volume of fluids
Presence of food
gastric emptying rate
intestinal motility
What factors of the membrane affect absorption of a drug?
Thickness of membrane can differ in different areas of GI tract
Pores in membrane for absorption of small water soluble drugs
Active transport mechanisms e.g. intrinsic factor for Vit B12 absorption
What is first pass metabolism?
This is the extent of metabolism that occurs before drug enters the systemic circulation- includes metabolism in the gut lumen, gut wall, lungs.
Where is the main sight of metabolism?
Liver
What is the portal vein?
All blood from the GI tract (excluding the oral cavity and distal rectum) drains through the portal vein and passes through the liver before its reaches the systematic (main) circulation (this is known as first pass)
What formulations are not subject to first pass metabolism?
sub-lingual, buccal and distal rectum formulations, transdermally
What is distribution?
The reversible transfer of drug from the bloodstream to the various other tissues & organs of the body If it wasn’t reversible process, then the drug would simply accumulate in the tissues/organs Drugs must be lipid-soluble to diffuse out of cells into extracellular fluid
Why is adipose tissue important?
It acts as a reservoir for lipophilic drugs
Key point
Diffusion is reversible: when tissue levels of the drug exceed those in ECCF & circulation, then the drug will passively diffuse back to bloodstream
What does the extent of distribution depend on?
The physiochemical properties of the drug (lipid solubility)
The extent to which it is bound to plasma proteins
The perfusion of the tissue (circulation) - with well perfused tissues there are generally no problems with distribution
The existence of any ‘special’ physiological barriers (e.g. blood-brain barrier, placenta)
What is protein binding?
Many drugs bind reversibly to plasma proteins including albumin (acidic drugs) and globulins (basic drugs)
Key point
Only free (unbound) drugs can distribute to tissues, cross biological membranes and be metabolised & excreted. Plasma proteins therefore act as a kind of drug reservoir
What is the main plasma protein?
Plasma albumin - strongly binds to a number of drugs e.g. warfarin, NSAIDs, sodium valproate
What affect would a low albumin have on drug distribution?
Hypoalbuminaenia could lead to increased free drug. e.g. thyroxine
How do drugs unbind from plasma proteins?
Only unbound or ‘free’ drug is available for distribution. Once the free portion has been distributed, the remaining bound potion re-equilibrates to allow release of free drug
What are some special barriers to distribution?
The blood-brain barrier can act as a barrier to some drugs. esp. more water-soluble agents. BBB has specialised collection of connective tissue cells in CNS with tight junctions that exclude certain substances.
Placenta, CSF (except when inflamed), bone/nails with poor perfusion.
What drugs penetrate the blood brain barrier?
Highly-lipid soluble drugs e.g. older sedating antihistamines, some beta-blockers, most CNS acting drugs
What is metabolism?
Is the alteration of a drug by the body to one or more chemically different molecules termed metabolites. Metabolism is regulated by enzymes in many tissues e.g., gut, skin, lung, main is liver. Main purpose is to prepare the molecule for excretion (i.e. make it more polar or water-soluble)
What is Phase 1 Metabolism?
Involves enzymatic conversion to a metabolite by a chemical reaction: hydrolysis, reduction, oxidation
What is the main metabolic enzyme in the liver?
Cytochrome P450 oxidase system - CYP450
How many isoenzymes are in CYP group?
- Subject to genetic variation in both ethic group & individuals
What are active metabolites?
Known as pro-drugs. Many metabolites are inactive pharmacologically, however some drugs produce active metabolites
What is Phase 2 Metabolism?
Another chemical structure to the drug or metabolite by a process known as conjugation.
What occurs in conjugation?
Conjugation increase the water solubility of the drug and prepares it for excretion via the kidney. e.g. glucuronic acid, glutathione, sulphate
What drugs may not undergo Phase 1 or Phase 2 pass?
Few drugs may be excreted unchanged especially if they are water soluble e.g. atenolol.
What is excretion?
Ultimately (usually following metabolism) a drug must be eliminated from the body. Some drugs or metabolites are excreted via lung, skin, faeces or kidney
What drugs can be unconjugated?
Some conjugated metabolites are excreted into the GI tract via the bile duct (rather than via kidney) a) and are then excreted in the faeces. However gut bacteria can unconjugated and a portion of the original metabolite can be reabsorbed (because now lipid soluble). This can result in enterohepatic circulation and prolongation of drug effect e.g. with hormones, NSAIDs,
What are the 3 phases of drug removal in the kidney?
Filtration at the glomerulus, active secretion into the proximal tubule, passive diffusion (reabsorption) from filtrate back to blood along the length of the renal tubule
What phases of drug removal can absorb soluble drugs?
Reabsorption. Active transport or secretion
What drugs are filtered?
Low molecular weight drugs - most drugs. Some drugs are not filtered but may meet requirements for active secretion from the arterioles into the nephron at the proximal tubule (need carrier protein)
What drugs are reabsorbed?
By passive diffusion if the drug is lipid soluble. If its water soluble it is excreted in urine
What is creatinine clearance?
Primary method for determining a patient’s glomerular filtration rate (GFR)
