Week 7: Drugs to Treat Cardiovascular Disease and Affecting Haemostasis Flashcards
A 60 year old man is found to have a persistently raised blood pressure of around 200/115. He also has signs and symptoms of mild congestive cardiac failure.
PMH: Type II diabetes controlled by diet alone. Osteoarthritis of both knees. Medication: Naproxen 500 mg twice daily.
What factors might be contributing to his hypertension?
Ca 80% of Type II diabetes sufferers also have hypertension. Likely to indicate a poor diet and obesity. Osteoarthritis also linked to obesity, will also restrict movement and amount of exercise performed.
Naproxen with other NSAIDs can cause blood pressure increases.
Stress.
A 60 year old man is found to have a persistently raised blood pressure of around 200/115. He also has signs and symptoms of mild congestive cardiac failure.
PMH: Type II diabetes controlled by diet alone. Osteoarthritis of both knees. Medication: Naproxen 500 mg twice daily.
Should you consider antihypertensive treatment at this level of blood pressure? What might he gain from effective control of his blood pressure?
He has severe hypertension, Yes
Heart failure is a likely result of his hypertension, reducing blood pressure should reduce the progression of heart failure by decreasing the afterload
A 60 year old man is found to have a persistently raised blood pressure of around 200/115. He also has signs and symptoms of mild congestive cardiac failure.
PMH: Type II diabetes controlled by diet alone. Osteoarthritis of both knees. Medication: Naproxen 500 mg twice daily.
What drug might be most suitable for first line treatment?
NICE guidelines state “Offer people aged under 55 years step 1 antihypertensive treatment with an angiotensin-converting enzyme (ACE) inhibitor or a low-cost angiotensin-II receptor blocker (ARB).
Offer step 1 antihypertensive treatment with a calcium-channel blocker (CCB) to people aged over 55 years and to black people of African or Caribbean family origin of any age. If a CCB is not suitable, for example because of oedema or intolerance, or if there is evidence of heart failure or a high risk of heart failure, offer a thiazide-like diuretic.”
As he is over 55 with mild heart failure NICE guidelines suggest use of a thiazide diuretic.
A 60 year old man is found to have a persistently raised blood pressure of around 200/115. He also has signs and symptoms of mild congestive cardiac failure.
PMH: Type II diabetes controlled by diet alone. Osteoarthritis of both knees. Medication: Naproxen 500 mg twice daily.
What target blood pressure would you aim for on treatment?
140/90 mmHg
A 60 year old man is found to have a persistently raised blood pressure of around 200/115. He also has signs and symptoms of mild congestive cardiac failure.
PMH: Type II diabetes controlled by diet alone. Osteoarthritis of both knees. Medication: Naproxen 500 mg twice daily.
As he is over 55 with mild heart failure NICE guidelines suggest use of a thiazide diuretic as first line treatment. This achieves a blood pressure of around 160/100. What action would you take?
Add an ACE Inhibitor or Angiotensin-II receptor blocker (ARB).
A 30 year old man has a medical examination for life assurance and is found to have a blood pressure of 170/110. He smokes 20 cigarettes daily and has no significant past medical history. His father had a myocardial infarct at the age of 50.
What additional information do you require?
Lifestyle; exercise and stress levels, diet.
Alcohol intake, recreational and over the counter drug use.
A 30 year old man has a medical examination for life assurance and is found to have a blood pressure of 170/110. He smokes 20 cigarettes daily and has no significant past medical history. His father had a myocardial infarct at the age of 50.
What investigations would you carry out to find a cause for his hypertension?
Urea & electrolytes, creatinine for renal function
Blood sugars, cholesterol
Repeat monitor of BP
A 30 year old man has a medical examination for life assurance and is found to have a blood pressure of 170/110. He smokes 20 cigarettes daily and has no significant past medical history. His father had a myocardial infarct at the age of 50. Similar blood pressure readings are obtained on several occasions. What action would you recommend?
Lifestyle changes; stop smoking, increase exercise, balanced diet and weight loss
Pharmacological intervention: an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-II receptor blocker
A 50-year-old man is admitted to hospital complaining of central, crushing chest pain. An acute anterior myocardial infarction is diagnosed. He receives treatment with aspirin, oxygen and thrombolysis. He makes an uncomplicated recovery. His only identifiable risk factor for coronary heart disease is smoking (20 cigarette-pack-year history) and his only significant previous medical history is of “asthma” for which he uses a salbutamol inhaler. 48 hours after admission he is asymptomatic, BP 110/78 mmHg, heart rate 102 beats per minute, respiratory and cardiovascular examinations are otherwise normal.
What drug treatments would you consider at this stage?
Aspirin and clopidogrel antiplatelet.
