STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

TABLE OF CONTENTS

INTRODUCTION .................................................................................................................................. 2

GOALS AND OBJECTIVES ................................................................................................................. 3

SELF-TEST TASKS 1 - 33 ................................................................................................................... 4

CASE SCENARIOS AND

MCQS ................................................................................................................................................. 21

Ó Royal Australasian College of Surgeons – December 2000 Page 1 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

INTRODUCTION

The material in this module is intended to be used in conjunction with the text of Chapter 37.1, Applied
Clinical Pharmacology for Surgeons by J M Potter and J E Payne in Toouli J et al, Integrated Basic
Surgical Sciences, Arnold, London, 2000.

This material is presented as a series of checks and questions. Many points are open-ended, and many of
the areas which you have read in this chapter are amplified elsewhere, either within other chapters in the text
or within some of the modular material. Some of the material is also supplementary, as the constraints of
preparing material for a text limit the material which could be included. I trust that you will enjoy the cross-
referencing and indexing which will be necessary to answer these questions. The questions are designed to
emphasise the important take-home message of each section.

The short chapter can only be an introduction to practical pharmacology, and should become a framework
for subsequent practice. It is a sobering observation that the majority of drugs now in clinical use were not
available before the 1960s. This refers not just to individual compounds but to drug groups and therapeutic
approaches. There is constant revisiting or redefining of our understanding of the mechanism of drug action.
As the practice of surgery changes, so does our understanding and use of drugs.

Ó Royal Australasian College of Surgeons – December 2000 Page 2 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

GOALS AND OBJECTIVES

The material in this module and in the Chapter in Integrated Basic Surgical Sciences relates to Curriculum
Objectives in Pharmacology: General Objectives PA59-61 and Specific Objectives PA 62-69.

Ó Royal Australasian College of Surgeons – December 2000 Page 3 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

SELF-TEST TASKS 1 - 33

Q1 What is/are the appropriate assay(s) for monitoring warfarin as an anticoagulant and why?

Q2 Name two members of the family of HMG-CoA reductase inhibitors. What is the most usual pathway
of metabolism of this family of drugs and what is its relevance?

Q3 Why do ACE inhibitors have a significant effect on the respiratory system and is it of clinical
relevance?

Q4 Why is the use of atropine successful in preventing or reversing cardiovascular symptoms, but not
those at the neuromuscular synapse?

Q5 What is the difference between so-called COX-1 and COX-2? What may be the implication for the
development of future therapy?

Q6 Apoptosis is an integral part of the cellular response to cytotoxics. Comment.

Q7 Do you think Mohammed Ali would benefit from the use of carbidopa? Why or why not?

Q8 Why may nitric oxide have a future use in the treatment of ARDS?

Q9 Name and compare the major pharmacological approaches to the treatment of gout.

Ó Royal Australasian College of Surgeons – December 2000 Page 4 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q10 Using digoxin as an example, why is the application of therapeutic drug monitoring (TDM) not just the
measurement of a drug in a biological fluid?

Q11 List the major pharmacological approaches to prevention and treatment of upper GI ulceration.

Q12 What are the major risks, predictable and unpredictable, associated with the use of local anaesthetics?

Q13 What is GABA? What drugs depend upon altered receptor response to GABA?

Q14 What major cardiovascular responses do calcium channel blockers produce? What other role(s) may
they have?

Q15 What are the target receptors for the anti-emetic effects of ondansetron-like compounds?

Q16 Which patient groups may be more likely to suffer from ‘scoline apnoea’?

Q17 What are the major risks associated with the use of cyclosporin A?

Q18 Explain the ‘flu-like’ syndrome, which may accompany the use of GM-CSF.

Q19 Comment on the use of the haematocrit as a screening test in competitive cyclists.

Ó Royal Australasian College of Surgeons – December 2000 Page 5 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q20 Compare the likely latent periods between administration of spironolactone and frusemide in the
production of a diuresis.

Q21 Tamoxifen lowers the concentration of plasma LDL in post-menopausal women. True or false?

Q22 Match the following compounds and the major metabolic pathways:

adrenaline oxidation
azathioprine monoamine oxidase
codeine pseudocholinesterase
cortisone cytochrome P450 3A4
mivacurium thiopurine methyl transferase
theophylline CYP 2D6

Q23 The following drugs are recognised as causing cholestasis – True or false?
rifampicin, phenytoin, flucloxacillin, testosterone

Q24 Which of the following drugs have significant renal excretion?

gentamicin, azathioprine, lithium, morphine

Q25 Match the following pairs of organ damage and drug:

Acute interstitial nephritis Amphotericin B
Acute Tubular Necrosis (ATN) ketoprofen
Glomerular damage D-penicillamine
Myoglobinuria penicillin G
simvastatin

Ó Royal Australasian College of Surgeons – December 2000 Page 6 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q26 “The administration of metoclopramide prior to giving paracetamol will improve the efficacy of
paracetamol in migraine”. Comment.

