Theme 1: Drugs (Pharm/M&R/Infection)

Question 1

What is Reason’s Model of Accident Causation?

Answer 1

The Swiss cheese model. There are many layers of cheese, each with a hole representing a hazard. These ‘hazards’ must all line up for there to be an accident.

Question 2

How can errors be subdivided?

Answer 2

Mistakes - knowledge-based or rule-based; Skill-based - slips (action-based) and lapses (memory-based); Violations (deliberately not following rules)

Question 3

What are the requirements for a safe prescription (hint: there are 6)?

Answer 3

Right drug, dose, route, site, frequency and patient.

Question 4

What is pharmacokinetics?

Answer 4

What the body does to the drug. Can be divided into four stages: ADME (Absorption, Distribution, Metabolism, Elimination).

Question 5

What is bioavailability and how could you calculate it?

Answer 5

It is the fraction of a dose which finds it way into a body compartment (usually circulation). Amount reaching body compartment / intravenous bioavailability (which is 100%).

Question 6

What factors affect bioavailability?

Answer 6

Those affecting absorption: drug formulation, age, food (drugs, in general, are more lipid-soluble), vomiting/malabsorption. First pass metabolism affects bioavailability.

Question 7

What is first pass metabolism and where can it occur?

Answer 7

Any metabolism occuring before the drug reaches the systemic circulation. The gut lumen - gastric acid, proteolytic enzymes, grapefruit juice (CY P450 3A4 inhibitor) (e.g. benzylpenicillin, insulin, ciclosporin) The gut wall - P-glycoprotein efflux pumps drugs out of the intestinal enterocytes back into the lumen (e.g. ciclosporin) The liver (e.g. propanalol)

Question 8

Which two factors affect drug distribution?

Answer 8

Protein binding and Volume of Distribution (V_d).

Question 9

Even when the drug reaches the circulation, not all of it is active. Why is this?

Answer 9

Proteins will bind to proteins circulating in the blood (e.g. albumin). Only the concentration of drugs that is free (unbound) will be active and show a pharmacological effect.

Question 10

Changes in drug distribution can occur as a result of changes in protein binding. These are only significant if 3 factors are met. What are they?

Answer 10

High protein binding (‘reserve’ of drug circulating); Low V_d (drug stays predominantly in the plasma); Narrow therapeutic window (increases in free drug are likely to lead to toxicity).

Question 11

What factors can affect protein binding?

Answer 11

Hypoalbunimaemia, pregnancy, renal failure and displacement by other drugs.

Question 12

How can V_d theoretically be calculated?

Answer 12

Dose / [Drug]_t0

Question 13

What is V_d proportional to?

Answer 13

Half-life (T_1/2).

Question 14

What is V_d inversely proportional to?

Answer 14

Clearance.

Question 15

How much of a 70 kg man’s body weight is fluid? How is this fluid divided?

Answer 15

~40L is fluid 25L is ICF; 15L is ECF - 12L is interstitial fluid; 3L is plasma (excludes RBC mass).

Approximately: 2/3 : 1/4 : 1/12

Question 16

Asides from protein binding and V_d what else can affect tissue distribution?

Answer 16

Specific receptor sites in tissues, lipid solubility, drug interactions, regional blood flow, etc.

Question 17

Which family of enzymes are heavily involved in drug metabolism and where are they predominantly found?

Answer 17

Cytochrome p450 which are mainly found in the liver (some found in gut and lung).

Question 18

What type of reactions occur in Phase 1 metabolism?

Answer 18

Oxidation/reduction, hydrolysis, dealkylation - normally increasing the drug’s pharmacological activity.

Question 19

What type of reactions occur in Phase 2 metabolism?

Answer 19

Glucuronidation, sulphation, conjugation with glutathione/N-acetyl - increasing water-solubility of the drugs, aiding with rapid elimination. At this stage the drug will normally be pharmacologically inactive.

Question 20

What factors can affect Phase 1 metabolism?

Answer 20

CY p450 enzymes can be induced/inhibited by certain drugs. Also age, liver disease/hepatic perfusion and cigarette and alcohol consumption can have similar effects.

Question 21

Name some important inhibitors of the Cytochrome P450 family?

Answer 21

OAKDEVICES - Omeprazole, Amiodaraone, Ketoconazole, Disulfiram, Erythromycin, Valproate, Isoniazid, Cimetidine, Ethanol (binge), Sulfonamides.

Also… Grapefruit Juice!

Question 22

Name some important inducers of the Cytochrome P450 family?

Answer 22

PCBRAS - Phenytoin, Carbemazepines, Barbiturates, Rifampicin, Alcohol (chronic), Sulphonylureas.

Question 23

Why is it important to be aware of inhibitors and inducers of the Cytochrome P450 system?

Answer 23

It is important for drug prescribing (appropriate dosing). Over the counter medications such as St John’s Wort can both induce and inhibit the enzyme system and can lead to development of ADRs.

Question 24

What is the main route of drug elimination? How else may drugs be eliminated?

Answer 24

Main: the kidneys. Others routes: lungs, breast milk, sweat, tears, other secretions..

