Cardiovascular Drugs Flashcards
(332 cards)
1
Q
Name some antiplatelet drugs
A
Aspirin
ADP receptor antagonists (clopidogrel, prasugrel, ticagrelor, ticlopidine)
Glycoprotein IIb/IIIa antagonists (tirofiban)
Dipyridamole
Cilostazol
2
Q
What is the mechanism of action of aspirin?
A
Irreversibly acetylates cyclo-oxygenase
Prevents production of thromboxane A2
Inhibits platelet aggregation
3
Q
What are the indications for aspirin?
A
Low dose for secondary prevention following MI, TIA/stroke, and for patients with angina or peripheral vascular disease
May have a role in primary prevention
4
Q
What is the mechanism of action of ADP receptor antagonists (clopidogrel, prasugrel, ticagrelor) ?
A
Inhibit the binding of ADP to its receptors on platelets
Inhibiting the activation of GP IIb/IIIa receptors required for platelets to bind to fibrinogen and each other
5
Q
What are the indications for Clopidogrel?
A
Clopidogrel - Prevention of atherosclerotic events in patients with a recent MI or stroke and in those with established peripheral arterial disease
Prophylaxis of thrombotic events in ACS (non-ST elevation) (with aspirin)
Prevent thrombotic events associated with PCI with or without coronary stenting (with aspirin)
Prevention of atherothrombotic and thromboembolic events in patients with AF and at least one risk factor for a vascular event (with aspirin) if unsuitable for warfarin
TIA or acute ischaemic stroke for patients with aspirin hypersensitivity or those intolerant of aspiring despite addition of PPI
6
Q
Name some ADP receptor antagonists
A
Clopidogrel
Prasugrel
Ticagrelor
Ticlopidine
7
Q
Name some Glycoprotein IIb/IIIa antagonists
A
Abciximab
Eptifibatide
Tirofiban
8
Q
What are the indications for prasugrel?
A
Prevent atherothrombotic events in patients with ACS undergoing PCI - with aspirin
Coronary angiography within 48 hours for admission for unstable angina or NSTEMI
Alternative to clopidogrel in some patients undergoing PCI
9
Q
What are the indications for Ticagrelor?
A
Prevention of atherothrombotic events in patients with ACS, including those undergoing PCI (alternative to clopidogrel)- with aspirin
10
Q
What are the indications for tirofiban?
A
In combination with UFH, aspirin and clopidogrel:
- prevention of early MI in patients with unstable angina or NSTEMI with last episode of chest pain within 12 hours - angiography planned for 4-48 hours after diagnosis - specialist supervision
- reduction of major cardiovascular events in patients with STEMI intended for PCI - specialist supervision
11
Q
What is the mechanism of action of GP IIb/IIIa antagonists?
A
Bind to GP IIb/IIIa and block the binding to fibrinogen (and vWF for abciximab)
Prevention of platelet aggregation
12
Q
What are the indications for abciximab?
A
Given to patients undergoing PCI with aspirin and heparin to prevent cardiac ischaemic complications - specialist use only
Patients with unstable angina where PCI is planned in the next 24 hours and conventional medications aren’t working - specialist use only
13
Q
What are the indications for eptifibatide?
A
In combination with UFH and aspirin for prevention of early myocardial infarction in unstable angina and NSTEMI and last episode of chest pain within 24 hours
14
Q
What is the mechanism of action of dipyridamole?
A
Coronary vasodilator
Increases intracellular cAMP by inhibiting cyclic nucleotide phosphodiesterase
Results in decreased thromboxane A2 synthesis
Potential the effect of prostacyclin —> antagonise the stickiness - decreasing adhesion to thrombogenic surfaces
15
Q
What are the indications for dipyridamole?
A
Secondary prevention of TIA and ischaemic strokes (not associated with AF) - with aspirin or alone
With anticoagulants for prophylaxis of thromboembolism associated with prosthetic heart valves
myocardial imaging
16
Q
What is the mechanism of action of cilostazol?
A
Oral antiplatelet that also vasodilates
Inhibits phosphodiesterase type III - prevents degradation of cAMP - increases cAMP in platelets and vasculature - prevents platelet aggregation and promotes vasodilation
Decreases plasma triglycerides
Increases HDLs
17
Q
What are the indications for cilostazol?
A
Intermittent claudication without rest pain or peripheral tissue necrosis
18
Q
What are some important ADRs to aspirin?
A
Increased bleeding time
Increased risk of haemorrhage - stroke, GI haemorrhage, subconjunctival
Bronchospasm
Hypersensitivity skin reactions
High dose/analgesic dose - increased risk of toxicity - tinnitus, deafness, confusion, hyperventilation, vasodilation and sweating
19
Q
What are some important drug interactions with aspirin?
A
NSAIDs - ibuprofen - obstructs access of aspirin to COX-1 - immediate release aspirin should be taken 60 minutes before or 8 hours after ibuprofen
20
Q
What are some important ADRs from clopidogrel?
A
Common: Abdominal pain Bleeding disorder (GI and intracranial) Diarrhoea Dyspepsia Very rare: Thrombotic thrombocytopenic purpura
21
Q
What are some important contraindications for clopidogrel?
A
Active bleeding
22
Q
What are some important interactions with clopidogrel?
A
Omeprazole and esomeprazole inhibit the CYP 450 enzyme that converts the prodrug clopidogrel to the active drug- should not be administered concurrently
23
Q
What are some important ADRs associated with prasugrel?
A
Common or very common: Anaemia GI haemorrhage Haematoma Haematuria Haemorrhage Intracranial haemorrhage Rash Hypersensitivity
Frequency not known:
Thrombotic thrombocytopenic purpura
24
Q
What are some important contraindications for prasugrel?
A
Active bleeding
History of stroke or TIA
25
What are some important contraindications for aspirin?
Active peptic ulceration, bleeding disorders (antiplatelet dose), children <16 years - risk of Reye’s syndrome, haemophilia, previous peptic ulceration (analgesic dose), severe cardiac failure (analgesic dose)
26
What are some important ADRs from ticagrelor?
Common or very common:
Bruising
Dyspnoea
Haemorrhage
27
What are some important interactions with ticagrelor?
Diminished effectiveness with concomitant use of aspirin dose >100mg
28
What are some important contraindications for ticegrelor?
Active bleeding
| Previous intracranial haemorrhage
29
What are the monitoring requirements for ticagrelor?
Monitor renal function 1 month after initiation
30
What are some important ADRs associated with abciximab?
```
Common or very common:
Bleeding
Bradycardia
Chest pain
Fever
Hypotension
Thrombocytopenia
Vomiting
```
Rare:
Adult respiratory distress
Cardiac tamponade
Hypersensitivity
31
What are some important interactions with abciximab?
Other anticoagulants - bleeding risk
32
What are some important contraindications for abciximab?
```
Active internal bleeding
Hypertensive retinopathy
Severe hypertension
Major surgery within last two months
Thrombocytopenia
Vasculitis
```
33
What are the monitoring requirements for abciximab?
Do baseline haematology tests (including bleeding times)
Monitor Hb and Haematocrit 12 and 24 hours after administration
And paltelet count 2-4 hours and 24 hours after administration
34
What are some important ADRs from eptifibatide?
Common:
Bleeding
Rare:
Anaphylaxis
Rash
35
What are some important interactions with eptifibatide?
Other anticoagulants - bleeding
36
What are some important contraindications for eptifibatide?
Abnormal bleeding within 30 days, history of haemorrhagic stroke, increased INR, major surgery or trauma within 6 weeks, severe hypertension, thrombocytopenia, stroke within 30 days
37
What are the monitoring requirements for eptifibatide?
Do baseline haematology tests including bleeding times
| Test Hb, haematocrit and platelet levels 6 hours after administration and then at least once daily
38
What are the important ADRs from tirofiban?
```
Bleeding
Fever
Headache
Nausea
Reversible thrombocytopenia
```
39
What are some important interactions with tirofiban?
Other anticoagulants - bleeding
40
What are some important contraindications for tirofiban?
Abnormal bleeding within 30 days
History of aneurysm or haemorrhagic stroke
History of neoplasm or intracranial disease
Increased INR, prothrombin time
Stroke within 30 days
Severe hypertension
Thrombocytopenia
41
What are the monitoring requirements for tirofiban?
Monitor carefully if eGFR <60
| Monitor Hb, haematocrit and platelet count before treatment, 2-6 hours after and then at least once daily
42
What are some important ADRs from Dipyridamole?
```
Throbbing headache
Orthostatic hypotension
Hypersensitivity
Worsening symptoms of coronary artery disease (coronary steal phenomenon)
Thrombocytopenia
```
43
What are some important contraindications for dipyridamole?
Unstable angina (coronary steal phenomenon)
44
What are some important ADRs from cilostazol?
