Pharmacology

Question 1

What is zero-order kinetics?
What are the implications of drugs with zero-order kinetics?
Give examples of drugs that follow zero order kinetics.

Answer 1

Zero-order kinetics (FEW DRUGS) is when the amount of drug eliminated per unit time is CONSTANT.
Hence ELIMINATION IS CONSTANT.
There is NO half-life, and steady state is not dependent on half-life measurements.

The more drug you have, the longer it stays in the body.
Hence there is a risk of TOXICITY and you need to monitor the drug levels closely. Any change in dosing regimen can cause a disproportionately exaggerated change in drug level, hence only change the dose in the SMALLEST increments and monitor drug levels closely.

Some drugs are SATURABLE, i.e. elimination rate is constant until you reach a saturation of elimination (at VMax)

Examples = “PEA”
Phenytoin
EtOH/Alcohol
Aspirin

Question 2

Describe first-order kinetics.

Answer 2

First order kinetics (MOST DRUGS) is when the amount of drug that is eliminated per unit time is dependent on the drug’s plasma CONCENTRATION.
It is completely dependent on HALF LIFE.

This means that the rate of elimination of the drug is proportional to the plasma concentration ie. the more drug in your body, the faster the rate of elimination.

First-order kinetics gives us PREDICTABILITY, that is:

• we know how the drug will be eliminated by 50% (by its half-life).
• we know that it takes 5 half-lives to eliminate a drug or reach a steady state

Question 3

What do Cyp450 INDUCERS do?

Give examples of Cyp Inducers

Answer 3

Inducers DECREASE the levels of many drugs.
ie. makes drugs less effective.

Mnemonic = “CRAP B.S. GPS “induces” my rage!!!”

Carbamazepine
Rifampicin *** (potent Cyp 3A4 inducer!)
Alcohol - CHRONIC
Phenytoin

Barbiturates
St Johns Wort

Griseofulvin
Phenobarbital
Sulfonylureas

Question 4

What do Cyp450 INHIBITORS do?

Give examples (mnemonic)

Give examples of drugs that inhibit the isotypes Cyp3A4 and Cyp 2D6.

Answer 4

CYP inhibitors are more clinically relevant.
Inhibitors = TOXICITY.
Inhibitors increase the levels of many drugs.

Mnemonic for “inhibitors”-
VICK’S FACE All Over GQ “stops” ladies in their tracks.

Valproate
Isoniazid
Cimetidine *** (potent inhibitor)
Ketoconazole
Sulfonamides
Fluconazole
Alcohol - ACUTE
Chloramphenicol
Erythromycin *** (all macrolides except azithro)
Amiodarone
Omeprazole
Grapefruit juice
Quinidine

CYP3A4:
Lots of drugs are metabolised by Cyp3A4 eg. WARFARIN, cyclosporinA (CSA), Quinidine, Carbamazepine, Methylprednisolone.

Cyp3A4 INHIBITORS - Erythromycin, -Azoles (Fluconazole, Ketoconazole), Verapamil, Diltiazem, Keppra.

Hence Cyp3A4 inhibitors cause warfarin toxicity by increasing warfarin drug levels.

CYP2D6:
Cyp2D6 metabolises Codeine (a prodrug), Perhexiline and Timolol.
Cyp2D6 INHIBITORS - Quinidine ***, neuroleptics, fluoxetine.

Hence Quinidine/Cyp2D6 inhibitors cause TOXIC effects of Codeine (increased metabolism to morphine) and Perhexiline (CCB), Timolol (too much beta blockade)

Question 5

Most drugs increase INR.

Give examples of drugs that DECREASE INR.

Answer 5

Carbamazepine, Phenytoin, RIFAMPICIN, Cholestyramine, St John’s Wort

(ALL of these are Cyp450 INDUCERS, except Cholestyramine which is a binder/sequestrant)

Question 5

What are the pharmacokinetic changes seen in the elderly?

