Cardiovascular Modulators

Question 1

Cardiac disease is fundamentally a problem w/ blood flow…

Answer 1

• Not enough getting INTO the heart.
  – e.g. hypertrophic cardiomyopathy.
• Not enough being pumped OUT of the heart.
  – e.g. DCM, mitral regurgitation.
• Note: not enough IN inevitable means not enough OUT.
• Results in decreased CO.

Question 2

Compensatory mechanisms for cardiac disease.

Answer 2

Activation of sympathetic nervous system.
- B1 receptors – tachycardia, contractility.
- a1 receptors – vasoconstriction (afterload).
Renin-Angiotensin-Aldosterone System (RAAS).
- Na+, water retention, increased blood volume – preload.
- Vasoconstriction – afterload.
- Vasopressin (ADH) – afterload and preload.
- Remodelling – contractility.

Question 3

Congestive heart failure results…

Answer 3

Increased preload and afterload and decreased contractility lead to increased atrial pressures.
- LA: increased pulmonary vein pressure&raquo_space; pulmonary oedema.
- RA: increased systemic venous pressure&raquo_space; pleural effusion and ascites.

Question 4

Goals of CHF therapy and how achieved.

Answer 4

Decrease preload:
- Diuretics.
- Venodilators.
Improve contractility:
- Positive inotropes.
Decrease afterload:
- Arteriodilators.
Address maladaptive compensatory mechanisms:
- RAAS modulators.
Note: many drugs have more than one effect.

Question 5

1. Loop diuretics and their admin routes.
2. Thiazide diuretic and admin route.
3. Potassium sparing diuretics and routes.
4. Site of action for Furosemide and torasemide.
5. Site of action of the thiazide diuretics.
6. Site of action of the potassium sparing diuretics.

Answer 5

1. Furosemide - IV, IM, SQ, PO.
   Torasemide - PO.
2. Hydrochlorothiazide - PO.
3. Mineralocorticoid (Aldosterone) receptor antagonists - Spironolactone, eplerenone – PO.
   Renal epithelial Na+ channel inhibitors.
   - Amiloride – PO.
4. Ascending thick limb of loop of Henle.
5. Distal convoluted tubule.
6. Right at the end.

Question 6

Sodium reabsorption % along the nephron.

Answer 6

60% at proximal tubule.
34% at thick ascending loop of Henle.
6% at distal tubule.

Question 7

1. What do the loop diuretics do?
2. Result of this.

Answer 7

1. • Block Na+-K+- 2Cl- symport in thick ascending loop of Henle.
     - Inhibit reabsorption of ~25% of filtered sodium load.
2. Distal nephron segments cannot resorb additional solute so get marked natriuresis and diuresis

Question 8

Net effect of loop diuretics.

Answer 8

• Loss of Na+ K+ Cl- Ca2+ Mg2+ and H+ with water.
• Hyponatraemia and extracellular volume depletion (intravascular and interstitial).
• Hypokalaemia (most common).
• Hypochloraemic alkalosis.
• Hypocalcaemia and hypomagnesaemia.

Question 9

Indications for loop diuretics.

Answer 9

CHF.
- use IV in emergency.
- use orally once stabilised.
Hypercalcaemia.
Hyperkalaemia.
AKI.
Exercise induced pulmonary haemorrhage
Udder oedema.

Question 10

1. What is the most important drug to use to stabilise a patient on CHF?
2. Venous effect of furosemide?
3. Effect of furosemide.
4. Important considerations when administering furosemide.

Answer 10

1. Furosemide.
2. Venodilation - also helps decrease preload.
3. Mobilises oedema, prevents ongoing Na/water retention, reduces preload.
   Causes RAAS activation.
4. Monitor RR for normalisation (reducing oedema) and allow patient free access to water – risk AKI.

Question 11

Furosemide pharmacology.

Answer 11

• Active secretion into tubular lumen.
  – if not in lumen, not working.
• ~50-60% excreted unchanged in urine.
• IV admin:
  – peak effect 30mins.
  – duration of action 2-3hrs.
• Oral admin:
  – peak effect 1-2hrs.
  – duration of action 6hrs.

Question 12

Torasemide pharmacology.

Answer 12

Can only be given orally.
Longer half life (8hrs), duration of action (12hrs) and more potent.
Blocks mineralocorticoid receptor.
- Anti-aldosterone effect.
If refractory to standard therapy.
Monitor electrolytes and kidney function.
- due to potency.

Question 13

Adverse effects of loop diuretics.

Answer 13

Relate to fluid and electrolyte balance particularly:
- Hyponatraemia and extracellular volume depletion.
- Hypokalaemia.
- Hypochloraemic alkalosis.
- Hypocalcaemia and hypomagnesaemia.
Ototoxicity in cats.
GIT disturbances.

Question 14

Managing adverse effects of loop diuretics.

Answer 14

• Regular monitoring of electrolytes and renal function.
• Consider use of potassium sparing diuretics.
• Adequate dietary intake of potassium.
• Avoid drugs that potentiate risks.

Question 15

Thiazide diuretics pharmacology.