Beta-blockers, Ca channel blockers and ACE Inhibitors may be considered
A 50-year-old man is admitted to hospital complaining of central, crushing chest pain. An acute anterior myocardial infarction is diagnosed. He receives treatment with aspirin, oxygen and thrombolysis. He makes an uncomplicated recovery. His only identifiable risk factor for coronary heart disease is smoking (20 cigarette-pack-year history) and his only significant previous medical history is of “asthma” for which he uses a salbutamol inhaler. 48 hours after admission he is asymptomatic, BP 110/78 mmHg, heart rate 102 beats per minute, respiratory and cardiovascular examinations are otherwise normal.
An echocardiogram confirms significant left ventricular dysfunction in spite of normal examination. You decide to initiate ACE inhibitor therapy.
What mechanisms underlie the beneficial therapeutic effect of ACE inhibitors in this clinical situation?
Reduce cardiac workload by acting indirectly as a vasodilator of the capacitance and resistance vessels to reduce blood pressure.
A 50-year-old man is admitted to hospital for an acute anterior myocardial infarction. He makes an uncomplicated recovery. His only identifiable risk factor for CHD is smoking (20 cigarette-pack-year history) and his only significant previous medical history is of “asthma” for which he uses a salbutamol inhaler. 48 hours after admission he is asymptomatic, BP 110/78 mmHg, heart rate 102 beats per minute, respiratory and cardiovascular examinations are otherwise normal.
An echocardiogram confirms significant left ventricular dysfunction in spite of normal examination. You decide to initiate ACE inhibitor therapy.
What are the possible adverse effects of ACE inhibitors and how would you monitor the patient for these?
ACE inhibitors can cause hypotension (note this patient has normal blood pressure and maybe a risk here) and renal impairment. A persistent dry cough is a common side effect.
A 50-year-old man is admitted to hospital for an acute anterior myocardial infarction. He makes an uncomplicated recovery. His only identifiable risk factor for CHD is smoking (20 cigarette-pack-year history) and his only significant previous medical history is of “asthma” for which he uses a salbutamol inhaler. 48 hours after admission he is asymptomatic, BP 110/78 mmHg, heart rate 102 beats per minute, respiratory and cardiovascular examinations are otherwise normal.
An echocardiogram confirms significant left ventricular dysfunction in spite of normal examination. You decide to initiate ACE inhibitor therapy.
What other pharmacological and non-pharmacological factors would you consider in the clinical treatment of this man?
Advise on giving up smoking
Consider statins – could be beneficial for secondary effects even if LDL-C is not a concern
A 78-year-old lady is discharged from hospital following an episode of congestive cardiac failure secondary to ischaemic heart disease. Her previous medical history is otherwise unremarkable.
She is subsequently reviewed in out-patient clinic and describes dizziness on standing, and on exertion. Her medications are: Aspirin 150mg daily, Simvastatin 40mg nocte, Lisinopril 10mg daily, Bumetanide 3mg twice daily, Metolazone 2.5mg daily.
On clinical examination her BP is 105/65 mmHg supine, HR 90 beats per minute, jugular venous pressure not raised. On auscultation of her praecordium you hear a pan-systolic murmur of mitral regurgitation. She has no clinical sign of pulmonary or peripheral oedema.
Why is she experiencing dizziness? And how might you demonstrate this?
Orthostatic (or postural) hypotension
BP sitting vs standing, tilt table if available
A 78-year-old lady has congestive cardiac failure secondary to ischaemic heart disease. In out-patient clinic she describes dizziness on standing, and on exertion. Her medications are: Aspirin 150mg daily, Simvastatin 40mg nocte, Lisinopril 10mg daily, Bumetanide 3mg twice daily, Metolazone 2.5mg daily.
On clinical examination her BP is 105/65 mmHg supine, HR 90 beats per minute, jugular venous pressure not raised. On auscultation of her praecordium you hear a pan-systolic murmur of mitral regurgitation. She has no clinical sign of pulmonary or peripheral oedema.
What biochemical abnormalities might you expect to find on blood testing?
Electrolyte imbalance and kidney function: urea and creatinine could be increased especially if she is showing signs of dehydration
A 78-year-old lady has congestive cardiac failure secondary to ischaemic heart disease. In out-patient clinic she describes dizziness on standing, and on exertion. Her medications are: Aspirin 150mg daily, Simvastatin 40mg nocte, Lisinopril 10mg daily, Bumetanide 3mg twice daily, Metolazone 2.5mg daily.
On clinical examination her BP is 105/65 mmHg supine, HR 90 beats per minute, jugular venous pressure not raised. On auscultation of her praecordium you hear a pan-systolic murmur of mitral regurgitation. She has no clinical sign of pulmonary or peripheral oedema.
Reduce the diuretic dose:
intially stop metolazone and monitor situation from there.
A 78-year-old lady has congestive cardiac failure secondary to ischaemic heart disease.
She is reviewed in clinic and describes dizziness on standing, and on exertion. Her medications are: Aspirin 150mg daily, Simvastatin 40mg nocte, Lisinopril 10mg daily, Bumetanide 3mg twice daily, Metolazone 2.5mg daily.
