PK 1 Flashcards
What does ADME stand for?
Absorption
Distribution
Metabolism
Excretion
Why is swallowing considered the odd one out in terms of routes of drug administration?
Because drugs taken this way will be subject to first pass metabolism
What are the parenteral routes of administration?
- Topical
- Ocular
- Subcut
- Intradermal
- IM
- IV
- Inhalation
What are the 3 types of enteral administration?
Sublingual
Swallowing
Rectal
What are Lipinskis rules?
That compounds easily absorbed:
- Low degree of ionisation
- High lipid/ water partition in non ionised form (lipophilic)
- Relatively low molecular weight
Discuss the important of pH on drug absorbtion
- Drugs with a charge struggle to cross membranes
- Many drugs are either weak acids/ bases
- Weak acids are neutral in protonated form and weak bases are charged in the protonated from.
- If pH < pKa: favours acid absorption and low membrane permeability for bases because they aren’t charged
(vice versa if pH>pKa)
Describe first pass metabolism
- Drug is metabolised BEFORE reaching systemic circulation
- Have a lipid soluble active drug -> phase 1 is anabolic (normally oxidation) results in a drug derivative which may/ may not be inactive-> phase 2 is anabolic (involves an endogenous water soluble molecule being bolted onto the DD) -> results in a water soluble metabolite which is usually inactive.
- DO NOT HAVE TO GO PHASE 1 THEN 2, CAN GO STRAIGHT TO PHASE 2.
- Also phase 1 may inactivate the drug and make it able to be excreted.
- Aim is to make lipophilic drugs water soluble so they can be excreted.
What is enterohepatic recirculation?
- Parent drug and metabolites may be recycled
- In the liver they can enter the bile canniculi where they can then reach the duodenum and become absorbed again. (the drug follows the bile salts)
- Can recirculate several times before entering systemic circulation
Where are the drug metabolising enzymes found?
In the smooth ER of the hepatocytes
What do CYP450s do?
Insert an Oxygen between a C and H
Describe phase 1 drug metabolism
- CYP450 adds an oxygen to the drug molecule, forming a drug derivative.
- This either forms a water soluble drug which may be active OR
- Transferase bolts on an endogenous water soluble molecule which produces a water soluble drug that is usually inactive
What properties can phase 1 change?
Efficacy
Toxicity
Activity
Where do you find the majority of CYP enzymes?
Liver
some also present in cell wall of the intestine
What factors can effect drug absorption from enteral routes?
- Age (elderly have less proteins/ water)
- Chronic illness (more change of adverse reaction)
- pH of GI tract (changes with age)
- Temperature (cold blooded animals have variable metabolism changes with seasons)
What is the advantage of parenteral administration routes?
Bypass first metabolism
List different parenteral administration routes
- Topical: skin (slow/ sustained effects) eye drops (frequent reapplication needed) nasal (local systemic effect)
- Intradermal (slow absorption)
- Subcut (fat layer can trap lipid soluble components)
- IM (fast)
- IV (fast and allows accurate control BUT drug cannot be recalled, give slowly and infusion better than bolus, normally use on narrow therapeutic index drugs)
Which routes can drugs be excreted from the body?
- Kidneys
- Hepatobiliary
- Lungs
- Milk
- Sweat
What is a xenobiotic?
Any agent that is foreign to the body (e.g. drug)
Describe renal excretion of drugs
- Glomerular passive filtration:
Describe renal excretion of drugs
- Glomerular passive filtration: Influenced by GFR/ protein binding. Most drugs can filter but not if bound.
- Secretion: in proximal tubule. Transporters= OCT and OATs these recognise weak acids/ bases and pump drugs into lumen of nephron.
- Reabsorption: distal tubule, depends on lipophilicity, polarity and urine pH
How do you calculate the filtration excretion of the kidneys?
Filtration excretion= GFR x fu
What impact does metabolic acidosis/ alkalosis have on renal drug excretion?
- If the urine is alkaline then it favours reabsorption of weak bases and excretion of acids. (the acid drug is trapped in the urine as it cannot cross the barrier in nonprotonated form)
(this would be the case in UTIs as increased bicarb trapped making urine alkaline)
What can the outcomes of drug interactions be to the action of the drugs?
- Enhancement of one or more drugs
- Totally new effects
- Inhibition of one of more drugs
- No change
Give examples of pharmaceutical drug interactions
- Insulin denatured by glucose
- Diazepam sticks to plastics
Give examples of physical incompatibilities in drug interactions
Insolubility
How can drugs be chemically incompatible with one another?
- pH: stability of drug can be pH dependent
- Oxidation/ reduction
Give examples of pharmacokinetic drug interactions
- Absorption
- Excretion
- Alpha 2 agonists reduce circulation which can effect clearance/ elimination
- Metabolism: enzyme inhibition/ induction
What is the impact of competitive inhibition of the half life?
- Inhibitor slows down rate of metabolism which can increase half life
What does grapefruit juice do to CYP enzymes?
Can inhibits metabolism of the drug as it inhibits the CYP enzyme so would cause higher doses and may cause toxicity issues
What is enzyme induction?
Drugs that increase expression of P450 enzymes so increase rate of metabolism.
Can lead to adverse reactions e.g. hepatitis
What are some examples of pharmacodynamic drug interactions?
Receptor sites
- agonist/ antagonist
- synergistic effects
- summation/ potentiation/ synergism
