15a – Cardiovascular Pharmacology Flashcards
Hemodynamic considerations for heart failure: preload
-pressure form venous system
o Needs to be sufficient to fill R. and L. side of heart
o *need a MINIMUM
o Don’t want too much=excessive amount of blood (stretch too much and weaken muscles)
Hemodynamic considerations for heart failure: afterload
-pressure in arteries
o If too constricted=more difficult to generate enough pressure to push the blood forwards
o Want to try and reduce it so blood can be pushed out with reduced workload
2 types of cardiomyopathy
- Hypertrophic cardiomyopathy
- Dilated cardiomyopathy
Hypertrophic cardiomyopathy
- Most common form of heart failure in CATS
- *lots of muscle that can generate lots of FORCE but volume in chamber is smaller and walls can be STIFFER (lower preload)
- *want to try and relax the muscle
Dilated cardiomyopathy
- Most common form of heart failure in DOGS
- Certain breeds predisposed (ex. Boxers)
- Cats develop it if diet low in taurine (not seen often anymore)
- Grain-free diets? (no genetic component)
- *Sarcomeres are added in series=large ventricle that is thinner=can not generate as much FORCE
o NEED TO MAKE IT GENERATE MORE FORCE
Cardiac insufficiency/failure due to
- Reduced SV or CO secondary to other reasons
- Abnormal rates (bradycardia, tachycardia)
What are reasons that SV or CO may be reduced? (causing cardiac failure)
- Reduced preload (hypovolemia, hypertrophic cardiomyopathy or pericardial effusion)
- Impaired contractility (dilated cardiomyopathy)
- Increased afterload (severe hypertension, aorta/pulmonic stenosis)
- Inadequate valve function
What is something that can cause bradycardia?
- Third degree AV block
o Excitations not going through - *decreased HR=CO can’t be high enough
What are some things that can cause tachycardia?
- Atrial fibrillation
- Ventricular tachycardia
- *no longer ADAPTIVE: even though increased HR, getting decreased SV and CO will be decreased
Heart failure symptoms: chronic
- Cardiomegaly
- R. vs. L. ventricular failure
- *failure on one side eventually leads to failure on OTHER SIDE
- Arrhythmias (especially tachycardia): risk of SUDDEN death
L. ventricular failure symptoms
- Blood accumulates in lungs
- Pulmonary edema
- Poor peripheral perfusion
R. ventricular failure symptoms
- Leads to edema in venous side
- Subcutaneous edema
- Ascites (make them have a lower appetite: cachexia)
- Hepatojugular reflex
Consequences, complications and compensations in heart failure: IN THE HEART
- Decrease contractility or reduced SV=insufficient CO
o Decrease BP=decrease baroreceptor activity (less stretch)=increase sympathetic activity (decrease PS stimulation)
Consequences, complications and compensations in heart failure: increased S leads to
o Vasoconstriction=increase TPR=increased afterload=more work heart needs to do
*makes situation worse (normally would fix BP in an acute response)
o Increases HR and contractility
*makes situation worse)
o Increase ADH=increase blood volume=venous pressure=return to ventricles (OVERFILLING: forcing it to work harder!)
Consequences, complications and compensations in heart failure: decreased renal blood flow
o Increase renin (S stimulation also contributes)=activation of RAAS cascade
Vasoconstrict=increase afterload
Increased ADH
*increased aldosterone: retain more Na and expand blood volume=even more into the failing heart to work more
If too high HR
- Tachycardia
- Can’t fill enough during diastole
- Handled better in dilated vs. hypertrophic cardiomyopathy
What are some positive inotropic agents?
- Pimobendan (‘inodilator’)
- Digoxin
- Dobutamine
Pimobendan (‘inodilator’)
- Phosphodiesterase inhibitor (relative of Viagra)
- Positive inotrope (increase contractility) and arterial VASODILATOR
- May enhance sensitivity of cardiac contractile proteins to calcium
- Induces ‘well-being’ and INCREASES appetite
- **Shown to increase survival in dogs with DCM or mitral valve insufficiency (double or triple)
Pimobendan actions in heart (cardiomyocyte)
- Accumulation of cAMP=increase sensitivity of contractile elements to Ca2+
- *mimics beta-1 adrenergic receptor like effect in all cardiomyocytes
Pimobendan actions in vascular smooth muscle (arteriol size)
- Accumulation of cAMP(cGMP)=vasodilation=reduce peripheral resistance=decreased afterload
- *Decreases work that the heart needs to do to get a good SV
Digoxin
- Digitalis glycosides isolated from FOXGLOVE
- Inhibits Na/K ATPase (want PARTIAL INHIBITION)
- Positive inotropic effect
- Negative chronotropic (decrease HR) and dromotropic (decrease speed on conduction) effect
- *one of most highly TOXIC drugs used clinically
- Secondarily: leads to increased peripheral tissue perfusion (Ex. increased renal output)
Digoxin actions on cardiomyocytes
- Inhibits Na/K pump=increased Na inside
- Excess Na removed by Na/Ca exchanger=working harder=more Ca inside
- *Ca-induced Ca release=more Ca=enhanced contraction
- SECONDARY EFFECT OF INCREAED CALCIUM
Na/K pump role in cardiomyocytes
- Maintain resting membrane potential
- *can NOT inhibit them all
o Why digoxin can be toxic
Digoxin actions in conductor cells and Purkinje fibers
- Decrease conduction velocity
- Increased refractory period
o Take longer to ‘reset’ resting membrane potential (Na/K pumps) - *more difficult to spread excitation
Digoxin actions on baroreceptor reflex
- Enhanced sensitivity to stretch=decrease sympathetic activation
o GOOD: no overactivation of sympathetic in heart failure
Digoxin vs. Pimobendan
- Cheaper, but does NOT
o Improve appetite
o Increase survival - “reduces effects’
Other good effects of Digoxin
- Increased PS tone
- Decreased S tone (baroreceptor: sense increased stretch more easily)
Side effects of Digoxin
- Death
- Anorexia (CNS effects)
- Vomiting and diarrhea
- AV block or ventricular arrhythmias
- *Hypokalemia can precipitate arrhythmias
- **follow up after putting an animal on it
Hypokalemia and arrhythmias even in absence of Digoxin
- no K to exchange for Na in the cell=’inhibiting/reducing’ Na/K pump ability to function
What blocks Digoxin effects?
