Clinical Cases Flashcards
Pharmacology of Diabetes
A 72 year old woman, Mrs Wallace, attends a GP appointment for a routine health check. Her BMI is 31, her blood pressure is 144/92mmHg, and a brief history reveals her mother dies of diabetes, although Mrs Wallace reports no polyuria, polydipsia or weight loss. Her GP a routine NHS health check.
During a follow up appointment, Mrs Wallace’s blood tests reveal the following:
HbA1c is 65 mmol/mol
LDL-cholesterol 5.18 mmol/L
HDL-cholesterol 0.8 mmol/L
Triglycerides 6.53 mmol/L.
Urinalysis shows glycosuria but no ketones.
Her blood pressure is 148/91HHmg.
A further appointment confirmed the elevated HbA1c.
What is the patient’s problem?
- Hyperglycaemic
- Hypertensive
- Glycosuria
- Obese
- Hypercholesterolaemia (Dyslipidaemia)
Pharmacology of Diabetes
A 72 year old woman, Mrs Wallace, attends a GP appointment for a routine health check. Her BMI is 31, her blood pressure is 144/92mmHg, and a brief history reveals her mother dies of diabetes, although Mrs Wallace reports no polyuria, polydipsia or weight loss. Her GP a routine NHS health check.
During a follow up appointment, Mrs Wallace’s blood tests reveal the following:
HbA1c is 65 mmol/mol
LDL-cholesterol 5.18 mmol/L
HDL-cholesterol 0.8 mmol/L
Triglycerides 6.53 mmol/L.
Urinalysis shows glycosuria but no ketones.
Her blood pressure is 148/91HHmg.
A further appointment confirmed the elevated HbA1c.
What is the therapeutic objective for this patient?
- Lower blood glucose (High glucose damages blood vessels)
- Lower blood pressure (High blood pressure could lead to hypertrophy -> heart failure)
- Lose weight (Excess weight can lead to increase in blood pressure)
- Decrease LDL (High LDL can lead to atherosclerosis -> CVD -> Heart failure)
Pharmacology of Diabetes
A 72 year old woman, Mrs Wallace, attends a GP appointment for a routine health check. Her BMI is 31, her blood pressure is 144/92mmHg, and a brief history reveals her mother dies of diabetes, although Mrs Wallace reports no polyuria, polydipsia or weight loss. Her GP a routine NHS health check.
During a follow up appointment, Mrs Wallace’s blood tests reveal the following:
HbA1c is 65 mmol/mol
LDL-cholesterol 5.18 mmol/L
HDL-cholesterol 0.8 mmol/L
Triglycerides 6.53 mmol/L.
Urinalysis shows glycosuria but no ketones.
Her blood pressure is 148/91HHmg.
A further appointment confirmed the elevated HbA1c.
For this tutorial, we are going to focus on the treatment of type 2 diabetes. Using the algorithm below (derived from the NICE guidance for treatment) what would you prescribe for Mrs Wallace?
- Lifestyle intervention (excercise and healthier diet)
Pharmacology of Diabetes
A 72 year old woman, Mrs Wallace, attends a GP appointment for a routine health check. Her BMI is 31, her blood pressure is 144/92mmHg, and a brief history reveals her mother dies of diabetes, although Mrs Wallace reports no polyuria, polydipsia or weight loss. Her GP a routine NHS health check.
During a follow up appointment, Mrs Wallace’s blood tests reveal the following:
HbA1c is 65 mmol/mol
LDL-cholesterol 5.18 mmol/L
HDL-cholesterol 0.8 mmol/L
Triglycerides 6.53 mmol/L.
Urinalysis shows glycosuria but no ketones.
Her blood pressure is 148/91HHmg.
A further appointment confirmed the elevated HbA1c.
Consider the molecular structure of metformin. How do you think the molecular structure of metformin would influence it’s absorption into the blood and distribution to body tissues?
Charged -> cannot be absorbed through the cell membrane (has an active transport mechanisms - organic cation transporter 1)
- If the pKa of the drug and the pH of the tissue are equal, then the drug will be equally dissociated between the two forms i.e. 50% ionised and 50% unionised.
- A weak acid is going to be more unionised in areas of low pH like the stomach and a weak base is going to be more unionised in areas of higher pH like the blood and urine.
- Ionised molecules are water soluble and can go through the blood to tissues
Pharmacology of Diabetes
A 72 year old woman, Mrs Wallace, attends a GP appointment for a routine health check. Her BMI is 31, her blood pressure is 144/92mmHg, and a brief history reveals her mother dies of diabetes, although Mrs Wallace reports no polyuria, polydipsia or weight loss. Her GP a routine NHS health check.
During a follow up appointment, Mrs Wallace’s blood tests reveal the following:
HbA1c is 65 mmol/mol
LDL-cholesterol 5.18 mmol/L
HDL-cholesterol 0.8 mmol/L
Triglycerides 6.53 mmol/L.
Urinalysis shows glycosuria but no ketones.
Her blood pressure is 148/91HHmg.
A further appointment confirmed the elevated HbA1c.
The expression of the organic cation transporter 1 (OCT-1) is highest in the following tissues: Liver hepatocytes (highest expression), the small intestinal enterocytes and the renal proximal tubules. Why do you think this is relevant to the pharmacokinetics of orally administered metformin?
Expressed in the liver -> side of action - better
Expressed in the kindey -> to be excreted
Expressed in the small intestine -> to be absorbed
Pharmacology of Diabetes
A 72 year old woman, Mrs Wallace, attends a GP appointment for a routine health check. Her BMI is 31, her blood pressure is 144/92mmHg, and a brief history reveals her mother dies of diabetes, although Mrs Wallace reports no polyuria, polydipsia or weight loss. Her GP a routine NHS health check.
During a follow up appointment, Mrs Wallace’s blood tests reveal the following:
HbA1c is 65 mmol/mol
LDL-cholesterol 5.18 mmol/L
HDL-cholesterol 0.8 mmol/L
Triglycerides 6.53 mmol/L.
Urinalysis shows glycosuria but no ketones.
Her blood pressure is 148/91HHmg.
A further appointment confirmed the elevated HbA1c.
PMH: Two-year history of “recurrent urinary tract infection”.
Mrs Wallace is provided with lifestyle advice and several months later is started on standard release metformin (500mg/day;oral). Despite this treatment approach, 6 months later Mrs Wallace is attending a regular GP appointment and her HBA1c has only fallen to 62mmol/mol. What would you do next?
Dual therapy of metformin with DDP-4 inhibitor
Pharmacology of Diabetes
A 72 year old woman, Mrs Wallace, attends a GP appointment for a routine health check. Her BMI is 31, her blood pressure is 144/92mmHg, and a brief history reveals her mother dies of diabetes, although Mrs Wallace reports no polyuria, polydipsia or weight loss. Her GP a routine NHS health check.
During a follow up appointment, Mrs Wallace’s blood tests reveal the following:
HbA1c is 65 mmol/mol
LDL-cholesterol 5.18 mmol/L
HDL-cholesterol 0.8 mmol/L
Triglycerides 6.53 mmol/L.
Urinalysis shows glycosuria but no ketones.
Her blood pressure is 148/91HHmg.
A further appointment confirmed the elevated HbA1c.
PMH: Two-year history of “recurrent urinary tract infection”.
10 years later and Mrs Wallace has a stabilized Hb1Ac of 62mmol/mol. Her drug treatment for her diabetes remains unchanged – metformin and sitagliptin. However, during this time, Mrs Wallace has developed chronic kidney disease. NOTE - It is CLINICALLY very important that you monitor kidney function in any patient on metformin with signs of renal impairment. Mrs Wallace’s most recent serum creatinine estimated her GFR at 37. The table below describes how metformin administration should be changed based on underlying kidney function (eGFR). How should you change the treatment strategy for Mrs Wallace and why do you think renal impairment could cause problems for diabetic patients on metformin?