Q27 The absorption of which drugs may be affected by the presence of cholestatic jaundice and why?

Q28 What is P-glycoprotein?

Q29 In constipation due to high dose opioid use, which laxative(s) is/are most likely to be effective and
why?

Q30 Why are doses of drugs, which are administered by inhalation or via the buccal mucosa, smaller than
the orally administered preparation? Give examples.

Q31 All drugs are cleared by first order kinetics. True or false?

Q32 A one compartment model of drug distribution refers to the route of elimination. True or false?

Q33 In Therapeutic Drug Monitoring (TDM), a peak concentration may be helpful in the diagnosis of
possible clinical toxicity. True or false?

Ó Royal Australasian College of Surgeons – December 2000 Page 7 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Think Answers and Commentaries

Q1 What is/are the appropriate assay(s) for monitoring warfarin as an anticoagulant and why?

A1 Prothrombin time (PTT) expressed as the INR (International Normalised Ratio) is used to monitor
adequacy of warfarin dosing. Warfarin is a competitive inhibitor of vitamin K reductase, reducing the
carboxylation of coagulation factors II, VII, IX and X. The carboxylated forms of these factors are much
more potent in the coagulation cascade than the decarboxylated forms.

Q2 Name two members of the family of HMG-CoA reductase inhibitors. What is the most usual pathway
of metabolism of this family of drugs and what is its relevance?

A2 The HMG-CoA reductase inhibitors, used in the treatment of hyper-cholesterolaemia, are frequently
referred to as the ‘statins’. The first member of the group, which was used widely in clinical practice is
simvastatin. Newer members include atorvastatin, cerivastatin, fluvastatin and pravastatin. As a group
they are all metabolised via the cytochrome P450 family, most commonly via the CYP 3A4 isozyme.
There are two important consequences of their metabolism via this pathway. The first is the possible
inhibitory effect on the metabolism of other compounds which utilise the same pathway, resulting in
drug interactions such as seen with warfarin, cyclosporin A, HIV protease inhibitors and antifungal
drugs such as ketoconazole. The second effect may relate to the major side effects of myositis,
rhabdomyolysis and hepatitis. Metabolism of these compounds appears to be associated with
excessive production of free radicals, which results in cellular damage.

Q3 Why do ACE inhibitors have a significant effect on the respiratory system and is it of clinical
relevance?

A3 Angiotensin-converting enzyme inhibitors (ACEI) include the drugs captopril, enalapril, quinapril,
trindolapril and ramipril. The mechanism of action of their antihypertensive effect is via inhibition of
ACE, decreasing the formation of angiotensin II. This has two main effects, firstly directly reducing
production of the pressor agent itself, but also secondly interrupting the renin-angiotensin loop, and the
subsequent secretion of aldosterone. Inhibition of ACE also decreases the metabolism of bradykinin,
one of the promotors of the inflammatory response. In the respiratory tree, accumulation of bradykinin
causes a dry cough and in susceptible patients, may precipitate or worsen asthma.

Ó Royal Australasian College of Surgeons – December 2000 Page 8 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q4 Why is the use of atropine successful in preventing or reversing cardiovascular symptoms, but not
those at the neuromuscular synapse?

A4 The effect of atropine on the cardiovascular system as compared with that on skeletal muscle is a
dramatic demonstration of the differential distribution of muscarinic compared with nicotinic receptors.
Atropine is the competitive antagonist of acetylcholine at muscarinic receptors, the distribution of which
is primarily post synaptic within the parasympathetic nervous system. The post-synaptic cholinergic
receptor of the neuromuscular junction is nicotinic.

Q5 What is the difference between so-called COX-1 and COX-2? What may be the implication for the
development of future therapy?

A5 COX-1 and COX-2 are the two isozymes of cyclo-oxygenase, the pivotal enzyme which catalyses the
conversion of arachidonic acid to the prostanoids. COX-1 is the constitutive form of the enzyme (ie is
always present in tissue), whereas COX-2 is the isoform which is induced in inflammatory cells in
response to an inflammatory stimulus. The potential for the development of specific inhibitors of COX-2
is being exploited in an effort to reduce the wide-spread and non-specific side effects which accompany
the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and which are due primarily to the inhibition
of COX-1.

Q6 Apoptosis is an integral part of the cellular response to cytotoxics. Comment.

