Applied Pharmacology/Integrated Clinical Case Cover Sheet – Internal and External Topics

Allocated Part 2 Drug:    Monopril
Allocated Part 3 Drug:    Lipitor
Patient Background (Part 1)
For much of his life Howard Bloom had rarely visited his GP, however in the last 5 years he has needed to see his GP with increasing frequency to address a number of ongoing medical conditions. The following baseline characteristics were recorded at Mr Bloom’s last GP visit, which was two week ago:
Age    64years
Height    176cm
Weight    98kg
Blood Pressure    154/89mmHg
Pulse    68bpm
Relationship Status    Married for 34 years
Dependants    Two children; son aged 31 y/o and daughter aged 28y/o
Occupation    Senior marketing executive
Smoking status    Non-smoker
Alcohol consumption    Social drinker (6 to 10 std drinks / week) with history of heavy drinking (30 to 40 std drinks / week)  until 5 years ago
Biochemical analysis    Fasting blood glucose    11.3 mmol/L (healthy 3 – 5.4mmol/L)
HbA1c    8.1 (healthy < 4.8)
eGFR (measured as creatinine clearance)    73mL/min (healthy > 90mL/min)
Child-Pugh score    5 (healthy < 5)
Cholesterol    6.8mmol/L (healthy < 5.5mmol/L)
Plasma albumin    39g/dL (healthy 32 to 54 g/L)
Prescription medications    Altven (75mg OD), Cardiprin (100mg OD), Diaformin (1000mg BD), Dithiazide (25mg OD), Endone (5mg PRN), Monopril (10mg OD), Noten (50mg OD),Probitor (20mg OD) and Zocor (40mg OD).
Medical history    History ofcongestive heart failure, depression, gastro-oesophageal reflux, hypertension, ischaemic heart disease, type-2 diabetesand recent surgery to repair a partially torn ligament in left shoulder (2 weeks ago).

As an experience paramedic with a sound knowledge of pharmacology, you recognise several of the medications that Mr Bloom is currently taking and can link them to the pre-existing conditions identified by Mr Bloom in his medical history.
1.    For each of the patient’s prescription medications complete the following tables:
Altven
Generic name
Drug class
Approved indications
Indication specific to Mr Bloom
Regulatory schedule
Cardiprin
Generic name
Drug class
Approved indications
Indication specific to Mr Bloom
Regulatory schedule
Diaformin
Generic name
Drug class
Approved indications
Indication specific to Mr Bloom
Regulatory schedule
Dithiazide
Generic name
Drug class
Approved indications
Indication specific to Mr Bloom
Regulatory schedule
Endone
Generic name
Drug class
Approved indications
Indication specific to Mr Bloom
Regulatory schedule
Monopril
Generic name
Drug class
Approved indications
Indication specific to Mr Bloom
Regulatory schedule
Noten
Generic name
Drug class
Approved indications
Indication specific to Mr Bloom
Regulatory schedule
Probitor
Generic name
Drug class
Approved indications
Indication specific to Mr Bloom
Regulatory schedule
Zocor
Generic name
Drug class
Approved indications
Indication specific to Mr Bloom
Regulatory schedule

Scenario (Part 2)
At 7:00am on a Wednesday morning, Mr Bloom called 000 after experiencing a sudden onset of shortness of breath and chest pain while lying in bed shortly after waking up. You attend the call and perform an initial assessment which reveals the following information:
Primary complaint    Feeling of pressure on chest, uncomfortable (nauseous) feeling in stomach, dizziness when standing.
Level of consciousness    Alert and conscious, can recall the time, identity and location.
Airway and breathing    Airway is clear however patient is visibly short of breath.
Circulation    Radial pulse is ~84beats/min, strong and regular.

While sitting with Howard, he tells you that in addition to his prescription medications he is also currently taking a number of complementary and herbal preparations that were recommended to him by his son-in-law, these include Blackmores Joint Formula (OD), Nature’s Way Brain and Memory supplement (OD) and Blackmores Mood Support St John’s Wort supplement (OD).

