Lecture 4- PK and PD worked examples Flashcards
Bioavailability Calculation
Aspirin is a pro drug developed to overcome the unpalatable taste and irritation caused by early salicylic acid preparations. Its metabolites afford different actions including acting as an anti-inflammatory and as an antiplatelet drug.
408 mg of a 600 mg oral dose of aspirin reaches the plasma.
1) What is the oral bioavailability of the drug? Give your answer as a percentage.
408/600 x 100 =68% bioavailability
oral bioavailability is always
less than 1
A new antibiotic drug is given orally and its pharmacokinetics are being established. In a group of trial patients it is found that 80% of the original oral dose is physically absorbed across the gut wall. During its passage across the tissues of the gut wall, a further 10% of the drug that crossed the gut wall is metabolised. The remaining antibiotic then passes through the hepatic portal vein into the liver. In the first pass of the liver, a further 20% of the antibiotic undergoes hepatic first pass metabolism.
In the trial, a single oral dose of 0.2g of the antibiotic drug is given.
2) Calculate the oral bioavailability of this drug as a percentage.
80% of 0.2 g= 0.16g aborbed by the gut wall
10% of the drug is metabolised in the gut wall
therefore 90% of 0.16= 0.144
next, 20% of the drug is metabolised via first pass metabolism
therefore 80% of 0.144 = 0.1152
therefore bioavailability=
0.115/0.2= 58%
The oral dose of many drugs is often larger than that administered via IM or IV routes to overcome the inactivation and metabolism in the intestinal wall and or liver.
4) Why may a drug be preferentially delivered by oral administration? Provide an example.
- convenience
- scared of needles
- more pleasant
- compliance
Buprenorphine is an opioid receptor partial agonist that is prescribed in a number of formulations as an analgesic. It is also prescribed in combination with naloxone – an opioid receptor antagonist as an adjunct to opioid dependency therapy. The combination therapy is given sublingually where the bioavailability of the naloxone, like the oral route is extremely low.
5) Explain in terms of bioavailability why the combination preparation helps manage patients who are susceptible to narcotic abuse.
- Buprenorphine is an analgesic (opioid receptor partial agonist) that can be abused (narcotic abuse)
- Buprenorphine has a lower biovailability (gives less of a hit) if taken orally so some people inject the drug- however this is very dangerous
- Buprenorphine is therefore given with naloxone as a pill
- naloxone has a very low oral bioavailability so will not inhibit the buprenorphine when taken orally, but very high bioavailability if give IV
- would be very antagnistic to Buprenorphine (therefore pt wouldnt feel hit/ is safe
Lidocaine is often used as a local anaesthetic agent which may be administered subcutaneously or intramuscularly at many sites. The perfusion rate and associated peak plasma concentrations of lidocaine are greater when administered intramuscularly.
Why is adrenaline often co administered? Comment on the mechanism of action of adrenaline and how this action may be useful in helping lidocaine achieve local anaesthesia.
adrenaline binds to local alpha adrenoreceptors causing vasconstriction of local blood vessels therefore reducing perfusion of tissue therefore lidcaine carried away slower and has longer painkilling effect- also reduces bleeding
Remember that Vd is simply a
proportionality factor between the total amount of drug in the body against the concentration of the drug measured in the plasma.
If there is lots of drug in the body but only a small concentration is measured in the plasma then Vd is
relatively large.
if there is a small amount of drug in the body but the concentration measured in the plasma is large the Vd will
be relatively small
units of Vd
The concentration of drug in the plasma is measured as an amount/volume (typically μg/mL or mg/L) and the amount of drug in the body simply as a mass (typically ng, μg or mg).
Therefore, Vd is reported as a volume in litres (L) – all other units cancel out.
if drug 1 has a Vd of 0.08L/Kg (i.e. if the person was 70kg then Vd = 0.08 x 70kg) indicate how it distributes between the major fluid compartments?
low Vd
- suggests low distribution in body compartments
- drug mainly found in plasma
if drug 2 has a Vd of 3.4L/Kg (i.e. if the person was 70kg then Vd = 3.4 x 70kg) indicate how it distributes between the major fluid compartments?
high Vd
- highly distributed among major fluid compartments
- low amount in plasma
pharmacokinetic paramaters e.g. Vd can vary in individuals based on
developmental status - from a child to an adult; health status - cancer often causes significant weight/tissue loss.