On clinical examination her BP is 105/65 mmHg supine, HR 90 beats per minute, jugular venous pressure not raised. On auscultation of her praecordium you hear a pan-systolic murmur of mitral regurgitation. She has no clinical sign of pulmonary or peripheral oedema.
Would a beta-blocker be appropriate in this situation?
Not immediately as the patient needs to stabilise, however a beta-blocker may be beneficial longer term.
A 78-year-old lady has congestive cardiac failure secondary to ischaemic heart disease. In out-patient clinic she describes dizziness on standing, and on exertion. Her medications are: Aspirin 150mg daily, Simvastatin 40mg nocte, Lisinopril 10mg daily, Bumetanide 3mg twice daily, Metolazone 2.5mg daily.
On clinical examination her BP is 105/65 mmHg supine, HR 90 beats per minute, jugular venous pressure not raised. On auscultation of her praecordium you hear a pan-systolic murmur of mitral regurgitation. She has no clinical sign of pulmonary or peripheral oedema.
How might this problem be prevented in future?
Was the decision to add a second diuretic correct? This situation may have been avoided if only the loop diuretic was prescribed, however presumably the metolazone was considered necessary in this case.
Dual diuretics are more usually prescribed in hospital rather than primary care, presumably her blood pressure was reviewed prior to her discharge and wasn’t considered a problem, but if she had no oedema and a stable blood pressure could the metolazone have been discontinued on discharge?
A 78-year-old woman presents with breathlessness. She has a history of IHD and severe bi-ventricular failure. Patient is dyspnoeic at rest with evidence of pulmonary oedema and severe peripheral oedema up to and including her abdominal wall.
What other information from the medical history is important?
Kidney or liver disease?
Urination problems
Current medication (diuretics show ADRs with NSAIDs, digoxin and lithium)
Allergy to Sulfa antibiotics (some loop diuretics also cause allergy)
A 78-year-old woman presents with breathlessness. She has a history of IHD and severe bi-ventricular failure. Patient is dyspnoeic at rest with evidence of pulmonary oedema and severe peripheral oedema up to and including her abdominal wall.
What is the initial therapeutic management?
Oxygen maybe required to maintain blood saturation
Use diuretics to target hypervolaemia, this is likely to be combined with an ACE inhibitor to reduce the preload and afterload.
A 78-year-old woman presents with breathlessness. She has a history of IHD and severe bi-ventricular failure. Patient is dyspnoeic at rest with evidence of pulmonary oedema and severe peripheral oedema up to and including her abdominal wall.
The treatment includes furosemide. What is furosemide’s mechanism of action?
A loop diuretic, it binds to and inhibits the Na-K-2Cl cotransporter on the luminal surface of the thick ascending limb of the loop of Henle. This inhibits Na+ reabsorption, and so also reduces water reabsorption.
A 78-year-old woman presents with breathlessness. She has a history of IHD and severe bi-ventricular failure. Patient is dyspnoeic at rest with evidence of pulmonary oedema and severe peripheral oedema up to and including her abdominal wall. The treatment includes furosemide.
What route of administration would you consider? Why?
What are the potential biochemical consequences of furosemide?
Can be delivered i.v. or orally, orally takes 1 hour whereas i.v. starts working within 5 mins
Potential for hypokalaemia, while hyperglycaemia is a common side effect too.
A 78-year-old woman presents with breathlessness. She has a history of IHD and severe bi-ventricular failure. Patient is dyspnoeic at rest with evidence of pulmonary oedema and severe peripheral oedema up to and including her abdominal wall. The treatment includes furosemide.
The treatment includes furosemide.
Would you consider alternative diuretics?
Other classes of diuretics exist and maybe more suitable for this patient. Could consider thiazides or potassium or calcium sparing diuretics if you are concerned about electrolyte imbalance
A 72-year old man with hypertension was prescribed ibuprofen for acute gout 10 days ago. He presented to the ED with nausea and loss of appetite. His other drug therapy included: Ramipril 10 mg and Bendroflumethiazide 2.5 mg daily.
Admission investigations: Na+ 134 mmol/l K+ 4.2 mmol/l Urea 22 Creatinine 360
Explain the potential causes for his renal failure.
Age. Hypertension can cause chronic kidney disease.
Increased uric acid levels in gout are exacerbated by bendroflumethiazide. Crystallisation of urea in kidney can cause renal damage.
ACE Inhibitors such as Ramipril can cause renal damage
Ibuprofen and other NSAIDs can cause chronic kidney failure, however this is usually over a more prolonged period of time.
A 72-year old man with hypertension was prescribed ibuprofen for acute gout 10 days ago. He presented to the ED with nausea and loss of appetite. His other drug therapy included: Ramipril 10 mg and Bendroflumethiazide 2.5 mg daily.
Admission investigations: Na+ 134 mmol/l K+ 4.2 mmol/l Urea 22 Creatinine 360
What other immediate investigations would you request? Detail your initial management plan.