Decrease metformin by 50%
Pharmacology of Anticonvulsants
Essie is a 21 year old university student who has been referred to a first seizure/urgent assessment neurology clinic from A&E after a single episode of collapse with jerking. She is unable to give you much of a history. She was at her boyfriend’s house, sitting and chatting on the sofa, and the next thing she remembers is feeling disorientated on the floor. Essie comments that she had been feeling quite stressed lately and had not had much sleep as she had been trying to complete an assignment due in this week. Essie’s boyfriend confirms that Essie lost consciousness and then started convulsing before she ‘came around’ a few minutes later, but wasn’t herself for half an hour or so. He also mentions that occasionally Essie makes strange quick jerk of her arms when she wakes up in the morning. Essie also remembers a similar episode 18months ago – one minute she was putting her gym clothes on and next she was on the floor feeling confused. She didn’t tell anyone about it as she was a little embarrassed.
A full physical examination is performed and Essie is sent for an EEG. The results are shown below:
* In A&E – Urea, electrolytes , calcium and glucose: All normal
* General and neurological examinations were normal.
* EEG results are shown below:
What is the patient’s problem?
Generalized tonic–clonic seizure (Epilepsy)
* A grand mal seizure causes a loss of consciousness and violent muscle contractions
Pharmacology of Anticonvulsants
Essie is a 21 year old university student who has been referred to a first seizure/urgent assessment neurology clinic from A&E after a single episode of collapse with jerking. She is unable to give you much of a history. She was at her boyfriend’s house, sitting and chatting on the sofa, and the next thing she remembers is feeling disorientated on the floor. Essie comments that she had been feeling quite stressed lately and had not had much sleep as she had been trying to complete an assignment due in this week. Essie’s boyfriend confirms that Essie lost consciousness and then started convulsing before she ‘came around’ a few minutes later, but wasn’t herself for half an hour or so. He also mentions that occasionally Essie makes strange quick jerk of her arms when she wakes up in the morning. Essie also remembers a similar episode 18months ago – one minute she was putting her gym clothes on and next she was on the floor feeling confused. She didn’t tell anyone about it as she was a little embarrassed.
What is the therapeutic objective for this patient?
- Stop epileptic seizures, without a lot of side effects to maintain a normal lifestyle
- Improve sleep
- Reduce stress
Pharmacology of Anticonvulsants
Essie is a 21 year old university student who has been referred to a first seizure/urgent assessment neurology clinic from A&E after a single episode of collapse with jerking. She is unable to give you much of a history. She was at her boyfriend’s house, sitting and chatting on the sofa, and the next thing she remembers is feeling disorientated on the floor. Essie comments that she had been feeling quite stressed lately and had not had much sleep as she had been trying to complete an assignment due in this week. Essie’s boyfriend confirms that Essie lost consciousness and then started convulsing before she ‘came around’ a few minutes later, but wasn’t herself for half an hour or so. He also mentions that occasionally Essie makes strange quick jerk of her arms when she wakes up in the morning. Essie also remembers a similar episode 18months ago – one minute she was putting her gym clothes on and next she was on the floor feeling confused. She didn’t tell anyone about it as she was a little embarrassed.
The table below has been extracted from the NICE guidelines for the treatment of epilepsy. Which drug treatment should you offer Essie in the first instance and explain the mechanism of action of your drug of choice?
- Lamotrigine (voltage-sensitive sodium channels antagonist)
GTCS First line treatment / Young woman - child baring age
Pharmacology of Anticonvulsants
Essie is a 21 year old university student who has been referred to a first seizure/urgent assessment neurology clinic from A&E after a single episode of collapse with jerking. She is unable to give you much of a history. She was at her boyfriend’s house, sitting and chatting on the sofa, and the next thing she remembers is feeling disorientated on the floor. Essie comments that she had been feeling quite stressed lately and had not had much sleep as she had been trying to complete an assignment due in this week. Essie’s boyfriend confirms that Essie lost consciousness and then started convulsing before she ‘came around’ a few minutes later, but wasn’t herself for half an hour or so. He also mentions that occasionally Essie makes strange quick jerk of her arms when she wakes up in the morning. Essie also remembers a similar episode 18months ago – one minute she was putting her gym clothes on and next she was on the floor feeling confused. She didn’t tell anyone about it as she was a little embarrassed.
Essie becomes stable on lamotrigine and also uses psychological interventions (e.g. behavior therapy) to help improve her quality of life. Essie visits her GP as she has now decided that she wants to on the combined oral contraceptive pill. Consider the two figures below. The first figure shows blood concentrations of lamotrigine (administered alone – open circles) and lamotrigine plus the combined oral contraceptive pill (closed circles). The second figure shows blood concentrations of ethinyl estradiol (combined oral contraceptive pill administered alone – open circles) and the combined oral contraceptive pill plus lamotrigine (closed circles). What are the take home points for both figures and provide a suggest explanation for this?
Oestradiol pill leads to a decreased concentration of lamotrigine to a fifth compared to concentration of lamotrigine 24h post administration.
* Increased metabolism / decrease absorption / increase excretion
* On COC increased seizure frequency.
GTCS First line treatment / Young woman - child baring age
Pharmacology of Anticonvulsants
Essie is a 21 year old university student who has been referred to a first seizure/urgent assessment neurology clinic from A&E after a single episode of collapse with jerking. She is unable to give you much of a history. She was at her boyfriend’s house, sitting and chatting on the sofa, and the next thing she remembers is feeling disorientated on the floor. Essie comments that she had been feeling quite stressed lately and had not had much sleep as she had been trying to complete an assignment due in this week. Essie’s boyfriend confirms that Essie lost consciousness and then started convulsing before she ‘came around’ a few minutes later, but wasn’t herself for half an hour or so. He also mentions that occasionally Essie makes strange quick jerk of her arms when she wakes up in the morning. Essie also remembers a similar episode 18months ago – one minute she was putting her gym clothes on and next she was on the floor feeling confused. She didn’t tell anyone about it as she was a little embarrassed.
Essie was provided with the oral contraceptive pill, and over the next 3 months kept a diary of her seizure frequency. She noted that she was having more seizures during the second and third week of the four week contraceptive cycle. Her GP increased the dose of lamotrigine 2 fold. This reduced the seizure frequency, but Essie noted that she felt particularly drowsy during the fourth week of the contraceptive cycle. What do you think is going on?
- The side effects of the lamotrigine includes drowsiness. As there was an increased dose administered the side effects became more noticable and that is why essie was feeling drowsy.
- On 4th week she is on placebo -> increased concentration of lamotrigine since no metabolised as fast
GTCS First line treatment / Young woman - child baring age
Pharmacology of Anticonvulsants
Essie is a 21 year old university student who has been referred to a first seizure/urgent assessment neurology clinic from A&E after a single episode of collapse with jerking. She is unable to give you much of a history. She was at her boyfriend’s house, sitting and chatting on the sofa, and the next thing she remembers is feeling disorientated on the floor. Essie comments that she had been feeling quite stressed lately and had not had much sleep as she had been trying to complete an assignment due in this week. Essie’s boyfriend confirms that Essie lost consciousness and then started convulsing before she ‘came around’ a few minutes later, but wasn’t herself for half an hour or so. He also mentions that occasionally Essie makes strange quick jerk of her arms when she wakes up in the morning. Essie also remembers a similar episode 18months ago – one minute she was putting her gym clothes on and next she was on the floor feeling confused. She didn’t tell anyone about it as she was a little embarrassed.
Two other drugs for the treatment of generalized tonic clonic seizures are sodium valproate and levetiracetam. Compare the mechanism of action of these two drugs.
- Sodium valproate: GABA transaminase antagonist
- Levetiracetam: synaptic vesicle protein 2A (SV2A) agonist
Pharmacology of Anticonvulsants
Essie is a 21 year old university student who has been referred to a first seizure/urgent assessment neurology clinic from A&E after a single episode of collapse with jerking. She is unable to give you much of a history. She was at her boyfriend’s house, sitting and chatting on the sofa, and the next thing she remembers is feeling disorientated on the floor. Essie comments that she had been feeling quite stressed lately and had not had much sleep as she had been trying to complete an assignment due in this week. Essie’s boyfriend confirms that Essie lost consciousness and then started convulsing before she ‘came around’ a few minutes later, but wasn’t herself for half an hour or so. He also mentions that occasionally Essie makes strange quick jerk of her arms when she wakes up in the morning. Essie also remembers a similar episode 18months ago – one minute she was putting her gym clothes on and next she was on the floor feeling confused. She didn’t tell anyone about it as she was a little embarrassed.