Two female patients in their early twenties are being assessed for treatment with haloperidol, a highly lipophilic antipsychotic agent that may be prescribed in patients suffering from bipolar or schizophrenic disorders (it is also used as an antiemetic and will be discussed later in the unit). Both patients are 1.7m in height, but one patient weighs 46 kg, the other 90 kg.
Given the apparent Vd for haloperidol is about 1400L, how would you expect this weight difference to affect Vd values in these patients?
46kg –> smaller Vd (less body tissue to distribute to
90kg –> higher Vd (more fat= lipophilic drugs will distribute more)
Two female patients in their early twenties are being assessed for treatment with haloperidol, a highly lipophilic antipsychotic agent that may be prescribed in patients suffering from bipolar or schizophrenic disorders (it is also used as an antiemetic and will be discussed later in the unit). Both patients are 1.7m in height, but one patient weighs 46 kg, the other 90 kg.
How do you think this information may affect your initial choice of dosing regimen with haloperidol in each of these patients?
for lighter patient= reduced dose (high plasma conc due to low Vd- needs less drug)
Amiodarone is a class III antiarrhythmic drug which can be administered either orally or intravenously. It has an extremely long half-life in the order of 50-60 days and requires a prolonged loading dose schedule.
10) Explain how the apparent volume of distribution is approximately 71 L/kg.
only small amount of frug will stay in the plasma with such a large Vd therefore we need more drug, however has a very long hald life so risk of toxicity
Most drugs over their therapeutic range will follow first order elimination kinetics meaning…
The same proportion of the drug and or its metabolites will be removed in a given time period.
Clearance, whether that be hepatic, renal or through other organs is measured as
a volume per unit time (typically mL/min or L/hr) and so it is the volume of plasma that is cleared of a drug within a given time.
rate of elimination is the product of
the clearance and the plasma concentration of the drug (L/hr x mg/L which gives us mg/hr)
therefore clearance = rate of elimination/ plasma conc
As with Vd, variation in clearance between and within individuals affects their ability to eliminate drugs. In this example, a 53 yr old man is admitted to hospital with a chronic skin infection and suspected pneumonia. He has a long history of alcohol abuse and is severely jaundiced with suspected renal failure. He is also malnourished with a BMI of 19.
Before you begin any drug therapy, what effect might you expect there to be on clearance of any drugs you might prescribe?
- renal failure= decreased clearance
- alcohol can induce P450
- Jaundice = reduced clearance
- low BMI- lower Vd- need less drug
- low albumin to carry drug to be cleared by the liver
half life equation
half life and plasma steady state
A new antiepileptic drug GSK7890 is undergoing phase II clinical trials. The average Vd has been reported as 70L and the overall clearance was 35 ml min-1 .
12) What is the t1/2 in hours for this new drug?
convert 35ml to 0.0351
0693 x 70/0.0351= 1,386
in hours
1,386/60= 23 hours
3) To illustrate the shape of first order kinetics, on the graph below draw a simple plot of drug concentration vs. time
a) for a drug given IV that is eliminated rapidly within about two hours
b) for a drug given IV that is completely eliminated more slowly within about 10-12 hours
c) If these two drugs had similar values for their Vd, what would most likely explain the difference in their respective half-lives?
Steady state plamsa concentration (Css) is the
plasma concentration of a drug achieved when regular doses of a drug being administered (by any route) equals the amount of drug that is being eliminated
Css is the aim of most therapeuric protocols to ensure that a consistent plasma concentration of a drug within the therapeutic window is maintained.
calculating Css
we combine clearance and rate of adminstration equations
what factors will change Css
Oral bioavailibilty for a given drug doesnt change, similarly clearance doesn’t change if drug elimination mechanisms remain constant. It is therefore clear that either changing the dose (D) or dose frequency (t) will change the Css.
