MCQ

Question 1

Name the 4 stages of pharmacokinetics

Answer 1

‘What the body does to the drug’
ADME
1. Absorption
2. Distribution
3. Metabolism
4. Excretion

Question 2

Pharmacokinetics: absorption

Answer 2

Following oral administration, some of the drug will be absorbed through the stomach lining into the blood. However, most drugs will be absorbed in the small intestines. This is because the small intestines are adapted for absorption by having a very extensive surface area.

Blood leaving the stomach and small intestines goes directly to the liver via the hepatic portal vein
- Any drug taken orally will go first to the liver before it reaches the general (systemic) circulation

Question 3

Pharmacokinetics: distribution

Answer 3

Distribution describes the process of dispersion or dissemination of drugs throughout the fluids and tissues of the body.

Drugs are not distributed equally in the different fluids and tissues.
- Fat soluble drugs will concentrate in adipose tissue, and water soluble drugs in body water
- A number of drugs cannot cross the blood brain barrier

When drugs circulate in the bloodstream some of the drug binds to proteins in the plasma and some of the drug remains free/unbound in the plasma.
- The ‘bound’ drug is effectively inactive as the protein-drug complex is too large to leave the blood capillaries and enter the tissue fluid surrounding the body cells
- The ‘free’ drug is small enough to pass through the capillary wall and enter the tissue fluid to exert its effect on the cells

Things that affect protein binding such as older age or other drugs, may affect the amount of drug available to the tissues

Question 4

Explain, using the principle of distribution, the difference between sedating and non-sedating antihistamines

Answer 4

Sedating antihistamines, such as chlorphenamine, cause drowsiness by binding to histamine receptors in the brain. By contrast, non-sedating antihistamines (e.g. cetirizine) cannot cross the blood brain barrier to bind to histamine receptors in the brain

Question 5

Pharmacokinetics: metabolism

Answer 5

The transformation of drugs into more water soluble components to aid excretion. Mainly occurs in the liver.
- But drugs may also be metabolised in the GI tract, the plasma and the lungs. Morphine, for example, is metabolised mainly in the liver but also in the mucosal cells of the small intestine.

Some of the drug is chemically altered by the gut and liver in a process called first pass metabolism. First pass metabolism has a significant impact on how much of a drug is available to exert its effects on the body.
- This happens before the drug reaches systemic circulation

The drug is then further metabolised by the liver when it reaches systemic circulation. Everything that enters the bloodstream (whether swallowed, injected, inhaled, absorbed through the skin, or produced by the body itself) is metabolised by the liver.

Metabolism can reduce activity or create other active metabolites (for pro-drugs). However, the main purpose of metabolism is to make the drug into something more water soluble so that it can be excreted from the body by the kidneys. There are two main phases:
1. Phase 1
This is mainly carried out by cytochrome P450 enzymes which oxidise drugs.
A number of drugs can bind to CYP450 enzymes to increase (enzyme induction) or reduce their activity (enzyme inhibition).
2. Phase 2
A large ionised molecule is added to the drug. This acts to increase the water solubility of the drug.

In general, drugs undergo phase 1 and then phase 2 metabolism. However, some drugs will only undergo phase 1 and some will undergo only phase 2.

Factors that affect the function of the liver, such as disease and aging, can affect how much of a drug is metabolised.

Question 6

Which routes avoid first pass metabolism?

Answer 6

• Parenteral (injected directly to systemic circulation)
• Transdermal patches
• Suppositories
• Buccal and sublingual

These drugs are, however, metabolised by the liver once they enter systemic circulation

Question 7

Give an example of a two drugs which are extensively broken down by first pass metabolism

Answer 7

Glyceryl trinitrate and buprenorphine.

If they were swallowed, they would be almost entirely metabolised by the liver via first pass metabolism, rendering them ineffective.

The sublingual route avoids the first pass metabolism because the drug is directly absorbed into the systemic circulation diffusing into the blood through tissues under the tongue. They can also be given transdermally as patches, with the drug absorbed by capillaries underneath the skin.