Essie stopped taking her lamotrigine for a couple of weeks after feeling particularly drowsy leading up to an important set of exams. During this period, Essie had a continuous convulsive seizure that lasted over 6 minutes. Essie’s boyfriend takes her to hospital to be treated. Whilst being assessed in hospital, Essie has another seizure.
The route of administration is different depending on whether Essie is in hospital (in this case) or out of hospital. Can you explain why?
- In hospital is intravenous lorazepam and usual anticonvulsant therapy (lemotrigine). Repeat the 4mg dose of lorazepam if needed after 10 to 20 mins. It is administered IV as there is a faster effct and the absorption is better (almost 100%).
Pharmacology of Depression
Curtis Nash (47 years old) was recently diagnosed with hypertension and prescribed losartan (angiotensin 2 receptor blocker (25mg once daily). He visits his GP 4 weeks after starting his treatment to check his blood pressure. It remains high at 147/91mmHg. Curtis seems uneasy throughout the check-up and when the GP enquires about this, he eventually discloses that his mood has been unusually low recently and that he ‘can’t seem to enjoy anything anymore’. On top of this he mentions that his self-esteem has been really low, he has difficulties getting to sleep and an inability to think clearly, describing a ‘fog’ in his head. He reveals that he has felt like this for over a month now and the GP is the first person he has spoken to about it. He goes into great detail about the ‘strains’ that this has put on his relationship with his wife, as well as his performance in his job, where he works as a schoolteacher.
After hearing the initial history, the GP uses the Patient Health Questionnaire 9 (PHQ-9) to screen for depression (the PHQ-9 is a nine item questionnaire designed to screen for depression in primary care). The results for Curtis are shown below.
What is the therapeutic objective for this patient?
- Treat depression
- Improve sleep cycle
- Improve self esteem
- Improve his ability to think clearly
- Improve mood
Pharmacology of Depression
Curtis Nash (47 years old) was recently diagnosed with hypertension and prescribed losartan (angiotensin 2 receptor blocker (25mg once daily). He visits his GP 4 weeks after starting his treatment to check his blood pressure. It remains high at 147/91mmHg. Curtis seems uneasy throughout the check-up and when the GP enquires about this, he eventually discloses that his mood has been unusually low recently and that he ‘can’t seem to enjoy anything anymore’. On top of this he mentions that his self-esteem has been really low, he has difficulties getting to sleep and an inability to think clearly, describing a ‘fog’ in his head. He reveals that he has felt like this for over a month now and the GP is the first person he has spoken to about it. He goes into great detail about the ‘strains’ that this has put on his relationship with his wife, as well as his performance in his job, where he works as a schoolteacher.
After hearing the initial history, the GP uses the Patient Health Questionnaire 9 (PHQ-9) to screen for depression (the PHQ-9 is a nine item questionnaire designed to screen for depression in primary care). The results for Curtis are shown below.
What is the patient’s problem?
Moderate Depression
Pharmacology of Depression
Curtis Nash (47 years old) was recently diagnosed with hypertension and prescribed losartan (angiotensin 2 receptor blocker (25mg once daily). He visits his GP 4 weeks after starting his treatment to check his blood pressure. It remains high at 147/91mmHg. Curtis seems uneasy throughout the check-up and when the GP enquires about this, he eventually discloses that his mood has been unusually low recently and that he ‘can’t seem to enjoy anything anymore’. On top of this he mentions that his self-esteem has been really low, he has difficulties getting to sleep and an inability to think clearly, describing a ‘fog’ in his head. He reveals that he has felt like this for over a month now and the GP is the first person he has spoken to about it. He goes into great detail about the ‘strains’ that this has put on his relationship with his wife, as well as his performance in his job, where he works as a schoolteacher.
After hearing the initial history, the GP uses the Patient Health Questionnaire 9 (PHQ-9) to screen for depression (the PHQ-9 is a nine item questionnaire designed to screen for depression in primary care). The results for Curtis are shown below.
After confirming a diagnosis of major depressive disorder, the GP spends considerable time explaining the treatment options to Curtis. Despite the GP informing Curtis of the benefits of counselling, self-help programmes and cognitive behavioural therapy, Curtis is adamant that he would like a ‘pill’ to help treat his depression. The GP talks to Curtis about the different types of anti-depressants and the side effects associated with them. She recommends a selective serotonin reuptake inhibitor (SSRI), because they typically have fewer side effects than other anti-depressants. In addition to his anti-hypertensive medication, the only other drug Curtis currently takes is low dose erythromycin to help treat chronic prostatitis.
The three most commonly prescribed SSRIs are;
* Sertraline
* Citalopram
* Fluoxetine
What is the mechanism of action of SSRIs?
- SSRIs binds on the serotonin transporters on the presynaptic neurones of the CNS
- Inhibits the reabsorption of sertonin (5-HT)
- Accumulation of serotonin
- Serotonin in the central nervous system plays a role in the regulation of mood, personality, and wakefulness
Pharmacology of Depression
Curtis Nash (47 years old) was recently diagnosed with hypertension and prescribed losartan (angiotensin 2 receptor blocker (25mg once daily). He visits his GP 4 weeks after starting his treatment to check his blood pressure. It remains high at 147/91mmHg. Curtis seems uneasy throughout the check-up and when the GP enquires about this, he eventually discloses that his mood has been unusually low recently and that he ‘can’t seem to enjoy anything anymore’. On top of this he mentions that his self-esteem has been really low, he has difficulties getting to sleep and an inability to think clearly, describing a ‘fog’ in his head. He reveals that he has felt like this for over a month now and the GP is the first person he has spoken to about it. He goes into great detail about the ‘strains’ that this has put on his relationship with his wife, as well as his performance in his job, where he works as a schoolteacher.
After hearing the initial history, the GP uses the Patient Health Questionnaire 9 (PHQ-9) to screen for depression (the PHQ-9 is a nine item questionnaire designed to screen for depression in primary care). The results for Curtis are shown below.
After confirming a diagnosis of major depressive disorder, the GP spends considerable time explaining the treatment options to Curtis. Despite the GP informing Curtis of the benefits of counselling, self-help programmes and cognitive behavioural therapy, Curtis is adamant that he would like a ‘pill’ to help treat his depression. The GP talks to Curtis about the different types of anti-depressants and the side effects associated with them. She recommends a selective serotonin reuptake inhibitor (SSRI), because they typically have fewer side effects than other anti-depressants. In addition to his anti-hypertensive medication, the only other drug Curtis currently takes is low dose erythromycin to help treat chronic prostatitis.
The three most commonly prescribed SSRIs are;
* Sertraline
* Citalopram
* Fluoxetine
Considering Curtis’ medical history, which SSRI would you most definitely avoid?
Citalopram
* Both erythromycin and citalopram prolong the QT interval. Most manufacturers advise avoiding the use of two or more drugs that are associated with QT prolongation. Increasing age, female sex, cardiac disease, and some metabolic disturbances (notably hypokalaemia) predispose to QT prolongation.
* Severity of interaction: Severe
Pharmacology of Depression
Curtis Nash (47 years old) was recently diagnosed with hypertension and prescribed losartan (angiotensin 2 receptor blocker (25mg once daily). He visits his GP 4 weeks after starting his treatment to check his blood pressure. It remains high at 147/91mmHg. Curtis seems uneasy throughout the check-up and when the GP enquires about this, he eventually discloses that his mood has been unusually low recently and that he ‘can’t seem to enjoy anything anymore’. On top of this he mentions that his self-esteem has been really low, he has difficulties getting to sleep and an inability to think clearly, describing a ‘fog’ in his head. He reveals that he has felt like this for over a month now and the GP is the first person he has spoken to about it. He goes into great detail about the ‘strains’ that this has put on his relationship with his wife, as well as his performance in his job, where he works as a schoolteacher.
After hearing the initial history, the GP uses the Patient Health Questionnaire 9 (PHQ-9) to screen for depression (the PHQ-9 is a nine item questionnaire designed to screen for depression in primary care). The results for Curtis are shown below.