Question 25

Which processes determine the renal excretion of a drug?

Answer 25

Glomerular filtration (unbound drugs e.g. gentamicin - proportional to GFR)
Passive tubular reabsorption (affected by urine flow rate and pH, e.g. aspirin),
Active tubular secretion.

Question 26

How are GFR and clearance linked?

Answer 26

They are normally equal.

Question 27

Explain 1^st Order kinetics.

Answer 27

Rate of elimination of the drug is proportional to the concentration of the drug. Therefore constant fraction of drug eliminated in unit time. T_1/2 can be defined.

Question 28

Explain Zero Order kinetics.

Answer 28

The rate of elimination of the drug is constant. T_1/2 is not constant.

Question 29

Which drugs follow Zero Order kinetics?

Answer 29

Warfarin, pheyntoin, aspirin, alcohol. However all drugs display Zero Order kinetics at high enough doses (when receptors/enzymes become saturated).

Question 30

Why do Zero Order drugs have an increased risk of toxicity?

Answer 30

The concentration of these drugs will increase greatly even with doses increasing in small increments. This means it is more difficult to give an appropriate dose which falls within the therapeutic window. Drug monitoring is essential.

Question 31

When is drug monitoring required?

Answer 31

Zero Order drugs;
Long T_1/2;
Narrow therapeutic window;
Increased risk of drug-drug interactions (e.g. NSAIDs have a very high affinity for protein binding!)
Known toxic effects;
Monitoring therapeutic effect.

Question 32

How long does it take for a steady state to be reached, when there is multiple dosing?

Answer 32

3-5 Half-lives. It will also take 3-5 Half-lives to eliminate the majority of the drug.

Question 33

What are loading doses and when might they be considered?

Answer 33

Larger dose than would be given to reach a steady state in order to achieve a rapid therapeutic effect. Used more frequently for drugs with a long half life (which will mean they have a large V_d), e.g. digoxin.

Question 34

Failure of which organs may require loading or maintenance doses to be adjusted?

Answer 34

The organs involved in clearance, (almost always) the kidneys. Loading doses can still remain much the same in renal failure unless very severe. Maintenance doses must be reduced if renal failure leads to reduced clearance.

Question 35

Describe the metabolism of paracetamol when a non-toxic dose has been taken.

Answer 35

Most goes straight to Phase 2 reactions: 60% is conjugated by glucuronide; 30% is conjugated by sulfate. A small proportion (10%) will go through Phase 1 and be metabolised to NAPQI (by the CYP450 system) a highly reactive metabolite, toxic to hepatocytes. NAPQI is conjugated by glutathione producing inactive metabolites.

Question 36

Describe the metabolism of paracetamol when a toxic dose has been taken.

Answer 36

The pathway which allows paracetamol to undergo Phase 1 reaction becomes saturated because of glutathione depletion. This results in the accumulation of NAPQI.

Question 37

How should a paracetamol overdose be treated?

Answer 37

Activated charcoal can be given within 4 hours of overdose - this reduces further absorption of the paracetamol. N-acetylcysteine (parvolex) can be given (when appropriate) between 4 and 36 hours which helps restore glutathione levels.

Question 38

How could you calculate the loading dose?

Answer 38

V_d x [Drug]_target e.g. 10L x 100mg/L = 1g

Question 39

What is the elimination rate constant (k)?

Answer 39

It is the slope of the curve (where time vs plasma concentration). k = Cl / V_d.

Question 40

How can the elimination rate constant be used to calculate T_1/2?

Answer 40

T_1/2 = loge 0.5 / k;

Given that k = Cl / V_d;

T_1/2 = 0.693 / (Cl/V_d); therefore T_1/2 = 0.693V_d / Cl,

Question 41

How are clearance and renal function (or GFR) related?

Answer 41

They are proportional to each other (and inversely proportional to T_1/2.

Question 42

Do all drugs remain in the plasma?

Answer 42

No they have varying volumes of distribution and may spread out towards fat (if lipophilic) or muscle as well. It is the unbound drug in the plasma that will exert its therapeutic effect.

Question 43

What is pharmacodynamics?

Answer 43

The study of what the drug does to the body.

Question 44

What is the Michaelis-Menten curve?

Answer 44

A Michaelis-Menten curve is a graph of concentration vs rate of reaction (looks like a rectangular hyperbole) - it is indicative of a 1st Order reaction.

Question 45

What is a Lineweaver-Burk Plot and what can be calculated from it?

Answer 45

A Lineweaver-Burk Plot is a ‘reciprocal’ of the Michaelis-Menten curve (1/concentration vs 1/rate of reaction), and will be linear in 1st Order kinetics. The gradient is V_max / K_m and the intercepts can be used to calculate V_max and K_m.

Question 46

In Michaelis-Menten mechanics, what is K_m?

Answer 46

K_m is the substrate concentration at half of V_max.

Question 47

What is drug selectivity?

Answer 47

If a drug is highly selective for its target, there is a reduced chance of drug interaction with other targets and there will be less side effects.

Question 48

What is drug specificity?