Question 8

Explain how transdermal application works

Answer 8

Drugs delivered transdermally enter the blood via a meshwork of small arteries, veins, and capillaries in the skin. However, only very small drug molecules can enter the body through the skin.

Absorption through skin is generally slower but produces a steady, long-term effect that avoids the first-pass effect.

However, absorption of medication is affected by blood flow to the skin. For this reason, heat and cold applications should not be used over transdermal medications. Additionally, as adults age, they often have less subcutaneous fat, resulting in decreased absorption of medication from transdermal patches that require adequate subcutaneous fat stores for proper absorption.

Question 9

What is a prodrug? Give an example.

Answer 9

A pro-drug is an inactive precursor which is converted to an active drug by metabolism.

Codeine (pro-drug) is metabolised to morphine (active drug)

Question 10

Describe the metabolism of codeine (and the impact of rapid and slow metabolisers)

Answer 10

Codeine is a pro-drug which is metabolised in the liver to morphine and this is what is responsible
for the analgesia.

Some people are rapid metabolisers of codeine, resulting in unexpectedly high levels of morphine which lead to respiratory depression.

Conversely, some people are slow metabolisers and get little benefit from codeine. This is due to slow metabolism from codeine to morphine.

Codeine should only be used for acute, moderate pain in children over 12 years and only if other pain killers (analgesics) did not work due to risk of respiratory depression

Question 11

What is bioavailability?

Answer 11

Bioavailability is the proportion of drug that enters the circulation after a dose is administered.

For IV drugs, it can be assumed to be 100% as the drug is delivered directly into the blood circulation. For oral drugs, it can be considerably less
- Some of the tablet may not be absorbed from GI tract and some may be lost during first pass metabolism before reaching systemic circulation

For example the bioavailability of the opioid pain killer Oxycodone is 60-87% which means only 60-87% of the orally administered dose reaches the systemic circulation.

Question 12

Explain why the equivalent subcutaneous dose of morphine is half the oral dose.

Answer 12

This is because the bioavailability of oral morphine is much less than morphine given by injection. This difference is largely due to the first pass metabolism of morphine when administered orally.

Some oral morphine may also not completely dissolve or be absorbed in the gut wall.

Question 13

Describe what is meant by a narrow therapeutic index.

Answer 13

The difference between the blood levels that need to be reached for a drug to be effective, and the level above which the drug is toxic.

Small differences in dose or blood concentration may lead to therapeutic failures or adverse drug reactions.
- Examples: digoxin, gentamicin, vancomycin and lithium.

It is often necessary to adjust the dose according to measurement of the actual blood level achieved in the person taking it.

Changes in the brand or formulation can result in toxic or sub therapeutic levels in the blood because of differences in bioavailability
- For example, the bioavailability of Lanoxin (Digoxin) elixir is 75% compared to 63% for Lanoxin tablets. For many drugs this does not matter clinically but, in cases where the drug has a narrow therapeutic index, it can be important.

Question 14

Explain what is meant by a drug’s half-life

Answer 14

The plasma half-life of a drug is the time it takes for the concentration of the drug in the plasma to reduce by half.

It is a constant for any given drug, although a range is often given as some people metabolise and excrete drugs faster than others.

It can take 4 to 5 half-lives for a drug to be excreted
- Its effects should get less and less every day as the drug is excreted

It also takes 5 half lives for a drug to reach steady state. At steady state the amount leaving the circulation equals that entering the circulation.

Question 15

Pharmacokinetics: elimination

Answer 15

Elimination is the process of the drug being cleared from systemic circulation.

The remaining drugs and metabolites in the bloodstream are filtered by the kidney, where a portion undergoes reabsorption back into the bloodstream, and the remainder is excreted in the urine.

As the liver filters blood, some drugs and their metabolites are actively transported by hepatocytes to bile.

Another potential route of excretion is the lungs. For example, drugs like alcohol and the anesthetic gases are often eliminated by the lungs.

Kidney and liver function often decrease with age, which can lead to decreased metabolism and excretion of medications. Subsequently, medication may have a prolonged half-life with a greater potential for toxicity due to elevated circulating drug levels.