Headache
| GI side effects (diarrhoea, dyspepsia, abdominal pain etc.)
45
What are some important contraindications for cilostazol?
```
Heart failure - increases mortality
Unstable angina
In past 6 months stroke, MI
History of tachyarhythmias, atrial flutter QT prolongation
Active peptic ulcer
Poorly controlled hypertension
Diabetic retinopathy
```
46
What are some interactions with cilostazol?
Concurrent use with 2 or more antiplatelets or anticoagulants contraindicated - bleeding risk
47
Name some anticoagulant drug classes
DOACs
Warfarin
Heparins
48
Name some DOACs and which factor they are specific to
```
Factor Xa inhibitors:
Apixaban
Rivaroxaban
Fondaparinux
Thrombin (Factor II) inhibitors:
Dabigatran
Bivalirudin
```
49
What is the advantage of using DOACs as opposed to warfarin?
Do not require regular monitoring and dose adjustment
50
What are the disadvantages of DOACs?
Not currently an antidote
| Except for idarucizumab (monoclonal antibody) for dabigatran
51
What are the indications for using a DOAC?
Prophylaxis - prevention of venous thromboembolism in high risk patients e.g. post-op
- prevention of stroke in AF and atrial flutter
Therapeutic - treatment of venous thromboembolic disease DVT and PE
52
What is the main indication for fondaparinux?
In management of ACS
53
What are the contraindications for DOACs?
Severe renal/liver impairment, active bleeding, lesion at risk of bleeding, low clotting factors
54
What are the important side effects of DOACs?
Haemorrhage, anaemia
| Abdominal pain, diarrhoea, dyspepsia, nausea
55
What are the important interactions with DOACs?
Heparin
| Clopidogrel
56
Name some LMWHs
Dalteparin
Enoxaparin
Tinzaparin
57
What is the indication for LMWHs?
First line in prevention and initial treatment of venous thromboembolism
Second line in ACS treatment (NSTEMI, unstable angina)
Second line in STEMI treatment when not undergoing PCI
58
What are the contraindications for heparins?
Bleeding disorder, platelets <60x10^9/L, previous heparin induced thrombocytopenia, peptic ulcer, cerebral haemorrhage, severe hypertension, neurosurgery
Renal failure - decrease dose for prophylactic purposes- use UFH for therapeutic treatment
59
What are the side effects of heparins?
Haemorrhage
Thrombocytopenia
Rare:
Hyperkalaemia, osteoporosis, priapism, alopecia, skin necrosis
Hypersensitivity, angioedema, anaphylaxis, urticaria
60
How are heparins monitored?
Platelet count before treatment and regularly if taken for more than 4 days
K+ before treatment and regularly if taken for more than 7 days
61
How are LMWHs monitored?
If patient has increased risk of bleeding, monitor anti-factor Xa activity
62
What is the management of heparin overdose?
Stop the heparin
| Protamine sulfate is the antidote - given if bleeding (doesnt completely reverse the effects of LMWH)
63
What are the indications for UFH?
Prophylaxis and treatment of thromboembolism (DVT, PE)
Third line in treatment of ACS (unstable angina and NSTEMI)
And third line in treatment of STEMI if not undergoing CI
64
How is UFH monitored?
Same as all heparins
| Monitor with APTT and adjust dose
65
What are the advantages of UFH v.s. LMWH?
Rapid onset and short half life
| Fully reversible with protamine sulfate
66
What are the advantages of LMWH over UFH?
Longer half life - only needs to be given once or twice a day
More predictable response
Usually doesn’t need monitoring
67
What are the indications for warfarin use?
Prophylaxis of stroke and venous thromboembolism following insertion of prosthetic heart valve
68
What are the contraindications for warfarin?
Peptic ulcer, bleeding disorders, severe hypertension, pregnancy
Elderly and past GI bleeds - use with caution
69
What are the side effects of warfarin?
Calciphylaxis
Bleeding
GI (nausea, vomiting, pancreatitis, diarrhoea)
Liver - jaundice, hepatic dysfunction
Pyrexia
Purpura, skin necrosis, rash, purple toes
70
How are the important interactions with warfarin?
Vitamin K - major changes in diet (Eating more salad and vegetables, drinking green tea) and alcohol consumption can affect anticoagulant control
Pomegranates can increase your INR in response to warfarin
71
How is warfarin monitored?
Initial prothrombin time determined
INR - every day at first and eventually every 12 weeks
Monitored more frequently if comorbidities such as liver and renal impairment
72
What is the management of warfarin overdose?
INR 5-8 with no bleeding - withold 1-2 doses. Restart warfarin at a lower maintenance dose once INR<5
INR 5-8, minor bleed - stop warfarin and admit for urgent IV vitamin K (slowly given). Restart warfarin when INR <5
INR >8, no bleed - stop warfarin and seek haematology advice
INR >8, minor bleed - stop warfarin and admit for urgent IV vitamin K. Check INR daily - repeat vitamin K if too high after 24 hours. Restart warfarin at lower dose when INR <5
Major bleed - Stop warfarin. Give prothrombin complex concentrate 50 units/kg or FFP 15mL/kg and 5-10mg vitamin K IV. Discuss with haematologist
73
What are the disadvantages of vitamin K for warfarin reversal?
May take several hours to work
| Can cause prolonged resistance when restarting warfarin
74
What are the differences between PCC and FFP for major bleed in warfarin overdose?
PCC contains a concentrate of factors II, VII, IX and X and provides a more complete and rapid reversal of warfarin than FFP
75
Name some Beta-blockers
```
Propranolol (non-specific)
Bisoprolol (B1 specific)
Metoprolol
Esmolol
Atenolol
Betaxolol
```
76
What are the indications for beta blockers?
```
Angina
Hypertension
Antidysrhythmic
Post MI (reduces mortality)
Heart failure (with caution
```
77
What are the contraindications of beta blockers?
Severe asthma/COPD
| Heart block
78
What are the side effects of beta blockers?
Lethargy
Erectile dysfunction
Nightmares
Headache
79
How are beta blockers monitored
Monitor lung function in patients with COPD or asthma
80
What are some important interactions with beta blockers?
Verapamil
Decreased by NSAIDs
Lipophilic (propranolol) metabolised by the liver and concentrations increased by cimetidine
81
Name some ACE inhibitors
```
Ramipril
Captopril
Enalapril
Lisinopril
Fosinopril
Quinapril
Perindopril
```
82
What are the indications for ACE inhibitors?
Hypertension
Heart failure
Post-MI - with clinical evidence of heart failure
Prevention of cardiovascular events in patients with atherosclerotic disease or with DM
83
What are the contraindications for ACE inhibitors?
- Aliskiren if eGFR <60 or diabetes
- Hypersensitivity
- Pregnancy (foetal malformations!!)
- Renal artery stenosis – reversal of angiotensin 2-mediated constriction of efferent arteriole results in reduced GFR
- Caution in peripheral vascular disease as this may be associated with undiagnosed renal artery stenosis
84
What are some important interactions with ACE inhibitors?
Decreased by NSAIDs, oestrogens
- Risk of profound first dose hypotension with loop diuretics and enhanced hypotensive effect with other anti-hypertensive agents
- Increased risk of renal impairment with NSAIDs
- Enhanced hypoglycaemic effect of insulin, metformin and sulfonylureas
- Effects are antagonised by corticosteroids
85
What are some side effects of ACE inhibitors?
Dry cough, urticaria
| Angioedema, renal failure, hyperkalaemia
86
Name the classes of diuretics
Loop diuretics
Thiazides
Potassium-sparing
87
Name some loop diuretics
Furosemide
| Bumetanide
88
What channel is inhibited by loop diuretics?
Na/2Cl/K in the loop of Henle
89
What are the indications for loop diuretics?
```
Heart failure
Actuate pulmonary oedema
Hypercalcaemia (with fluids)
Nephrotic syndrome
Liver cirrhosis (not 1st line)
```
90
What are the contraindications for loop diuretics?
- Severe hypokalaemia/ hyponatreamia
- Hypovolaemia
- Renal failure due to nephrotoxic drugs
- Comatose patients with liver cirrhosis
- Anuria
- Patients with a low GFR may require higher doses due to diuretic resistance due to poor perfusion to target tissue
91
What are the important side effects of loop diuretics?
- Electrolyte disturbances (hypokalaemia, hyponatraemia, hypocalcaemia)
- Hypotension
- Tinnitus and deafness
- GI disturbance
- Dyslipidaemia
Furosemide: Ototoxicity.
Bumetanide: Myalgia.
92
What are the important interactions with loop diuretics?