A6 Apoptosis is a cellular physiological mechanism which has a significant role in the turnover of cells
within tissues and organs and thus in the modelling of organs. There are numerous normal
physiological triggers which will initiate apoptosis. These vary from hormones (application or
withdrawal) to nutritional state. There are also pathological triggers including ischaemia. Many of the
cytotoxic drugs used in the treatment of malignancy (eg alkylating agents, antimetabolites and cytotoxic
antibiotics) are active in the S phase of cell growth: ie that part of the cell cycle in which there is active
synthesis of DNA. The presence of altered DNA triggers the initiation of apoptosis. This is different
from the action of drugs such as the vinca alkaloids which act during mitosis.

Ó Royal Australasian College of Surgeons – December 2000 Page 9 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q7 Do you think Mohammed Ali would benefit from the use of carbidopa? Why or why not?

A7 For l-dopa to have an effect, it is necessary to have some functioning cells capable of secreting
dopamine within the basal ganglia. It is debatable whether there would be sufficient numbers of such
cells now existing in the individual in question. It is immaterial to this question as to the form of
administered l-dopa in terms of its potential functionality. However, clearly, the aim of the formulation of
carbidopa is to limit the number of peripheral/systemic side-effects whilst promoting maximal CNS
response.

Q8 Why may nitric oxide have a future use in the treatment of ARDS?

A8 ARDS (adult respiratory distress syndrome) is an important and not uncommon complication of multi-
organ failure (for instance multi-organ failure accompanying severe sepsis). It is characterised by acute
pulmonary hypertension. There is intrapulmonary shunting, with subsequent hypoxia. Inhalation of
nitric oxide produces vasodilatation within the pulmonary vasculature. At lower concentrations, it has a
direct effect on the vasculature of the alveoli in which it is present and thus reduces any shunting: ie by
administering it by inhalation, directly to the site where it is required, it is made relatively specific for
those alveoli. Nitric oxide in high concentration is potentially toxic and causes pulmonary oedema.

Q9 Name and compare the major pharmacological approaches to the treatment of gout.

A9 The broad categories of causes of gout can be divided into those in which there is over-production of
uric acid, and those in which there is under-secretion. Thus these characteristics may define an
approach to the treatment of gout, whilst the other major consideration is the possible treatment of the
inflammatory component of gout.
· To reduce synthesis of uric acid – allopurinol.
· To encourage renal excretion of uric acid – high dose aspirin or probenecid.
· NSAIDs – in high dose in treatment of inflammation and pain of attack of gout.
· Colchicine – both prophylactically and in the acute attack to decrease inflammatory component by
altering white cell mobility (beware chronic toxicity).
· Finally – diet or alcohol moderation/alteration.

Ó Royal Australasian College of Surgeons – December 2000 Page 10 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q10 Using digoxin as an example, why is the application of therapeutic drug monitoring (TDM) not just the
measurement of a drug in a biological fluid?

A10 Therapeutic Drug Monitoring (TDM) in its broadest definition is the measurement of a drug and/or its
metabolite in the appropriate biological medium, taking into account the timing of the sample, the
clinical context and patient and organ response, and the established reference range for that drug. The
organ response alone may be a sufficient index for TDM (eg blood pressure in the treatment of
hypertension). The aim of TDM is to improve efficacy and limit toxicity. Digoxin illustrates some of
these points very well. The optimal time at which the concentration of digoxin correlates with plasma
concentration is 6 hours after administration of the dose (as shown by correlation with ECG). Most
correctly the reference range should refer to samples collected at this time. In reality however, the
majority of samples for digoxin is collected at approximately 12 hours after the last dose, or immediately
prior to the next dose administration.

The net result of administration of digoxin is increased cardiac output with increased stroke volume and
changes in the rate of conduction of the action potential through myocardial tissue. The mechanism of
+
action of digoxin, which produces this response is its competitive binding at the extra-cellular K binding
+ +
site of Na /K ATPase in the cell membrane. Therefore the concentration of K+ in the extracellular fluid
will influence the net effect of digoxin: in hypokalaemia the effect will be increased, in hyperkalaemia it
will be decreased.

A further consideration in interpreting TDM results is whether or not the concentration is at steady state.
This is related to the clearance half life of the drug. If the renal function is normal, in an adult the half
life of digoxin is approximately 36 hours. As creatinine clearance increases in renal failure, the half life
increases. Thus, unless a loading dose has been given, the estimated time to approach steady state
(ie 5 half lives) will be over 7 days with normal renal function, and significantly longer than this as renal
function deteriorates.

In summary, the following should be considered:

· The timing of the sample in relation to the dose
· What is the reason for monitoring?
· The potential contribution of other factors in the patient (eg electrolytes, renal function etc)
· Is the patient at steady state?

Ó Royal Australasian College of Surgeons – December 2000 Page 11 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q11 List the major pharmacological approaches to prevention and treatment of upper GI ulceration.