Question 16

How do conditions such as heart failure impact drug elimination?

Answer 16

Heart failure can affect systemic blood flow to the kidney, resulting in decreased filtration and elimination of drugs

Question 17

How do conditions such as shock, hypovolemia and hypotension impact drug elimination?

Answer 17

Conditions such as shock, hypovolemia, or hypotension cause decreased liver perfusion (reduced blood flow), reducing drug metabolism and excretion. Medicines may require dose reduction.

Question 18

What is pharmacodynamics?

Answer 18

‘What the drug does to the body’
This includes the mechanism of drug action, and the side effects they cause.

In order for a drug to exert an effect, it must first come into contact with, and bind to, the cells of the body it is acting upon.

Many drug receptors are protein molecules on the surface of a cell. Drugs bind to these receptors to cause a response in the cell.
- The following are common binding sites for drugs: receptors, enzymes and carrier molecules
- Different drugs have different shapes and will only bind to certain proteins in the body.

Drugs can be agonists, antagonists or partial agonists
- Agonists bind to a receptor and activate it to produce a response
- Antagonists occupy the receptors but do not activate them. They block the receptor so that an agonist cannot exert its effect
- Partial agonists bind to receptors to cause a response but the response is less than the maximum possible

Question 19

Give an example of an agonist and how it works

Answer 19

Adrenaline is an agonist.

It binds to beta receptors on heart muscle cells to set off a chain of events which leads to the heart beating faster and more forcefully.

Question 20

Give an example of a partial agonist and how it works

Answer 20

Buprenorphine is a partial agonist

This makes it a useful drug in the treatment of opioid dependence, where the opioid agonist heroin (diamorphine) is replaced by buprenorphine to prevent withdrawal symptoms

Question 21

What is an enzyme inhibitor? Give an example.

Answer 21

Enzymes are chemicals (usually proteins) that speed up the chemical reactions and keep cells functioning.

Drugs acting as enzyme inhibitors, bind to the enzyme and decrease its activity.

An example of an enzyme inhibitors are NSAIDs
- Ibuprofen binds to and inhibits enzymes called cyclo-oxygenases (COXs). COXs are enzymes which are needed to make a group of inflammatory molecules called prostaglandins. Prostaglandins cause pain and fever. Ibuprofen inhibits the COXs and reduces the amount of prostaglandins synthesised, reducing pain and fever.

Question 22

What are transporter proteins?
Give an example of a drug acting on transporter proteins.

Answer 22

Transporter proteins are located in the cell membrane. Their function is to transport substances across the cell membrane.

Between nerve cells there is a gap called a synapse. In order for a message to be carried from one cell to another, a chemical called a neurotransmitter is needed.

A good example of a drug acting on transporter proteins are SSRIs.
- Serotonin is a type of neurotransmitter
- Antidepressant drugs act to increase the level of neurotransmitters in the synapse. SSRIs do this by preventing the reuptake of serotonin from the synapse, this means more serotonin is available for longer to stimulate serotonin receptors on the nerve cell on the other side of the synapse.

Question 23

Explain the interaction between clozapine/olanzapine and smoking

Answer 23

Tobacco smoking can induce CYP450 enzymes, thereby increasing their activity and increasing the metabolism of drugs.

Clozapine and olanzapine are metabolised by CYP450 enzymes. When induced, higher doses are needed as metabolism is faster. When patients stop smoking, dose reduction is needed as metabolism slows and the drug accumulates in the plasma. This increases the risk of toxicity and side effects.

Question 24

Describe the changes in pharmacokinetics in elderly patients

Answer 24

As we age, total body water and muscle mass decrease while percentage of body fat increases leading to hydrophilic drugs having an increased plasma concentration (Volume of distribution decreases)

The half-life of lipophilic drugs will be increased due to increased number of adipose tissue, meaning that less drug is available in the plasma to be metabolised.