Serum albumin and glucose
Urine analysis for proteinuria, haematuria and creatinine clearance
Ultrasound
eGFR = 15 ml/min/1.73m2 stage 4 point at which dialysis could be considered, along with ureamia
Consider using a different class of diuretic away from the thiazide, but maintain the Ramipril as ACE Inhibitors are generally preferred in kidney disease.
Corticosteriods make an alternative to ibuprofen for gout.
Give lifestyle advice regarding gout and renal failure in particular dietary changes
A 68 yr old man with severe osteoarthritis of his right hip is admitted for an elective total hip replacement. He smokes 30 cigarettes a day and admits to drinking approximately 7 bottles of wine a week.
Post operatively he complains of pain and swelling in his left leg and a left deep vein thrombosis is diagnosed.
What precautions may have been taken to try and prevent his thrombosis occurring?
Physiotherapy
Anticoagulants
A 68 yr old man with severe osteoarthritis of his right hip is admitted for an elective total hip replacement. He smokes 30 cigarettes a day and admits to drinking approximately 7 bottles of wine a week.
Post operatively he complains of pain and swelling in his left leg and a left deep vein thrombosis is diagnosed.
Once the deep vein thrombosis has been diagnosed, how would you initiate his treatment?
What advice/counselling would you give to him about his treatment?
Anti-coagulants to prevent the clot enlarging
Heparin for immediate effect, 24 hour dose of low molecular weight heparins.
Switch to warfarin for oral use on discharge – need to check his arthritis medication for ADRs
Compression stocking
A 68 yr old man with severe osteoarthritis of his right hip is admitted to hospital for an elective total hip replacement. He smokes 30 cigarettes a day and admits to drinking approximately 7 bottles of wine a week.
Post operatively he complains of pain and swelling in his left leg and a left deep vein thrombosis is diagnosed.
After discharge from hospital, he comes back to the outpatient clinic complaining of increased and easy bruising. His INR is found to be greater than 10.
What may have caused this? What options are available to you to treat this situation and what would you suggest is the best course of action?
Likely to be excess alcohol, but potentially use of a pain killer like aspirin or paracetamol or certain foods in diet.
A 74-year old woman with stable angina. Her only medication is Aspirin 150mg a day. She complains of frequent symptoms of indigestion. Why might this be the case?
What might the GP do to help her?
Aspirin can cause damage to stomach directly on ingestion and systemically. Clinical burden due to ulceration, haemorrhage and even perforation seen with long term high dose elderly users.
Consider an alternative angina treatment eg Glyceryl Trinitrate (GTN) spray or calcium channel blocker
A 74-year old woman with stable angina. Her only medication is Aspirin 150mg a day.
It transpires that she is left to continue on Aspirin treatment. One day she is admitted to hospital with pleuritic chest pain and with a suspected, but unconfirmed diagnosis of pulmonary embolism.
Whilst awaiting further investigation how would you manage her initially?
NICE guidelines state “if a patient has a ‘likely’ probability of PE, treatment with either low molecular weight heparin, or fondaparinux should be started while waiting for confirmation, and stopped if the scan result is negative”
A 74-year old woman with a history of stable angina. Her only medication is Aspirin 150mg a day.
It transpires that she is left to continue on Aspirin treatment. One day she is admitted to hospital with pleuritic chest pain and with a suspected, but unconfirmed diagnosis of pulmonary embolism.
After her initial management she is noted to have widespread purpura. What might this be due to?
Could be a combination of the anticoagulant and aspirin
A 74-year old woman with a history of stable angina consults her GP. Her only medication is Aspirin 150mg a day.
It transpires that she is left to continue on Aspirin treatment. One day she is admitted to hospital with pleuritic chest pain and with a suspected, but unconfirmed diagnosis of pulmonary embolism.
Prior to being discharged from hospital she starts to develop a chest infection and is treated with the antibiotic erythromycin according to bacterial sensitivity. Will this affect your subsequent management? If so, how and why?
Erythromycin inhibits the metabolism and subsequent clearance of warfarin from the body. Therefore she should not be started on warfarin before she has completed her antibiotic treatment.
A 74-year old woman with a history of stable angina. Her only medication is Aspirin 150mg a day. Admitted to hospital with pleuritic chest pain and with a suspected diagnosis of pulmonary embolism.
Prior to being discharged from hospital she starts to develop a chest infection and is treated with the antibiotic erythromycin according to bacterial sensitivity.
One month after discharge she suffers a fall at home, resulting in a fracture of her left neck of femur.
With respect to her current treatment, what are your main concerns for her?
Assuming the anticoagulation treatment is successful there will be concealed bleeding with haematoma around the fracture site. Depending on the severity this could cause anaemia requiring a blood transfusion.
Potential bleeding elsewhere too and head or other injuries.
She needs surgery but the risks of uncontrolled bleeding are high on warfarin. A target INR for surgery is <1.5
SIGN111 ‘Management of hip fracture in older people’ states “Withholding warfarin combined with administration of oral or intravenous vitamin K is recommended if reversal of the anticoagulant effects of warfarin to permit earlier surgery is deemed appropriate.”