After confirming a diagnosis of major depressive disorder, the GP spends considerable time explaining the treatment options to Curtis. Despite the GP informing Curtis of the benefits of counselling, self-help programmes and cognitive behavioural therapy, Curtis is adamant that he would like a ‘pill’ to help treat his depression. The GP talks to Curtis about the different types of anti-depressants and the side effects associated with them. She recommends a selective serotonin reuptake inhibitor (SSRI), because they typically have fewer side effects than other anti-depressants. In addition to his anti-hypertensive medication, the only other drug Curtis currently takes is low dose erythromycin to help treat chronic prostatitis.
The GP prescribes sertraline, 50mg orally once a day. The GP discusses with Curtis that sertraline may take some time to start working, but that he might experience side effects before this. She urges him that he is to continue taking the drug until the GP can see him again in two weeks time.
The data above shows the effect of increasing the SSRI dose on (i) reduction in depression rating and (ii) dropouts due to adverse effects.
Important note – sertraline, citalopram and fluoxetine are included in this study, but the dose for each is normalized to fluoxetine. This means that the study has established equivalence dosing e.g. 50mg sertraline is equivalent to 20mg fluoxetine.
What are the key take home messages from the data in the two dose response curves above?
- Increase in dose leads to increase in drop outs, because of the side effects
- Increase in dose up to 30mg increase effectiveness. Above 30mg decrease in effectiveness, because of saturation of 5-HT
Pharmacology of Depression
Curtis Nash (47 years old) was recently diagnosed with hypertension and prescribed losartan (angiotensin 2 receptor blocker (25mg once daily). He visits his GP 4 weeks after starting his treatment to check his blood pressure. It remains high at 147/91mmHg. Curtis seems uneasy throughout the check-up and when the GP enquires about this, he eventually discloses that his mood has been unusually low recently and that he ‘can’t seem to enjoy anything anymore’. On top of this he mentions that his self-esteem has been really low, he has difficulties getting to sleep and an inability to think clearly, describing a ‘fog’ in his head. He reveals that he has felt like this for over a month now and the GP is the first person he has spoken to about it. He goes into great detail about the ‘strains’ that this has put on his relationship with his wife, as well as his performance in his job, where he works as a schoolteacher.
After hearing the initial history, the GP uses the Patient Health Questionnaire 9 (PHQ-9) to screen for depression (the PHQ-9 is a nine item questionnaire designed to screen for depression in primary care). The results for Curtis are shown below.
After confirming a diagnosis of major depressive disorder, the GP spends considerable time explaining the treatment options to Curtis. Despite the GP informing Curtis of the benefits of counselling, self-help programmes and cognitive behavioural therapy, Curtis is adamant that he would like a ‘pill’ to help treat his depression. The GP talks to Curtis about the different types of anti-depressants and the side effects associated with them. She recommends a selective serotonin reuptake inhibitor (SSRI), because they typically have fewer side effects than other anti-depressants. In addition to his anti-hypertensive medication, the only other drug Curtis currently takes is low dose erythromycin to help treat chronic prostatitis.
The GP prescribes sertraline, 50mg orally once a day. The GP discusses with Curtis that sertraline may take some time to start working, but that he might experience side effects before this. She urges him that he is to continue taking the drug until the GP can see him again in two weeks time.
The data above shows the effect of increasing the SSRI dose on (i) reduction in depression rating and (ii) dropouts due to adverse effects.
Important note – sertraline, citalopram and fluoxetine are included in this study, but the dose for each is normalized to fluoxetine. This means that the study has established equivalence dosing e.g. 50mg sertraline is equivalent to 20mg fluoxetine.
Which drug – venlafaxine or mirtazapine – should the GP prescribe next and why?
Mirtazapine
* Noradrenaline mediates the sympathetic nervous system effects on the heart
* Histamine (H1) receptors have sedating properties, to help with sleep
Pharmacology of Depression
Curtis Nash (47 years old) was recently diagnosed with hypertension and prescribed losartan (angiotensin 2 receptor blocker (25mg once daily). He visits his GP 4 weeks after starting his treatment to check his blood pressure. It remains high at 147/91mmHg. Curtis seems uneasy throughout the check-up and when the GP enquires about this, he eventually discloses that his mood has been unusually low recently and that he ‘can’t seem to enjoy anything anymore’. On top of this he mentions that his self-esteem has been really low, he has difficulties getting to sleep and an inability to think clearly, describing a ‘fog’ in his head. He reveals that he has felt like this for over a month now and the GP is the first person he has spoken to about it. He goes into great detail about the ‘strains’ that this has put on his relationship with his wife, as well as his performance in his job, where he works as a schoolteacher.
After hearing the initial history, the GP uses the Patient Health Questionnaire 9 (PHQ-9) to screen for depression (the PHQ-9 is a nine item questionnaire designed to screen for depression in primary care). The results for Curtis are shown below.
After confirming a diagnosis of major depressive disorder, the GP spends considerable time explaining the treatment options to Curtis. Despite the GP informing Curtis of the benefits of counselling, self-help programmes and cognitive behavioural therapy, Curtis is adamant that he would like a ‘pill’ to help treat his depression. The GP talks to Curtis about the different types of anti-depressants and the side effects associated with them. She recommends a selective serotonin reuptake inhibitor (SSRI), because they typically have fewer side effects than other anti-depressants. In addition to his anti-hypertensive medication, the only other drug Curtis currently takes is low dose erythromycin to help treat chronic prostatitis.
The GP prescribes sertraline, 50mg orally once a day. The GP discusses with Curtis that sertraline may take some time to start working, but that he might experience side effects before this. She urges him that he is to continue taking the drug until the GP can see him again in two weeks time.
The data above shows the effect of increasing the SSRI dose on (i) reduction in depression rating and (ii) dropouts due to adverse effects.
Important note – sertraline, citalopram and fluoxetine are included in this study, but the dose for each is normalized to fluoxetine. This means that the study has established equivalence dosing e.g. 50mg sertraline is equivalent to 20mg fluoxetine.
The GP prescribes mirtazapine (15mg, orally once daily) for Curtis. 4 weeks later, Curtis returns to his GP. He is sleeping much better and feels that his concentration has improved. He still has days where he suffers with low mood, but they are less frequent than before. The GP agrees to see Curtis again in 4 weeks to check on his progress. The table above indicates the binding affinity for some of the key drug targets for mirtazapine. The key effect of each receptor sub-type is also shown. Explain the data found in this table.
- Lowest dose effect -> Sedation
- Higher dose effect -> Anti-depressant effect
- Maximum dose effect -> Anti-emetic effects
Pharmacology of Hypertension
Mrs Joanne Turner is a 64 year old lady who has suffered with rheumatoid arthritis for 9 years and in the last year she has found her mobility is severely restricted and she is in pain even at rest. She attends a pre-operative appointment for a total right knee arthroplasty (replacement) at her local hospital. At the appointment, Mrs Turner’s blood pressure is measured at 149/93mmHg. She is recommended to attend her GP to follow up for potential hypertension. Mrs Turner attends her GP on two subsequent occasions when her blood pressure is 147/92mmHg and 145/91mmHg respectively. She is offered ambulatory blood pressure monitoring by her GP. Apart from the pain associated with her rheumatoid arthritis, Mrs Turner feels generally well, although she does smoke (< 10 per day). Her height and weight are 167cm and 85kg respectively.
What is the patient’s problem?
https://www.qrisk.org/three/index.php
Q-Risk: 14.9%
* Hypertension
* High BMI
* Rheumatoid arthritis
* Smoking
Pharmacology of Hypertension
Mrs Joanne Turner is a 64 year old lady who has suffered with rheumatoid arthritis for 9 years and in the last year she has found her mobility is severely restricted and she is in pain even at rest. She attends a pre-operative appointment for a total right knee arthroplasty (replacement) at her local hospital. At the appointment, Mrs Turner’s blood pressure is measured at 149/93mmHg. She is recommended to attend her GP to follow up for potential hypertension. Mrs Turner attends her GP on two subsequent occasions when her blood pressure is 147/92mmHg and 145/91mmHg respectively. She is offered ambulatory blood pressure monitoring by her GP. Apart from the pain associated with her rheumatoid arthritis, Mrs Turner feels generally well, although she does smoke (< 10 per day). Her height and weight are 167cm and 85kg respectively.
