2 - Pharmacokinetics and Pharmacodynamics Flashcards
What is pharmacokinetics and pharmacodynamics?
- Pharmacokinetics: what the body does to the drug
- Pharmacodynamics: what the drug does to the body
What are some of the pharmacokinetic facts we need to know about a drug before it can be approved for use?
What are some factors that can affect the pharmacokinetics/Vd of a drug?
What is bioavailabilty and what is it affected by?
Amount of drug that gets to the systemic circulation unchanged!
Affected by: formulation, age, food (chelation), vomiting, malabsorption (Crohn’s), first pass metabolism in liver and gut
100% in IV
Why is metformin available in different preparations?
- Modified slow release only needs to be taken once a day, less likely to have GI side effects
- More expensive to have extended release but patients more likely to adhere if less side effects
- Most of the time different preparations are just branding, e.g nurofen period pain
What are some factors that affect the distribution of a drug?
- Blood flow
- Lipophilicity
- Hydrophilicty
- Protein binding (difficult to distribute when bound)
- Vd
- Pregnancy
- Hypoalbuminaemia
- Renal failure
- Other drugs displacing the original drug from protein binding
What is the multicompartment model of drug distribution?
When prescribing a patient a second drug, when should you be really careful with the first drug interactions?
- Second drug may displace first so more first drug that can elicit a response
- Be careful if first drug is highly protein bound, has a narrow therapeutic index, low Vd
How do you work out the volume of distribution?
- Larger Vd than body water means it is absorbed by the adipose tissue
- Larger weight, more adipose so larger Vd so need higher dose
What are the two phases of drug metabolism?
What CYP’s are affected by smoking and alcohol, and what else can they be affected by?
- Age
- Hepatic disease
- Blood flow to liver
- Alcohol and Cigarette smoking (CYP450 inhibited in acute, induced in chronic)
What changes can CYP450 enzymes make to a drug?
- Can inactivate active drugs
- Can activate inactive drugs, e.g Levodopa
- Can covert active drug into another one e.g codeine to morphine
What is the most common CYP that metabolises drugs and what CYP is an example of genetic variations?
- CYP3A4
- CYP2D6 absent in some caucasians and over expressed in 30% of Africans. Has substrates like beta blockers and SSRIs
When dosing two different patients for a drug, what should you think about in terms of the metabolism of the drug?
- Race
- Sex (women slower ethanol metaboliser)
- Self induced metabolism with drugs e.g Carbamazepine
- If they are taking St John’s Wort (inducer of CYP3A4)
- Weight
- Smoking and drinking status
- Age
What routes can drugs be eliminated from the body?
- Mainly through the kidney
- Faeces
- Hair
- Sweat
- Tears
- Saliva
- Breast milk
- Genital secretions
What type of drug molecules are excreted renally?
- Low weight polar molecules
- Clearance mainly affected by GFR
What type of drug molecules are excreted hepatically and therefore into the faeces?
Usually high molecular weight molecules, conjugated with glucaronic acid
How can cardiac disease affect the elimination of a drug?
- Reduces perfusion to the organs, like liver and kidney so less clearance
What is the definition of zero and first order kinetics?
First: rate of elimination proportional to drug level, can determine half life
Zero: rate of elimination constant, most drugs in high concentrations, can’t calculate half life and more likely to have toxicitiy
What is renal clearance and the units for this equation?
- Volume of blood cleared per unit time (ml/min)
- Rate of elimination/Drug conc in plasma
How do you work out the half life of a drug?
- Can only do if 1st order
- Large Vd means small elimination rate which means long half life
What are some examples of drugs that are zero order?
- High doses of normal drugs
- Phenytoin
- Salicyclic acid (aspirin)
- Alcohol
What are some characteristics of a drug that would mean you need to closely monitor the patient whilst they were on the drug?
- Zero order kinetics
- Long half life
- Narrow therapeutic window
- Drug/drug interactions
- Reported toxic effects
How do you get to a steady state of a drug and how can this be used in an equation?
- Reached in 5 half lives, if large half life give loading dose
- Same with termination, takes 5 half lives to be removed from body so important when prescribing new drugs to ask about old drugs, e.g amiodarone
- Need to get to steady state for optimal therapeutic benefit
How can you work out Css?
Therefore to change drug plasma concentration need to change dose of drug or dose interval
When would you give a loading dose, and how would you calculate this?
- If you need a drug to have a rapid onset or if it has a long half life
- e.g digoxin for AF with heart failure has half life of a week so give a loading dose. if too high can get digitoxic
When designing a dosing schedule of a drug for a patient what are some factors we need to think about?
How can you measure a patient’s response to a drug to see if it is achieving what we want it to?
- Physiological measurements, e.g BP after antihypertensives
- Feeling
- Appearance
- Primary and secondary prevention
How do we work out therapeutic index?
What is an inverse agonist and a neutral antagonist?
- Drug binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist so antagonises and opposes
- Neutral antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either
Why is the volume of distribution apparent and how is it worked out?
As it is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma
What is the difference between clearance and elimination rate?
- Clearance is volume of blood completely cleared per unit of time, it is a proportionality factor and stays constant
- Elimination rate is amount cleared and as the concentration of drug in the plasma decreases, the elimination rate decreases
How can you work out clearance if the drug is at steady state concentration?
If a patient needs a loading dose of a drug via IV of 1521mg and the iv can adminster 10mg/ml at a maximum of 50mg/min, what is the smallest rate of infusion?
- 1521/10 = 152.1 ml needs to be administered
- Maximum of 5ml/min
What is a functional antagonist?
Why do we titrate drugs when introducing and terminating them?
- For maximum benefit without adverse effects
- Helps identify safe and optimal level on individual patient level
- Start low and work up to full dose or until side effects are seen
Is the plasma steady state reached quicker if the rate of infusion of an IV drug drug is doubled?
No - the steady state concentration will be higher but still takes 5 half lives
A 46 year old femal patient (70kg) is prescribed ramipril. She takes 5mg OD. The peak plasma concentration is 0.06mg/L. What is the apparent volume of distribution?
1.2L/kg
(remember to divide the litres by kg)
Why does the combination preparation of buprenorphine and naloxone help manage patients who are susceptible to narcotic abuse?
- Stops withdrawal symptoms as the buprenorphine can still activate some receptors but naloxone antagonist has a higher affinity
- If patient decides to inject the drug to get the buprenorphine fix it will not be very good due to the bioavailability
Why is adrenaline administered with lidocaine for local anaesthesia?
Has a vasoconstrictive effect to lower the elimination of lidocain so it stays around in the area for longer
If two patients are prescribed the same drug but one is 10kg heavier than the other, what will this mean for the doses needed?
Patient who is 10kg heavier will need a higher dose as drug will have a higher volume of distribution as goes into more of the adipose
Why are beta-blockers contraindicated in asthmatics?
Bronchoconstriction at B2 receptors
Why do you get a dry cough with ACEi?
Build up of bradykinin (bronchial vasodilator)