A11 · Decreasing the secretion of gastric acid H2 receptor antagonists (antihistamines) such as
cimetidine, ranitidine; or proton pump inhibitors eg omeprazole.
· Neutralisation of secreted acid: antacids, eg magnesium trisilicate, aluminium hydroxide.
· Protection of the mucosa (cytoprotective agents): Bismuth chelate, sucralfate, misoprostol.
· Treatment of Helicobacter pylori: triple therapy using combination antibiotics and either omeprazole
or bismuth.
· Avoidance or modification of dosage or choice of NSAIDs.

Q12 What are the major risks, predictable and unpredictable, associated with the use of local anaesthetics?

A12 · Due to administration: eg trauma to structures.

· Due to adjunctive compounds such as adrenaline or noradrenaline: eg prolonged ischemia,
administration near terminal end-artery etc.
· Due to pharmacological action of local anaesthetic in high dose: eg cardiac (arrhythmias,
hypotension) or CNS (convulsions).
· Due to immunological reaction to agent: eg anaphylaxis.
· Specific cases such as administration in epidural with respiratory problems.
· Prolonged anaesthesia and damage sustained to structure consequently if not protected:
eg corneal damage from rubbing the eye, biting tongue following dental work, burning etc.

Q13 What is GABA? What drugs depend upon altered receptor response to GABA?

A13 Gamma aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the CNS. Benzodiazepines
(either as agonists such as diazepam or midazolam, or antagonists such as flumazenil), barbiturates
(used as anticonvulsants or anaesthetics) and neurosteroids influence GABAA receptors, whilst
baclofen is an agonist at GABAB receptors.

Ó Royal Australasian College of Surgeons – December 2000 Page 12 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q14 What major cardiovascular responses do calcium channel blockers produce? What other role(s) may
they have?

A14 The calcium channel blockers as a group may be considered as antihypertensives and antiarrhythmics.
The properties vary slightly between individual members of the group. Nifedipine is being used for its
vasodilatory properties to limit severe Raynaud’s phenomenon. In addition they are being used as
‘sparing agents’ to reduce doses of cyclosporin for instance, as they bind to P-glycoprotein and
increase bioavailability from the gut.

Q15 What are the target receptors for the anti-emetic effects of ondansetron-like compounds?

A15 Whilst traditional anti-emetics have been anticholinergic (antimuscarinic) and antihistaminic
(H1-receptor antagonists), ondansetron is one of the selective 5-HT3-receptor antagonists. Other
members in the group include tropisetron and granisetron. The 5-HT3-receptor antagonists are of
particular use in preventing and treating the vomiting caused by cytotoxic drugs. The receptors are
located within the chemoreceptor trigger zone (CTZ) on the floor of the fourth ventricle. It is considered
also that 5-HT3-receptors are in the gut. In contrast, motion sickness which arises from labyrinthine
activity in the middle ear, may be prevented by antimuscarinic drugs such as hyoscine. The other
receptor group which is involved in the complex reflexes, which result in vomiting, is the D2-receptor.
Dopamine antagonists such as metoclopramide and the phenothiazines act at the level of the CTZ.

Q16 Which patient groups may be more likely to suffer from ‘scoline apnoea’?

A16 Scoline is the original commercial formulation of succinyl dicholine (suxamethonium), which is a non-
competitive, depolarising neuromuscular blocker. It is metabolised by plasma (pseudo) cholinesterase,
and in individuals with decreased enzyme activity the resulting prolonged skeletal muscle paralysis was
most clinically apparent as respiratory apnoea. Decreased cholinesterase activity may be primary due
to inheritance of either an atypical form, some of which have markedly decreased activity, or secondary
(acquired). The latter occurs in severe liver disease when synthesis is decreased, in chronic exposure
to organophosphates (eg agriculture workers) and malnutrition. Whilst the use of suxamethonium has
decreased, its modern equivalent is the competitive neuromuscular blocker mivacurium.

Ó Royal Australasian College of Surgeons – December 2000 Page 13 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q17 What are the major risks associated with the use of cyclosporin A?

A17 Cyclosporin A is an immunosuppressant whose major targets are helper and cytotoxic T lymphocytes.
In suppressing their activation, the immune system is rendered less capable of dealing with infections
caused by virus, fungi and mycobacteria. Therefore there is a likely increase in infection, particular of
the so-called opportunistic nature. With decreased immune surveillance there is an increase in the
incidence of malignant disease (approximately twice that of an age-matched group). In non-immune-
related side effects the largest group is significant nephrotoxicity. Other side effects include hirsuitism
and gingival hyperplasia.

Q18 Explain the ‘flu-like’ syndrome, which may accompany the use of GM-CSF.

