ADME Flashcards
Passive diffusion
Most important mechanism
Applies to non-polar drugs
Conc gradient is the driving force
No energy required
Facilitated diffusion
Appears to depend on a oscillating carrier protein
Depends on the conc gard
No energy required
Sugars/amino acids
Active Transport
Can proceed against a conc grad requires energy can become saturated allows accumulation of specific compounds removes waste product
Endocytosis
internalisation of large molecule by cell
mainly for drugs with a molecular weight higher than 1000
Drug absorption
The passage or a drug form the site of administration into the general circulation
Rate of absorption
how rapidly does the drug get from its site of administration to the general circulation?
Extent of absorption
how much of the administered does enters the general circulation
What is bioavailability
F - the area under the concentration time curve
the patients exposure to the drug
What is the minimum therapeutic level?
The level above which a drug needs to reach in order to produce a response
What are the enteral routes of drug administration?
per Ossa
Sublingual
Rectal
What are the parenteral routes of drug administration
Intravenous Sub cut Intradermal IM lungs
What is the rate and extent of IV administration
Immediate absorption
100% aborption
What is the rate and extent of oral administration
Rate is gradual
extent is incomplete
What are the advantages of IV administration?
very rapid
precise control (100% F)
avoids problems of absorption
Good for irritating drugs
What are the disadvantages of IV?
skill required
Careful preparation of injected material (sterile)
no recall so is hazardous
What are the advantages of po administration?
Safe
convenient
What are the disadvantages of po administration?
slow
unpredictable with regard to rate, extent and reproducibility
What are the factors influencing the bioavaliability of oral drugs
Decomposition ir gastric acid decompositon by gut enzymes Degradation by gut microorganisms Food in gut may alter absorption rate Metabolism by gut wall enzymes Metabolism by liver enzymes
What is the rate limiting step of oral drugs?
The gastric emptying determines how quickly it is let into the small intestine to be absorbed.
Intestinal motility and interactions with food are also important
What are the sites of drug metabolism?
Liver GI bacteria and proteases Intestinal wall enzymes Plasma (esterases) Specialised tissue
What is a prodrug?
A drug that has it’s activity promoted by metabolism
What is an example of a drug that produces toxic metabolites when metabolised?
Paracetamol
What is an example of a drug that has no change in activity when metabolised?
Valium (diazepam)
What is phase 1 of a drug metabolism reaction?
The point is to make the drug more susceptible to phase 2 reactions
Oxidation
Reduction
Hydrolysis
What is phase 2 of a drug metabolism reaction?
The point is to make the molecule more polar so that it’s an ideal substrates for active transport and excretion
Glucuronide
Sulphate
Amino acids GSH
Acetlyation.methylation
What is the most important reaction for phase 1 metabolism of drugs?
Oxidation
What happens during oxidation?
The most important class of enzymes are the cytochrome P450 dependent mixed function oxidase system located in the smooth ER. Requires oxygen, NADPH and cytochrome P450 reductase
Describe the metabolism of Phenytoin
Phase 1 - hydroxylated to become slightly more soluble in water and inactive
Phase 2 - Becomes very soluble in water and highly lipophillic after conjungation by UDP transferase
compound is removed from liver and then 90% of it is excreted in urine
What is the effect of age on drug metabolism?
It decreases it
Which group has a higher metabolism and so requires a higher maintenance dose
Neonates
Why do smokers have a higher metabolism?
Because there is a compound in cigarettes that can induce synthesis of metabolizing proteins in the liver
How is drug metabolism inducted?
Enzyme synthesis is initiated wihtin 24h of exposure but the effect decreases over 1-3 weeks.
Cigarette smoking BBQ meat Cruciferous veges High protein diet Insecticides PCBs Barbituates Pheytoin Rifampcin St johns wort
How is drug metabolism inhibited?
rapid onset within 1 day
Exaggerated response with a risk of toxicity(no breakdown of drug)
Reversible inhinibtors Cimetidine Ketoconazole quinolones HIV protease inhibitors Grapefruit juice
Heavy metals
Lead
Cadium
Mercury
What is the outcome of the standard does of most drugs in a patient population?
20% will have no response
20% will get adverse effects
50-60% will get some therapeutic benefit
What is excretion?
The process whereby compounds are removed from the body to the external environment
What are the sites of drug excretion?
Kidney
Biliary excretion - important for drugs with a Mw >400 and ionized
Lungs
What are the three main mechanisms of excretion by the kidney?
- Glomerluar filtration of the unbound drug (130ml/min)
- Active secretion of both free and protein bound drug by transporters. (Anions or cations)
- Filtrate 100fold concenrated in tubules for a favourable conc grad for reabsorption by passive diffusion (lipid soluble will pass back into body)
What are the factors influencing renal drug excretion?
Gender (males higher)
Age (decreases with age)
Pregnancy (increases)
Disease
How can you alter the renal excretion of drugs?
Competitive inhibition of tubular secretion (there is a second drug that has a higher affinity so decreases the excretion of the first drug)
e.g. penicillin decreased by probenecid
Influence of pH (sodium bicarbonate > increased excretion by stopping the reabsorption by ionising weak acids)(Ammonium chloride > increased excretion of amphetamines etc)
Urinary flow rate (dilutes drug conc in tubule > decreased conc grad > increased excretion)
The effect of urinary flow rate on drug clearance is……?
Linear
If someone overdoses on amphetamine what can you give them?
Ammonium cholride as this will increase the excretion of the drug from teh kidney