2.    Using only peer reviewed literature sources identify and evaluate the evidence for three CLINICALLY RELEVANT interactions that may occur between Mr Bloom’s prescription medications andthe active ingredients in the complementary and herbal preparations that Mr Bloomis currently taking.
Your discussion should incorporate the:
•    Type of interaction (i.e. pharmacokinetic or pharmacodynamic)
•    Mechanism of interaction (e.g. reduced clearance by inhibition of drug metabolising enzyme x)
•    Clinical consequences of the interaction
•    Strength of the evidence (e.g. anecdotal report, mechanistic reasoning, clinical trial, etc) for the interaction, including the citation for any reference material.
Interaction 1: (prescription medication) / (complementary / herbal medicine)

Interaction 2: (prescription medication) / (complementary / herbal medicine)

Interaction 3: (prescription medication) / (complementary / herbal medicine)

You note that the patient is taking a relatively large, but not unreasonable, number of medications for an individual of his age. Recalling your undergraduate studies in pharmacology, you consider how each of these medications may be working in order to elicit their therapeutic effect.

3.    For your ‘ALLOCATED PART 2 DRUG’ (see PARA3006 FLO site for allocations) explain how the interaction of the drug with its molecular target(s) leads to a change in physiology, which in turn manifest as the therapeutic effect when used to treat MR BLOOM’S SPECIFIC condition.

4.    For the drug and indication discussed in Question 3, critically review one ORIGINAL RESEARCH PEER REVIEWED journal article that reports the evidence for the clinical effectiveness of this drug in HUMANS.
a.    Identify the article:
•    Provide a full citation (reference) for the article
•    Briefly describe your reason for selecting this article

b.    For the selected article, summarise and evaluate the appropriateness of the:
•    Type of study (e.g. randomised control trial, observational study or anecdotal report).
•    Comparator agent (e.g. placebo or gold standard therapy).
•    Sample size (i.e. the number of study participants).
•    Measures of effectiveness (i.e. how was the effectiveness of this drug assessed).

c.    On the basis of these criteria, for the article you have revieweddiscuss YOUR interpretation of the strength of the evidence for the clinical effectiveness of the drug.

During your initial treatment you administer oxygen and set up a 3 lead cardiac monitor, which shows that the patient is in normal sinus rhythm with a rate of 83 beats/min. You perform a thorough history and physical examination, which reveals:
Symptoms    Chest pain, nausea, diaphoresis, pale, cool skin.
Onset    “The pain began really suddenly just after I woke up, about an hour ago. I was about to get out of bed when the pain began”
Provocation    “No matter what I try to do, the pain won’t go away”
Quality    “It feels like someone is pressing really hard on my chest”
Radiation    The pain appears to be localised to the patient’s chest
Severity    8 on a scale of 1 to 10
Chest examination    No signs of trauma, expansion is normal and symmetrical
Breathing sounds    Nil adventitious sounds
Jugular veins    Not elevated
Blood pressure    161/91mmHg
Pulse    83 beats/min, strong and regular
Respiration    22 breaths/min
Oxygen saturation    98% (on 100% oxygen)
Allergies     “I am allergic to penicillin”
Last oral intake    “I had a cup of tea and two biscuits before I went to bed last night”

After consulting with your partner, you determine that it is appropriate to administer glyceryl trinitrate (GTN) to Mr Bloomin the form of a sublingual spray.

5.    Critically review one PEER REVIEWED JOURNAL ARTICLE that discusses the mortality benefit obtained by administering GTN in this scenario.
a.    Identify the article:
•    Provide a full citation (reference) for the article
•    Briefly describe your reason for selecting this article

b.    For the selected article, summarise and evaluate the appropriateness of the:
•    Type of study (e.g. randomised control trial, observational study or anecdotal report).
•    Comparator agent (e.g. placebo or gold standard therapy).
•    Sample size (i.e. the number of study participants).
•    Measures of effectiveness (i.e. how was the effectiveness of this drug assessed).

c.    On the basis of this critical review, summarise YOUR interpretation of the evidence for the mortality benefit associated with administering GTN to a patient in Mr Bloom’s situation and comment on any additional reasons why GTN may be used in this setting.

Prior to administering the GTN to Mr Bloom, you explain to him what you are about to do and ask him some additional questions regarding factors that may affect the way he responds to this drug.
6.    Making reference to your paramedic service’s treatment guidelines, discuss any factors regarding a patient’s vital signs and medical history that should be considered prior to administering GTN.
a.    Identify thefactors

b.    Discuss the consequences/risks of not addressing each factor.

c.    Discuss the risk / benefit relationship that must be considered for each factor.

d.    Identify a strategy for addressing each factor.