A18 Granulocyte-macrophage colony stimulating factor (GM-CSF) acts on several stem cell lines in the
bone marrow, resulting in increased production of neutrophils, monocytes and platelets. Accompanying
this increase in cell number is an excess release of cytokines from the newly synthesised cells. The
systemic response to these includes hypotension, tachycardia and breathlessness. In addition, if any
pathology investigations are undertaken at that time, it is not uncommon for an increase in lactate
dehydrogenase (LD) to be seen, which may confuse the unsuspecting observer.

Q19 Comment on the use of the haematocrit as a screening test in competitive cyclists.

A19 Haematocrit, which expresses the volume of circulating red cells as the percentage of a blood sample
which they occupy, is a common haematological device. However, the obverse of the cellular
component of a blood sample is the fluid component. If the haematocrit is to be used as a surrogate for
measurement of erythropoietin, then the sample must be collected under controlled, defined conditions
of rest and posture on all occasions. Just as blood pressure will fall and stabilise when an individual is
kept at rest for 30 minutes, so will the concentration of plasma proteins (and haematocrit) decrease by
at least 10%. Further significant concentration will occur with dehydration, and with prolonged venous
obstruction by tourniquet.

Ó Royal Australasian College of Surgeons – December 2000 Page 14 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q20 Compare the likely latent periods between administration of spironolactone and frusemide in the
production of a diuresis.

A20 Frusemide is a loop diuretic whose mechanism of action in the renal tubule is one of direct inhibition of
the active transport of chloride ions in the ascending limb of the loop of Henle. This has very rapid
effects on the resorption of water from the opposite descending limb.

Spironolactone on the other hand is a competitive antagonist of the mineralocorticoid receptor in the
distal convoluted tubule and the collecting duct of the nephron. Its effect is to prevent the synthesis of
new protein for the Na+/K+ transport system in the tubular epithelium, and therefore the onset of effect
depends upon the half life of the existing system. A diuresis usually occurs at about 48 hours.
Spironolactone’s efficacy is greatest in cases in which there is significant hyperaldosteronism, primary
or secondary.

Q21 Tamoxifen lowers the concentration of plasma LDL in post-menopausal women. True or false?

A21 True. Tamoxifen is a partial agonist of oestrogen receptors. Although its predominant pharmacological
role is in its anti-oestrogen mode to inhibit the binding of naturally occurring oestrogens in breast tissue,
tamoxifen has sufficient potency to cause a change in the secretion of lipoproteins so that the
circulating lipid concentrations (particularly as reflected in cholesterol) more closely resemble
premenopausal than post menopausal values.

Ó Royal Australasian College of Surgeons – December 2000 Page 15 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q22 Match the following compounds and the major metabolic pathways:

adrenaline oxidation
azathioprine monoamine oxidase
codeine pseudocholinesterase
cortisone cytochrome P450 3A4
mivacurium thiopurine methyl transferase
theophylline CYP 2D6

A22 Cortisone/oxidation
Adrenaline/monoamine oxidase
Mivacurium/pseudocholinesterase
Theophylline/cytochrome P450 3A4
Azathioprine/thiopurine methyl transferase
Codeine/CYP 2D6

Q23 The following drugs are recognised as causing cholestasis – True or false?
Rifampicin, phenytoin, flucloxacillin, testosterone.

A23 Rifampicin False

Phenytoin False
Flucloxacillin True
Testosterone True
(Not all drug-induced jaundice is cholestatic in origin).

Q24 Which of the following drugs have significant renal excretion?

Gentamicin, azathioprine, lithium, morphine.

A24 Gentamicin True

Azathioprine False
Lithium True
Morphine False (metabolite does, not morphine itself)

Ó Royal Australasian College of Surgeons – December 2000 Page 16 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q25 Match the following pairs of organ damage and drug:

Acute interstitial nephritis Amphotericin B
Acute Tubular Necrosis (ATN) ketoprofen
Glomerular damage D-penicillamine
Myoglobinuria penicillin G (benzyl penicilline)
simvastatin

A25 Acute Tubular Necrosis (ATN)/amphotericin B/ketoprofen

Acute interstitial nephritis/penicillin G
Glomerular damage/D-penicillamine
Myoglobinuria/simvastatin

Q26 “The administration of metoclopramide prior to giving paracetamol will improve the efficacy of
paracetamol in migraine”. Comment.

A26 In an attack of migraine, there is significant gastric stasis, which commences during the prodromal
period. Drugs are predominantly absorbed from the small intestine, not from the stomach. Therefore, in
gastric stasis, absorption is delayed. Metoclopramide increases gastric emptying and intestinal motility,
and therefore if administered prior to oral paracetamol or other medication, there is improved absorption
of the drug.

Q27 The absorption of which drugs may be affected by the presence of cholestatic jaundice and why?

