Pharmacology (Autosaved)

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A 44-year-old Bangladeshi man with a history of mitral stenosis and atrial fibrillation is diagnosed with tuberculosis. He is commenced on anti-tuberculosis therapy. Three weeks after starting treatment his INR has increased to 5.6. Which one of the following medications is most likely to be responsible for this increase?

Pyrazinamide

Isoniazid

Rifampicin

Ethambutol

Streptomycin

Next question

Isoniazid inhibits the P450 system

It is important when answering questions relating to liver enzymes to be sure whether the question is asking about induction or inhibition. Drugs causing induction are often well known and Candidates may rush to give these as the answer. A raised INR is a result of inhibited liver enzymes

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P450 enzyme system

Induction usually requires prolonged exposure to the inducing drug, as opposed to P450 inhibitors, where effects are often seen rapidly

Inducers of the P450 system include

antiepileptics: phenytoin, carbamazepine

barbiturates: phenobarbitone

rifampicin

St John's Wort

chronic alcohol intake

griseofulvin

smoking (affects CYP1A2, reason why smokers require more aminophylline)

Inhibitors of the P450 system include

antibiotics: ciprofloxacin, erythromycin

isoniazid

cimetidine, omeprazole

amiodarone

allopurinol

imidazoles: ketoconazole, fluconazole

SSRIs: fluoxetine, sertraline

ritonavir

sodium valproate

acute alcohol intake

quinupristin

A 56-year-old woman presents to the Emergency Department with central crushing chest pain and ST elevation of 3 mm in leads II, III and aVF. Which one of the following is an

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absolute contraindication to thrombolysis?

History of peptic ulcer disease

Menstruation

Pre-proliferative diabetic retinopathy

Stroke 12 months ago

Known intracranial neoplasm

Next question

Whilst local policies vary, an intracranial neoplasm is considered an absolute contraindication to thrombolysis. The other options are relative contraindications.

Thrombolysis

Thrombolytic drugs activate plasminogen to form plasmin. This in turn degrades fibrin and help breaks up thrombi. They in primarily used in patients who present with a ST elevation myocardial infarction. Other indications include acute ischaemic stroke and pulmonary embolism, although strict inclusion criteria apply.

Examples

alteplase

tenecteplase

streptokinase

Contraindications to thrombolysis

active internal bleeding

recent haemorrhage, trauma or surgery (including dental extraction)

coagulation and bleeding disorders

intracranial neoplasm

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stroke < 3 months

aortic dissection

recent head injury

pregnancy

severe hypertension

Side-effects

haemorrhage

hypotension - more common with streptokinase

allergic reactions may occur with streptokinase

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Nicorandil is most useful in the management of:

Hypertension

Heart failure

Angina

Atrial fibrillation

Acute coronary syndrome

Next question

Nicorandil is a potassium channel activator which has a vasodilatory effect on the coronary arteries. Side-effects include headache, flushingand anal ulceration.

Angina pectoris: drug management

The management of stable angina comprises lifestyle changes, medication, percutaneous coronary intervention and surgery. NICE produced guidelines in 2011 covering the management of stable angina

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Medication

all patients should receive aspirin and a statin in the absence of any contraindication

sublingual glyceryl trinitrate to abort angina attacks

NICE recommend using either a beta-blocker or a calicum channel blocker first-line based on 'comorbidities, contraindications and the person's preference'

if a calcium channel blocker is used as monotherapy a rate-limiting one such as verapamil or diltiazem should be used. If used in combination with a beta-blocker then use a long-acting dihydropyridine calcium-channel blocker (e.g. modified-release nifedipine). Remember that beta-blockers should not be prescribed concurrently with verapamil (risk of complete heart block)

if there is a poor response to initial treatment then medication should be increased to the maximum tolerated dose (e.g. for atenolol 100mg od)

if a patient is still symptomatic after monotherapy with a beta-blocker add a calcium channel blocker and vice versa

if a patient is on monotherapy and cannot tolerate the addition of a calcium channel blocker or a beta-blocker then consider one of the following drugs: a long-acting nitrate, ivabradine, nicorandil or ranolazine

if a patient is taking both a beta-blocker and a calcium-channel blocker then only add a third drug whilst a patient is awaiting assessment for PCI or CABG