Protein binding refers to the amount of the drug bound to albumin in the blood.
- Protein binding can act as a reservoir as the drug is released slowly, causing a prolonged action
- Serum albumin decreases in older adults
- Levels also impacted by malnutrition and liver disease
- Creates unique issues with medicines that are highly protein bound such as levodopa, warfarin and phenytoin
- If an older adult has low albumin, there are fewer albumin to hold the drug and render it inactive, leaving more free drug

Metabolism by the liver may significantly decline in the older adult (due to reduced liver perfusion).First-pass metabolism also decreases with aging, so older adults may have higher free circulating drug concentrations.

They will also experience decreased blood flow to tissues within the GI tract. In addition, there may be changes in the gastric (stomach) pH that may alter the absorption of certain medications.

Question 25

What are the different types of adverse drug reactions?

Answer 25

**Type A** * Augmented reactions * An exaggeration of a drug's normal effects * These are predictable from the drug's pharmacology and are usually dose-dependent and common * These reactions are more likely than other reactions to be discovered in clinical trials before licensing * **Example:** constipation caused by opioids, hypoglycaemia caused by antidiabetics * **Management:** reduce dose or hold drug **Type B** * Bizarre reactions * These type of reactions are not pharmacologically predictable, and not obviously dose-dependent * Tend to be rare, therefore remaining undiscovered until post-licensing * Reactions are often severe and associated with high mortality. It often occurs in patients who are ‘hypersusceptible’ due to immunological or genetic factors * **Example:** anaphylaxis caused by penicillins, fatal aplastic anaemia with chloramphenicol * **Management:** stop drug and avoid in future **Type C** * Chronic reactions - occur after prolonged continuous exposure to a drug e.g. osteoporosis after chronic use of corticosteroids **Type D** * Delayed reactions - delayed until after drug exposure making it difficult to identify e.g. carcinogenic or teratogenic effects **Type E** * End reactions - occur after abrupt drug withdrawal e.g. withdrawal symptoms after stopping SSRIs

Question 26

Nitrazepam is a sleeping tablet and nitrazepam tablets have a half- life of 24 to 40 hours. Explain what is meant by half- life and why a drug with such a long half- life would be less suitable for prescribing in an elderly patient.

Answer 26

Half-life is the amount of time it takes for the concentration of drug in the body to reduce by half. It takes about 5 half-lives for a drug to be cleared. Nitrazepam has a half-life of 24 - 40 hours therefore it would take 120 - 200 hours (5 - 8.3 days) for it to be fully cleared out of the body. Elderly patients are more likely to have reduced renal function, therefore they are likely to take longer to eliminate the nitrazepam. In addition, the increase in adipose tissues with age means that the half-lives of lipophilic drugs is prolonged. This puts them at higher risk of side effects such as respiratory depression, confusion and agitation. Its effects will also be prolonged, resulting in increased drowsiness and increased likelihood of falls and fracture.

Question 27

Drug A inhibits the production of a CYP450 enzyme. Drug B is metabolised by this enzyme. Explain metabolism and the possible consequences of taking these two drugs together.

Answer 27

Metabolism is the process of transforming a drug into more soluble components, so that it more easily cleared by the kidneys. This is mainly done by the liver. By inhibiting the production of the CYP450 enzyme, Drug A causes a decrease in the metabolism of Drug B. This results in reduced clearance and increased plasma concentration. This can result in increased therapeutic effect, which may result in overtreatment, and potentially higher than recommended levels. In addition, there is also increased risk of side effects as more drug is available to act on other tissues. If the two drugs are taken together, the dose of drug B will need to be reduced to account for the interaction.

Question 28

Outline the pharmacokinetic changes in the older adult that would suggest caution when prescribing a drug with a narrow therapeutic range, for example Digoxin

Answer 28

Drugs with a narrow therapeutic index have a small therapeutic window and small changes to their plasma levels can result in subtherapeutic effect or toxicity. Elderly people tend to have reduced glomerular filtration, resulting in reduced renal function. This results in reduced drug elimination, and increased accumulation, resulting in potential toxicity. For example, for digoxin, they may experience bradycardia. Elderly people also have reduced plasma protein binding due to reduced albumin levels. This means that more free, active drug is present in the plasma, increasing risk of toxicity. They also have less hepatic blood flow which means that metabolism is slower, prolonging the half-life of drugs. Therefore the effect of the drug is prolonged which can result in falls and fracture.