Answer 15

Act in DCT on Na+-Cl- symport.
Secondary active transport.
Increase delivery of Na+ to distal tubule.
Moderate diuretics effect.
Peak effect at 4hrs, duration of action 12hrs.

Question 16

1. Side effects of thiazide diuretics.
2. Monitoring when prescribing thiazide diuretics.

Answer 16

1. • Hypokalaemia.
     - Hypercalcaemia.
     - Azotaemia.
2. • Electrolytes.
     - Renal function.

Question 17

1. On what receptor do potassium-sparing diuretics act? Normal action of this receptor?
2. How is this receptor affected by potassium-sparing diuretics?

Answer 17

1. Mineralocorticoid receptor.
   - Aldosterone binds to receptor in cytoplasm.
   - Hormone-receptor complex moves into nucleus.
   - Target DNA sequence.
   - Aldosterone-induced proteins produced.
2. Antagonises it.
   - Competitively blocks Na+/K+/ATPase exchanger.

Question 18

1. Give example of potassium-sparing diuretic.
2. Level of diuretic effect of this drug.
3. Time of peak effect of this drug.
4. Time of steady state reached.
5. How does it work in a cardiological way?

Answer 18

1. Spironolactone.
2. Weak - only when RAAS activated.
3. 2-4hrs.
4. Day 2.
5. Acts on myocardium and vasculature to inhibit aldosterone-mediated fibrosis and remodelling (evidence weak).

Question 19

Indications for spironolactone.

Answer 19

CHF (PO).
- Used in combination w/ loop or thiazide diuretics.
- Protective effects (anti-remodelling).
Hyperaldosteronism.
Hepatic disease.

Question 20

Spironolactone pharmacology.

Answer 20

• No secretion into renal tubule required to exert effect.
• Oral formulation:
  – Spironolactone only –> Prilactone.
  – Spironolactone plus benazepril (ACEi)
  –> Cardalis.
• Use once daily.

Question 21

1. Spironolactone adverse effects.
2. Measures to be taken when administering spironolactone.

Answer 21

1. Hyperkalaemia (potassium sparing).
   Hyponatraemia and reduced ECF volume.
   Non-specific binding to other steroid hormone receptors.
   Facial dermatitis (maine coons).
2. Careful monitoring of potassium levels.
   Avoid in hyperkalaemic or hyponatraemic patients.

Question 22

1. What do potassium sparing diuretics do?
2. Most commonly used potassium sparing diuretic used in vet med?

Answer 22

1. Inhibit renal epithelial Na+ channel.
   - Mild increase in excretion NaCl.
   - Retention of K+.
2. Amiloride PO.
   - formulated w/ hydrochlorothiazide (Moduretic).

Question 23

1. Amiloride indications.
2. Amiloride adverse effects.
3. Monitoring for Amiloride administration.
4. Onset of action and duration of action of Amiloride?

Answer 23

1. CHF.
2. Hyperkalaemia.
   - May be exacerbated by ACE inhibitors.
3. Monitor electrolytes (esp. potassium). and renal function.
4. Onset 2hrs, duration 24hrs (humans).

Question 24

Mechanisms of diuretic resistance.

Answer 24

Impaired absorption.
Increased Na+ absorption.
Tubular hypertrophy.
RAAS activation.
**generally have to start at low dose and increase as time goes on, to a point where the dose increases do not have an effect.

Question 25

Therapeutic strategies for diuretic resistance.

Answer 25

Furosemide.
- Increase dose.
- SC, IV.
Torasemide - more potent.
Sequential nephron blockade.
- Hydrochlorothiazide.
- Spironolactone / Amiloride.
Monitor kidney function!

Question 26

Diuretic drugs – other uses – carbonic anhydrase inhibitors.

Answer 26

• Acetazolamide (PO), dorzolamide (topical).
  – Glaucoma.
  – Onset of action 30mins, peak effect 5hrs, duration of action 7hrs.
  – Adverse effects = metabolic acidosis, hypokalaemia.
  – Monitor electrolytes and acid-base balance (cause acidosis by messing w/ hydrogen transport across the tubule).

Question 27

Diuretic drugs – other uses – osmotic diuretics.

Answer 27

Mannitol (IV).
- Increased intracranial pressure.
- Increases osmolarity of blood and renal filtrate.
– draws fluid from tissues (e.g. brain and kidney).
- Onset of action 30-60mins, peak effect 1hr, duration of action 6-8hrs.
- Adverse effects – dehydration, electrolyte imbalances.
- Action in proximal convoluted tubule.

Question 28

Positive inotropic drugs – Pimobendan e.g. Vetmedin…
1. Route of admin.
2. Indications.
3. Mechanisms of action.
4. PO peak effect.
5. Adverse effects.
6. Onset of action.

Answer 28

1. PO, IV.
2. Heart disease (preclinical mitral valve disease and DCM) and CHF.
3. Sensitises troponin to CA2+.
   - positive inotrope.
   Phosphodiesterase 3 inhibitor (cAMP).
   - systemic vasodilation.
4. 2-4hrs.
5. GIT disturbances (often flavoured).
6. 30-60mins.