Nitrate tolerance

many patients who take nitrates develop tolerance and experience reduced efficacy

the BNF advises that patients who develop tolerance should take the second dose of isosorbide mononitrate after 8 hours, rather than after 12 hours. This allows blood-nitrate levels to fall for 4 hours and maintains effectiveness

this effect is not seen in patients who take modified release isosorbide mononitrate

Ivabradine

a new class of anti-anginal drug which works by reducing the heart rate

acts on the If ('funny') ion current which is highly expressed in the sinoatrial node, reducing cardiac pacemaker activity

adverse effects: visual effects, particular luminous phenomena, are common. Bradycardia, due to the mechanism of action, may also be seen

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there is no evidence currently of superiority over existing treatments of stable angina

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A 54-year-old man with a history of hypertension comes for review. He currently takes lisinopril 10mg od, simvastatin 40mg on and aspirin 75mg od. His blood pressure is well controlled at 124/76 mmHg but he also mentions that he is due to have a tooth extraction next week. What advice should be given with regards to his aspirin use?

Take aspirin as normal but take tranexamic 1g tds acid 24 hours before and after procedure

Stop 72 hours before, restart 24 hours after procedure


Take aspirin as normal


Next question

In the BNF section 'Prescribing in dental practice' it advises that patients in this situation should continue taking anti-platelets as normal

Aspirin

Aspirin works by blocking the action of both cyclooxygenase-1 and 2. Cyclooxygenase is responsible for prostaglandin, prostacyclin and thromboxane synthesis. The blocking of thromboxane A2 formation in platelets reduces the ability of platelets to aggregate which has lead to the widespread use of low-dose aspirin in cardiovascular disease. Until recent guidelines changed all patients with established cardiovascular disease took aspirin if there was no contraindication. Following the 2010 technology appraisal of clopidogrel this is no longer the case*.

Two recent trials (the Aspirin for Asymptomatic Atherosclerosis and the Antithrombotic Trialists Collaboration) have cast doubt on the use of aspirin in primary prevention of cardiovascular disease. Guidelines have not yet changed to reflect this. However the Medicines and Healthcare products Regulatory Agency (MHRA) issued a drug safety update in January 2010 reminding prescribers that aspirin is not licensed for primary prevention.

What do the current guidelines recommend?

first-line for patients with ischaemic heart disease

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Potentiates

oral hypoglycaemics warfarin steroids

*NICE now recommend clopidogrel first-line following an ischaemic stroke and for peripheral arterial disease. For TIAs the situation is more complex. Recent Royal College of Physician (RCP) guidelines support the use of clopidogrel in TIAs. However the older NICE guidelines still recommend aspirin + dipyridamole - a position the RCP state is 'illogical'

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In the Vaughan Williams classification of antiarrhythmics verapamil is an example of a:

Class Ia agent

Class Ib agent

Class II agent

Class III agent

Class IV agent

Next question

Antiarrhythmics: Vaughan Williams classification

The Vaughan Williams classification of antiarrhythmics is still widely used although it should be noted that a number of common drugs are not included in the classification e.g. adenosine, atropine, digoxin and magnesium

AP = action potential

Class ExamplesMechanism of action Notes

Ia QuinidineProcainamideDisopyramide

Block sodium channels

Quinidine toxicity causes cinchonism (headache, tinnitus, thrombocytopaenia)

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Class ExamplesMechanism of action Notes

Increases AP duration Procainamide may cause drug-induced

lupus

Ib LidocaineMexiletineTocainide


Decreases AP duration

Ic FlecainideEncainidePropafenone


No effect on AP duration

II PropranololAtenololBisoprololMetoprolol

Beta-adrenoceptor antagonists

III AmiodaroneSotalolIbutilideBretylium

Block potassium channels

IV Verapamil Diltiazem

Calcium channel blockers

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What is the mechanism of action of heparin?