What is the therapeutic objective for this patient?
- Lower BMI
- Stop smoking
- Lower BP
- Manage Rheumatoid arthritis
Pharmacology of Hypertension
Mrs Joanne Turner is a 64 year old lady who has suffered with rheumatoid arthritis for 9 years and in the last year she has found her mobility is severely restricted and she is in pain even at rest. She attends a pre-operative appointment for a total right knee arthroplasty (replacement) at her local hospital. At the appointment, Mrs Turner’s blood pressure is measured at 149/93mmHg. She is recommended to attend her GP to follow up for potential hypertension. Mrs Turner attends her GP on two subsequent occasions when her blood pressure is 147/92mmHg and 145/91mmHg respectively. She is offered ambulatory blood pressure monitoring by her GP. Apart from the pain associated with her rheumatoid arthritis, Mrs Turner feels generally well, although she does smoke (< 10 per day). Her height and weight are 167cm and 85kg respectively.
The NICE guidelines for the treatment of hypertension would suggest that Mrs Turner is treated with a calcium channel blocker.
The two most commonly prescribed calcium channel blockers are amlodipine and felodipine (both 5mg once daily as a starting dose).
The table above shows some of the key pharmacokinetic properties of felodipine and amlodipine.
What is the mechanism of action of calcium channel blockers in the treatment of hypertension?
https://pathways.nice.org.uk/pathways/hypertension#path=view%3A/pathways/hypertension/treatment-steps-for-hypertension.xml&content=view-node%3Anodes-step-1-ccb
- Block L-type calcium channel (predominantly on smooth muscular vescels)
- Decrease in calcium influx
- Inhibition of myosin light chain kinase & prevention of cross-bridge formation
- Vasodilation
- Decrease in blood pressure
Pharmacology of Hypertension
Mrs Joanne Turner is a 64 year old lady who has suffered with rheumatoid arthritis for 9 years and in the last year she has found her mobility is severely restricted and she is in pain even at rest. She attends a pre-operative appointment for a total right knee arthroplasty (replacement) at her local hospital. At the appointment, Mrs Turner’s blood pressure is measured at 149/93mmHg. She is recommended to attend her GP to follow up for potential hypertension. Mrs Turner attends her GP on two subsequent occasions when her blood pressure is 147/92mmHg and 145/91mmHg respectively. She is offered ambulatory blood pressure monitoring by her GP. Apart from the pain associated with her rheumatoid arthritis, Mrs Turner feels generally well, although she does smoke (< 10 per day). Her height and weight are 167cm and 85kg respectively.
The NICE guidelines for the treatment of hypertension would suggest that Mrs Turner is treated with a calcium channel blocker.
The two most commonly prescribed calcium channel blockers are amlodipine and felodipine (both 5mg once daily as a starting dose).
The table above shows some of the key pharmacokinetic properties of felodipine and amlodipine.
Based on the information above, suggest the key differences in treating Mrs Turner with amlodipine versus felodipine.
- Clearance: Clearance is the measure of the ability of the body to eliminate a drug. Clearance by means of various organs of elimination is additive. Elimination of drug may occur as a result of processes that occur in the liver, kidney, and other organs.
- Elimination half-life: Elimination half-life is the length of time required for the concentration of a particular drug to decrease to half of its starting dose in the body.
- Time to peak plasma plasma levels: Time to peak concentration is the time required for a drug to reach peak concentration in plasma. The faster the absorption rate, the lower is the time to peak plasma concentration.
- Time to peak plasma levels is irrelevant in this case as we are treating a chronic disease so we are after a good overall coverage (in this case over 24h).
- Amlodipine has a longer elimination half-life so by the time you take the drug again its effect is still ongoing.
- Amlodipine has a slow onset to avoid reflex tachycardia.
Pharmacology of Hypertension
Mrs Joanne Turner is a 64 year old lady who has suffered with rheumatoid arthritis for 9 years and in the last year she has found her mobility is severely restricted and she is in pain even at rest. She attends a pre-operative appointment for a total right knee arthroplasty (replacement) at her local hospital. At the appointment, Mrs Turner’s blood pressure is measured at 149/93mmHg. She is recommended to attend her GP to follow up for potential hypertension. Mrs Turner attends her GP on two subsequent occasions when her blood pressure is 147/92mmHg and 145/91mmHg respectively. She is offered ambulatory blood pressure monitoring by her GP. Apart from the pain associated with her rheumatoid arthritis, Mrs Turner feels generally well, although she does smoke (< 10 per day). Her height and weight are 167cm and 85kg respectively.
The NICE guidelines for the treatment of hypertension would suggest that Mrs Turner is treated with a calcium channel blocker.
The two most commonly prescribed calcium channel blockers are amlodipine and felodipine (both 5mg once daily as a starting dose).
The table above shows some of the key pharmacokinetic properties of felodipine and amlodipine.
Mrs Turner returns to her GP, 3 weeks later to discuss her hypertensive medication. She has been suffering with swollen ankles since she started on amlodipine. She did look at the advice on the NHS website about elevating her legs to try and reduce the oedema, but she found it too painful on her knee. The GP discusses alternative anti-hypertensive medications with Mrs Turner. The first drug class the GP mentions are the angiotensin converting enzyme (ACE) inhibitors.
What is the mechanism of action of ACE inhibitors in the treatment of hypertension?
- Inhibit the angiotensin converting enzyme
- Prevent conversion of angiotensin I to angiotensin II by ACE
- Decrease sympathetic nervous stimulation
- Decrease vasoconstriction
- Decrease Blood Pressure
Pharmacology of Hypertension
Mrs Joanne Turner is a 64 year old lady who has suffered with rheumatoid arthritis for 9 years and in the last year she has found her mobility is severely restricted and she is in pain even at rest. She attends a pre-operative appointment for a total right knee arthroplasty (replacement) at her local hospital. At the appointment, Mrs Turner’s blood pressure is measured at 149/93mmHg. She is recommended to attend her GP to follow up for potential hypertension. Mrs Turner attends her GP on two subsequent occasions when her blood pressure is 147/92mmHg and 145/91mmHg respectively. She is offered ambulatory blood pressure monitoring by her GP. Apart from the pain associated with her rheumatoid arthritis, Mrs Turner feels generally well, although she does smoke (< 10 per day). Her height and weight are 167cm and 85kg respectively.
The NICE guidelines for the treatment of hypertension would suggest that Mrs Turner is treated with a calcium channel blocker.
The two most commonly prescribed calcium channel blockers are amlodipine and felodipine (both 5mg once daily as a starting dose).
The table above shows some of the key pharmacokinetic properties of felodipine and amlodipine.
Mrs Turner returns to her GP, 3 weeks later to discuss her hypertensive medication. She has been suffering with swollen ankles since she started on amlodipine. She did look at the advice on the NHS website about elevating her legs to try and reduce the oedema, but she found it too painful on her knee. The GP discusses alternative anti-hypertensive medications with Mrs Turner. The first drug class the GP mentions are the angiotensin converting enzyme (ACE) inhibitors.
If Mrs Turner were to start an ACE inhibitor, the advice would be to check renal function (eGFR), serum electrolytes (especially blood potassium) and blood pressure 1-2 weeks after starting treatment.
Why might ACE inhibitors have a negative effect on eGFR and serum potassium?
- ACEi stimulates Na+ reabsorption, that may cause hyperkalaemia in response
- Decrease in angiotensin II -> Decrease in pressure of efferent arteriole -> Decrease glomerular pressure -> May cause renal failure, so eGFR must be monitored
Pharmacology of Hypertension
Mrs Joanne Turner is a 64 year old lady who has suffered with rheumatoid arthritis for 9 years and in the last year she has found her mobility is severely restricted and she is in pain even at rest. She attends a pre-operative appointment for a total right knee arthroplasty (replacement) at her local hospital. At the appointment, Mrs Turner’s blood pressure is measured at 149/93mmHg. She is recommended to attend her GP to follow up for potential hypertension. Mrs Turner attends her GP on two subsequent occasions when her blood pressure is 147/92mmHg and 145/91mmHg respectively. She is offered ambulatory blood pressure monitoring by her GP. Apart from the pain associated with her rheumatoid arthritis, Mrs Turner feels generally well, although she does smoke (< 10 per day). Her height and weight are 167cm and 85kg respectively.