- Risk of cardiotoxicity when given with Digoxin
- Risk of ototoxicity when given with aminoglycosides or vacomycin
- Enhanced hypotensive effect with other antihypertensives
- Can reduce lithium excretion
- NSAIDs can reduce the effectiveness of loop diuretics (due to a reduction in GFR)
93
Why is IV furosemide given in acute pulmonary oedema?
Venodilator
94
Name some thiazide diuretics?
Bendroflumathiazide
Indapamide (thiazide-like diuretic)
Metolazone
95
What are the indications for thiazides?
Hypertension
Heart failure
Isolated systolic hypertension
Oedema
Indapamide has a vasodilatory effect at low doses
96
Which channel do thiazides act on?
Na/Cl in the DCT
97
What are the contraindications for thiazides?
- Electrolyte disturbances
- Addison’s disease
- Avoid in breastfeeding mothers due to suppression of lactation
- ineffective in renal failure
98
What are the side effects of thiazides?
- Hypokalaemia
- Increased urea and uric acid levels – DO NOT USE IF THE PATIENT HAS GOUT!! Can also cause Gout! - hyperuricaemia
- Impaired glucose tolerance - hyperglycaemia
- LDL Cholesterol and TAG levels increased
- Activates renin angiotensin system
- Reduces Calcium loss in the urine - hypercalcaemia
Other side effects:
- Postural hypotension
- Hyponatraemia
- low magnesium
- Male sexual dysfunction
- Suppression of lactation
99
What are the important interactions with thiazides?
NSAIDS decrease effect
100
Name some potassium sparing diuretics
Aldosterone antagonists:
Spironolactone
Eplerenone
ENaC blockers:
Amiloride
Triamterene
101
What are the indications for aldosterone antagonist diuretics?
Indications:
- Congestive heart failure
- Oedema and ascites in liver disease
- Post-MI heart failure
- Nephrotic syndrome
- Primary hyperaldosteronism (Conn’s syndrome)
- Preferred drug for ascites and oedema in cirrhosis
- Used in addition to loop diuretics in heart failure and confers a survival advantage
- Used as additional therapt in hypertension not controlled by ACEI + CCB + Thiazide
- add to loop diuretics/ thiazides to prevent potassium changes
102
What are the contraindications for aldosterone antagonists?
- Electrolyte disturbances – including hyperkalaemia and hyponatraemia
- Caution in renal impairment
- Avoid use along with potassium supplements
103
What are the side effects of aldosterone antagonists?
- Hyperkalaemia (K+ sparing effect)
- GI disturbance
- Anti-androgenic effects (spironolactone – menstrual irregularities in females, gynacomastia and hypogonadism in males)
104
What are the monitoring requirements for aldosterone antagonists?
Monitor U+E for potassium
105
What are the channels acted on by amiloride/triamterene?
ENaC in the late DCT and collect duct
106
Which channels are acted on by aldosterone antagonists?
Competitive antagonist at the intracellular aldosterone receptors in renal tubules causing reduced production of aldosterone-induced proteins. This indirectly reduces the activity of Na/K ATPase in the collective ducts, increasing the excretion of Na and decreasing K+ loss. Spironolactone, in particular, also acts on receptors in other tissues, including androgen receptors.
In the late DCT and collecting duct
107
What are the indications for amiloride/triamterene?
- Mild diuretic with K+ sparing effect
- Usually used in combination with K+ loosing diuretics to minimise K+ loss
- Oedema
108
What are the side effects of amiloride/triamterene?
- Diarrhoea
- Hyperkalaemia
- Nausea
- Vomiting
109
What are the contraindications for amiloride/triamterene?
Addison’s disease
Anuria
Hyperkalaemia
110
What are the monitoring requirements for amiloride/triamterene?
Monitor U+Es particularly in renal impairment
111
Name some vasodilators
Nitrates (dilates veins and large arteries):
Isosorbide mononitrate
Glyceryl trinitrate
Vasodilator antihypertensives:
Hydralazine (dilates arterioles)
Sodium nitroprusside
Alpha-blocker (dilates arteries and veins)
Prazosin
Doxazosin
112
What are the indications for vasodilators?
Heart failure, IHD, hypertension
113
What is the mechanism of action of nitrates?
Metabolised to nitric oxide that activates guanylyl cyclase, increasing the production of cGMP in vascular tissue. This secondary messenger causes smooth muscle relaxation resulting in coronary artery dilation (increasing oxygen supply to myocardium) and systemic venodilatation (reducing the preload and thereby reducing oxygen demand).
114
What are the contraindications for nitrates?
Contraindications:
- Hypersensivity to nitrates
- Hypotension/ hypovolaemia
- Cardiac outflow obstruction (aortic stenosis, cardiac tamponade, hypertrophic obstructive cardiomyopathy, constrictive pericarditis)
- Closed angle glaucoma
115
What are the side effects of nitrates?
- Postural hypotension
- Headache
- Tachycardia
- Dizziness
116
What are the important interactions with nitrates?
Reduce anticoagulant effect of low molecular weight heparin
| Risk of severe hypotension with phosphodiesterase type 5 inhibitors
117
What are the indications for vasodilator antihypertensives?
Hypertensive emergency – BP often over 220/120.
118
What is the mechanism of action of vasodilator antihypertensives?
Mimics the action of endogenous nitric oxide on vascular smooth muscle, acting as a potent vasodilator.
119
What are the contraindications for vasodilator antihypertensives?
Compensatory hypertension
Leber’s optic atrophy
Severe vitamin B12 deficiency
120
What are the side effects of vasodilator antihypertensives?
Sudden BP drop —> headache, nausea, dizziness, retching, abdominal pain, palpitation, anxiety
121
What are the monitoring requirements for vasodilators?
Monitor BP
122
What are the indications for alpha adrenoceptor blockers?
- Hypertension
| - Benign Prostatic Hyperplasia
123
What is the mechanism of action of alpha adrenoreceptor antagonists?
Inhibits alpha 1 adrenoreceptors in arterioles, thereby reducing tone of the vascular smooth muscle and reducing total peripheral resistance. Inhibition of alpha 1 adrenoceptors in periurethral prostatic stroma results in relaxation of internal urethral sphincter and some relief of obstructive urinary symptoms in males.
Properties:
- Selective antagonism at post-synaptic alpha 1 adrenoceptors and antagonise the contractile effects of noradrenaline on vascular smooth muscle
- Reduce peripheral vascular resistance
- More effect in the upright provision
- Benign effect on plasma lipids / glucose
- Safe in renal disease
124
What are the contraindications for alpha adrenoreceptor antagonists?
History of micturition syncope
History of postural hypotension
CHF due to mechanical obstruction e.g. aortic stenosis
125
What are the side effects of alpha adrenoreceptor antagonists?
- Postural hypotension
- Dizziness
- Headache and fatigue
- Oedema
- Anxiety
- Back pain
- Coughing
- Dyspnoea
- Fatigue
- Influenza like symptoms
- Paraesthesia
- Vertigo
126
Name some calcium antagonists
Dihydropyridines:
- nifedipine
- amlodipine
Non-dihydropyridines:
- verapamil
- diltiazem
127
What are the indications for dihydropyridines?
Hypertension and angina
128
What are the indications for non-dihydropyridines?
Hypertension, angina and dysrhythmias
129
What is the mechanism of action of calcium antagonists?
Bind to specific alpha subunit of L type calcium channels
Decrease calcium entry into cells through voltage-sensitive channels in smooth muscle
Promote coronary and peripheral vasodilation
Reduce myocardial oxygen consumption
Dihydropyridines highly vascular selective - cause a reflex tachycardia - can be used with beta blockers
Non-dihydropyridines - less selective - act directly on cardiac tissue - reduce contractility - slow conduction at the AV and SA nodes in addition to their other properties- cant be used with beta blockers
130
What are the contraindications for calcium antagonists?
- Cardiogenic shock
- LVF
- Second or third degree heart block
- WPW or other aberrant pathways
- Bradycardia
- Unstable angina
non-dihydropyridines - already on a beta blocker
131
What are the important side effects of calcium antagonists?
- Bradycardia
- Reflex tachycardia
- Hypotension
- Vasodilatory effects (flushing, headache, ankle swelling (diuretic unresponsive), palpitations) – due to sympathetic nervous system activation
- Constipation
- Heart failure (decreased LV function)
- Oedema
- Gingival hyperplasia
Verapamil:
- Constipation
- Risk of bradycardia
- Reduce myocardial contractility – negative inotrope – can worsen heart failure
Diltiazem:
- Risk of bradycardia
- Less negative inotropic effect than Verapamil – can worsen heart failure
132
What are the important interactions with calcium antagonists?
- Enhanced hypotensive effects with antihypertensive’s and alcohol
Non-dihydropyridines:
- Increased risk of AV block, bradycardia, severe hypotension and heart failure if verapamil or diltiazem are given with beta blockers
133
Name a cardiac glycoside
Digoxin
134
What class of drugs does digoxin belong to?