Question 29

Positive inotropic drugs – Dobutamine…
1. Route of admin.
2. Indications.
3. Mech of action.
4. Monitoring and why?

Answer 29

1. IV.
   - Continuous rate infusion (CRI) – max 72hrs.
   –> plasma half life v short (2mins).
2. Severe CHF w/ hypotension (i.e. ICU).
3. Beta adrenergic agonist (B1>B2>a). Potently increases contractility.
   Increases SV, BP, pulse strength, tissue perfusion.
4. Monitor ECG – increase HR and can provoke arrhythmias.

Question 30

Renin-angiotensin-aldosterone-system modulators…
1. Angiotensin converting enzyme (ACE) inhibitors (list).
2. Aldosterone inhibitors.

Answer 30

1. Anything ending in “pril”.
   - Benazepril.
   - Enalapril.
   - Ramipril.
   (inhibit conversion of angiotensin 1 to angiotensin 2).
2. Spironolactone – blocks release of aldosterone from the adrenal glands.

Question 31

1. What do ACE inhibitors do?
2. Monitoring while administering ACE inhibitors.
3. ACE inhibitor peak effect PO.
4. ACE inhibitor DOA.
5. ACE inhibitor adverse effects.

Answer 31

1. Reduce Na+ and water retention.
   Vasodilation. - reduces pre- and afterload.
   Anti-remodelling.
   Anti-adrenergic.
   Decrease BP.
2. Monitor electrolytes and kidney function and BP.
3. 2hrs.
4. 30hrs.
5. Azotaemia.
   Hyperkalaemia.
   Hypotension.

Question 32

Vasodilators…
1. Indication.
2. What do venodilators do?
3. What do arteriodilators do?

Answer 32

1. Severe CHF.
2. Reduce preload.
3. Reduce afterload.

Question 33

Vasodilators – Nitroglycerine ointment…
1. Route of admin.
2. Action.
Vasodilators – Sodium nitroprusside…
3. Route of admin.
4. Action.
5. DOA.
6. Considerations when administering.
7. What if given for more than a couple of days in people?

Answer 33

1. Topical.
2. Venodilation.
   Converted to nitric oxide in circulation.
3. IV - CRI.
4. Dilates veins and arterioles (decrease pre- AND afterload), converted to nitric oxide in the circulation.
5. 1-10mins.
6. Sensitive to light so need to wrap up giving set to protect from light.
7. Accumulation of cyanide as a metabolite (short term solution).

Question 34

Vasodilators – Hydralazine…
1. Route admin.
2. Action.
3. PO peak effect.
4. PO DoA.

Answer 34

1. PO, IV CRI.
2. Dilates arterioles via direct effect on vascular smooth muscle.
3. 3-5hrs.
4. 11-13hrs.

Question 35

Vasodilators – Phosphodiesterase inhibitors…
1. Route of admin.
2. List some and which they inhibit.
3. Monitoring for vasodilator administration.

Answer 35

1. PO, IV.
2. Pimobendan inhibits phosphodiesterase 3 (breaks down cAMP which is important in systemic vasculature).
   Sildenafil inhibits phosphodiesterase 5 (breaks down cyclic GMP which is important in pulmonary vasculature).
3. Monitor BP.

Question 36

Other drugs used in heart disease.

Answer 36

Sympatholytics – beta blockers.
Pulmonary arteriodilators.
Antiarrhythmics.

Question 37

1. Most commonly used beta blocker used in vet med.
2. Route of admin?
3. Action?
4. Peak effect?
5. Indications.

Answer 37

1. Atenolol.
2. Oral.
3. Blocks cardiac B1-adrenergic receptors.
   Reduces HR and contractility.
   Reduces inappropriate tachycardia and arrhythmias.
   Prolongs diastole, improving coronary perfusion.
4. 3hrs.
5. Obstruction of ventricular outflow e.g. severe aortic stenosis, hypertrophic obstructive cardiomyopathy.

Question 38

Atenolol and the patient.

Answer 38

May reduce clinical signs (e.g. syncope).
No evidence of improvement of quatity of life, only quality of life.
Do not use in heart failure.
- Monitor HR and RR.

Question 39

1. Pulmonary arteriodilators indication?
2. Drug example.
3. Action.
4. Peak effect.
5. Monitoring?

Answer 39

1. Pulmonary hypertension due to left sided filling pressures or primary respiratory disease.
2. Sildenafil (Viagra).
3. Inhibits phosphodiesterase 5 (cGMP).
4. 30-120mins.
5. BP.

Question 40

Emergency CHF therapy approach.

Answer 40

Minimise stress.
- Consider mild sedation (e.g. butorphanol).
O2.
Furosemide (IV/IM).
Positive inotropes:
- Pimobendan (PO if safe to swallow).
- Dobutamine IV CRI (hypotension) (severe).
Vasodilation:
- Nitrates / hydralazine.

Question 41

Chronic CHF therapy approach.

Answer 41

• Furosemide PO.
• Pimobendan PO.
• ACEi PO.
• Spironolactone PO.
  – Cardalis –> benezapril + spironolactone.