A 74-year old woman with a history of stable angina consults her GP. Her only medication is Aspirin 150mg a day.
It transpires that she is left to continue on Aspirin treatment. One day she is admitted to hospital with pleuritic chest pain and with a suspected, but unconfirmed diagnosis of pulmonary embolism.
Prior to being discharged from hospital she starts to develop a chest infection and is treated with the antibiotic erythromycin according to bacterial sensitivity.
One month after discharge she suffers a fall at home, resulting in a fracture of her left neck of femur. The orthopaedic surgeons advise that the best treatment for her is to undergo pinning of her fracture within the next week if possible.
How would you manage her anticoagulation therapy peri-operatively?
Hip fracture is best operated early, within 24 hours, but this would be dangerous in the presence of anticoagulation so there is a balance between the risks of surgical bleeding versus the possibility of DVT and or PE. Therefore warfarin must be withdrawn, but an alternative may be required.
Plan:
Refer to the hospital’s Anticoagulant guidelines
Stop warfarin and administer vitamin K if appropriate (SIGN111), monitor INR daily.
Bridge the anticoagulant gap with LMW heparin, starting at admission, stopping 12 hours before surgery and restarting 6–12 hours after surgery (NICE CG92). Operate once INR<1.5
Other considerations:
Consult haematologist for latest advice on new anticoagulants that may be suitable or fresh frozen plasma administration to replace clotting factors
A 65 year old man presents with central chest pain at sudden onset. His ECG shows acute 4 mm ST elevation in leads V2-V6.
What further information do you need to plan his initial medical treatment?
Onset time – assess suitability for percutaneous coronary intervention (PCI, coronary angioplasty)
Serial ECG changes
Coronary angiography
Troponin levels
Previous cardiac history, especially if given streptokinase
Other concurrent medications
Results of FBC, urea & electrolytes, glucose and lipids blood tests
A 65 year old man presents with central chest pain at sudden onset. His ECG shows acute 4 mm ST elevation in leads V2-V6.
What immediate treatments would you give?
Oxygen if oxygen saturation is less than 94%
Analgesia e.g. diamorphine injection
Aspirin
Sublingual GTN
Then plan for percutaneous coronary intervention (PCI, coronary angioplasty) or thrombolysis (if PCI not available within 120 mins of thrombolysis) (NICE CG167)
Later consider use of an ACE inhibitor or beta blocker and DVT prophylaxis.
A 55 year old man presents with a 6 hour history of crushing central chest pain and ECG evidence of acute myocardial infarction.
You consider immediate thrombolytic therapy. What are the options available and how would you decide which of the agents that are available to use?
Thrombolytic agents convert plasminogen to plasmin which acts as a fibrinolytic to dissolve clots.
Options include:
Streptokinase – original agent but with ADRs, including being antigenic and so for one use only
Alteplase a recombinant tissue plasminogen activator rtPA, newer class of agents with fewer side effects that can be used after a previous dose of streptokinase.
A 55 year old man presents with a 6 hour history of crushing central chest pain and ECG evidence of acute myocardial infarction.
You consider immediate thrombolytic therapy.
What complications of thrombolytic treatment might occur, how common are they and how should they be managed?
Risk of haemorrhage (especially cerebral and GI)
Hypotension, antigenic reactions and even myocardial rupture.
Most complications are rare e.g. estimates for cerebral haemorrhage and stroke around 1%.
Allergic reaction with streptokinase can be managed with oxygen, antihistamines, steroids and if necessary adrenaline.
A 55 year old man presents with a 6 hour history of crushing central chest pain and ECG evidence of acute myocardial infarction.
You consider immediate thrombolytic therapy. Four hours later he develops difficulty finding his words and is noted to have right facial weakness with reduced power in the right arm. What might have caused this? What investigations would you carry out?
FAST: Face, Arm, Speech, Time
A stroke caused by cerebral haemorrhage
CT scan of head
Later on swallow assessment, physiotherapy, speech therapy and further CT
A 55 year old man presents with a 6 hour history of crushing central chest pain and ECG evidence of acute myocardial infarction.
You consider immediate thrombolytic therapy. Four hours later he develops difficulty finding his words and is noted to have right facial weakness with reduced power in the right arm.
The diagnosis of cerebral haemorrhage is confirmed. How common is this complication, and what factors predispose to it?
Around 1% Factors include: Previous history of a bleed or stroke Hypertension Recent head injury or recent neurosurgery
What is the indication for dual diuretic therapy in heart failure?
Refractory heart failure, in cases where a loop diuretic has been insufficient to treat oedema and so the thiazide has been added to the treatment.
A 65 year old man presents with central chest pain at sudden onset. His ECG shows acute 4 mm ST elevation in leads V2-V6.
What information would you give the patient at this stage? How would you assess the effectiveness of your immediate treatment?
This is a serious life changing event – lifestyle changes
Best results from PCI but this may not be available in which case thrombolysis will help.