A27 Drugs which are lipid-soluble are most efficiently absorbed when incorporated into micelles. This
requires the presence of bile salts, the concentrations of which are significantly decreased in cholestatic
jaudice. Drugs which are included in this category include fat soluble vitamins (A,D, E and K), digoxin,
cyclosporin. Changes in the formulation of drugs can be used to limit this problem and increase
bioavailability: (eg the Neoral formulation of cyclosporin compared to its original Sandimmun
preparation).

Ó Royal Australasian College of Surgeons – December 2000 Page 17 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q28 What is P-glycoprotein?

A28 P-glycoprotein is an ATP-dependent, membrane-associated transport protein. It is expressed in the

epithelial cells of the intestinal mucosa, renal proximal tubules and hepatocyte canalicular membrane
for instance. It is also in the endothelial cells of the blood-brain-barrier. In all cases its functional
direction of excretion is from the cells into the adjacent lumen; or in the case of the CNS, results in
exclusion of a compound from the CNS. Its carrier characteristics allow it to bind very variable
structures, ranging from digoxin to steroids to cytotoxic drugs. It is the latter area in the development of
acquired resistance to chemotherapy that a closely related protein family (multi-drug resistance
proteins, mdr) were first identified. Apart from its important role in integrity of the blood brain barrier,
P-glycoprotein has a major role in influencing drug bioavailability and drug excretion. For instance,
drugs such as diltiazem may be used to competitively inhibit transport, and thus increase the absorption
of compounds such as cyclosporin or phenytoin. In considering the mdr-proteins, the same type of
inhibition may be used to increase the concentration of some cytotoxic agents within the cytoplasm of
cells during treatment of leukemia following relapse.

Q29 In constipation due to high dose opioid use, which laxative(s) is/are most likely to be effective and why?

A29 Opioids cause constipation through an inhibitory action on the myenteric plexus of the gut wall, both by
direct action on the smooth muscle as well as via a centrally mediated effect. There is a decrease in
tone and motility of the gut wall. The involvement of the myenteric plexus means that any laxative
compound which relies upon a reflex response to increased intraluminal volume will not be effective in
morphine-associated constipation. For instance neither increasing dietary fibre nor bulk laxatives such
as methylcellulose or plant gums will be effective. Direct stimulants such as senna (anthracene
derivative) are most likely to be effective.

Ó Royal Australasian College of Surgeons – December 2000 Page 18 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q30 Why are doses of drugs, which are administered by inhalation or via the buccal mucosa, smaller than
the orally administered preparation? Give examples.

A30 This effect is directly due to the contribution of the so-called first pass effect or first pass clearance to
limiting bioavailability of some drugs. Drugs which are subject to significant breakdown either within the
intestinal lumen, or to metabolism in the gut mucosa or a large percentage of which is removed from the
portal blood on its first pass of blood through the liver, have low bioavailability. If the drug is
administered by an alternative route, so that the absorbed drug is not subject to these imposts, then a
higher percentage of the administered dose will reach the systemic circulation and ultimately the target
organ. For instance, nitroglycerin is broken down in both the gastric pH and metabolised in gut wall. It is
common practice to administer it by placing a tablet under the tongue, the absorbed drug then passing
via the right side of the heart to its required sites of action. Salbutamol, used as a bronchodilator, is
commonly administered by inhalation. Not only is the dose smaller, but in this case relative selectivity is
acquired, with the side-effect profile being limited by administration close to site of desired effect.

Q31 All drugs are cleared by first order kinetics. True or false?

A31 False. The majority of medications and toxic compounds are metabolised according to first order
kinetics; the amount of drug cleared at any one time is proportional to the concentration in the blood or
plasma (eg renal clearance of gentamicin). This results in concentration-time curve which is
exponential in nature. Relatively few (but important) drugs are cleared according to zero order kinetics:
ie a fixed amount of drug is cleared per unit time independent of concentration. The concentration–time
relationship in this case is described by a straight line. The most common example of the latter is the
clearance of ethylalcohol from blood and is the basis of the calculations used in drink-driving legislation.
In some drugs whose pathway is subject to saturable kinetics (dose-related), at higher doses when the
capacity of the pathway is limited, clearance changes from first order to zero order kinetics
(eg phenytoin).

Ó Royal Australasian College of Surgeons – December 2000 Page 19 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q32 A one compartment model of drug distribution refers to the route of elimination. True or false?