Question 29

Ahmed is 80 years old. He comes to request a prescription for the sleeping tablet Nitrazepam. However Nitrazepam is not recommended for use in the elderly. Give and explain three **pharmacodynamic** reasons why this is the case.

Answer 29

Pharmacodynamics are what the drug does to the body. Nitrazepan is a benzodiazepine which can be sedating. It's effects are prolonged due to age related reductions in drug clearance. This puts elderly people at higher risk of falls, and subsequently, fractures. It also puts them at high risk of fatal side effects such as respiratory depression, which are dose related. In addition, nitrazepam can cause postural hypotension, exacerbating falls risk. Confusion is also a common side effect which is more common in elderly patients. This may incorrectly be diagnosed as dementia or psychosis, potentially resulting in a prescribing cascade.

Question 30

Enalapril usually has a half life of 11 hours. It is excreted in the urine with little liver metabolism. The time to steady state is 4 days. Explain the term steady state. In a patient with renal impairment explain how the time to steady state will be affected giving reasons for your answer.

Answer 30

Steady state is reached when the amount of drug in the systemic circulation is equal to the amount of drug being excreted. Steady state is usually reached after 5 half-lives. Enalapril is an ACE inhibitor and is renally excreted. In people with renal impairment, the drug is not cleared as efficiently as in people with normal renal function. This means that there is a build up of the drug in systemic circulation and half-life is prolonged. Time to steady state = 5 x T1/2 therefore increased T1/2 increases time to reach steady state. In addition, because it undergoes little liver metabolism, less of the drug is metabolised to inactive components which make it easier to clear. This results in a potentiated effect (potentially resulting in low blood pressure) and increased risk of toxicity and side effects.

Question 31

Using pharmacokinetics, explain the interaction between antiplatelets and warfarin

Answer 31

Aspirin and warfarin compete for the same plasma protein-binding site Administering both drugs at the same time will increase the amount of unbound drug in the plasma, thereby increasing their effects and increasing the risk of bleeding

Question 32

Explain how blood flow impacts distribution

Answer 32

Distribution occurs most rapidly into tissues with a greater number of blood vessels that allow high blood flow (such as the lungs, kidneys, liver, brain). Distribution occurs least rapidly in tissues with fewer numbers of blood vessels (such as fat), resulting in low blood flow. However, lipophilic drugs (i.e., drugs that dissolve in lipid environments) disproportionately distribute into adipose tissue in obese subjects. The permeability of capillaries is tissue-dependent. Capillaries of the liver and kidney are porous, allowing for greater permeability. Distribution rates are relatively slower or nonexistent into the central nervous system because of the tight junction between capillary endothelial cells and the blood-brain barrier.

Question 33

Describe the interaction between MAO inhibitors and cough medicines (phenylephrine, dextromethorphan)

Answer 33

Monoamine oxidase inhibitors (MAOIs) block monoamine oxidase, the enzyme that breaks down serotonin and dopamine. Thus increasing the concentration of serotonin and dopamine in the central nervous system. However, phenylephrine and dextromethorphan can also increase the levels of serotonin and dopamine (by inhibiting their reuptake) thus increasing risk of serotonin syndrome and raised blood pressure

Question 34

Describe the impact of drug competition for enzyme binding sites

Answer 34

Drugs that share metabolic pathways can “compete” for the same binding sites on enzymes, thus decreasing the efficiency of their metabolism. For example, alcohol and some sedatives are metabolised by the cytochrome P450 enzyme and only a limited number of these enzymes exist to break these drugs down. Therefore, if a patient takes a sedative after drinking alcohol, the sedative is not well-metabolised because most of cytochrome P450 enzymes are filled by alcohol molecules. This results in reduced excretion and high levels of both drugs in the body with enhanced effects.