Explain risks vs benefits of procedures
Often may undergo angio at a later date
Plan for cardiac rehabilitation /physiotherapy
A 65 year old man presents with central chest pain at sudden onset. His ECG shows acute 4 mm ST elevation in leads V2-V6.
How would you assess the effectiveness of your immediate treatment?
Improvement in pain relief Improvement in serial ECGs Coronary angiography Monitor cardiac markers e.g. troponin Monitor for further complications e.g. heart failure
True or false?
High blood pressure very seldom causes symptoms.
True.
It is therefore not a
‘disease’ but a risk factor for future vascular disease.
List 3 organs impacted by hypertension
The organs affected by
sustained hypertension are the brain, the heart, the arterial system, the
kidney and the eye.
True or false?
Hypertension is rarely (<5%) secondary to a definable cause
True.
Hypertension is rarely (<5%) secondary to a definable cause such as renal
or endocrine disease or coarctation of the aorta. In most patients the basis is
‘essential’ or primary hypertension, which is often familial.
Secondary causes of hypertension
Can be secondary to a definable cause such as renal
(interstitial or renovascular) or endocrine (phaeochromocytoma, Conn’s,
Cushing’s) disease or coarctation of the aorta.
How oral contraceptive pills impact blood pressure?
raise BP
the oral contraceptive pill and corticosteroids can raise the blood pressure, as can sustained high alcohol intake.
How corticosteroids impact blood pressure?
raise BP
the oral contraceptive pill and corticosteroids can raise the blood pressure, as can sustained high alcohol intake.
How does sustained high alcohol intake impact blood pressure?
raise BP
the oral contraceptive pill and corticosteroids can raise the blood pressure, as can sustained high alcohol intake.
List two medications that can raise BP.
the oral contraceptive pill and corticosteroids can raise the blood pressure
What two factors are considered important in determining whether drug therapy should be offered for hypertension
I. The sustained level of blood pressure
II. The overall cardiovascular risk profile
for e.g. For patients with
diabetes, high blood pressure is particularly adverse and should be
stringently controlled.
Thresholds for drug treatment of hypertension
Sustained pressure ≥160 mm systolic and ≥100 mm diastolic justify drug
treatment. At levels of 140-159 systolic and 90-99 diastolic, the decision
depends on the overall cardiovascular risk profile (is there >15% risk of a
cardiovascular event in the next 10 years?) and the presence or absence of
end organ damage in the heart (LVH), eye or kidney.
In the presence of
diabetes, the treatment threshold is 140mm systolic or 90 mm diastolic, with
a target level of <130/80mm on treatment.
List 5 types of drugs used to treat hypertension
I. Thiazide Diuretics
II. Beta-adrenoceptor blocking drugs
III. Angiotensin converting enzyme (ACE) inhibitors
IV. Calcium-channel blocking drugs
V. Other agents for resistant hypertension or patients intolerant of
other agents: angiotensin-II receptor antagonists, alpha-blockers,
vasodilators and centrally acting drugs.
Mechanism of thiazide diuretics in managing hypertension
Thiazide diuretics (e.g. bendrofluazide) have direct vasodilating properties as well as natriuretic action.
Patient is prescribed thiazide diuretics for hypertension. What are some important side effects?
Side effects include gout, hypokalaemia and mild
impairment of glucose tolerance (all rare).
Mechanism of beta blockers in managing hypertension
Beta-blockers (e.g. atenolol) have their main action on the heart by reducing
myocardial contractility.
Side effects of beta blockers
Side effects include cold extremities and impaired
exercise capacity (fairly common), bronchospasm (important to avoid in
asthmatic patients), precipitation of acute heart failure, bradycardia.
Positively indicated with concurrent angina, chronic heart failure or past
myocardial infarction.
Mechanism of ACE inhibitors in managing hypertension
ACE inhibitors (e.g. lisinopril) lower angiotensin-II (A-II) levels and thereby cause vasodilatation and natriuresis.
Why should renal function by monitored when starting a patient on ACE inhibitors?
First-dose hypotension can occur, especially in patients who are volume-depleted and/or on diuretics. Rarely, a sharp and potentially irreversible decline in renal function may occur in patients with (probably unsuspected) renal artery stenosis; renal function should be monitored when starting or increasing ACE inhibitor dose.
Your patient is prescribed ACE inhibitors for hypertension but develops a significant dry cough. What suitable alternative medication could you use?
A-II receptor antagonists (e.g.
losartan) do not cause cough but act otherwise similarly to ACE inhibitors – a
suitable substitute
Are ACE inhibitors indicted in a patient with hypertension and concurrent heart failure?
Yes
ACE inhibitors are generally well tolerated, and
positively indicated with concurrent heart failure.
Which hypertensive medication is Positively indicated with concurrent angina?
Calcium-channel blocking drugs
Dihydropyridines can cause vasodilator side
effects
Mechanism of Calcium channel blockers in managing hypertension
Calcium-channel blocking drugs are of three pharmacological classes. All are
effective in lowering blood pressure but some (the dihydropyridines e.g.
amlodipine) are predominantly vasodilators while others (e.g. diltiazem and
verapamil) appear to act mainly or partially via an effect on myocardial
contractility.