The NICE guidelines for the treatment of hypertension would suggest that Mrs Turner is treated with a calcium channel blocker.
The two most commonly prescribed calcium channel blockers are amlodipine and felodipine (both 5mg once daily as a starting dose).
The table above shows some of the key pharmacokinetic properties of felodipine and amlodipine.
Mrs Turner returns to her GP, 3 weeks later to discuss her hypertensive medication. She has been suffering with swollen ankles since she started on amlodipine. She did look at the advice on the NHS website about elevating her legs to try and reduce the oedema, but she found it too painful on her knee. The GP discusses alternative anti-hypertensive medications with Mrs Turner. The first drug class the GP mentions are the angiotensin converting enzyme (ACE) inhibitors.
If Mrs Turner were to start an ACE inhibitor, the advice would be to check renal function (eGFR), serum electrolytes (especially blood potassium) and blood pressure 1-2 weeks after starting treatment.
Mrs Turner and her GP decide against the ACE inhibitors as they worry that if this increases her blood potassium it might result in a cancellation of her knee replacement (a common occurrence in individuals awaiting surgery). As a result, Mrs Turner agrees to switch to a thiazide-like diuretic – indapamide (2.5mg orally once a day).
What is the mechanism of action of indapamide?
- Thiazide / thiazide-likediuretics block the Na+/Cl-cotransporter in the early DCT
- Na+/Cl-reabsorption is inhibited
- Increased osmolarity of the tubular fluid
- Decrease osmotic gradient for water reabsorption in the collecting duct
- Decrease in volume of fluid in body
- Decrease in bloop pressure
Pharmacology of Hypertension
Mrs Joanne Turner is a 64 year old lady who has suffered with rheumatoid arthritis for 9 years and in the last year she has found her mobility is severely restricted and she is in pain even at rest. She attends a pre-operative appointment for a total right knee arthroplasty (replacement) at her local hospital. At the appointment, Mrs Turner’s blood pressure is measured at 149/93mmHg. She is recommended to attend her GP to follow up for potential hypertension. Mrs Turner attends her GP on two subsequent occasions when her blood pressure is 147/92mmHg and 145/91mmHg respectively. She is offered ambulatory blood pressure monitoring by her GP. Apart from the pain associated with her rheumatoid arthritis, Mrs Turner feels generally well, although she does smoke (< 10 per day). Her height and weight are 167cm and 85kg respectively.
The NICE guidelines for the treatment of hypertension would suggest that Mrs Turner is treated with a calcium channel blocker.
The two most commonly prescribed calcium channel blockers are amlodipine and felodipine (both 5mg once daily as a starting dose).
The table above shows some of the key pharmacokinetic properties of felodipine and amlodipine.
Mrs Turner returns to her GP, 3 weeks later to discuss her hypertensive medication. She has been suffering with swollen ankles since she started on amlodipine. She did look at the advice on the NHS website about elevating her legs to try and reduce the oedema, but she found it too painful on her knee. The GP discusses alternative anti-hypertensive medications with Mrs Turner. The first drug class the GP mentions are the angiotensin converting enzyme (ACE) inhibitors.
If Mrs Turner were to start an ACE inhibitor, the advice would be to check renal function (eGFR), serum electrolytes (especially blood potassium) and blood pressure 1-2 weeks after starting treatment.
Mrs Turner and her GP decide against the ACE inhibitors as they worry that if this increases her blood potassium it might result in a cancellation of her knee replacement (a common occurrence in individuals awaiting surgery). As a result, Mrs Turner agrees to switch to a thiazide-like diuretic – indapamide (2.5mg orally once a day).
Indapamide (and other thiazide-like diuretics) are excreted unchanged in the urine.
Why is this a vital part of the therapeutic action of thiazide-like diuretics
Not metabolised in the liver -> Gets to the kidneys UNCHANGED -> Has the desired effect on the apical side of the distal tubule
Pharmacology of Asthma
Katie Lucero (3 years) is brought to A&E by her parents as she is having great difficulty in breathing. Katie has a whistle like wheeze when exhaling and is occasionally coughing. She also has a slight temperature (38.2oC). Further history and physical examination reveal nothing. Her parents state that apart from minor childhood infections she has never been ill before and she has never needed to take any drugs apart from ibuprofen for children.
Further questions asked by the doctor:
* Is there a family history of asthma? No family history
* How often do symptoms occur? Mostly when she has a cold or other infection. Sometimes when it is very cold outside.
* Does coughing wake your child at night? Actually, she has had a couple of episodes in the last few months.
* Do the symptoms accompany a cold or are they unrelated to colds? They definitely are most common when she has a cold or other infection.
* How long do they last? Has only ever been for a few minutes until today. This is definitely the worst. It’s been going for well over an hour now.
* Has your child needed emergency care for breathing difficulties? No
* Does your child have any known pollen, dust, pet or food allergies? No
* Is your child exposed to cigarette smoke or other airborne irritants? No
Katie is administered inhaled salbutamol (2.5mg; short acting beta 2 agonist) via an oxygen-driven nebulizer every 20minutes and she recovers within an hour.
On leaving hospital, she is prescribed salbutamol as a reliever therapy for future symptom relief. Katie is also provided with a spacer to help with delivery to the lungs.
The guidelines via the BNF are below.
What do you notice about the two methods of administration of salbutamol and why do you think the inhalation route is preferred over the oral route?
- Oral requires 10 times more dose
- Aerosol acts faster
Pharmacology of GORD/Peptic Ulcer Disease
Alun Davies is a 71-year-old man who has previously been diagnosed with osteoarthritis and prescribed diclofenac gel (1%) and regular paracetamol (500-1000mg orally every 6 hours when required) to help with the pain.
He returns to his GP 2 months later and is complaining of bilateral knee pain despite taking his medications as instructed. He states that the diclofenac and paracetamol have certainly reduced his pain, but he still has moderate pain when walking or carrying out strenuous activities such as gardening. He is concerned that the pain is restricting his mobility and he has not been able to carry out the exercises that he has been advised to do to increase his general aerobic fitness and muscle strength. His GP prescribes naproxen (250-500mg orally twice daily when required) as an additional analgesic.
Mr Davies returns to his GP 1 month after taking the naproxen and states that the pain associated with his osteoarthritis is much improved. However, he has been suffering with intermittent upper abdominal pain for the last 2 weeks. He describes the pain as a dull, gnawing ache. The pain sometimes wakes him at night.
Mr Davies is subsequently diagnosed with peptic ulcer disease. There is no active bleeding and he is Helicobacter pylori negative.
The data in figure 1 below shows the duration of treatment for patients (aged 70 above) prescribed proton pump inhibitors. Blue = maximum dosage (40mg daily for omeprazole, red = maintenance dosage (2omg daily for omeprazole. Revisit the treatment algorithm for peptic ulcer disease and compare with the data in figure 1.
https://bestpractice.bmj.com/topics/en-gb/3000205/investigations
What is the key take home message when comparing the guidance for omeprazole treatment (and PPIs in general) with the data in figure 1?
- BMJ suggests 20mg daily for omeprazole
- As one can see in the bar chart above, more people are willing to continue on PPIs when on maintenance dosage of peptitc ulcer disease (long term) instead of maximum doasage. Possible because there less or less severe side-effects.
Pharmacology of Pain
Mr Allen Chow (23 years old, 178 cm, 70kg) has a telephone consultation with his GP complaining of 2 days of abdominal pain, vomiting and loose stools. He describes his abdominal pain as centralised, crampy and intermittent. He has opened his bowels 3 times today with watery diarrhoea. He has projectile vomited twice. There is no blood in his vomitus or stools. He is passing urine regularly. He does not have a fever and is able to tolerate oral fluids. He does not recall any recent meals out and has not travelled abroad in over 6 months.
He has no significant past medical history and takes no regular medication. His father has a history of gastric ulcers. He is currently a PhD student in Art History. He smokes 2-3 cigarettes a day, occasionally uses cannabis, and drinks 8-10 units of alcohol/week.