Answer 5

1. Decreased Clearance (decreased renal and hepatic function)
2. Decreased Volume of distribution (decreased lean body mass, decreased water, INCReased FAT)
3. Decreased Protein Binding (decreased serum albumin)
4. Polypharmacy (drug interactions)

Question 6

What is P-glycoprotein?
What are some substrates of P-gp?
Name some inhibitors

Answer 6

P glycoprotein is an efflux protein in the wall of the GIT.

Substrates include:

• DIGOXIN (fully renally excreted but still undergoes some drug-drug interactions due to P-gp)
• CyclosporinA
• Steroids - Aldosterone, Hydrocort, Dexa, Estrogen, Progesterone
• Chemotherapy agents - Doxo/daunorubicin, Paclitaxel, Dactinomycin, Vinblastine, Vincristine
• HIV protease inhibitors - Indinavir, Nelfinavir, Ritonavir, Saquinavir

P-gp INHIBITORS (ie increase toxicity of above drugs)
Amiodarone, -Azoles, Ceftriaxone, Clarithromycin, Verapamil, Diltiazem
“AA,CC, CCBs”

**The strongest pharmacodynamic interaction with Digoxin is Amiodarone. i.e. Amiodarone causes DIGOXIN TOXICITY **

Question 7

Protein Binding.

1. What drug is highly protein-bound?
2. What happens to this drug when there is a significant drop in plasma protein levels ie. in hypoalbuminaemia

Answer 7

1. Phenytoin
2. Low albumin results in lower protein binding, but the FREE CONCENTRATION of the drug is HIGHER.
   ie the pharmacodynamically active drug concentration is now higher

Question 8

What is the formula for renally-adjusting the dose for a patient with renal impairment?

Answer 8

Renal dose is

1-fu + (fu x CrCl of patient)

(Simplified calculation - from Deltamed)

Question 9

(GRAPH) Extended match question (A, B, C or D - may be more than 1 answer)

1. Which drug is most potent?
2. Which drug has the highest efficacy?
3. Which drug is a partial agonist?
4. If drug A was your pure agonist, which curve/s show that drug A is combined with a competitive agonist?

Answer 9

Efficacy = height
Potency = Left is most potent.

1. A
2. A = B = C have equal highest efficacy and ALL have reached the EMax 100%.
3. C because it never reaches EMax
4. B and D both have competitive agonists because efficacy is unchanged but it takes a bigger dose of the agonist to achieve the same effect

Question 10

Hepatic Clearance.

1. What is the formula for measuring hepatic clearance?
2. What is the difference between low and high hepatic extraction ratios?
3. Give examples of drugs with low and high extraction ratios

Answer 10

1. hepatic clearance = BLOODFLOW x hepatic extraction ratio
2. LOW EXTRACTION RATIO (less than 0.3)
   = LOW / No FIRST PASS EFFECT!!!
   The clearance of these drugs are dependent on PROTEIN BINDING and enzyme activity.

Examples of drugs with low extraction ratio:
- Warfarin
- Phenytoin
- Benzos, Diazepam
- NSAIDS
- Valproate
- Carbamazepine
These drugs are sensitive to changes in enzyme activity which is often the rate limiting step.

HIGH EXTRACTION RATIO (more than 0.7)
= HIGH FIRST PASS EFFECT. Cleared very efficiently by the liver.
The clearance of these drugs are mainly dependent on BLOODFLOW.
Unaffected by changes in BP or liver enzyme activity.

Examples of drugs with high extraction ratio:

• GTN (high 1st pass metabolism hence we give it topically)
• OPIATES eg Cocaine, Morphine, Lignocaine (hence given IV)
• Nicotine
• Propranolol

Question 11

Which drugs can cause gingival hyperplasia?

Answer 11

Phenytoin
CSA
Nifedipine

Question 12

What drugs can cause gynaecomastia?

Answer 12

Spironolactone
Cimetidine
OMEPRAZOLE
DIGOXIN
GNRH analogues
finasteride