SCRIPT: clinical kinetics Flashcards
4 stages of clinical kinetics (pharmacokinetics)
Absorption
Distribution
Metabolism
Elimination
Oral/enteral drug administration.
a) Why might it be preferable?
b) What other non-oral enteral route is there?
c) What oral route bypasses portal circulation? (benefits?)
d) Modified release (MR) / enteric-coated (EC) preparations
e) Can all drugs be crushed?
a) - Gut may be the target (eg. vancomycin*/ metronidazole for c.diff)
- Better tolerated / more acceptable to most
- Note: vancomycin is not absorbed via the GI tract, so is given orally for c.diff but must be given IV for systemic infections
b) Rectal
c) Buccal, sublingual
- Quicker onset as don’t have to wait to be absorbed in gut into the portal circulation
- No first pass metabolism - so likely achieve higher concentration
d) - MR - Slow rise in plasma concentration, generally a more prolonged effect
- EC - protect against stomach acidity
- Neither are appropriate for patients with ileostomy
e) MR drugs or enteric-coated drugs should not be crushed, as this affects its absorption and metabolism
Parenteral administration.
a) Types
b) Reasons
c) Who may be unsuitable for IM injections?
a) - IV - injection or infusion
- Intramuscular
- Subcutaneous
- Sublingual/ buccal
- Topical - transdermal patch/ gel, nasal, eyedrops
b) - Patient vomiting or unable to swallow/tolerate oral
- Rapid onset needed
- Drug not available in enteral form
- Small bowel disease (short bowel, ileus, etc.) - as most oral drugs absorbed in small bowel
c) - Morbidly obese
- Wasted/ cachectic
- Haemophiliac
Bioavailability.
a) What is it?
b) IV administration - bioavailability = ?
c) What factors affect bioavailability?
d) Given that the bioavailability for oral digoxin tablets is 0.7, how much IV digoxin would be required to replace an oral dose of 250 micrograms?
a) The amount of drug that reaches the systemic circulation so as to exert its effect
b) 100 %
c) - Enteral route - gastric emptying*, small bowel absorption (relevant in malabsorption, short bowel, etc.), first pass metabolism, excretion, GI transit time (relevant in ileus, diarrhoea, etc.)
- Highly protein bound drugs have less ‘free drug’ to act at receptor sites
- Highly lipid-soluble drugs are absorbed more into fat and muscle tissues
- First pass metabolism
- Renal disease - leads to increased drug accumulation if renally-excreted
- Drug interactions - eg. P450 inducers/inhibitors
- Crushing modified-release or enteric-coated drugs
- Main factor slowing gastric emptying rate is food (particularly fatty food) - think having a big fatty meal before a big sesh (slows rate of absorption into blood)
d) 250 x 0.7 = 175 micrograms
Half life (T 1/2).
a) Define
b) Time to peak concentration - IV vs oral?
c) How many half lives does it take to clear ~ 95% of a drug? (so if T 1/2 = 6 hours, how long to clear 95%?)
d) Half life of amiodarone
e) Digoxin has T 1/2 of 36 hours (if normal renal function). How long does elimination take?
f) What affects half life?
a) The time taken for the concentration of a drug to reduce by half
b) Immediate with IV. Variable with oral/ other routes
c) 5 half lives
- If T 1/2 = 6 hours… 95% will be cleared after 30 (6 x 5) hours
d) Around 60 days (2 months)
e) 36 x 5 = 180 hours (approx 1 week)
f) - Renal function - renal failure prolongs half life of renally-excreted drugs
- Hepatic function - liver failure prolongs half life of hepatic-excreted drugs
First-pass metabolism.
a) What is it?
b) Prodrugs which are metabolised to active form
c) Liver metabolism depends on what 2 factors?
d) Drugs that use CYP450 (so may be affected by enzyme inducers or inhibitors)
a) - Pre-systemic metabolism in the liver of enterally-absorbed drugs
- Can reduce the concentration of drugs, convert it to an active form or alter it/other drugs in some way
b) - Codeine to morphine
- Azathioprine to mercaptopurine
- Enalapril to enalaprilat
- Cyclophosphamide to phosphoramide mustard
c) - Liver function (function of cytochrome P450)
- Hepatic blood flow (can be reduced in shock, GI surgery, etc.)
d) LOTS of drugs, eg.
- Warfarin
- Statins - atorvastatin, simvastatin
- Propanolol
- Amitryptilline
Volume of distribution (Vd).
a) What is it? (formula?)
b) Why is it often much higher than the intravascular volume?
c) If a 1 gram (1000 mg) dose of drug X, given IV gives a plasma-drug concentration (Cp) of 50 milligrams/litre, calculate the Vd
d) Factors affecting Vd - drug solubility, protein-bound, patient factors
e) Effect of dehydration and oedema on drug dosing in water soluble drugs
f) Effect of fat patient / old patient on drug dosing in fat soluble drugs
g) Relationship between Vd and elimination rate
a) The theoretical volume of fluid that would be needed to achieve the actual plasma drug concentration (usually given in mL or L/kg body weight)
Vd = Total amount of drug in the body (X) /
Plasma-drug concentration (Cp)
b) Drug molecules distribute outside the vascular compartment
c) Vd = 1000/50 = 20 litres
d) - Water soluble drugs (eg. insulin, gentamicin, atenolol) have a low Vd (as mostly found in plasma)
- Lipid soluble drugs (eg. digoxin, morphine, diazepam) have a high Vd (as mostly absorbed into tissues)
- Highly protein-bound drugs (eg. warfarin) have a low Vd (as low free drug concentration for absorption)
- Patient: older /fatter patients have higher % body fat so will have higher Vd
e) - Dehydration - higher plasma concentrations so lower dose may be needed
- Oedema/pregnancy - lower plasma concentrations (as drawn into interstitial space) - so higher dose may be needed
f) - Drugs first enter the vascular compartment, then diffuse into the peripheral (fat) compartment - this occurs more with lipid-soluble drugs
- Patient with more fat = more absorption into fat tissues
- Fat tissues act as a reservoir for the drugs
- When drug is stopped, the concentration gradient reverses and drug diffuses back into the serum
- Effects of drugs may therefore be prolonged, so lower dose may be needed
g) - As Vd increases, elimination rate reduces (i.e. longer time to eliminate drug from body)
Highly protein-bound drugs.
