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ED Primary Exam > Week 11 Pharmacology - Angina, HTN, Anticoagulation > Flashcards

Week 11 Pharmacology - Angina, HTN, Anticoagulation Flashcards

1
Q

What are the two factors in the development of angina?

A

Decreased 02 supply
Increased O2 demand

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2
Q

What classes of medications are useful in the treatment of angina?

A

Nitrates
Beta-blockers
Calcium channel blockers

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3
Q

What is the mechanism of action of nitrates?

A

Nitrates when absorbed into venous and coronary artery smooth muscle cells, metabolised into NO, which actives Guanylate Cyclase –> cGMP –> PKG –> inhibits myosin light chain phosphatase and inhibit smooth muscle contraction

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4
Q

Why are nitrates helpful in treating anginal chest pain? How can they help cardiac perfusion?

A

Cause venodilation, leading to decreased pre-load and decreased SV, therefore decreased O2 demand. Vasodilatory effect on coronary arteries –> increased perfusion

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5
Q

What is the pharmacokinetics of nitrates?

A

A: Poor absorption, high first pass metabolism, therefore given SL/topically/IV
D: Highly lipid soluble, 220L Vd, t/12 2-8 mins
M: Hepatic (hydrolysis)
E: renal excretion of glucuronide metabolites

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6
Q

What are contraindications to nitrates?

A

Raised ICP
Right ventricular/inferior MI
Hypovolaemia
HOCM

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7
Q

What is tachyphylaxis in relation to nitrates?

A

Tolerance to nitrates develop with repeated use, if on regularly requires a ‘holiday’ period free from nitrates to prevent tachyphylaxis

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8
Q

What are the two major classifications of calcium channel blockers?

A

Dihydropyridine (amlodipine and nifedipine) and non-dihydropyridine CCB (verapamil, diltiazem)

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9
Q

How are CCB helpful in treating angina?

A

↓contractility - ↓O2 requirement
↓arteriolar tone - ↓TPR - ↓arterial and intravent pressure
↓ coronary artery spasm
Verap/dilt: ↓HR - ↓O2 demand (SA/AV nodes Ca dependent, slow response cells – most affected by verap>dilt>dihydro’s)

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10
Q

What are the major differences between dihydropyridines and non dihydropyridines?

A
  1. DHP act on receptor site removed from that of dilt/verapamil on L-type calcium channels
  2. Dihydropyridines are smooth muscle vascular selective (i.e. no cardiac calcium channel activity)
  3. Dihydros will cause reflex tachycardia (whereas verapamil will cause a bradycardia)
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11
Q

What is the PK of amlodipine?

A

A: well absorbed, 60% PO availability
D: Protein bound, T1/2 30-50 hours
M: Hepatic metabolism
E: Renal excretion of inactivated metabolites, 20-25% also in bile

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12
Q

What is mechanism of hydralazine?

A

Acts through the release of nitric oxide from endothelial cells (and then functions in much the same was as nitrates in that regard)

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13
Q

What is the mechanism by which Prazosin acts as an anti-hypertensive agent?

A

Selective alpha 1 receptor antagonism, acting only peripherally to prevent constriction of arterioles –> decreased TPR

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14
Q

What is the general mechanism of action of beta blockers?

A

Prevention of binding to beta adrenergic receptors, a GPCR which causes increased cAMP via adenylyl cyclase –> increased Ca2+ conductance. Reduction of HR and contractility –> negativity inotropy and chronotropy –> decreased output and therefore BP.

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15
Q

What is the general PK of beta blockers?

A

PK: Well absorbed, low bioavailability, large Vd, most metabolized by liver.

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16
Q

What are common examples of B1 selective beta blockers?

A

Metoprolol
Nebivolol
Atenolol
Bisoprolol
Esmolol

17
Q

What are common examples of non selective beta blockers?

A

Propranolol
Carvedilol
Labetalol
Sotalol

18
Q

What 3 beta blockers are approved for the use in heart failure patients?

A

Metoprolol
Bisoprolol
Carvedilol

19
Q

PK and toxicology of propranolol:

A

Non selective B-blocker with Na+ channel blockade effects
Rapidly absorbed orally, Wide Vd, hepatic clearance, peak concentration 1-3 hours post ingestion
Elimination: 95-100% of an ingested dose is excreted in the urine as metabolites and their conjugates.

Toxic effects mainly via cardiac and CNS effects:
CARDIAC: negative inotrope and chronotrope, Sodium-channel blockade in the myocardium leads to prolongation of the cardiac action potential with resultant QRS widening and potential for ventricular arrhythmias.
CNS: Blockade of sodium channels in the CNS produces neurotoxic effects, i.e. seizures and coma.

20
Q

What is the mechanism of action of ACEi?