Answer 48

Drugs being targeted at specific receptor subtypes e.g. ß1 - heart; ß2 - lungs.

Question 49

What is affinity and what can be used to measure it?

Answer 49

The likelihood of a molecule binding to a receptor. K_d is a measure of affinity: the concentration of molecules for there to be 50% of receptors bound.

Question 50

What is efficacy?

Answer 50

The likelihood that when a molecule has bound to a receptor that it will exert an effect. Antagonists have no efficacy.

Question 51

What is potency and what can be used to measure it?

Answer 51

The dose required to give a desired response. EC₅₀ is a measure of potency: it is the drug concentration that gives a 50% response.

Question 52

What is the therapeutic index and how could it be calculated?

Answer 52

It is a comparison of a dose that will cause therapeutic effect and one that will cause toxic effects. It is TD₅₀ / ED₅₀: the toxic and the minimum effective dose for 50% of the population.

Question 53

What is the function of having Phase 1 and Phase 2 metabolism?

Answer 53

Phase 1 metabolism undergoes chemical changes (through the CYP 450 family), making the drug molecule more reactive. In Phase 2 metabolism, the drug molecule is conjugated increasing solubility, allowing elimination. Not all drugs go through both Phase 1 and 2, (e.g. paracetamol may just go through Phase 2).

Question 54

With regards to the CYP 450 system, what are some of the primary differences in actions of inhibitors and inducers?

Answer 54

Inhibitors have a relatively quick onset (hours to days) and are related to T_1/2 and plasma concentration at time of interaction. Inducers increase the amount of enzyme present (usually Phase 1 processes); the rate will depend on drug and enzyme. Inducers usually take days to weeks to have an action.

Question 55

Why should patients be warned against drinking grapefruit juice if on certain medications?

Answer 55

It is a CYP 450 inhibitor and decreases the clearance of many drugs including simvastatin and amiodaraone (long QT syndrome). Can result in drug toxicity.

Question 56

What are the contraindications and indications to drink cranberry juice?

Answer 56

It inhibits CYP 2C9 which is involved with warfarin metabolism. This leads to to an enhanced anticoagulant effect and increased risk of haemorrhage.
However, may even be recommended in UTI treatment; it inhibits bacterial adherence to urothelium.

Question 57

How will drug activity be affected by a decrease in GFR (as a result of renal disease)? What problems may this result in?

Answer 57

These drugs will have an increased T_1/2 as a result of reduced clearance of renally excreted drugs (e.g. digoxin, aminoglycoside antibiotics). Electrolyte disturbances (e.g. K⁺) may result in toxicity or accumulation of nephrotoxins (e.g. gentamicin) will further damage kidney function.

Question 58

How will drug activity be affected by liver disease? Give an example of a drug that can result in severe ADRs when the liver is diseased.

Answer 58

There will be reduced clearance of hepatic metabolised drugs and CYP 450 activity. This means T_1/2 will increase and there is an increased risk of toxicity. A classic example is opiates in liver cirrhosis, small doses will accumulate and can result in coma.

Question 59

How will a fall in cardiac output (as a result of heart disease) affect drug activity?

Answer 59

There will be reduced organ perfusion, importantly of the liver and the kidneys. This will decrease clearance and increase T_1/2. Also there will be an excessive response to hypotensive agents.

Question 60

What is an ADR?

Answer 60

An adverse drug reaction is an unwanted or harmful reaction which occurs after administration of a drug(s) and is suspected or known to be due to the drug(s).

Question 61

Which factors increase the risk of ADRs?

Answer 61

Inappropriate prescribing;
Polypharmacy;
Patients at extremes of age (altered pharmacokinetic profile and/or co-morbidities);
Use of drugs with narrow therapeutic indexes;
Drugs being used near their minimum effective concentration (if metabolism increased, treatment failure).

Question 62

How can the severity of ADRs be divided?

Answer 62

Major (permanent / life-threatening)
Moderate (requires additional treatment)
Mild (trivial or unnoticeable).

Question 63

How should adverse events be reported?

Answer 63

Via the Yellow Card Scheme - a Datix form should be filled out which serves to notify that there has been an incident.

Question 64

How might drug-drug interactions come about?

Answer 64

Due to the non-selective nature of the drug (e.g. antidepressants interact with many receptor subtypes); Enhanced effect by other means (e.g. digoxin toxicity enhanced by hypokalaemia caused by a loop diuretic, such as Furosemide).

Question 65

The rate of metabolism of drugs such as warfarin and codeine displays a great deal of inter-patient variability. What is the study of this field known as?

Answer 65

Pharmacogenetics

Question 66

Which factors affect variability in drug response? (Hint: there are two broad classes)

Answer 66

Those related to the biological system (e.g. body weight/size; age and sex; genetics; condition of health; placebo effect).

Those related to the conditions of administration (e.g. dose, formulation, route of administration; repeated administration - drug resistance/tolerance-tachyphylaxis/allergy; drug interactions).

Question 67

Give some examples of sex steroids. What do they all have in common?

Answer 67

Testosterone, oestradiol, progesterone. They are all derived from cholesterol.