Define heart failure.
Heart failure is a state ‘in which the heart fails to maintain an adequate
circulation for the needs of the body despite an adequate filling pressure’.
Starling’s law of the heart
The force developed in the myocardium depends
on the degree to which the fibres are stretched (or the heart is filled).
In heart failure the heart can no longer produce the same amount of force (or
cardiac output) for a given level of filling.
Use starling’s law of the heart to explain the change that occurs in heart failure
Starling’s Law of the Heart - The force developed in the myocardium depends
on the degree to which the fibres are stretched (or the heart is filled).
In heart failure the heart can no longer produce the same amount of force (or
cardiac output) for a given level of filling.
What two systems are activated in heart failure in an attempt to maintain cardiac output?
The sympathetic nervous system and the Renin-Angiotensin-Aldosterone
System (RAAS) are both activated in heart failure in an attempt to maintain
cardiac output. These have the effect of making an already struggling heart
work.
The sympathetic nervous system and the Renin-Angiotensin-Aldosterone
System (RAAS) are both activated in heart failure in an attempt to maintain
cardiac output.
Why are these harmful in the context of heart failure?
These have the effect of making an already struggling heart
work harder. In addition, angiotensin II can damage the heart and other
organs.
ACE inhibitors thus have
an indirect vasodilatory and diuretic effects. Explain how.
ACE inhibitors are
used in the treatment of heart failure to prevent the production of
angiotensin II which is a powerful vasoconstrictor and promotes the release
of aldosterone from the adrenal cortex. Aldosterone causes salt and water
retention in the kidneys, increasing blood volume. ACE inhibitors thus have
an indirect vasodilatory and diuretic effect, both of which are beneficial in
the treatment of heart failure.
Goals of treatment of heart failure
o Symptomatic improvement o Delay progression of heart failure o Reduce mortality o Treat complications/associated conditions/cardiovascular risk factors
Define Thrombosis
Thrombosis is the local coagulation or clotting of the blood in a part of the
circulatory system.
In what context is virchow’s triad used?
What comprises the triad?
Virchow’s triad indicates the main factors which
predispose to thrombosis.
Stasis
Hypercoagulability
Endothelial injury
Does anticoagulation refer to venous or arterial thromboembolism?
both
prevention and treatment of thromboembolism,
What is prothrombin time?
The prothrombin time is the time taken for plasma to clot in the presence of
an extrinsic tissue factor.
How is prothrombin time reported in a standardised way?
In order to compare the clotting of a patient to a
normal control The International Normalised Ratio (INR) is used. This gives a standardised measure of the prothrombin time ratio; PTtest:PTnormal allowing
for the tissue factor used and is particularly used to monitor patients taking
warfarin.
Vitamin K promotes synthesis of prothrombin & which clotting factors?
VII, IX, X
as well as proteins C and S
Mechanism of action: Vitamin K antagonist anticoagulants
Vitamin K promotes synthesis of prothrombin & Factors VII, IX, X
(also Proteins C & S)
Competitively antagonised by coumarin derivatives e.g. Warfarin
Important Pharmacokinetics of Warfarin
GI absorption – oral dosing
Causes dose dependent reduction in Vit. K dependent factors, but:
Extreme variation in individual dose requirement
Monitor dose by INR
Differing degrees of anticoagulation, depending upon condition
Heavily protein bound
Gradual onset of activity.
Persisting anticoagulant action on cessation of treatment
Numerous drug interactions resulting in altered anticoagulant effect
o The majority are potentiating, but some are inhibiting
Hepatic metabolism by multiple CYP isoforms
Warfarin has numerous drug interactions resulting in altered anticoagulant effect. Are most potentiating or inhibiting?
Most warfarin DDI are potentiating, leading to increased bleeds
Adverse effects of warfarin
Excessive bleeding/bruising/purpura
In pregnancy – teratogenicity
Several of warfarin therapy
Antagonism of therapy by administration of Vitamin K
Heparin mechanism of action
Linear mucopolysaccharide chains (glycosaminoglycans) of variable length and Molecular Weight
Active site is a pentasaccharide sequence – this binds to Antithrombin
Markedly increases antithrombin-mediated inhibition of predominantly Thrombin and Xa, (but also Factors Ixa, Xia XIIa)
Important pharmacokinetics of Heparin
Poor GI absorption – therefore administered iv/sc
Rapid onset/offset of anticoagulant activity
Variable bioavailability due to binding to plasma proteins
Dose/effect monitored by APTT
Contrast the dosing routes of warfarin vs heparin
warfarin - GI absorption – oral dosing
heparin - Poor GI absorption – therefore administered iv/sc
How is the dose/effect monitored in warfarin vs heparin?