The GP diagnoses acute gastroenteritis based on the clinical history and advises regular oral fluids and simple analgesia, such as paracetamol 1g PO QDS PRN. He is advised to stay off work for 48 hours and reminded of the importance of good hygiene to avoid spread. Safety net advice is given, and Mr Chow is advised to seek medical advice if his symptoms persist, he feels more unwell, or he has symptoms of dehydration.
Mr Chow experiences a sudden worsening of his abdominal pain and presented to the Emergency Department. The pain progressively worsened over the preceding 2 hours and has moved to the right lower quadrant.
On examination, he appears unwell. His temperature is 38.1°C, heart rate 112 bpm regular, blood pressure 108/68 mmHg. He is extremely tender in the right iliac fossa, with guarding and rebound tenderness. Bowel sounds are present. Chest examination and heart sounds are normal.
His FBC shows a WCC of 14.2 x 109/l, and CRP of 89mg/l.
What is the patient’s problem?
Pain relief
Dehydration
Long term pain relief
Possible acute appendicitis
Pharmacology of Pain
Mr Allen Chow (23 years old, 178 cm, 70kg) has a telephone consultation with his GP complaining of 2 days of abdominal pain, vomiting and loose stools. He describes his abdominal pain as centralised, crampy and intermittent. He has opened his bowels 3 times today with watery diarrhoea. He has projectile vomited twice. There is no blood in his vomitus or stools. He is passing urine regularly. He does not have a fever and is able to tolerate oral fluids. He does not recall any recent meals out and has not travelled abroad in over 6 months.
He has no significant past medical history and takes no regular medication. His father has a history of gastric ulcers. He is currently a PhD student in Art History. He smokes 2-3 cigarettes a day, occasionally uses cannabis, and drinks 8-10 units of alcohol/week.
The GP diagnoses acute gastroenteritis based on the clinical history and advises regular oral fluids and simple analgesia, such as paracetamol 1g PO QDS PRN. He is advised to stay off work for 48 hours and reminded of the importance of good hygiene to avoid spread. Safety net advice is given, and Mr Chow is advised to seek medical advice if his symptoms persist, he feels more unwell, or he has symptoms of dehydration.
Mr Chow experiences a sudden worsening of his abdominal pain and presented to the Emergency Department. The pain progressively worsened over the preceding 2 hours and has moved to the right lower quadrant.
On examination, he appears unwell. His temperature is 38.1°C, heart rate 112 bpm regular, blood pressure 108/68 mmHg. He is extremely tender in the right iliac fossa, with guarding and rebound tenderness. Bowel sounds are present. Chest examination and heart sounds are normal.
His FBC shows a WCC of 14.2 x 109/l, and CRP of 89mg/l.
What are the therapeutic objectives?
- Hydration
- Analgesia
- Antibiotics
- Surgery
Possible acute appendicitis
Pharmacology of Pain
Mr Allen Chow (23 years old, 178 cm, 70kg) has a telephone consultation with his GP complaining of 2 days of abdominal pain, vomiting and loose stools. He describes his abdominal pain as centralised, crampy and intermittent. He has opened his bowels 3 times today with watery diarrhoea. He has projectile vomited twice. There is no blood in his vomitus or stools. He is passing urine regularly. He does not have a fever and is able to tolerate oral fluids. He does not recall any recent meals out and has not travelled abroad in over 6 months.
He has no significant past medical history and takes no regular medication. His father has a history of gastric ulcers. He is currently a PhD student in Art History. He smokes 2-3 cigarettes a day, occasionally uses cannabis, and drinks 8-10 units of alcohol/week.
The GP diagnoses acute gastroenteritis based on the clinical history and advises regular oral fluids and simple analgesia, such as paracetamol 1g PO QDS PRN. He is advised to stay off work for 48 hours and reminded of the importance of good hygiene to avoid spread. Safety net advice is given, and Mr Chow is advised to seek medical advice if his symptoms persist, he feels more unwell, or he has symptoms of dehydration.
Mr Chow experiences a sudden worsening of his abdominal pain and presented to the Emergency Department. The pain progressively worsened over the preceding 2 hours and has moved to the right lower quadrant.
On examination, he appears unwell. His temperature is 38.1°C, heart rate 112 bpm regular, blood pressure 108/68 mmHg. He is extremely tender in the right iliac fossa, with guarding and rebound tenderness. Bowel sounds are present. Chest examination and heart sounds are normal.
His FBC shows a WCC of 14.2 x 109/l, and CRP of 89mg/l.
Mr Chow is admitted under the surgical team and made nil by mouth. He is given intravenous maintenance fluids as well as intravenous morphine (initially 5mg every 4 hours – dose adjusted based on response) and prophylactic antibiotics (intravenous co-amoxiclav -1.2g every 8h).
Explain what effect morphine would have at a cellular level using the diagram provided.
- Inhibiting G-coupled opioid receptor
- Inhibit cAMP production
- Inhibit Ca2+ reabsorption
- Enhances K+ excretion
- Exocytosis in inhibited (does not release neurotransmiters)
- Cell is hyper polarised -> does not activate
- Exocytosis in inhibited (does not release neurotransmiters)
Opioids inhibit pain transmission at spinal and stimulatory centres and inhibit iinhibitors (Double negative / prob Gabba) on the descending pathway.
Pharmacology of Pain
Mr Allen Chow (23 years old, 178 cm, 70kg) has a telephone consultation with his GP complaining of 2 days of abdominal pain, vomiting and loose stools. He describes his abdominal pain as centralised, crampy and intermittent. He has opened his bowels 3 times today with watery diarrhoea. He has projectile vomited twice. There is no blood in his vomitus or stools. He is passing urine regularly. He does not have a fever and is able to tolerate oral fluids. He does not recall any recent meals out and has not travelled abroad in over 6 months.
He has no significant past medical history and takes no regular medication. His father has a history of gastric ulcers. He is currently a PhD student in Art History. He smokes 2-3 cigarettes a day, occasionally uses cannabis, and drinks 8-10 units of alcohol/week.
The GP diagnoses acute gastroenteritis based on the clinical history and advises regular oral fluids and simple analgesia, such as paracetamol 1g PO QDS PRN. He is advised to stay off work for 48 hours and reminded of the importance of good hygiene to avoid spread. Safety net advice is given, and Mr Chow is advised to seek medical advice if his symptoms persist, he feels more unwell, or he has symptoms of dehydration.
Mr Chow experiences a sudden worsening of his abdominal pain and presented to the Emergency Department. The pain progressively worsened over the preceding 2 hours and has moved to the right lower quadrant.
On examination, he appears unwell. His temperature is 38.1°C, heart rate 112 bpm regular, blood pressure 108/68 mmHg. He is extremely tender in the right iliac fossa, with guarding and rebound tenderness. Bowel sounds are present. Chest examination and heart sounds are normal.
His FBC shows a WCC of 14.2 x 109/l, and CRP of 89mg/l.
Mr Chow is admitted under the surgical team and made nil by mouth. He is given intravenous maintenance fluids as well as intravenous morphine (initially 5mg every 4 hours – dose adjusted based on response) and prophylactic antibiotics (intravenous co-amoxiclav -1.2g every 8h).
Explain what effect morphine would have at a cellular level using the diagram provided.
In order for opioids (or any drugs) to produce effects within the brain, it needs to be able to access the brain tissue. The major route for drug permeation into the brain is via passive diffusion. Lipid solubility is the major determinant of passive diffusion.
Once inside the brain, opioids need to bind to opioid receptors in order to produce any effect. In this case, it is the chemical structure of the drug that determines the ability to bind to the receptor.
You have been provided with five different opioids below, with information on their structure and lipid solubility. Discuss the ability of each of these opioids to produce opioid like effects in the brain
6-acetyl morphine is the best one
* Heroin is the only other one that can enter the brain but it would have no desirable effect (No OH at position 3)
* The rest cannot enter the brain (not between 1.5-2.7 oil water partition coefficient)
Pharmacology of Pain
Mr Allen Chow (23 years old, 178 cm, 70kg) has a telephone consultation with his GP complaining of 2 days of abdominal pain, vomiting and loose stools. He describes his abdominal pain as centralised, crampy and intermittent. He has opened his bowels 3 times today with watery diarrhoea. He has projectile vomited twice. There is no blood in his vomitus or stools. He is passing urine regularly. He does not have a fever and is able to tolerate oral fluids. He does not recall any recent meals out and has not travelled abroad in over 6 months.