Cardiac glycoside
135
What is the mechanism of action of digoxin?
It inhibits the Na/K+ ATPase in the myocardium and thereby reduces extrusion of Ca2+.
This prolongs the phases 4 and 0 of the cardiac AP resulting in an increase in end diastolic filling and force of contraction (in accordance with the Frank-Starling law of the heart). (Weakly positive inotrope)
Indirectly slows conduction at the SA node and AV node and centrally stimulates the Vagus nerve, resulting in a negative chronotropic effect.
136
What are the indications for digoxin?
- Treatment to reduce ventricular rates in Atrial fibrillation and flutter
- Heart failure - reserved for symptomatic despite ACE inhibitor therapy
137
What are the contraindications for digoxin?
- Complete heart block and second degree heart block
- Tachycardia associated with WPW syndrome
- Ventricular tachycardia/ fibrillation
- Myocarditis/ constrictive pericarditis
- Hypertonic cardiomyopathy
138
What are the important side effects of digoxin?
```
Arrhythmia (especially SVT with AV block)
Nausea
Decreased appetite
Yellow vision
Confusion
Gynaecomastia
Toxicity
```
139
What is the management of suspected digoxin toxicity?
ECG —> reverse tick
Digoxin levels
Check electrolytes potassium, magnesium and calcium
```
If confirmed :
Stop digoxin
Correct electrolyte imbalances
Treat arrhythmias
Consider IV DigiFab
```
140
How does age affect dose of digoxin?
Use lower dose int he elderly as more subject to toxicity
141
How is digoxin monitored?
Measure plasma levels of digoxin >6h after dose
Monitor serum electrolytes and renal function
Risk of toxicity increased if : low potassium, low magnesium or high calcium
Monitor plasma digoxin if in renal failure
142
What is an alternative name for sodium channel blockers?
Class I anti-arrythmics
143
Name some sodium channel blockers
Ia- Procainamide, quinidine, disopyramide
Ib - Lidocaine, mexiletine
Ic - Flecainide, propafenone
144
What are the indications for sodium channel blockers?
Procainamide - Acute IV treatment of supraventricular and ventricular arrhythmias
Quinidine - Maintains sinus rhythms in atrial fibrillation and flutter and to prevent recurrence
- Brugada syndrome – can prevent sudden cardiac death in these patients.
Lidocaine and mexiletine - Ventricular tachycardia (esp. during ischaemia)
Not used in atrial arrhythmias or AV junctional arrhythmias.
Flecainide and propafenone - AF cardioversion in patients without contraindications, arrhythmia prophylaxis in patients with WPW (in combination) or troublesome paroxysmal AF , premature ventricular contractions
145
What is the mechanism of action of type Ia sodium channel blockers?
Class 1 drugs restrict the rapid inflow of sodium through open or inactive (use dependence) voltage-sensitive sodium channels during the phase 0 and thus slow the maximum rate of depolarisation. Enables them to block cells that are discharging at an abnormally high frequency without interfering with the normal, low frequency beating of the heart
Class IA lengthen the Action potential duration and refractoriness.
Effects on Cardiac Activity:
- Reduces conduction (slows influx of Na in phase 0 of the action potential)
- Increase in the refractory period (inhibit potassium channels, block calcium channels and increase Na inactivation)
- Reduction in automaticity (reduction in spontaneous depolarisation in phase 4, fast potentials)
- Increase in threshold (Na+)
Effects on the ECG:
- Increase QRS
- +PR
- Increase QT
Quinidine - mild a-adrenergic blocking and anti-cholinergic actions
Procainamide - has less anti-cholinergic activity, no a-adrenergic blocking actions
Disopyramide - has more anti-cholinergic activity, no a-adrenergic blocking actions, greater negative inotropic effect, causes peripheral vasoconstriction - decrease in Myocardial contractility in systolic HF patients
146
What is the mechanism of action of class Ib sodium channel blockers?
Sodium channel blockage with shortened refractoriness.
Effect on cardiac activity:
- Fast binding offset kinetics (rapidly associate and dissociate) - effects manifested when depolarised or firing rapidly
- No change in Phase 0 in normal tissue (no tonic block)
- shorten phase 3 repolarisation and decrease the duration of the action potential
- ADP slightly decreased (normal tissue)
- Increased threshold (Na+)
- Reduction in Phase 0 conduction in fast beating or ischaemic tissue
Effects on ECG:
- None in normal, in fast beating or ischaemia, increase in QRS
147
What is the mechanism of action of class Ic sodium channel blockers?
Slowly dissociate from resting sodium channels and show prominent effects even at normal heart rates - safety?
suppresses phase 0 upstroke in Purkinje and myocardial fibres - causes marked slowing of conduction in all cardiac tissue - minor effect on duration of action potential and refractoriness
Increases in the threshold potential - automaticity reduced
Flecainide - Blocks potassium channels leading to increased action potential duration
Propafenone - doesnt block potassium channels - doesnt increase action potential direction as much as flecainide
Effects on ECG:
- Increased PR
- Increased QRS
- Increased QT
148
What are the contraindications for class Ia anti-arrhythmias (sodium channel blockers)?
Quinidine and disopyramide should not be used alone for AF or flutter due to enhanced AV conduction and heart rate may increase (anti cholinergic )
149
What are the side effects of class Ia anti-arrhythmias (sodium channel blockers)?
Disopyramide ADR:
The antimuscarinic activity is often a significant clinical problem causing dry mouth, blurred vision, glaucoma, micturition hesitancy and retention. Gastrointestinal symptoms, rash and agranulocytosis can also occur. Effects on the cardiovascular system include hypotension and heart failure (negative inotropic effect).
Side effects:
- Hypotension, (IV procainamide)
- reduced cardiac output
– Proarrhythmia (generation of a new arrhythmias e.g. Torsades de Points (increased QT interval)
- Dizziness, confusion insomnia, seizure
- Gastrointestinal effects (common)
- Lupus-like syndrome (esp procainamide)
- symptoms of cinchonism (quinidine)
150
What are the important interactions of class Ia antiarrhythmics (sodium channel blockers)?
Quinidine - inhibitor of CYP2D6 and P-glycoprotein
Quinidine and disopyramide should be used with caution with potent inhibitors of CYP3A4
Other drugs that can also cause QT prolongation
151
What are the monitoring requirements for class IA antiarrhythmics (sodium channel blockers)?
Disopyramide- monitor in breast feeding - infant for anti cholinergic/muscarinic effects
Monitor patient parameters - potassium levels, hypotension, hypoglycaemia, VT, VF, torsades de pointes
152
What are the contraindications for class Ib antiarrhythmics (sodium channel blockers)?
```
IV:
All grades of AV block
Severe myocardial depression
SA disorders
Caution with mexiletine and inhibitors of CYP2D6
```
Local:
Application to middle ear (ototoxicity)
Injection into infected/ inflamed/ damaged tissue
153
What are the important side effects of class Ib antiarrhythmics (sodium channel blockers)?
Side effects:
- Less proarrhythmic than Class 1A (less QT effect)
- Wide therapeutic index (lidocaine), mexiletine has narrow therapeutic index - caution with inhibitors of CYP2D6
- Little impairment of LV function
- no negative inotropic effect
- CNS effects: dizziness, drowsiness, nystagmus (toxicity), slurred speech, parenthesis, agitation, confusion, convulsions
- Abdominal upset, nausea, vomiting, dyspepsia - common
154
What are the monitoring requirements for class Ib antiarrhythmics (sodium channel blockers)?
ECG and have resuscitation kit available
155
What are the important interactions with class Ib antiarrhythmics (sodium channel blockers)?
Mexiletine with CYP2D6 inhibitors
| Beta blockers with lidocaine ?
156
What are the contraindications for class Ic antiarrhythmics (sodium channel blockers)?
Flecainide should not be used alone in atrial flutter:
- Give AV nodal blocking drugs to reduce ventricular rates in flutter
Abnormal LV function, atrial conduction defects, BBB, distal block, valvular heart disease, heart failure, history of MI and asymptomatic ventricular ectopic or asymptomatic ventricular tachycardias, long standing atrial fibrillation (cardioversion not attempted), second degree or greater AV block, sinus node dysfunction
Propafenone - asthma
157
What are the side effects of class Ic antiarrhythmics (sodium channel blockers)?
- Proarrythmia and sudden death especially with chronic use and in structural heart disease increases ventricular response to supraventricular arrhythmias
- CNS and gastrointestinal effects like other local anaesthetics
- oedema
- propafenone - bronchospasm
158
What are the important interactions with class Ic antiarrhythmics (sodium channel blockers)?
Beta blockers
Other drugs that prolong the QT interval
Caution when used with inhibitors of CYP2D6
159
What are the monitoring criteria for class Ic antiarrhythmics (sodium channel blockers)?