- Hyperkalemia
o K is ‘forced’ into cells=more Na can be exchanged than normal
o *would take a lot more Digoxin to overcome the force - *NEED a balance of K in the body (hypo- and hyper- kalemia are NOT great)
Dobutamine (or Dopamine)
- Beta1 and beta2 agonist
- Emergency use only:
o ARRHYTHMOGENIC=more likely to get an arrhythmia
o Get heart working well enough to get blood around (also then give diuretics to get rid of edema) - Exerts positive inotropic actions via beta1-adrenergic receptor AGONIST action
Dobutamine effects on cardiomyocyte
- Increase beta1 adrenergic receptor response=increase cAMP=increase
- *if use dopamine=increase renal blood flow as well
When are beta-blockers useful in heart failure?
- Chronic treatment of hypertrophic cardiomyopathy
- *both in HCM and CM due to INHIBITION of beta1 stimulated renin release
o Prevent RAAS and expansion of blood volume=reduces preload - Ex. used in cats
Why are beta-blockers useful in chronic treatment of HCM?
- Positive inotropes generally contraindicated
- Often HR so high and heart wall so rigid that diastolic filling is IMPAIRED
- *blocks effects of compensatory overactivation of heart by SNS
o Try and reduce HR: allow more filling in diastole
What beta-blockers are preferable and what is an example?
- Beta1 selective antagonists
- Ex. metoprolol (particularly in asthmatic patients)
What is an example of a mixed beta1 and alpha1 antagonist?
- Carvedilol
- Alpha1 inhibition=reduces afterload=better for heart to function and provide adequate CO
- HCM and DCM
- *increasingly being used
When do you use Digoxin?
- Heart failure
- Atrial fibrillation
Digoxin for atrial fibrillation
- Impairs ability of resting membrane to recover
- *profound affect to block AV node
What are 2 main types of vasodilators?
- ACE inhibitors
- Angiotensin type 1 receptor antagonists
ACE inhibitors
- Enalapril, benazepril, or imidipril
- *prevent formation of Ang II from Ang I by inhibiting angiotensin converting enzyme (ACE)
Angiotensin type 1 receptor (ARBs) antagonists
- Valsartan or telmisartan
- Block Ang II actions!
Both ACE inhibitors and AT1 receptor blockers
- Cause vasodilation: reduce venous and arterial pressure, therefore edema
- Prevent aldosterone release: decrease fluid retention/edema
*when get rid of edema=alleviate distress syndromes=improves quality of life
Enalapril (ACE inhibitor)
- show to significantly decrease clinical symptoms
- extend survival time by 92% in dogs
RAAS system: different drug actions
- stop the whole pathway=beta-adrenergic receptor antagonists in kidneys
- ARBs: prevent Ang II actions (no aldosterone or vasoconstriction)
- ACE: prevent getting Ang II and also break down of bradykinin (leads to more vasodilation)
Side effect of ACE inhibitors (humans for sure, maybe dogs+cats?)
- Tickle cough can develop within first few weeks
- *due to increased Bradykinin
- Animals: need to distinguish between cough they get from heart failure (PRODUCTIVE COUGH: removing fluid from lungs) OR if sudden (NON-PRODUCTIVE COUGH)
What are some other vasodilators that can be used for acute treatment and/or in severe cases?
- Nitroglycerin
- Sodium nitroprusside
- *both are broken down into NO! (NO dilates all vasculature)
Nitroglycerin
- Venodilator
Sodium nitroprusside
- Arteriolar and venodilator
What are some other vasodilators that are older (but cheap)?
- Alpha-blockers: proazosin (mainly arteriolar, some venodilation)
- Direct acting arteriolar dilators: hydralazine (veno and arteriolar dilator)
o Decrease Ca=decrease contraction
All vasodilators (except the main ones) may cause (LONG TERM)
- Excessive hypotension
- Reflex tachycardia
- Activation of RAAS system
*worsen situation
Nitro-vasodilators
- Have what could become an NO groups
- *rapidly metabolized in vascular space to free NO!
o NO bypasses endothelium and goes into vascular smooth muscle=increase cGMP=vasodilation - *especially venodilation!
Nitroprusside caution!
- Also has cyanide!
o Over a certain amount of time can limit ability to use it - *don’t be afraid of it: just don’t use long term (no more than a couple days!)
Example: if taken a drug (ex. Sildenafil or Viagra) that inhibits phosphodiesterase, and take a nitro-vasodilator
- *massive vasodilation effects! (coming from 2 streams!)
Diuretics in heart failure therapy
- Treatment of pulmonary edema
*want to get ride of excessive fluid, but NOT dehydrate the animal
When using diuretics in heart failure therapy beware of
- excessive diuresis leading to EXCESSIVE LOSS OF VENOUS RETURN
- HYPOkalemia potentiating digoxin action