He has no significant past medical history and takes no regular medication. His father has a history of gastric ulcers. He is currently a PhD student in Art History. He smokes 2-3 cigarettes a day, occasionally uses cannabis, and drinks 8-10 units of alcohol/week.
The GP diagnoses acute gastroenteritis based on the clinical history and advises regular oral fluids and simple analgesia, such as paracetamol 1g PO QDS PRN. He is advised to stay off work for 48 hours and reminded of the importance of good hygiene to avoid spread. Safety net advice is given, and Mr Chow is advised to seek medical advice if his symptoms persist, he feels more unwell, or he has symptoms of dehydration.
Mr Chow experiences a sudden worsening of his abdominal pain and presented to the Emergency Department. The pain progressively worsened over the preceding 2 hours and has moved to the right lower quadrant.
On examination, he appears unwell. His temperature is 38.1°C, heart rate 112 bpm regular, blood pressure 108/68 mmHg. He is extremely tender in the right iliac fossa, with guarding and rebound tenderness. Bowel sounds are present. Chest examination and heart sounds are normal.
His FBC shows a WCC of 14.2 x 109/l, and CRP of 89mg/l.
Mr Chow is admitted under the surgical team and made nil by mouth. He is given intravenous maintenance fluids as well as intravenous morphine (initially 5mg every 4 hours – dose adjusted based on response) and prophylactic antibiotics (intravenous co-amoxiclav -1.2g every 8h).
Explain what effect morphine would have at a cellular level using the diagram provided.
In order for opioids (or any drugs) to produce effects within the brain, it needs to be able to access the brain tissue. The major route for drug permeation into the brain is via passive diffusion. Lipid solubility is the major determinant of passive diffusion.
Once inside the brain, opioids need to bind to opioid receptors in order to produce any effect. In this case, it is the chemical structure of the drug that determines the ability to bind to the receptor.
You have been provided with five different opioids below, with information on their structure and lipid solubility. Discuss the ability of each of these opioids to produce opioid like effects in the brain.
Following a successful appendicectomy, Mr Chow is returned to the ward with patient-controlled analgesia containing IV morphine.
Later that day, a 2222 call is put out as Mr Chow is found unresponsive in his bed. An ABCDE assessment is done:
A – Patent.
B – Respiratory rate 6 breaths per minute, O2 sats 91%, chest is clear.
C – Heart rate 48 bpm regular, BP 74/59 mmHg, heart sounds normal.
D – Capillary blood glucose 4.7, AVPU unresponsive, pupils constricted bilaterally.
E – Temperature 36.7°C, abdomen surgical wound appears clean.
Mr Chow is suffering from opioid overdose. He is provided with ventilatory support (oxygen) and administered naloxone intravenously (0.5mg, repeat every 2 minutes with 0.2-0.4mg increments according to response).
1. What classical signs of opioid overdose is Mr Chow presenting with?
https://bestpractice.bmj.com/topics/en-gb/339/history-exam
Morphine is an opioid receptor agonist. Naloxone is an opioid receptor antagonist. Agonists possess affinity and efficacy for a receptor. Antagonists only possess affinity for a receptor. Compare the chemical structure of morphine and naloxone.
2. Which structural component do you think is important for efficacy?
a)
* Miosis
* Bradypnoea
* Altered mental status (Unconscious)
b)
* Ethyl group attached on the tertiary nitrogen appears to be the structural component important for the efficacy of morphine
* Once the tertiary nitrogen attachment becomes longer the efficacy decreases
Pharmacology of Pain
Mr Allen Chow (23 years old, 178 cm, 70kg) has a telephone consultation with his GP complaining of 2 days of abdominal pain, vomiting and loose stools. He describes his abdominal pain as centralised, crampy and intermittent. He has opened his bowels 3 times today with watery diarrhoea. He has projectile vomited twice. There is no blood in his vomitus or stools. He is passing urine regularly. He does not have a fever and is able to tolerate oral fluids. He does not recall any recent meals out and has not travelled abroad in over 6 months.
He has no significant past medical history and takes no regular medication. His father has a history of gastric ulcers. He is currently a PhD student in Art History. He smokes 2-3 cigarettes a day, occasionally uses cannabis, and drinks 8-10 units of alcohol/week.
The GP diagnoses acute gastroenteritis based on the clinical history and advises regular oral fluids and simple analgesia, such as paracetamol 1g PO QDS PRN. He is advised to stay off work for 48 hours and reminded of the importance of good hygiene to avoid spread. Safety net advice is given, and Mr Chow is advised to seek medical advice if his symptoms persist, he feels more unwell, or he has symptoms of dehydration.
Mr Chow experiences a sudden worsening of his abdominal pain and presented to the Emergency Department. The pain progressively worsened over the preceding 2 hours and has moved to the right lower quadrant.
On examination, he appears unwell. His temperature is 38.1°C, heart rate 112 bpm regular, blood pressure 108/68 mmHg. He is extremely tender in the right iliac fossa, with guarding and rebound tenderness. Bowel sounds are present. Chest examination and heart sounds are normal.
His FBC shows a WCC of 14.2 x 109/l, and CRP of 89mg/l.
Mr Chow is admitted under the surgical team and made nil by mouth. He is given intravenous maintenance fluids as well as intravenous morphine (initially 5mg every 4 hours – dose adjusted based on response) and prophylactic antibiotics (intravenous co-amoxiclav -1.2g every 8h).
Explain what effect morphine would have at a cellular level using the diagram provided.
In order for opioids (or any drugs) to produce effects within the brain, it needs to be able to access the brain tissue. The major route for drug permeation into the brain is via passive diffusion. Lipid solubility is the major determinant of passive diffusion.
Once inside the brain, opioids need to bind to opioid receptors in order to produce any effect. In this case, it is the chemical structure of the drug that determines the ability to bind to the receptor.
You have been provided with five different opioids below, with information on their structure and lipid solubility. Discuss the ability of each of these opioids to produce opioid like effects in the brain.
Following a successful appendicectomy, Mr Chow is returned to the ward with patient-controlled analgesia containing IV morphine.
Later that day, a 2222 call is put out as Mr Chow is found unresponsive in his bed. An ABCDE assessment is done:
A – Patent.
B – Respiratory rate 6 breaths per minute, O2 sats 91%, chest is clear.
C – Heart rate 48 bpm regular, BP 74/59 mmHg, heart sounds normal.
D – Capillary blood glucose 4.7, AVPU unresponsive, pupils constricted bilaterally.
E – Temperature 36.7°C, abdomen surgical wound appears clean.
Mr Chow is suffering from opioid overdose. He is provided with ventilatory support (oxygen) and administered naloxone intravenously (0.5mg, repeat every 2 minutes with 0.2-0.4mg increments according to response).
Morphine is an opioid receptor agonist. Naloxone is an opioid receptor antagonist. Agonists possess affinity and efficacy for a receptor. Antagonists only possess affinity for a receptor. Compare the chemical structure of morphine and naloxone.
After 3 days, Mr Chow’s renal function back to baseline and is now ready to be discharged. He is currently taking the following medications:
* Co-amoxiclav, 500/125mg, PO, TDS
* Morphine, 2.5mg, PO, QDS
* Lactulose, PO, 15mL, BD PRN
Mr Chow is still in pain at the site of the surgical incision, so the decision is made to provide him with oral codeine as pain relief to take away (TTA)(See individualized treatment reveal for dose conversion).
As noted previously, codeine is primarily a pro-drug for morphine. As you can see in the figure below, codeine can be metabolized to both norcodeine (inactive metabolite) AND morphine (active metabolite). In the liver, cytochrome P450 enzymes are responsible for this metabolism. CYP3A4 is responsible for ‘fast’ metabolism of codeine to norcodeine and CYP2A6 is responsible for ‘slow’ metabolism of codeine to morphine.
What do you think is the significance of this?
Codeine should have a similar efficacy to morphine but different affinity of morphine. Codein is catalysed into (slow) morphine or (fast) norcodeine. Acts like a slow release of morphine.