Once you have administered GTN to the patient, you perform a 12-lead ECG which differs from your initial 3-lead ECG and presents a clinical picture consistent with the example ECG shown in Figure 1:

Figure 1 – Example of a 12-lead ECG obtained from an individual experiencing the patient’s condition
(this is not Mr Bloom’s ECG)

On the basis of this 12-lead ECG, you diagnose that the patient is experiencing an ST elevation myocardial infarction (STEMI). Shortly after administering GTN, the patient describes his pain as a 5 (previously an 8). After rechecking the patient’s blood pressure (now 136/82mmHg), you load the patient into the ambulance to drive him to Flinders Medical Centre, undertaking an on-going assessment and treatment en-route:

Level of consciousness    Alert and conscious; can recall the time, identity and location.
Respiration    18 breaths/min, unlaboured.
Oxygen saturation    98% (on 2L/hr 100% oxygen).
Blood pressure    136/82mmHg
Pulse    81 beats/min, strong and regular.
Chest pain    4 on a scale of 1 to 10

While continuing to monitor the patient’s vital signs, you hand Mr Bloom a 300mg aspirin tablet and tell him to chew and swallow it.

7.    Critically review one PEER REVIEWED JOURNAL ARTICLE journal article that discusses the mortality benefit obtained by administering aspirin to a patient that has recently suffered a STEMI.
a.    Identify the article:
•    Provide a full citation (reference) for the article
•    Briefly describe your reason for selecting this article

b.    For the selected article, summarise and evaluate the appropriateness of the:
•    Type of study (e.g. randomised control trial, anecdotal report).
•    Study duration (i.e. for how long wereparticipantsmonitored following the intervention)
•    Sample size (i.e. the number of study participants).
•    Outcome measures (e.g. 3-month survival, 5-year survival, etc).

c.    On the basis of this critical review, briefly summarise YOUR interpretation of the evidence for the mortality benefit of administering aspirin to a patient in Mr Bloom’s situation.

Upon arrival at the Emergency Department at Flinders Medical Centre, you give a verbal report to the ED registrar and present them with the 12-lead ECG obtained in the field. The ED registrar immediately alerts the cardiology registrar who orders a repeat ECG, which confirms your findings. The cardiology registrar then administers 300mg of clopidogrel to Mr Bloom and organises for him to be moved to the Cath Lab for coronary angiography and possible stenting.

9.    Discuss the therapeutic mechanism of action of clopidogrel relevant to this scenario:
a.    Identify and describe the metabolic process that must occur within the body in order for clopidogrel to elicit a therapeutic effect.

b.    Describe how the interaction of clopidogrel (once it has undergone the metabolic process identified in Part a) with its molecular target accounts for the therapeutic effect of this drug.

As you provide your hand over and see Mr Bloom being taken to the Cath lab you recall that a number of factors such as genetic polymorphism and drug-drug interactions can alter both the effectiveness and tolerability of clopidogrel.
10.    Using onlyPEER REVIEWED literature sources identify and discuss any potential drug-drug interactions with Mr Bloom’s prescription medications that may alter the effectiveness of clopidogrel.
a.    For each interaction describe the:
•    Type of interaction (i.e. pharmacokinetic or pharmacodynamic)
•    Mechanism of interaction (e.g. impaired metabolism of clopidogrel)
•    Clinical consequences of the interaction

b.    List the sources of information and indicate the strength of the evidence (e.g. anecdotal report, clinical case, clinical trial, etc) for each of the interactions that you have identified

Follow-up (Part 3)
Mr Bloom remains in hospital for seven days following the successful insertion of a stent into the occluded coronary artery, during this time he contracts a bacterial infection, which following the failure of various other antibacterial drugs is eventuallytreated with long term use of Ciproxin (500mg TID). One month after his discharge from hospital, Mr Bloom visits his GP for a routine follow-up. During this consultation, Mr Bloom identifies to his GP thathe has recently been feeling more anxious than usual,that he is having a lot of trouble sleeping at night, and that for the last two weeks he has been feeling very nauseous every time he takes the Ciproxin tablets. Mr Bloom’s GP undertakes a physical examination, orders some blood tests and makes some modifications to his medications to address these ongoing medical problems.The physical examination and blood tests reveal the following changes from Mr Bloom’s baseline characteristics:

Weight    101kg
Baseline Blood Pressure    154/91mmHg
Baseline Pulse    71bpm
Biochemical analysis    Fasting blood glucose    11.8mmol/L (healthy 3 – 5.4mmol/L)
HbA1c    8.4 (healthy < 4.8)
GFR (as creatinine)    56mL/min (healthy > 90mL/min)
Child-Pugh score    6 (health < 5)
Cholesterol    6.8mmol/L (healthy < 5.5mmol/L)
Plasma albumin    22g/L (healthy 32 to 54 g/L)
New prescription medications list    Avapro (300mg OD),Cardiprin (100mg OD), Ciproxin (500mg TID), Diaformin (1500mg BD),Lasix (40mg OD), Lipitor (20mg OD), Maxalon (10mg BD),Noten (25mg OD), Plavix (75mg OD), Somac (40mg OD), and Valium (5mg OD).