A32 False. The compartment model describing the distribution and kinetics of any drug refers to a
mathematical concept. Whilst the route of elimination will influence the rate of clearance (and half life),
the compartmental description is generally independent of the route of elimination. If the distribution is
described as being a one compartment model of distribution, its clearance can be described by a single
exponential curve. Such a drug does not have a significant degree of protein or intracellular binding,
and it is most often confined to the intravascular or extracellular space: eg compare gentamicin and a
toxin such as paraquat. Even in cases of renal failure, although the clearance of the aminoglycoside is
limited and the half-life prolonged, the excretion is still described by a single curve. Paraquat, a very
toxic herbicide, has a very high volume of distribution, and is actively taken up into cells via the
polyamine system. If haemodialysis is undertaken as treatment, although the apparent blood
concentration may fall quite quickly, as soon as dialysis is ceased, there is re-equilibration of material
back out of cells, and the blood concentration rises again. If the drug clearance was followed without
intervention, it would resolve into at least two discrete exponential curves, and possibly more if the
individual lived long enough.

Q33 In Therapeutic Drug Monitoring (TDM), a peak concentration may be helpful in the diagnosis of
possible clinical toxicity. True or False?

A33 True, if the toxicity is related to concentration and is not a so-called idiosyncratic response. There
should ideally also be a history which relates the occurrence of symptoms to a particular time in the
dosing interval. For instance, cerebellar ataxia caused by phenytoin is best assessed by measurement
of phenytoin at trough or pre-dose concentrations, unless there is a clear history of slurred speech at
particular times of the day. It would be unusual in the latter case for the trough concentration to be
normal however. Lithium toxicity (muscle tremor and nausea) may be related by a good historian as
occurring 2 hours post–dose. Ideally, most clinical information would be best gained by sampling at
that time. If the clinical toxicity of phenytoin was a rash, then this is independent of concentration, and
TDM is not of value in making the diagnosis.

Ó Royal Australasian College of Surgeons – December 2000 Page 20 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

CASE SCENARIOS AND MCQS

CASE SCENARIO 1
Mr CC has cryptogenic cirrhosis and is admitted with peritonitis, for which an exploratory
laparotomy is necessary.

MCQS – TYPE X (MULTIPLE TRUE-FALSE)

Q1 The use of the following drugs during anaesthesia may lead to prolonged neuromuscular blockade in
this man
1. Suxamethonium
2. Atracurium
3. Gallamine
4. Mivacurium

Q2 Which of the following drugs would have significantly altered clearance in this patient because of his
cirrhosis?
1. Frusemide
2. Paracetamol
3. Aspirin
4. Gentamicin

Q3 If this patient developed cardiac failure and dysrhythmias post-operatively what would be the effect on
the following drugs?
1. the half-life of digoxin would be increased
2. the clearance of lignocaine would be increased
3. the half-life of vancomycin would be decreased
4. the clearance of metronidazole would be decreased

Ó Royal Australasian College of Surgeons – December 2000 Page 21 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

CASE SCENARIO 2
Ms SLE (30 years of age) has asceptic necrosis of the head of the right femur. She has been
taking prednisone (20 mg/day) for 5 years and has used various NSAIDs (currently she is taking
ketoprofen). She was recently commenced on azathioprine, in an attempt to limit her reliance on
steroids.

MCQS – TYPE X (MULTIPLE TRUE-FALSE)

Q1 On examination the appearances of her skin which would be consistent with long term glucocorticoid
use include
1. thin skin
2. bruising
3. acne
4. hirsutism

Q2 Laboratory investigations consistent with prednisone use would include

1. polycythaemia
2. hypernatraemia
3. hypoglycaemia
4. hyperbilirubinaemia

Q3 Important side effects of glucocorticoids include

1. pathological fractures
2. retinal detachment
3. pancreatitis
4. hypertension

Ó Royal Australasian College of Surgeons – December 2000 Page 22 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Answers and Commentaries

CASE SCENARIO 1

Q1 The use of the following drugs during anaesthesia may lead to prolonged neuromuscular blockade in
this man
1. Suxamethonium
2. Atracurium
3. Gallamine
4. Mivacurium

A1 1, 4 True; 2, 3 False
Both suxamethonium and mivacurium are metabolised by plasma (pseudo) cholinesterase, the
synthesis of which is decreased in liver disease. Atracurium usually has a short duration of action
because it undergoes spontaneous nonenzymatic rearrangement (Hoffman reaction) in plasma.
Gallamine is excreted almost entirely by the kidney.

Q2 Which of the following drugs would have significantly altered clearance in this patient because of his
cirrhosis?
1. Frusemide
2. Paracetamol
3. Aspirin
4. Gentamicin

A2 2, 3 True; 1, 4 False
Aspirin (acetylsalicylic acid) is metabolised by plasma esterases to salicylic acid, which in turn is
metabolised and conjugated in the liver. It has a saturable metabolism, and the half-life is increased in
cirrhosis, particularly if there is significant intra-hepatic shunting. Paracetamol is usually cleared by
conjugation in the liver, but if this pathway is saturated, the excess is metabolised by the cytochrome
P450 system. In severe liver cirrhosis, with a decrease in liver cell mass the toxicity of paracetamol is
significantly increased at doses of paracetamol usually considered to be without significant side-
effects, and hepatic necrosis can occur at total doses of less than 10 g.