ECG and resuscitation facilities available
160
What class of antiarrhythmic drugs does amiodarone belong to?
Class III
161
Name some class III antiarrhythmic drugs?
Amiodarone
Dronedarone
Sotalol
162
What is the mechanism of action of class III antiarrhythmic drugs?
```
Shows class I, II, III and IV actions as well as blocking alpha activity
Dominant effect is prolongation of action potential duration and the refractory period by blocking K+ channels
Sotalol also has potent nonselective beta blocker activity
```
163
What are the indications for class III antiarrhythmic drugs?
Wide range of tachyarrythmias
| CPR when defibrillation doesnt work
164
What are the contraindications for the use of class III antiarrhythmics ?
Amiodarone : Sinus bradycardia, thyroid dysfunction, iodine sensitivity, sinus node disease, SA block (except in cardiac arrest), severe conduction disturbances,
IV in circulatory collapse, severe respiratory failure, severe arterial hypotension
Dronedarone - symptomatic heart failure or permanent atrial fibrillation
Sotalol - asthma
165
What are the important side effects of class III antiarrhythmics ?
Amiodarone :
- Many serious that increase with time!
- Pulmonary fibrosis
- Hepatic injury
- Increase LDL cholesterol
- Thyroid disease
- Photosensitivity
- Optic neuritis (transient blindness)
Sotalol :
- Proarrhytmia
- Fatigue
- Insomnia
- bronchospasm
Dronedarone:
-hepatic injury
166
What are the important interactions with class III antiarrhythmics?
Other drugs that prolong QT
Inhibitors of CYP3A4
Inhibits CYP1A2, CYP2C9, CYP2D6 and P-glycoprotein
167
What is the monitoring requirement of class III antiarrhythmics ?
Amiodarone :
Thyroid function tests before treatment and every 6 months
Liver function tests before treatment and every 6 months
Serum potassium concentration before treatment
Chest x ray before treatment
IV:
ECG and resus available
Monitor LFTs carefully
sotalol:
Lung function (patients with obstructive airway disease)
Measurement of QTc and monitoring of ECG and electrolytes
168
What class of drugs does adenosine belong to?
Class V antiarrythmic
169
What is the mechanism of action of adenosine?
Naturally occurring purine nucleoside
At high doses deceases the conduction velocity, prolongs the refractory period and decreases automaticity in the AV node —>often high degree of AV block
Binds A1 receptors and activates K+ currents in AV and SV node, reducing ADP
Hyperpolarisation = decrease in heart rate
Dilates coronary and peripheral arteries
It is rapidly metabolised by circulating adenosine deaminase and is also taken up by erythrocytes and endothelial cells; hence its residence in plasma is brief ( t ½ < 2 s) and its duration of action is approximately 10-15 seconds - it must be given rapidly intravenously.
170
What are the indications for adenosine?
Drug of choice for abolishing acute SVT including reentrant (WPW)
Used to aid diagnosis of broad or narrow tachycardias (if atria continue to go at fast pace whilst the ventricles are slowed following adenosine, demonstrated by multiple p waves occurring before a qrs occurs —> shows atrial tachycardia, fibrillation or flutter depending on regularity)
Used with MPS scan in patients who cannot exercise or where exercise is inappropriate
171
What are the contraindications for adenosine?
Asthma, COPD
Decompensated heart failure, long QT, second or third degree heart block, sick sinus syndrome or severe hypotension
WPW
172
What are the important side effects associated with adenosine?
Flushing
Chest pain/angina
Hypotension
AV block, sinus pause, arrhythmia (bradycardia, asystole)
173
What are the monitoring requirements for adenosine ?
ECG
| Resuscitation facilities available
174
What cardiovascular use does magnesium sulfate have?
Used to treat acute severe arrhythmias (torsades de pointes and digoxin-induced)
175
What are the side effects of magnesium sulfate?
```
CNS (confusion, dizziness)
Hypermagnesaemia
Arrhythmias
Hypotension
GI (vomiting)
```
176
Name some angiotensin II receptor blockers
Losartan
Irbesartan
Valsartan
Candesartan
177
What is the mechanism of action of ARBs?
Acts as an antagonist at angiotensin (type 1) receptors. Prevent activation by angiotensin II. This prevents the angiotensin 2-mediated effects (arteriolar constriction and aldosterone release)
Produce arteriolar and venous dilation
Block aldosterone secretion
resulting in reduced afterload and reduced circulating volume, thereby reducing BP.
178
What are the indications for ARBs?
- Hypertension (first line treatment)
- Heart failure
- Diabetic nephropathy in type 2 diabetes
- LVH
179
What are the contraindications for ARBs?
- Pregnancy
- Renal artery stenosis
- Caution in peripheral vascular disease
180
What are the important side effects associated with ARBs?
- Renal failure
- Hypotension
- Hyperkalaemia
- Angioedema
181
What are the important interactions with ARBs?
- Risk of profound first dose hypotension with loop diuretics and enhanced hypotensive effect with other hypotensive agents
- Increased risk of renal impairment with NSAIDs
- Enhanced hypoglycamic effect of insulin, metformin and sulfonylurease
- Effects are antagonised by corticosteroids
182
What are the monitoring requirements for ARBs?
Monitor plasma potassium especially in elderly and renal impaired
183
What are the important interactions with adenosine?
Effect decreased by aminophylline
| Effect increased by dipyridamole
184
What is an alternative name for HMG CoA reductase inhibitors?
Statins
185
Name some statins
```
Lovastatin
Simvastatin
Pravastatin
Atorvastatin
Fluvastatin
Pitavastatin
Rosuvastatin
```
186
What is the mechanism of action of statins?
Competitive inhibitors of HMG CoA reductase (rate limiting step in cholesterol synthesis) - preventing the hepatic conversion of mevalonic acid to cholesterol.
Deplete the intracellular supply of cholesterol
Causes the cell to increases the number of LDL receptors on its surface
These bind and internalise circulating LDLs
Therefore both decreases cholesterol synthesis and increases LDL catabolism
Also decrease triglyceride levels and may increase HDL cholesterol levels in some patients
187
What are the indications for statins?
Lower cholesterol levels in primary hypercholesterolaemia or mixed hyperlipidaemia patients, Homozygous familial hypercholesterolaemia (Familial hypercholesterolaemia lack LDL receptors - benefit less )where other measures such as diet has not worked
Prevention of cardiovascular events in patients with atherosclerotic disease or diabetes mellitus
Some secondary benefits to statin treatment:
- Anti-inflammatory
- Plaque reduction
- Improved endothelial cell function
- Reduced thrombotic risk
188
What are the contraindications for statins?
Liver dysfunction
| Pregnancy and breast feeding
189
What are the important side effects of statins?
```
Myopathy and rhabdomyolysis (particularly if have renal insufficiency or are taking fibrates, nicotinic acid or erythromycin)
Interstitial lung disease
Hepatitis
GI disturbances
Hyperglycaemia
```
190
What are some important interactions with statins?
Erythromycin, fibrates and niacin - increased risk of myopathy and rhabdomyolysis
May increase the effect of warfarin
191
What are the monitoring requirements for statins?
Full lipid profile and thyroid function before starting treatment
LFTs before treatment, 3 months in and 12 months in
INR if on warfarin
Creatine kinase ( before treatment)
Diabetes - Fasted blood glucose Hb1aC before starting treatment and 3 months in
192
What is nicotinic acid also known as?
Niacin
193
What is the mechanism of action of niacin?
Strongly inhibits lipolysis in adipose tissue —-> reducing production of free fatty acids —> reduced triglyceride synthesis and VLDL production and therefore reduced LDL-C plasma concentrations (at gram doses)
Increases HDL-C plasma concentrations at high doses
194
What are the indications for niacin?
Useful in the treatment of familial hyperlipidaemias
And other severe hypercholesterolaemias often in combination with other agents
Can be used alone if statin not tolerated
195
What are the contraindications for niacin?
Hepatic disease/ unexplained LFT elevations (risk of hepatotoxicity)
Active peptic ulcer disease
Arterial bleeding
196
What are the important side effects of niacin?
```
Intense cutaneous flush (with uncomfortable feeling of warmth)
Pruritus
GI (nausea, abdominal pain)
Hyperuricaemia and gout
Hyperglycaemia
Hepatotoxicity
Activation of peptic ulcer
```
197
What are the monitoring requirements for niacin?
Monitor LFTs with hepatic impairment
198
Name some fibrates
Fenofibrate
Gemfibrozil
Bezafibrate
199
What is the mechanism of action of fibrates?