A 36 year old male weighing 70 kg has been admited to hospital with suspected sepsis. The attending doctor has decided to prescibe the aminoglycoside gentamicin. Partciular caution is needed when prescribing this drug as it has a very narrow therapeutic index. Because it is such a polar drug it has to be given parentally. The median effective dose is 2 μg/mL and the median maxium plasma concentration that should be achieved is 5 μg/mL.
What is the therapeutic index of gentamicin?
therapeutic index/ration = median toxic/ median therapeutic
5/2= 2.5
A 36 year old male weighing 70 kg has been admited to hospital with suspected sepsis. The attending doctor has decided to prescibe the aminoglycoside gentamicin. Partciular caution is needed when prescribing this drug as it has a very narrow therapeutic index. Because it is such a polar drug it has to be given parentally. The median effective dose is 2 μg/mL and the median maxium plasma concentration that should be achieved is 5 μg/mL.
The Vd is 0.25L/kg.
What i.v. dose should be administered to achieve 5μg/mL plasma
concentration?
0.25L/kg therefore 0.25 x 70kg= 17.5 L
dose = Vd x [plasma]
= 17.5l x 5= 87.5 mg (Ls cross out)
The reported t1/2 for gentamicin is between 2 and three hours.The measured clearance of gentamicin in this patient is 5L/h.
Does your patient show similar pharmacokinetics with respect to t1/2.?
The Vd is 0.25L/kg.
0.25 x70= 17.5 l (Vd)
therefore
how can you increase Css
increase dose
increase dose frequency
when are loading doseases employed
where it will take an extended period of time to reach the Css.
A loading dose will speed up plasma concentrations reaching a therapeutic level but remember it will not affect the time it takes to reach Css
loading dose required is proportional to
half life
Very large half-lifes such as that found with amioderone require extended loading dose schedules.
What cautions need to be bourne in mind when prescribing a loading dose?
may go into toxic range
- consider the patients body weight and the effect on Vd
- renal problems- affecting clearance
maintenance dose
dose that is needed to maintain a concentration of drug in the body that acheives therapeutic benefit.
drugs which dont have immedietely apparent therapeutic benefits e.g. statin and antihypertensives have problems with
adherence
If clearance remains unchanged during the course of long term treatment and 10mg of drug is eliminated per day, what daily dose is required?
10mg of drug/day
clearance= administration
If the plasma concentration of gentamycin, a predominantly renally excreted antibiotic is 4 mg/L, what will the rate of drug elimination be if 2% of the plasma is cleared?
rate of elimination = clearance x [drug] plasma
= (0.02 x 1L) x 4
= 0.08 mg/min
You will now be familiar with the concept of drug-drug interactions (DDI), which are a real clinical issue, particular as a result of comorbidities in the elderly and the associated polypharmacy. Sildenafil was originally developed for use in acute coronary syndromes but during early phase 1 clinical trials it was established that it showed little effect. Trial data however reported that one of the observed side effects was penile erection. Sildenafil was subsequently patented and approved for use in erectile dysfunction under the trade name Viagra.
22) Why would a physician ensure that sildenafil treatment was stopped when prescribing the long standing antianginal glyceryl trinitrate? Comment on the mechanism of action of both drugs.
sildenafil –> blocks phosphodiesterase 5 (which promotes breakdown of cGMP (therefore higher concs of cGMP–> erection)
glyceryl nitrate- vasodilator
together may cause prolonged/painful erections
Using your knowledge of their mechanism of action, explain how they may reduce blood pressure but are contraindicated in asthmatics.
B-blockers have higher selectivity for B1 receptors therefore decreases chronotropy and inotropy
- some selectivity for B2–> bronchoconstriction
Another class of drugs used in the management of primary hypertension and heart failure are angiotensin converting enzyme inhibitors.
24) A common side effect that you will become familiar with is a dry cough. Whydoesthisoccur?
bradykinin is a substrate for ACEi
build up of bradikinin causes vasodilation via NOS causing a dry cough