a) Give 3 examples
b) Warfarin and co-trimoxazole interaction - explain
c) Effect of malnutrition/ pregnancy on highly protein-bound drugs
a) Warfarin, phenytoin, amiodarone
b) - 97% warfarin is protein bound (inactive)
- 3% is free to attach to receptors/cross biological membranes and elicit a clinical response (active)
- Co-trimoxazole can lead to displacement of warfarin from albumin, leading to increased free (active) warfarin, which could potentially lead to toxicity
c) - There may be altered levels of albumin
- This can affect the amount of free drug available
- Hypoalbuminaemia - may require lower dose
Elimination.
a) First-order elimination
b) “Steady state”
c) Zero-order elimination
d) Clearance - define, units
e) Elimination rate equation
f) The function of which 2 organs is critical?
a) Drug clearance is a fixed proportion of total concentration - reduces with exponential decay
- At a certain point, the amount of drug administered during a dosing interval exactly replaces the amount of drug eliminated
- If it takes 6 hours to reduce by 50%, it will take 12 hours to reduce by 75% (T 1/2 = 6 hours)
b) When this equilibrium occurs (rate in = rate out), steady-state is reached
c) Drug clearance is a fixed ‘amount’ per hour (rather than a fixed proportion) is removed from the body (zero order elimination
- Due to enzymes being saturated above certain level (eg. alcohol, phenytoin)
d) - The hypothetical volume of blood from which the drug is completely removed per unit time
- It is expressed as units of volume per unit of time (e.g. litre/hour or ml/minute)
e) Elimination rate constant, k = Clearance / Vd
f) - Kidneys (most drugs are renally excreted via urine)
- Liver (some drugs secreted in bile and excreted via the faeces)
Therapeutic window.
a) Define
b) Which drug levels must be routinely measured due to them having a narrow therapeutic window?
c) When else may you want to measure drug levels?
d) Purpose of a loading dose
a) The interval between the lowest effective concentration and the minimum toxic concentration of a drug
b) Lithium, Gentamicin, Vancoymycin*, Digoxin**
* Note: if given orally for c.diff, the absorption into the blood will be negligible so no need to monitor plasma levels
**Digoxin levels only taken if toxicity suspected
c) In overdose - eg. paracetamol, salicylate
d) Build drug level up to therapeutic range quickly
Patient unable to swallow effectively post-stroke. What should you do in terms of prescribing her regular meds prior to a SALT assessment?
Review all medications and decide if any can be:
- Crushed / manipulated to ease administration safely (not if enteric coating/ modified-release)
- Omitted safely
- Switched to alternative drug in same class
- Given as alternative formulation (eg. liquid)
- Given enterally via an NG tube/ PEG, etc.
- Given via parenteral route (check for dose changes)
Excipients.
a) What are they?
b) Examples where they may causes problems
a) - Inactive parts of a drug formulation (make up 90% of the formulation)
- For ease of administration, pallatability, etc.
b) - Diabetes - sucrose formulations
- Lactose intolerance - lactose formulations
- High sodium content in drugs like paracetamol and co-codamol - 16 mmol of sodium per tablet - if patient taking 2x QDS = 128 mmol/ day
(recommended daily allowance = 100 mmol/day)
When to take certain medicines.
a) Iron - avoid taking with… ? (but what may help absorption?)
b) Colestyramine
c) Tetracyclines - don’t take with what - why?
d) Levothyroxine
e) Simvastatin
f) Amitryptilline
g) Alendronate
a) - Thyroxine
- Tetracyclines
- Ciprofloxacin
- Vitamin C may help iron absorption
b) - 1 hour before or 4–6 hours after the colestyramine
(because it acts by binding to bile salts but will also bind to other drugs taken with it)
c) - Dairy - Binds to the calcium and prevents absorption, so avoid milk, etc. (also the case for ciprofloxacin)
- Antacids
- Iron
d) Morning before breakfast
e) At night - therapeutic effect higher
f) At night - sedative
g) Before breakfast (30 mins, upright, full glass of water)
Which drugs should generally be prescribed by BRAND rather than using the cheapest generic form?
- why is this?
- Diltiazem
- Some antiepileptics
- Lithium salts
- Theophylline
- Some immunosuppressant therapies (e.g. tacrolimus)
This is because although generics will have bioequivalence with the brand, they may not have therapeutic equivalence - particularly important for these drugs which have a narrow therapeutic index and where mis-dosage may be dangerous
Also note, NHS sometimes uses biosimilars - these are different in that they are similar to (but not identical to) the original drug
Unlicensed vs. off-label
- Unlicensed medications are not licensed for use in the UK; occasionally they may be imported for use
- Off-label indications - drug licensed to treat one condition but used to treat another
(eg. amitryptilline is licensed for depression but commonly used off-label to treat neuropathic pain or migraine) - Also, crushing a tablet or altering another way renders it ‘off-label’ use (unless they specifically direct the user to crush it) as it is being used in a way other than that intended by the manufacturer