Activates peroxisome proliferator activated receptors
These bind to peroxisome proliferator response elements
This increases the expression of lipoprotein lipase and decreases apolipoprotein C2 concentration
Promotes breakdown of VLDL and chylomicrons and uptake of triglycerides into adipose etc. Causing decreased triglyceride concentrations
Fenofibrate is more effective than gemfibrozil at this
Also increase the levels of HDL cholesterol by increasing the expression of apo A1 and apo A2
10-20% reduction in LDL depending on specific drug
200
What are the indications for fibrates?
Mixed hyperlipidaemia: - as adjunct to diet and to statins if HDL and triglycerides not controlled, at high cardiovascular risk
- or as adjunct to diet and other appropriate measures if intolerant of statins or statins contraindicated
Severe hypertriglyceridaemia: - as adjunct to diet and other appropriate measures
201
What are the contraindications for fibrates?
Severe renal or hepatic dysfunction
| Preexisting gallbladder disease/primary biliary cirrhosis
202
What are the important side effects of fibrates?
Mild GI disturbances
Predispose to gallstone formation, increased risk of cholelithiasis
Myositis
Myopathy and rhabdomyolysis if taking gemfibrozil and statins together
203
What are the important interactions with fibrates?
Combined with statins - risk of myopathy and rhabdomyolysis
Enhanced INR with warfarin (potentiates its effect)
Increased risk of hypoglycaemia with diabetic medications
204
What are the monitoring requirements for fibrates?
Monitor transaminases every 3 months for 12 months following initiation
And periodically after this
Discontinue if greater than 3x upper limit of normal
Monitor serum creatinine during first 3 months and periodically thereafter - interrupt treatment if level is 50% above the upper limit of normal
205
Name some bile acid sequestrants
Cholestyramine
Colestipol
Colesevelam
206
What is the mechanism of action of bile acid sequestrants?
Bile acid sequestrants act by binding negatively charged bile acids in the small intestine
Preventing their reabsorption
This promotes hepatic conversion of cholesterol into bile acids (essential components of bile)
Therefore intracellular cholesterol concentrations decrease
The resultant up-regulation of LDL receptors on the surface of the liver cells increases the clearance of LDL-cholesterol from the plasma
Causes decreased plasma LDL-cholesterol levels
207
What are the indications for bile acid sequestrants?
Useful in combination with diet or niacin for treating Hyperlipidaemias (particularly type IIA and type IIB-unless homozygous) - or if not responded to diet/ other measures
Can relieve pruritus due to accumulation of bile acids in partial biliary obstruction and primary biliary cirrhosis
Primary prevention of CHD in men aged 35-59 with primary hypercholesterolaemia who have not responded to diet and other measures
Diarrhoea associated with crohn’s, ileal resection, vagotomy, diabetic vagal neuropathy and radiation
Accelerated elimination of teriflunomide/leflunomide
Colesevelam also indicated for Type 2 diabetes due to glucose lowering effects
208
What are the contraindications for bile acid sequestrants?
Biliary obstruction
Bowel obstruction
Hypertriglyceridaemia
209
What are the important side effects of bile acid sequestrants?
```
GI disturbances (constipation, nausea and flatulence)
Impaired absorption of fat soluble vitamins —> bleeding risk (low vitamin K)
May raise triglyceride levels —> hypertriglyceridaemia
```
210
What are the important interactions with bile acid sequestrants?
Take other drugs 1 hours before or 4-6 hours after bile acid sequestrants due to impaired absorption e.g. digoxin, warfarin and thyroxine
211
What are the monitoring requirements for bile acid sequestrants?
If taking colesevelam and ciclosporin - should have blood ciclosporin levels measured before during and after treatment with colesevelam
212
Name a cholesterol absorption inhibitor
Ezetimibe
213
What is the mechanism of action of cholesterol absorption inhibitors?
Selectively inhibit absorption of dietary and biliary cholesterol in the small intestine by blocking specific cholesterol transport protein NPC1L1 in the brush border.
Decreases amount of intestinal cholesterol reaching the liver
Reduced cholesterol stores in liver and therefore increased clearance from the blood
Lowers LDL by approximately 17%
Circulates enteroheptically reducing systemic exposure and delivering active agent back to site of action
214
What are the indications for cholesterol absorption inhibitors?
Adjunct to dietary measures and statin in primary and homozygous familial hypercholesterolaemia or if statin not tolerated/contraindicated
Adjunct to dietary measures in homozygous sitosterolaemia
215
What are the contraindications for cholesterol absorption inhibitors?
Moderate to severe hepatic insufficiency
216
What are the important side effects of cholesterol absorption inhibitors?
Fatigue
GI disturbance
Myalgia
Headache
217
What are the important interactions with cholesterol absorption inhibitors?
Increased risk of rhabdomyolysis when given with statin
Increased risk of gallstones when given with fibrates
Moderately increases exposure to ciclosporin and vice versa
218
Name some omega-3 fatty acids used for lowering triglycerides
Omacor
| Icosapent ethyl
219
What is the mechanism of action of omega-3 fatty acids?
Inhibit VLDL and triglyceride synthesis in the liver
220
What are the indications for prescribed omega-3 fatty acids (EPA only)
Difficult to get enough omega-3 from diet
Doesnt significantly raise LDL-C, unlike other fish oil supplements and dietary supply
Adjunct to other lipid lowering therapies for individuals with significantly elevated triglycerides (hypertriglyceridaemia)
Adjunct to secondary prevention in those who have had MI in the preceding 3 months
Not shown to reduce cardiovascular morbidity and mortality significantly
221
What are the important side effects from prescribed omega-3 fatty acids?
```
GI effects (abdo pain, nausea, diarrhoea)
Fishy aftertaste
```
222
What are the important interactions with prescribed omega-3 fatty acids?
Bleeding risk increased in those who are currently taking anticoagulants or antiplatelets
223
Name some tissue plasminogen activators
Alteplase
Reteplase
Tenecteplase
224
Name some thrombolytic agents
tPA:
Alteplase, reteplase, tenecteplase
Streptokinase
Urokinase
225
What is the mechanism of action of tPAs?
Rapidly activates plasminogen that is bound to fibrin in a thrombus or haemostatic plug (low doses - fibrin selective)
226
What are the indications for tPAs?
Alteplase - MI, massive PE and acute ischaemic stroke
Reteplase - acute MI, off-label in DVT and massive PE
Tenecteplase - acute MI
<12 hours after MI event is best
<3 hours after ischaemic stroke
227
What are the contraindications for tPAs?
Active pulmonary disease with cavitation
Acute pancreatitis
Coma, history of cerebrovascular disease
Aneurysm, aortic dissection, bacterial endocarditis, bleeding diatheses, coagulation defects, heavy vaginal bleeding, oesophageal varices, pericarditis, recent haemorrhage, recent surgery, recent symptoms of peptic ulcer, recent trauma, severe hypertension
Alteplase - convulsion accompanying stroke, history of stroke in patients with diabetes, hypo/hyperglycaemia, history of stroke in previous 3 months
228
What are some important side effects of tPAs?
Alteplase - orolingual angioedema (especially with ACE inhibitors)
Bleeding
Hypotension
229
What are the important interactions with tPAs?
ACE inhibitors - increased risk of angioedema
| Anticoagulants or antiplatelets - bleeding risk
230
What are the monitoring requirements for tPAs?
When used for ischaemic stroke - monitor for intracranial haemorrhage and monitor BP - consider antihypertensive if systolic >180 or diastolic >105
231
What is the mechanism of action of streptokinase?
Extracellular protein purified from culture broths of group C beta-haemolytic streptococci
Forms an active one-to-one Complex with plasminogen - enzymatically active - converts uncomplexed plasminogen to active plasmin
hydrolyses fibrin plugs but also catalyses fibrinogen and factor V and VII degradation (not specific to clots)
Rarely used
232
What are the indications for streptokinase ?
```
Acute MI
DVT
PE
Acute arterial thromboembolism
Central retinal venous or arterial thrombosis
```
233
What are the contraindications for streptokinase?
Active pulmonary disease with cavitation
Acute pancreatitis
Coma, history of cerebrovascular disease
Aneurysm, aortic dissection, bacterial endocarditis, bleeding diatheses, coagulation defects, heavy vaginal bleeding, oesophageal varices, pericarditis, recent haemorrhage, recent surgery, recent symptoms of peptic ulcer, recent trauma, severe hypertension
234
What are the important side effects associated with streptokinase?
allergic reactions and anaphylaxis
| Haemorrhage
235
What are the indications for tranexamic acid?
Fibrinolytic states (after GI surgery or prostatectomy etc.)
Menorrhagia
Hereditary angioedema
Epistaxis
Prevention and treatment of significant haemorrhage following trauma
236
What are the contraindications for tranexamic acid?
DIC
History of convulsions
Thromboembolic disease
237
What is the mechanism of action of tranexamic acid?