Heparin Dose/effect monitored by APTT
Warfarin prothrombin time via INR
Compare the actions of heparin and warfarin after treatment is stoped
Heparin - Rapid onset/offset of anticoagulant activity
Warfarin - Persisting anticoagulant action on cessation of treatment
Adverse effects of heparin
Bleeding/bruising
Thrombocytopenia
Osteoporosis (long term administration)
Reversal of heparin therapy
Protamine sulphate – causes dissociation of Heparin/Antithrombin complex and binds irreversibly to heparin
3 categories of Antiplatelet agents
- Thromboxane A2 inhibition: (e.g. Aspirin, Dipyridamole)
- latelet ADP receptor antagonists: (e.g. Clopidogrel, Ticlopidine)
- GpIIb/IIIa inhibitors:
Give an example of an Antiplatelet agent that works via thromboxane A2 inhibition
Aspirin – inhibits cyclooxygenase and therefore platelet
thromboxane A2 production. Also attenuates protective effect of gastric mucosal prostaglandins (through cyclocoxygenase inhibition)
– gastric erosions/ulcers may occur.
Dipyridamole – inhibits platelet phosphodiesterase – rising platelet
128eli levels inhibit Thromboxane A2 production.
How does aspirin act as an anti platelet agent?
inhibits cyclooxygenase and therefore platelet
thromboxane A2 production
Thromboxane A2 liberated from activated platelets – causes platelet aggregation
How does Clopidogrel act as an anti platelet agent?
ADP/ADP-receptor interaction – one of many stimuli for platelet
aggregation.
How do GpIIb/IIIa inhibitors: act as anti platelet agents?
Inhibit final common pathway of platelet aggregation – 3 classes:
o Monoclonal antibodies to GpIIb/IIIa receptor
o Peptide antagonists to GpIIb/IIIa receptor
o ‘Non-peptide’ small molecule antagonists of GpIIb/IIIa receptor
The normal clearance mechanism for thrombi is by which enzyme?
plasmin, a trypsin-like
enzyme which cleaves fibrin (and fibrinogen and several other coagulation factors including II, V and VIII).
What is the role of plasmin?
The normal clearance mechanism for thrombi is by plasmin, a trypsin-like
enzyme which cleaves fibrin (and fibrinogen and several other coagulation factors including II, V and VIII).
What is plasmin formed from?
Plasmin is formed from the circulating
precursor plasminogen, which binds to fibrin strands within a thrombus.
The
conversion of plasminogen to plasmin is achieved by a number of plasminogen activators. These activate plasminogen bound to fibrin. The fibrinolytic system is itself regulated by circulating
inhibitors.
What is the main underlying mechanism of fibrinolytic drugs?
Fibrinolytic drugs generate plasmin either themselves (e.g. tPA, approved
name alteplase) or by binding to and activating endogenous plasminogen
(e.g. the bacterial product streptokinase).
The former mechanism works
preferentially in the presence of fibrin and is therefore described as ‘clot specific’,
whereas streptokinase causes a degree of fibrinolytic activity in the
general circulation. The practical significance of this difference is uncertain.
Which fibrinolytic mechanism is described as “clot specific”?
Fibrinolytic drugs generate plasmin either themselves (e.g. tPA, approved
name alteplase) or by binding to and activating endogenous plasminogen
(e.g. the bacterial product streptokinase).
The former mechanism works
preferentially in the presence of fibrin and is therefore described as ‘clot specific’,
Why is streptokinase a potential allergen?
Streptokinase is a bacterial protein and therefore antigenic. It can cause
allergic reactions (major in about 0.1% of treated patients) and cannot be
used twice since it invariably generates blocking antibodies which persist for
many years.
In carefully selected patients, fibrinolytic drugs are used for the following 3 indications:
Acute myocardial infarction
Pulmonary embolism
Major venous thrombosis
Note: Trials have also examined the use of fibrinolytic agents in ischaemic stroke
(where a haemorrhagic mechanism has been excluded by CT or MRI scan),
but their use in this indication is not routine because of the associated risk of
induced cerebral haemorrhage and narrow time-window of potential benefit
Give 2 reasons why early treatment with fibrinolytic is important
- before the consequences of
vascular occlusion become irreversible. - as they age, thrombi
become more resistant to lysis. - The potential benefit of treatment declines
continuously over time, whereas the risks (see below) remain constant. - The window of opportunity is within approximately 12 hours for coronary
occlusion, rather longer for venous thrombo-embolism but only about 3
hours for ischaemic stroke.
Major contra-indications for fibrinolytic therapy
active peptic ulcer or other potential bleeding source, recent trauma or surgery, history of cerebral haemorrhage or stroke of uncertain aetiology, uncontrolled hypertension, and coagulation defect. Age per se is not a contraindication.
Streptokinase should not be
given to a patient who has received it in the past.
In the case of severe allergy or anaphylaxis in response to streptokinase, list 3 treatments that may be given
Severe allergy or anaphylaxis is treated with adrenaline, oxygen, intravenous fluids, an antihistamine and hydrocortisone as required.