Gentamicin is excreted by the kidney, and frusemide also is excreted mainly by the kidney.

Ó Royal Australasian College of Surgeons – December 2000 Page 23 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q3 If this patient developed cardiac failure and dysrhythmias post-operatively what would be the effect on
the following drugs?
1. the half-life of digoxin would be increased
2. the clearance of lignocaine would be increased
3. the half-life of vancomycin would be decreased
4. the clearance of metronidazole would be decreased

A3 1 True; 2, 3, 4 False
Significant cardiac failure causes decreased perfusion of both the kidney and the liver. Plasma half-
life is a pharmacokinetic function dependent upon the rate of clearance of a compound. Whether
decreased liver perfusion has an effect upon hepatic clearance depends upon whether the drug has a
high liver extraction and flow-dependent clearance (eg diltiazem, lignocaine, imiprimine, midazolam,
morphine, naloxone). For a drug with a high extraction ratio, changes due to enzyme induction or
hepatic disease should have little effect. Whilst metronidazole is metabolised in the liver, its clearance
is not flow dependent and cardiac failure will not significantly alter its half-life. Likewise changes in
plasma protein binding should have little influence on a flow-dependent drug. This can be compared
with drugs which have low extraction ratios in the liver, and whose clearance will be significantly
affected by changes in intrinsic clearance such as enzyme induction or inhibition, and by protein
binding (eg phenytoin, salicylic acid and warfarin).

Digoxin’s clearance is predominantly renal, both glomerular filtration and some active secretion down
the pathways for basic compounds. Its half-life is significantly increased by both decreased perfusion
of the kidney and by glomerular loss such as occurs with age. Vancomycin’s excretion entirely
depends upon glomerular filtration, and with the increase in half-life which would occur in cardiac
failure, the risk of toxicity is increased. Plasma level monitoring is therefore important.

Ó Royal Australasian College of Surgeons – December 2000 Page 24 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

CASE SCENARIO 2

Q1 On examination the appearances of her skin which would be consistent with long term glucocorticoid
use include
1. thin skin
2. bruising
3. acne
4. hirsutism

A2 1, 2, 3, 4 True
All features are consistent with glucocorticosteroid use and they can all contribute to the major
subjective dissatisfaction in some patients. Wound healing could also be delayed in this patient due to
steroid use. Other changes in physical appearance which are common with long term and/or high
dose glucocorticoid use include the ‘Cushingoid’ appearances of ‘moon facies’, redistribution of
adipose tissue (centripetally) to give the ‘buffalo hump’ at the back of the neck, and the thinning of the
limbs.

Q2 Laboratory investigations consistent with prednisone use would include

1. polycythaemia
2. hypernatraemia
3. hypoglycaemia
4. hyperbilirubinaemia

A2 1, 2 True; 3, 4 False
Bone marrow stem cells including those of the erythroid series are stimulated by glucocorticoids, and
in bone marrow aplasia for instance high dose steroid therapy may be initiated.

Prednisone is metabolised to prednisolone which has substantial agonist properties on the

mineralocorticoid receptors of the renal tubules. Although marked hypernatraemia is unusual in these
patients it can occur, and one would anticipate there should be a relative hypokalaemia accompanying
it.

Hyperglycaemia and glucose intolerance due to insulin resistance are common in patients on high
dose glucocorticoids. In cases when very high doses are being used, such as part of chemotherapy
regimes, it may be necessary to use insulin.

Unlike the oestrogenic and androgenic steroids, glucocorticoids per se do not cause hepatic
dysfunction.

Ó Royal Australasian College of Surgeons – December 2000 Page 25 of 26

 STEM MODULE: PHARMACOLOGY / PHARMACOKINETICS / DRUGS AND THERAPEUTICS

Q3 Important side effects of glucocorticoids include

1. pathological fractures
2. retinal detachment
3. pancreatitis
4. hypertension

A3 1, 3, 4 True; 2 False
Pathological fractures are one of the manifestations of the effect of corticosteroids on protein
synthesis. Other examples would include the proximal myopathy of the limb girdles, the thinning of the
skin (made more apparent by loss of subcutaneous fat in the limbs), cataracts, and delay in healing.
Changes in calcium balance associated with steroid use would also contribute to the pathological
fractures.

The major side-effects of steroids seen in the eye are cataract formation and glaucoma.

The underlying pathology of steroids causing pancreatitis is not understood. Not all patients appear to
have developed the severe diabetes mellitus or hyperlipidaemia which may predispose to its
occurrence.

Ó Royal Australasian College of Surgeons – December 2000 Page 26 of 26