A
  1. Dilate arteries and veins by blocking angiotensin II formation and inhibiting bradykinin metabolism. This vasodilation reduces arterial pressure, preload and afterload on the heart.
  2. Down regulate sympathetic adrenergic activity by blocking the facilitating effects of angiotensin II on sympathetic nerve release and reuptake of norepinephrine.
  3. Promote renal excretion of sodium and water (natriuretic and diuretic effects) by blocking the effects of angiotensin II in the kidney, blocking angiotensin II stimulation of aldosterone secretion, and by blocking angiotensin II stimulated ADH release. These actions blood volume, venous pressure and arterial pressure

**ACE inhibitors antagonise this enzyme to prevent/reduce the above effects

21
Q

What are the pharmacokinetics of ramipril?

A
22
Q

What is the brief outline of the arachidonic acid pathway?

A

Membrane phospholipids are converted into arachidonic acid by phospholipase A2 –> undergo enzymatic conversion by cyclo-oxygenase enzymes to cause production of prostaglandins and thromboxane

23
Q

What is the mechanism of action of aspirin?

A

Irreversible inhibition of COX-1 predominantly, causing decreased thromboxane A2 production in platelets, as well as inhibition of kallikrein system.

24
Q

What are the pharmacokinetics of aspirin?

A

A: Weak acid, therefore most absorption in stomach due to pH 3.5, able to cross membranes as unionised

D: Protein bound, Peak plasma level 1-2 hours

M: Rapid hydrolysis to acetic acid and salicylate by esterases in tissue and blood. Salicylate conjugated with glucuronide to form salicyuric acid. First order kinetics low doses, zero order higher doses.

E: Renal excreted, increased by alkalisation of urine (ionised, unable to be reabsorbed)

25
Q

What is the mechanism of clopidogrel? (as well as ticagrelor, prasugel)

A
  • Reduce platelet aggregation by inhibiting ADP pathway of platelets (thereby inhibiting interaction of platelets via GIIb/IIIa receptors
  • Irreversibly inhibits ADP P2Y12 receptor on platelets for life of platelet
  • Unlike aspirin, no effect on prostaglandin metabolism
26
Q

What are the PK of clopidogrel?

A

A: Prodrug, oral absorption

M: Hepatic metabolism to active and inactive metabolites
80% of platelet activity inhibited within five hours of loading dose of 300mg
Effects lasts for life of platelet, duration of anti-platelet effect 7-10 days

E: Following oral dose, 50% excreted in urine and 46% in faeces in next five days

27
Q

What is the mechanism of heparin?

A

Binds to and potentiates anti-thrombin III.

Antithrombin III (ATIII) normally inhibits clotting factor proteases, especially IIa (thrombin), IXa, and Xa, by forming stable complexes with them.

Heparin binds to and causes a conformational change of ATIII, exposing its active site for more rapid interaction with proteases and accelerating inhibition reactions 1000-fold –> exerting its anticoagulant effect

28
Q

What is the PK of heparin?

A

A: parental
D: small Vd, extensively protein bound, t1/2 40-90mins
M: Hepatic esterases
E: renal excreted

29
Q

What is the target of low molecular weight heparin (enoxaparin)?

A

Inhibits factor Xa directly

30
Q

What is the mechanism of warfarin?

A
  1. Blocks y-carboxylation of factors II (prothrombin), VII, IX, X, as well as endogenous proteins C and S, resulting in incomplete, inactive coagulation factor molecules
  2. Inhibits recycling of Vitamin K by blocking reduction of inactive Vitamin K to active form (Via K reductase inhibitor)
31
Q

What are the PK of warfarin?

A

A: 100% oral bioavailability
D: 99% bound to plasma proteins, Small volume of distribution
M: Hepatic metabolism
E: Small urinary excretion of unchanged drug
Half life 36 hours

32
Q

Why is there a delay in efficacy of warfarin as an anticoagulant?

A

Vit K reductase also responsible for formation of anti-coagulant factors C and S, so there will be a period of 8-12 hours where effect will be ‘cancelled out’

33
Q

What are the half lives of clotting factors and Protein C, and how does this affect INR over time (brief):

A

6, 24, 40, and 60 hours for factors VII, IX, X and II respectively
Protein C has a half life of 7 hours

34
Q

What is the mechanism of action of Dabigatran?

A

Competitive direct factor II (thrombin) inhibitor

35
Q

What is the pharmacokinetics of Dabigatran?

A

A – inactive pro-drug dabigatran etexilate with good oral absorption, peak anticoagulant effect occurs 1 -3 hours after ingestion
D – low binding to plasma proteins and a moderate volume of distribution
M – progrdug metabolised to dabigatran rapidly
E – renal excretion with half-life of ~12 hours (much higher if renal impairment: 28h if CrCl <30)

36
Q

What is the mechanism of action of rivaroxaban?

A

Factor Xa direct inhibitor

37
Q

What is the pharmacokinetics of rivaroxaban?

A

A: 80% oral bioavailability, peak 3 hrs plasma conc
D: Highly protein bound, low Vd
M: Some CYP3A4 metabolism
E: Majority unchanged renal excretion

38
Q

What is the mechanism of tranexamic acid?

A

Tranexamic acid is an analog of aminocaproic acid, a synthetic inhibitor of fibrinolysis which competitively inhibits plasminogen activation

ED Primary Exam (46 decks)

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