When Mr Bloom’s GP receives the biochemistry results from the blood tests that he has ordered he is a little concerned that Mr Bloom’s liver and kidney function appear to have declined. Worried that these reductions in hepaticand renal function may change Mr Bloom’s exposure to one or more of his medications, he checks over the pharmacokinetics of these drugs to see whether he needs to make any medication changes or dose adjustments.

Answer the following series of questions (11 to 17) for your ‘ALLOCATED PART 3 DRUG’(see PARA3006 FLO site for allocations) examining the pharmacokinetics of the drug in NORMAL/HEALTHY HUMANS:

Given that all of the medications that Mr Bloom is currently taking are administered orally, you initially consider how Mr Bloom’s physiology may affect the bioavailability of the drug.

11.    Consider the bioavailability of an oral administered dose of the drug:
a.    Citing an appropriate reference, state the bioavailability of the drug as a percentage.

b.    Identify whether the bioavailability of this drug is primarily affected by gastrointestinal absorption or first pass elimination.

c.    Discuss whether Mr Bloom’s altered hepatic function is likely to alter the bioavailability of the drug.

You then examine any potential changes in exposure to the drug that may result from altered distribution.
12.    Examine the extent of binding of the drug to plasma proteins:
d.    Citing an appropriate reference, state the percent bound (answer must be as a percentage).

e.    Showing all working out,calculate the unbound fraction (fu).

f.    Briefly comment on whether the change in Mr Bloom’s plasma albumin concentration is likely to alter protein binding of this drug, and what effect this may have on clearance.

13.    Examine the distribution of the drug within the body:
a.    Citing an appropriate reference, state the volume of distribution (VD) in either L/kg or L.

b.    Comment on whether the VD for the drug is large or small relative to volume of blood, and reflect on what this means in terms of the distribution of this drug.

You then consider potential changes in exposure to the drug that may result from altered the elimination of the drug
14.    Determine the primary route of elimination for this drug:
a.    Citing an appropriate reference, state the fraction excreted unchanged in the urine (fe).

b.    Using a diagram depict the major route of elimination for the drug identifying the:
•    Primary organ that is involved (i.e. liver or kidneys).
•    Major processes (e.g. metabolism, filtration, etc) and types of reactions
(e.g. functionalization or conjugation).
•    Key enzymes and/or transporter proteins that are involved in these processes
(e.g. CYP, UGT, PgP, OATP).

15.    Examine the systemic clearance for the drug:
a.    Citing an appropriate reference, state the total (systemic) clearance in L/hr.

b.    Individually calculate the renal and hepatic clearances (showing working out).
Renal Clearance:

Hepatic Clearance:

c.    Determine the classification of the clearance of the drug (e.g. low hepatic clearance)

d.    Referring to the equations used to calculate organ clearances and based on the classification of the clearance of the drug, JUSTIFY which determinants of clearance (e.g.hepatic enzyme activity, unbound fraction, organ perfusion, filtration, secretion or reabsorption) are important for thedrug.

Finally you reflect on the considerations identified for each processes involved in determining exposure to a drug, and on Mr Bloom’s circumstances andcurrent state of health and evaluate the factors that can change the clearance of a drug.

16.    Discuss the influence of patient (e.g. disease states) and environmental (e.g. alcohol, diet, smoking) factors that may alter the rate of clearance of the drug:

17.    Onthe basis of your investigation of the pharmacokinetics of the drug discuss WITH JUSTIFICATION whether YOU feel it would be appropriate to (1) continue using the drug without dose adjustment, (2) continue using the drug but adjust the dose, or (3) switch the patient to a more appropriate drug (need to provide an alternative option with reasoning).

References

Mark Sheet                                Integrated Clinical Case Assignment

Assessor:        Late Submission:    Yes/No
Comments:

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