2000 - Greg Summerfield is a 42 year-old investigative reporter with a national
TV network. He is brought to
the emergency room on Friday evening by friends who arrived at his townhouse
about 9pm for a small
social gathering and found Greg collapsed on his bathroom floor. “He seems to be
unconscious. We
got no response when we shook him or talked to him. He is an awful bluish colour
and he hardly
seems to be breathing at all” the friends say.
Question 6. (a) List key information about Greg.
(b) Suggest two hypotheses for the problem you consider most likely to
underlying Greg’s condition. For each, give a short rationale or explanation
(two or three sentences or flow diagram) indicating possible mechanisms linking
your hypothesis to the observations for Greg.
(15 minutes)
Question 7. Assume that it is not possible to get any useful history for the
patient. Outline up to four items of information from a physical exam or
laboratory tests that you would seek with highest priority. For each, indicate
how the information would help to confirm or eliminate, or differentiate
between, your hypotheses.
(15 minutes)
Question 8.
(a) Summarise, in a paragraph or two or with a flow diagram, what is now your
most favoured hypothesis for the cause of Greg’s condition, indicating briefly
how the new information helps support your favoured hypothesis or eliminate
alternatives.(More detailed explanations of various aspects of his condition
will be sought in parts (b) to (d) of the question below).
(10 minutes)
(b) Describe the normal controls of respiration in humans and discuss the
relationship between the values for “blood gases” observed in Greg and his
respiration rate.
Suggest reasons for each of the abnormal values.
(12 minutes)
(c) Would Greg’s condition, as reflected in the blood gas data, affect the
ability of hemoglobin to deliver the available O2 to the tissues? Explain.
(5 minutes)
(d) Could O2 delivery to tissues be relevant to Greg’s unconscious state?
Explain your answer.
(8 minutes)
The Medical Officer concludes that the findings are strongly suggestive of a
heroin overdose. She “bags and masks” the patient (ie provides ventilatory
support with oxygen) and gives an intravenous injection of naloxone (0.4 mg).
The naloxone acts within minutes to reverse the respiratory depression caused by
heroin and its metabolites (monoacetyl morphine, morphine) via their action at m
receptors in the brain stem respiratory centres. Greg begins to regain
consciousness. The ventilatory support is
removed and Greg’s respiratory rate increases towards normal. Because of an
unusually busy night in the emergency room, Greg is not closely monitored and 30
minutes later is found to be barely conscious and breathing at 8 breaths/min. A
further intravenous dose of naloxone is given and a naloxone infusion
established. He regains consciousness and his respiration reverts to a normal
rate. After 2 hours the naloxone infusion is discontinued. Normal respiration is
maintained during a subsequent 4 hour period of observation. Heroin is highly
lipid soluble. It is metabolised to the more polar metabolites monoacetyl
morphine and then morphine, which also depress respiration. Circulating morphine
is subsequently converted to morphine glucuronide. The structure of naloxone,
also highly lipid soluble, is shown. Naloxone in the circulation is converted to
naloxone glucuronide.Question 9. Using the information given:
(a) Suggest how naloxone reverses the respiratory effects of heroin and its
metabolites.
(4 minutes)
(b) You may know nothing about m receptors but from your general knowledge of
receptor structure and function, suggest likely structural features of the m
receptor to account for its function during Greg’s heroin overdose and
subsequent treatment.
(7 minutes)
(c) Suggest why the initial dose of naloxone is effective for only a short time
before respiration is again depressed; and why, after some hours, normal
breathing is again possible without further naloxone treatment.
(6 minutes)
Question 10. Soon after beginning the naloxone infusion, a sample of Greg’s
urine is collected and sent to the laboratory for analysis. What would you
expect to be the relative amounts of heroin and naloxone and their respective
metabolites in the urine? Explain your answer.
(8 minutes)
2001 - Question 2.
(a) What are the principal biological functions of drug metabolism in the body?
Does drug metabolism always achieve these desired outcomes? Explain.
[5 minutes]
(b) Explain, preferably using a diagram, how excretion of drugs in urine is
facilitated by biotransformation of drugs via functionalisation and conjugation
reactions.
[5 minutes]
(c) A patient is being treated with a drug which has a systemic clearance of 5
L/h in healthy subjects. If the fraction of the drug excreted unchanged in the
urine (fe) is 0.2, explain whether hepatic dysfunction or renal dysfunction is
more likely to require adjustment of drug dosage rate. Support your answer with
clearance calculations.
[5 minutes]
2001 - Question 5.
Various stressful conditions act via the central nervous system to cause release
of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. This
peptide hormone moves via the circulation to the adrenal cortex where it
stimulates cells to convert stored cholesterol to the steroid hormone, cortisol,
which is released into the blood. ACTH works by increasing cyclic AMP
concentration in target cells which leads to activation of an enzyme (a lipase)
which catalyses the breakdown of cholesterol esters to give free cholesterol for
hormone synthesis.
From your general knowledge of cellular signal transduction and the action of
hormones, suggest likely mechanisms for the following:
(a) the initial interaction of ACTH with a target cell and how this leads to an
increase in cyclicAMP in the cell.