Competitively inhibits the activation of plasminogen to plasmin
At much higher concentrations it is a non competitive inhibitor of plasmin
Therefore prevents fibrinolysis
238
What are the important side effects of tranexamic acid?
```
diarrhoea
Nausea
Vomiting
Thrombosis
CVA
Seizure
Muscle necrosis
```
239
What are the monitoring requirements for tranexamic acid?
FBC
Muscle enzymes
Blood pressure
LFTs in hereditary angioedema
240
What is the mechanism of action of protamine sulfate?
Positively charged
Interacts with negatively charged heparin
Forms stable complex which has no anticoagulant activity
241
What are the contraindications for protamine sulfate?
Allergy to protamine
242
What are the potential side effects of protamine sulfate?
Excessive doses can have anticoagulant effect - rebound bleeding
Hypersensitivity, angioedema, anaphylaxis, flushing
Bradycardia, dyspnoea, hypertension, hypotension
Nausea and vomiting
243
What are the monitoring requirements for protamine sulfate?
Monitor blood clotting tests such as activated partial thromboplastin time
244
What are the indications for vitamin K ?
```
Major bleeding on warfarin
INR >8 with minor bleeding
INR 5-8 with minor bleeding
INR >8 no bleeding
Reversal of warfarin prior to emergency or elective surgery
```
245
How should vitamin K be administered in a bleeding patient?
Oral or IV
| SC is not as effective
246
Other than vitamin K what else should be given to a patient if immediate heamostasis is required?
Fresh frozen plasma
247
What are the important side effects of vitamin K?
Skin reactions
Anaphylaxis
(Should be given slowly IV to minimise risk of hypersensitivity )
248
What are the monitoring requirements for protamine sulfate?
Coagulation monitoring
BP
HR
249
What are the monitoring requirements for vitamin K?
PT/INR
250
Name a selective renin inhibitor
Aliskiren
251
What is the indication for aliskiren?
Hypertension
| Alone or in combination
252
What is the mechanism of action of aliskiren?
Directly inhibits renin
Aliskiren binds to a pocket on the renin molecule, blocking cleavage of the angiotensinogen to angiotensin 1. It reduces the plasma renin activity by 50-80%. Vasodilatory properties leading to BP reduction.
Lowers BP as effectively as ARBs, ACE i and thiazides
253
What are the contraindications for aliskiren?
Concomitant treatment with ACE i or ARBs in patients with eGFR <60 or with diabetes mellitus - risk of hyperkalaemia, hypotension and renal impairment
Hereditary angioedema, idiopathic angioedema
PREGNANCY
Caution in patients with salt or volume depletion, CHF, risk of renal impairment, history of angioedema, concomitant use of diuretics, ACEI orARBs (hypotension risk)
254
What are the important side effects of aliskiren?
```
Diarrhoea
Cough
Angioedema
Arthralgia
Dizziness
Hyperkalaemia
```
255
What are the monitoring requirements for aliskiren?
Plasma potassium concentration in renal impairment
| Monitor patients with history of angioedema carefully
256
What are some important interactions with aliskiren?
Metabolised by CYP3A4- subject to many drug interactions
257
Name some centrally acting adrenergic drugs (a2 agonists)
Clonidine
| Methyldopa
258
What is the indication for Clonidine?
Hypertension - if not responded to treatment with two or more drugs
Hypertension complicated by renal disease - does not decrease renal blood flow or GFR
Prevention of recurrent migraine
Prevention of vascular headache
Menopause - particularly vasomotor and flushing
259
What are the contraindications for Clonidine?
Severe bradyarrhythmia - due to 2nd or 3rd heart block or sick sinus syndrome
260
What are the important side effects of Clonidine?
Sedation
Dry mouth
Constipation
Rebound hypertension following abrupt withdrawal
261
What is the mechanism of action of clonidine?
Acts centrally as an a2 agonist to produce inhibition of sympathetic vasomotor centres in the brainstem, decreasing sympathetic outflow to the periphery and reducing total peripheral resistance and blood pressure
262
What are the monitoring requirements for clonidine?
Withdrawn slowly if discontinuation required
263
What is the mechanism of action of methyl dopa?
A2 agonist that is converted to methylnoradrenaline centrally and diminishes adrenergic outflow from the CNS —> reducing blood pressure
264
What are the indications for methyldopa?
Hypertension in pregnancy
265
What are the important side effects of methyl dopa?
Sedation and drowsiness
266
Name a carbonic anhydrase inhibitor
Acetazolamide
267
What is the mechanism of action of acetazolamide?
Inhibits carbonic anhydrase (catalyses CO2 + H2O —> H2CO3 —> H+ and HCO3-)
This enzyme is located intracellularly and on the apical membrane of the proximal tubular epithelium
Decreased ability to exchange Na+ for H+
Results in a mild diuresis
HCO3- is retained in the lumen - raises pH of urine - this loss of bicarbonate causes a hyperchloraemic metabolic acidosis and decreases diuretic efficacy following several days of therapy
Phosphate excretion is also increased by unknown mechanism
Reduces the formation of aqueous humour in the eye by around 50%
268
What are the indications for acetazolamide?
Reduction of intraocular pressure in patients with chronic open-angle glaucoma, or perioperatively in closed angle glaucoma
Epilepsy
Prevents mountain sickness
269
What are the contraindications for acetazolamide?
Adrenocortical insufficiency
Hyperchloraemic acidosis
Hypokalaemia
Hyponatraemia
Long term administration in open angle glaucoma
Hepatic cirrhosis - could lead to decreased excretion of NH4+
270
What are the important side effects of acetazolamide?
```
Metabolic acidosis
Potassium depletion
Renal stone formation
Drowsiness
Parenthesis
Ataxia
Depression
Diarrhoea
Dizziness
Excitement
Fatigue
Irritability
Flushing
Nausea
Headache
Thirst
```
271
What are the important interactions with acetazolamide?
High dose aspirin - risk of severe toxic reaction
| Lithium - alters the concentration
272
What are the monitoring requirements for acetazolamide?
FBC
Plasma electrolyte
With long term use
273
Name some prescribed osmotic diuretics
Mannitol
274
What are the indications for mannitol?
Cerebral oedema
Raised intraocular pressure
Add on therapy for cystic fibrosis
Maintaining ruin flow following acute toxic ingestion of substances capable of producing acute renal failure - saves the patient from dialysis
275
What is the mechanism of action of mannitol?
Filtered substances that undergo little or no reabsorption cause an increase in urinary output due to the higher osmolality of the tubular fluid preventing water reabsorption
Osmotic diuresis
Only small amount of salt is excreted - not useful for Na+ retention
276
What are contraindications for mannitol?
IV use - anuria, intracranial bleeding, severe cardiac failure, severe dehydration, severe pulmonary oedema
277
What are the important side effects of mannitol?
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Cough
Haemoptysis
Headache
Pharyngolaryngeal pain
Throat irritation
Vomiting
Wheezing
```
278
What are the monitoring requirements for mannitol?
Assess cardiac function before infusion
| Monitor fluid and electrolyte balance, serum osmolality, cardiac, pulmonary and renal function
279
Name some beta-adrenergic agonists
Dobutamine
| Dopamine
280
What is the mechanism of action of beta adrenergic agonists?
Improve cardiac performance by causing positive inotropic effects and vasodilation
Increase in intracellular cAMP
Activation of protein kinase
Phosphorylase slow calcium channels
Increasing calcium entry into myocardial cells and enhancing contraction
281
What are the indications for beta adrenergic agonists?
Cardiac stress testing
| Inotropic support in infarction, cardiac surgery, cardiomyopathies, septic shock, cardiogenic shock, acute heart failure
282
What are the contraindications for beta adrenergic agonists?
Phaeochromocytoma
283
What are the important side effects of beta adrenergic agonists?
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psychosis
Close angle glaucoma
AV block
Bradycardia
Cardiac arrest
Coronary artery spasm
Hypokalaemia
MI
Petechial bleeding
```
284
What are the important interactions with beta adrenergic agonists?
Beta blockers - risk of hypertension and bradycardia
285
What are the monitoring requirements for beta adrenergic agonists?
Serum potassium concentration
286
Name a phosphodiesterase inhibitor
Milrinone
287
What is the mechanism of action of phosphodiesterase inhibitors
Increases intracellular cAMP
| Increases intracellular calcium and therefore cardiac contractility
288
What are the indications for phosphodiesterase inhibitors?
Short term treatment of severe congestive heart failure unresponsive to treatment
Acute heart failure including low output state following surgery
289
What are the contraindications for phosphodiesterase inhibitors?
Severe hypovolaemia
290
What are the side effects of phosphodiesterase inhibitors?
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Ectopic beats
Hypotension
Headaches
Supraventricular arrhythmias
VT
```
291
What are the monitoring requirements for phosphodiesterase inhibitors?
