M&R 9.1 - Pharmokinetics Flashcards
What is pharmokinetics?
What the body does to a drug
What is drug formulation?
A mixture in a particular state supplied to a patient
What needs to be considered when supplying a drug?
- Solid? - Solubility and acid stability in stomach
- Liquid? - Quickly absorbed in the gut
- Compliance? - Is it simple e.g. 1 per day is easier
- Drug-drug interactions
What can happen if the wrong drug formulation/administration is given?
Adverse effects e.g. poisoning, unnecessary treatment etc
What is drug administration?
The path in which a drug is taken into the body
What are the benefits of using a specific site of drug administration?
- Concentrates drug at site of action
- Limits absorption in other areas
- Limits side affects
Give some sites of drug administration (7)
- Sublingual (under the tongue)
- Oral
- Inhalation
- Transdermal patch
- Rectal
- Topical )on skin)
- Intravenously, intramuscularly, subcutaneously
What needs to be considered when administering a drug?
- Safety of route
- Health of patient e.g. unable to swallow = no oral
- Prevention of complications
What is oral bioavailability?
The proportion of a drug given orally (or any other way except IV) that reaches circulation without changing
How is oral bioavailability measured?
- Amount (1st pass metabolism, gut absorption)
- Rate (Pharmaceutical factors e.g. tablet, liquid)
What is the therapeutic ratio?
- Maximum tolerated dose/ minimum tolerated dose
- Shows how dangerous a drug is
What does a narrow therapeutic index indicate? Why?
- Drug is more dangerous
- Concentration to get unwanted adverse side effects is close to the concentration to get desired therapeutic ratio
How can the therapeutic ratio be changed? Why?
- Change in formulation
- Absorbs/dissolves more slowly so doesn’t peak in toxic concentration range
What is first pass metabolism?
- Drug is administered orally
- Absorbed by the digestive system
- Transported by hepatic portal system and portal vein
- Reaches liver FIRST before being metabolised
What is the significance of first pass metabolism?
Due to being metabolised in the liver first, the concentration of the drug is decreased greatly before reaching systemic circulation
Which methods of administration do not undergo the first pass effect? Why?
- Sublingual
- Intramuscular etc
- Inhalation
- Rectal
- Travel around the rest of the body before reaching the liver
How can liver cirrhosis affect oral bioavailability?
- Decreases hepatic clearance
- Not broken down in liver so more is unchanged
- Increases bioavailability
What does a high hepatic extraction signify?
Low bioavailability
What is volume distribution?
The theoretical volume that the drug is distributed into if done instantly
How can volume distribution be measured?
- Extrapolate plasma concentration to 0 time
- Amount given/ plasma concentration at 0 time
How does albumin act as a reservoir for drugs?
- Binds to albumin
- Dissociation = increased free drugs
- Is eliminated/ goes to target receptor and produces an effect
What does drug displacement cause? When is this important?
- Protein binding drug interactions
When:
- High binding to albumin
- Small volume of distribution (increases concentration)
- Low therapeutic ratio
What is the relationship between dose and albumin binding sites during at class 1 (object)?
Dose is SMALLER THAN albumin binding sites
What is the relationship between dose and albumin binding sites during at class 2 (precipitant)?
Dose is GREATER THAN albumin binding sites
How can class 1 and class 2 be used simultaneously?
- Class 2 displaces class one
- Class 1 concentration increases
- Increases toxicity of class 1
Give some examples of object and precipitant drugs
- Warfarin = O, aspirin = P
- Tolbutamide = O, Sulphonamides = P
- Phenytoin = O, Valproate = P
What is meant by a first order drug?
- Rate of elimination is proportional to drug level per unit time
- Increased concentration = increased rate of removal
- Can predict therapeutic ratio when dose is increased
- Can have a half life
How can you tell if a drug is first order?
- Linear scale = not a straight line it’s an inverted downwards curve thing
- Log scale = straight line
What is meant by a zero order drug?
- Rate of elimination is constant
- Therapeutic ratio can suddenly increase when elimination mechanisms saturate (different in different people)
How can you tell if a drug is zero order?
Line is straight when scale is linear
What is the equation for rate of metabolism?
Vmax [C] / Km + [C]
same as for enzymes
When does metabolism of drug lead to a steady state?
- After 5 half lives
- A loading dose (initial high dose) is needed if an immediate effect needs to happen
What happens during phase 1 of drug metabolism?
- Hydrolysis
- Reduction
- Oxidation
- Exposes a reactive group so drug can be conjugated
What happens during phase 2 of drug metabolism?
- Forms a conjugation product (usually inactive)
- More polar and water soluble so is easier to excrete in bile
What is required in the liver for drug metabolism?
- Cytochrome p450 enzyme system
- NADPH (high energy cofactor)
What features of a drug are needed for it to be able to interact with other drugs?
- Inducible
- Inhabitable
What conditions lead to drug interactions?
- Low therapeutic ratio
- Used at a minimum effective concentration e.g. OC pill
- Follows 0 order kinetics (once enzyme is saturated, small change in concentration = large change in plasma concentration)
Give some examples of inducers and effectors
- Phenobarbitone induces Warfarin
- Rifampicin induces OC pill (metabolised more quickly so decreases dose)
- Cimetidine inhibits Warfarin (excessive anticoagulation)
When can drugs ONLY be renally excreted?
Only when unbound (free fraction) can they be filtered in the golmerulus as it is not permeable to proteins
Describe the process of active secretion. Where does it happen?
- Transfer from the peritubular capillaries to the renal tubular lumen
- Proximal tubule
What is the function of active secretion?
Removes toxins etc. from the blood to be excreted in the urine
What is active secretion?
The passive reabsorption of lipid soluable, unionised drug, influenced by pH
How are weak acids removed from the blood?
- Make urine more alkaline
- Ionises drug so decreases tubular absorption
How are weak bases removed from the blood?
- Make urine more acidic
- ionises drug so decreases tubular absorption