Activates antithrombin III

Vitamin K antagonist

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Activates tissue plasminogen activator

Inhibits antithrombin III

Inhibits protein C

Next question

Heparin

There are two main types of heparin - unfractionated, 'standard' heparin or low molecular weight heparin (LMWH). Heparins generally act by activating antithrombin III. Unfractionated heparin forms a complex which inhibits thrombin, factors Xa, IXa, XIa and XIIa. LMWH however only increases the action of antithrombin III on factor Xa

The table below shows the differences between standard heparin and LMWH:

Standard heparinLow molecular weight heparin (LMWH)

Administration Intravenous Subcutaneous

Duration of action

Short Long

Mechanism of action

Activates antithrombin III. Forms a complex that inhibits thrombin, factors Xa, IXa, Xia and XIIa

Activates antithrombin III. Forms a complex that inhibits factor Xa

Side-effects BleedingHeparin-induced thrombocytopaenia (HIT)Osteoporosis

Bleeding

Lower risk of HIT and osteoporosis with LMWH

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Standard heparinLow molecular weight heparin (LMWH)

Monitoring Activated partial thromboplastin time (APTT)

Anti-Factor Xa (although routine monitoring is not required)

NotesUseful in situations where there is a high risk of bleeding as anticoagulation can be terminated rapidly

Now standard in the management of venous thromboembolism treatment and prophylaxis and acute coronary syndromes

Heparin-induced thrombocytopaenia (HIT)

immune mediated - antibodies form which cause the activation of platelets

usually does not develop until after 5-10 days of treatment

despite being associated with low platelets HIT is actually a prothrombotic condition

features include a greater than 50% reduction in platelets, thrombosis and skin allergy

treatment options include alternative anticoagulants such as lepirudin and danaparoid

Both unfractionated and low-molecular weight heparin can cause hyperkalaemia. This is thought to be caused by inhibition of aldosterone secretion.

Heparin overdose may be reversed by protamine sulphate, although this only partially reverses the effect of LMWH.

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A patient is given aspirin 300 mg after developing an acute coronary syndrome. What is the mechanism of action of aspirin to achieve an antiplatelet effect?

Inhibits the production of thromboxane A2

Inhibits ADP binding to its platelet receptor

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Inhibits the production of prostaglandin H2

Glycoprotein IIb/IIIa receptor antagonist

Inhibits the production of prostacyclin (PGI2)

Next question

Acute coronary syndrome: management of NSTEMI

NICE produced guidelines in 2013 on the Secondary prevention in primary and secondary care for patients following a myocardial infarction management of unstable angina and non-ST elevation myocardial infarction (NSTEMI). These superceded the 2010 guidelines which advocated a risk-based approach to management which determined whether drugs such as clopidogrel were given.

All patients should receive

aspirin 300mg

nitrates or morphine to relieve chest pain if required

Whilst it is common that non-hypoxic patients receive oxygen therapy there is little evidence to support this approach. The 2008 British Thoracic Society oxygen therapy guidelines advise not giving oxygen unless the patient is hypoxic.

Antithrombin treatment. Fondaparinux should be offered to patients who are not at a high risk of bleeding and who are not having angiography within the next 24 hours. If angiography is likely within 24 hours or a patients creatinine is > 265 µmol/l unfractionated heparin should be given.

Clopidogrel 300mg should be given to all patients and continued for 12 months.

Intravenous glycoprotein IIb/IIIa receptor antagonists (eptifibatide or tirofiban) should be given to patients who have an intermediate or higher risk of adverse cardiovascular events (predicted 6-month mortality above 3.0%), and who are scheduled to undergo angiography within 96 hours of hospital admission.

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Coronary angiography should be considered within 96 hours of first admissionto hospital to patients who have a predicted 6-month mortality above 3.0%. It should also be performed as soon as possible in patients who are clinically unstable.

The table below summaries the mechanism of action of drugs commonly used in the management of acute coronary syndrome:

Medication Mechanism of action

Aspirin Antiplatelet - inhibits the production of thromboxane A2

Clopidogrel Antiplatelet - inhibits ADP binding to its platelet receptor

Enoxaparin Activates antithrombin III, which in turn potentiates the inhibition of coagulation factors Xa

Fondaparinux Activates antithrombin III, which in turn potentiates the inhibition of coagulation factors Xa

Bivalirudin Reversible direct thrombin inhibitor

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Pharmacology (Autosaved)