BP, HR, ECG, central venous pressure, fluid and electrolyte status, renal function, platelet count, hepatic enzymes
292
What is the mechanism of action of ranolazine?
Inhibits the late phase of the sodium current
Improving oxygen supply and demand equation
Reduces intracellular sodium and calcium overload - thereby improving diastolic function
Antianginal as well as antiarrhythmic properties
293
What is the indication for ranolazine?
adjunctive therapy for stable angina not controlled by or intolerant of first line therapies
294
What are the important interactions with ranolazine?
Dont give with other drugs that can prolong the QT interval
| Drugs that interfere with CYP3A, CYP2D6 or P-glycoprotein
295
What are the important side effects of ranolazine?
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Prolonged QT
Asthenia (weakness)
Constipation
Dizziness
Headache
Nausea
Vomiting
```
296
What class of drugs does ranolazine belong to?
Sodium channel blocker
297
What class of drugs does ivabradine belong to?
SA node funny current blocker
298
What is the mechanism of action of ivabradine?
Specifically inhibit the If channel at the SA node
Delay depolarisation and sinus node activation
Slows heart rate without significantly affecting BP
Decreases myocardial oxygen consumption and improving diastolic perfusion time to enhance supply
299
What are the indications for ivabradine?
Angina
HF
Off license in autonomic tachycardia syndromes
300
What are the contraindications for ivabradine?
```
Acute MI
Cardiogenic shock
Congenital QT syndrome
HR <70 for angina or <75 for HF
After cerebrovascular incident
Pacemaker patients
2nd or 3rd degree heart block
Severe hypotension
Sick sinus syndrome
Sinoatrial block
Unstable angina
Unstable or acute HF
Pregnancy
```
301
What are the important side effects of ivabradine?
```
AF
Blurred vision
Bradycardia
Dizziness
First degree Heart block
Headache
Phosphenes
Ventricular extrasystoles
Visual disturbances
```
302
What are the important interactions with ivabradine?
Calcium antagonists
| Other drugs that may prolong the QT
303
What are the monitoring requirements for ivabradine?
Monitor for AF
| Monitor for bradycardia especially after dose increase and discontinue if <50 bpm or continues despite dose reduction
304
What class does vernakalant belong to?
K+ channel blockers
305
What is the mechanism of action of vernakalant?
Mechanism:
- Blocks atrial specific K+ channels
Cardiac effects:
- Slows atrial conduction
- Increased potency with higher heart rates
306
What are the indications for vernakalant?
Converts recent onset AF to sinus rhythm
307
What are the important side effects of vernakalant?
Side effects:
- Hypotension
- AV block
- Sneezing and taste disturbances
308
What class of drugs does atropine belong to?
Muscarinic antagonist
309
What is the mechanism of action of atropine?
Blocks vagal activity to speed AV conduction and increase HR
310
What are the indications for atropine?
Bradycardia following excessive beta blocker use or MI
311
What are the contraindications for atropine?
```
GI obstruction
Intestinal atony
Myasthenia gravis
Paralytic ileus
Prostatic enlargement
Pyloric stenosis
Severe UC
Significant bladder outflow obstruction/urinary retention
Toxic megacolon
```
312
What are the important side effects of atropine?
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Constipation
Dilation of pupils with loss of accommodation
Dry mouth
Photophobia
Reduced bronchial secretion
Dry skin
Urinary retention
Blurred vision
Drowsiness
```
313
What class of drugs does nicorandil belong to?
K+ channel activator
314
What is the mechanism of action of nicorandil?
Potassium channel opener with additional nitrate effects at high doses
Both an arterial and venous dilator
Activation of potassium channels leads to hyperpolarisation of smooth muscle cells, decreasing intracellular calcium and followed by arterial dilation and afterload reduction
Decreases preload by increasing amount of blood in capacitance vessels
315
What are the indications for nicorandil?
Prophylaxis and treatment of stable angina (2nd line)
316
What are the contraindications for nicorandil?
Acute pulmonary oedema, cardiogenic shock, hypovolaemia, LVF with low filling pressures, severe hypotension
317
What are the important side effects of nicorandil?
```
Cutaneous vasodilation with flushing
Dizziness
Headache
Increase in HR
Nausea
Rectal bleeding
Vomiting
Weakness
```
318
What are the important interactions with nicorandil?
Thought to increase the risk of GI perforation when given with NSAIDs, steroids and others
319
What is the mechanism of action of heparin?
Uses its unique pentasaccharide sequence to bind to antithrombin III
Antithrombin III is usually involved in the inactivation of clotting factors II and X
But heparin causes a conformational change and catalyses the process - speeds up the process
UFH accelerates interaction with both thrombin and Factor Xa where as LMWH only accelerates the interaction with Fator Xa
320
What is the mechanism of action of bivalirudin?
Selective direct thrombin inhibitors that reversibly inhibit the catalytic site of both free and clot-bound thrombin
321
What is the mechanism of action of fondaparinux?
Selectively inhibits only factor Xa
| Binds to antithrombin III and potentiates the inhibition of Factor Xa by 300-1000 fold
322
What is the disadvantage of fondaparinux ?
No available agent for reversal of bleeding
323
What is the mechanism of action of dabigatran?
An oral direct thrombin inhibitor - both clot-bound and free thrombin
324
What is the mechanism of action of rivaroxaban and apixaban?
Oral inhibitors of Factor Xa - bind to the active site preventing its ability to convert prothrombin to thrombin
325
What is the mechanism of action of warfarin?
Factors II, VII, IX and X require vitamin K as a cofactor for posttranslational modification (carboxylating the glutamic acid residues - in order to bind calcium - essential for interaction between clotting factors and platelets) during synthesis by the liver
The resultant reduced vitamin K is converted to vitamin K epoxide
Vitamin k epoxide reductase - the enzyme that is inhibited by warfarin - usually regenerates vitamin K from vitamin K epoxide
Warfarin therefore results in clotting factors with diminished activity (10-40% of normal)
Not immediate effect
72-96 hrs (unlike heparin )
326
What is the mechanism of action of thiazide diuretics?
Act mainly in the DCT to decrease reabsorption of Na+
Inhibit Na/Cl cotransporter on the luminal membrane of the tubules
Increase the concentration of Na+ and Cl- in the tubular fluid
Have to reach the tubular lumen to be effective - decreased renal function makes them less effective
Causes diuresis of hyperosmlar urine
Causes loss of potassium
Loss of magnesium
Decrease loss of calcium
Initial reduction in BP due to decreased blood volume and therefore decreased CO
Somehow induce vasodilation of arterioles - unknown mechanism
327
What is the mechanism of action of loop diuretics
Inhibit the cotransport of Na/K/2Cl in the luminal membrane of the ascending limb of loop of henle
Greatest diuretics effect since ascending limb accounts for reabsorption of 25-30% of filtered NaCl and downstream sites are unable to compensate for the increase Na+ load in the tubular fluid
Increased Na+, K+ and Ca2+ loss as well as diuresis - however hypocalcaemia does not normally result as calcium is reabsorbed in the DCT
May increase renal blood flow by enhancing prostaglandin synthesis
328
What is the mechanism of action of spiranolactone and eplerenone?
Spiranolactone is a synthetic steroid that antagonises aldosterone at intracellular receptor sites rendering the spironolactone receptor complex inactive - prevents translocation of this complex into the nucleus of the target cell, ultimately resulting in a failure to produce mediator proteins that normally stimulate the Na/K exchange sites of the collecting tubule
Prevents Na+ reabsorption and therefore K+ and H+ secretion
Eplerenone has actions comparable but less endocrine effects
329
What is the mechanism of action of amiloride and triamterene?
Block Na+ transport channels (ENaC) in collecting tubule
| Resulting in decreased Na/K exchange - does not depend on aldosterone
330
What is the mechanism of action of ACE inhibitors?
Block angiotensin converting enzyme
PRevent the cleavage of angiotensin I to angiotensin II
Also diminish the inactivation of bradykinin (vasodilator- increases NO and prostacyclin production )
Indirectly reduce aldosterone levels
Lower BP by reducing peripheral vascular resistance without reflexively increasing CO, HR or contractility
Decrease afterload and preload by decreasing vascular resistance and venous tone,
also reduce the retention of Na and H2O (low aldosterone)
Also blunt the aldosterone and adrenaline increase seen in HF
331
What is the mechanism of action of beta blockers?
Reduce blood pressure primarily by reducing CO
Can also decrease sympathetic outflow from the CNS and inhibit the release of renin from the kidneys - decreasing angiotensin II and aldosterone
Can have selective or non selective (both b1 and 2)
332
What are the monitoring requirements for ACE inhibitors ?
```
Potassium levels
Serum creatinine (particularly if underlying renal disease)
```