[7 minutes]
(b) how an elevated concentration of cyclic AMP in the cell could lead to
activation of the lipase.
[5 minutes]
(c) the sequence of events in the target cell when ACTH concentration in the
blood falls.
[5 minutes]2003 - 4. You attend a patient who has been brought to the
Emergency Dzpartment by ambulance shortly before midnight. The team of ambulance
paramedics had treated him as a suspected case of heroin overdose as he lay
semi-conscious in the street outside an inner city hotel.
(a). In addition to the semi-conscious state. what are the 2 card nal signs of
heroin overdose?
[2 min]
(b) Describe the primary actions of opioids on neurons, which underlie the
effects of heroin.
[5 min]
The paramedics advise that to treat the overdose. they administered the drug
naloxone by intravenous injection and that the patient responded appropriately.
(c) What is the cellular mechanism of action of naloxone?
[2 min]
(d) Why was naloxone administered intravenously rather than orally?
[2 min]
When you see the patient he is conscious and able to communicate clearly,
although he is somewhat sedated. He tells you that he had self-administered
heroin intravenously at about I0:30 pm using a newly purchased street sample of
unknown purity. Naloxone was adirrnistered at 11:30 pm and it is now 11:50 pm.
Cardiovascular parameters (blood pressure 120/70. hzart rate 75 beats/min) and
respiration rate (10 breathes/min) are within normal ranges.
(e) Naloxone and morphine have the following pharmacokineti: parameters:
Volume of distribution (Litres) Morphine280 Naloxone 180
Systemic clearance (Litres/hour) Morphine 70 Naloxone 90
Calculate the elimination half-life of morphine and naloxone. E:-plain how these
values influence subsequent treatment.
[4 min]
2004 - Question 3.
a) Many drugs when administered intravenously elicit a greater response than if
they are administered orally. Explain why this is the case.
(4 marks)
b) Explain, preferably with the aid of diagram(s), how drug metabolism reactions
facilitate the renal excretion of lipophilic drugs.
(6 marks)
Question 5.
Intravenous injection of morphine is used in a patient to treat moderate to
severe post-operative pain. After an initial dose, the analgesia is effective
but after some hours the patient is complaining of significant pain.
a) Describe in general terms how the concentration of a drug in blood determines
the receptor-mediated effect produced by that drug.
(4 marks)
b) Outline the general mechanisms responsible for the progressive decrease in
the concentration of a drug such as morphine in the body over time.
(6 marks)
c) The volume of distribution of morphine in this patient is 240 litres and the
systemic clearance is 60 litres/hour. Calculate the elimination half-life of
morphine, showing how you did the calculation.
(2 marks)
2006 - Question 5.
A patient is receiving 15 mg morphine, as an intravenous injection, every 4
hours. The patient’s doctor wishes to replace intravenous morphine with orally
administered morphine.
(a) Explain the two primary determinants of the bioavailability of an orally
administered drug.
(3 marks)
(b) Estimate the dose of oral morphine necessary to provide the same analgesic
response as the intravenous dose (ie 15 mg every 4 hours), given the hepatic
clearance of morphine is 60 L/hr and liver blood flow is 90 L/hr. Show all
calculations and state any assumptions.
(5 marks)
(c) Morphine is cleared largely by hepatic metabolism.
(i) List the three principal roles (or functional outcomes) of drug metabolism
(2 marks)
(ii) Explain, preferably in diagrammatic form, how metabolism enhances the
excretion of a lipophilic drug from the body.
(5 marks)
2007 - Question 4.
A new opioid receptor agonist (drug X) has been developed for use as an
alternative analgesic to morphine.
(a) Drug X is 10 times more potent than morphine and has twice the maximal
efficacy of morphine.
Using the same set of axes, sketch labelled log concentration-response curves
for morphine and drug
X that illustrate the differences in potency and maximal efficacy.
(5 marks)
(b) The pharmacokinetic parameters for drug X and morphine are:
Systemic clearance (CLs) Morphine 60 L/hr Drug X9 L/hr
Volume of distribution (V) Morphine 240 L Drug X 180 L
.
Showing all calculations compare the elimination half-lives of morphine and drug
X. Comment on the implications of these values for the frequency of dosing.
(5 marks)
2008 - Question 4.
a) Drugs act on physiological systems via interactions with molecular targets.
i. List the four primary classes of molecular target for drugs
(2 marks)
ii. Choose one of these classes of molecular target and briefly describe how its
activity can be altered by a drug to produce a pharmacological response.
(4 marks)
(b) Pharmacokinetic parameters were determined for two new drugs:
Drug
Fe = (fraction of drug excreted unchanged in urine)
CLS = (systemic clearance)
Vd = (volume of distribution)
TP-E
Fe 0.1 CLS 10L/hr Vd 400L
TP-F
Fe 1.0 CLS 9L/hr Vd 27L
.
i. Calculate the renal clearance, hepatic clearance and elimination half life
for each drug.
(3 marks)
ii. Comment on the relative effects of renal and hepatic dysfunction on the
systemic clearance of TP-E and TP-F and implications for drug dosage.
(3 marks)