Heart Disease and Blood Pressure Flashcards
What does ACEi stand for? What does it do?
Angiotensin-converting enzyme inhibitors that disrupt the renin-angiotensin-aldosterone system (RAAS).
Which organs does angiotensin II act on and what is the outcome of its mechanism of action?
Converted from Angiotensin I by angiotensin-converting enzyme (ACE)
Angiotensin II is a hormone that binds to receptors in various tissues to exert various effects.
Acts on the adrenal cortex, causing it to release aldosterone.
stimulates vasoconstriction in systemic arterioles
Promotes sodium reabsorption in proximal convoluted tubules of the kidneys.
In the CNS:
It acts on the hypothalamus to stimulate thirst and encourage water intake
It induces the posterior pituitary to release antidiuretic hormone
It reduces the sensitivity of the baroreceptors’ response to increase blood pressure
What is the role of angiotensin-converting enzyme?
It converts Angiotensin I to angiotensin II.
What are some effects of angiotensin-converting enzyme inhibition (ACEi)?
decrease proteinuria
promote vasodilation and ventilation
reduce plasma volume
All of the above sums to decrease systolic blood pressure
ACEi can also decrease the metabolism of vasodilatory agent bradykinin resulting in decrease in vascular tone.
What is first line of treatment for systemic hypertension in dogs?
ACE inhibitors
What are two of the most common ACEi?
Enalapril and Benazepril
Is ACEi a recommended first line treatment for SHT in cats? Why?
ACEi is not a recommended fist line treatment for cats as it does not sufficiently nor consistently lower blood pressure.
Benazepril may be beneficial in conjunction with calcium channel blocker.
What is the concern with ACEi in patients who are dehydrated or azotemic?
There is potential to worsen glomerular filtration rate and renal function through preferential dilation of the efferent arteriole that would thereby decrease glomerular filtration pressure.
Overall risk is low unless the patient also being treated with diuretic therapy or the patient has severe azotemia.
Which electrolyte imbalance might ACEi administration contribute?
hyperkalemia secondary to inhibition of aldosterone. However, this is unlikely to be clinically relevant event when given in conjunction with aldosterone antagonist such as spironolactone.
What effects do angiotensin receptor blockers (ARBs) exert?
Blocks the ability of angiotensin II to activate its receptors.
It does not affect the metabolism of bradykinin.
What is a contraindication for angiotensin receptor blockers (ARBs)?
Do not use in severely dehydrated or azotemic patients
What class of drug is Spironolactone?
aldosterone antagonist
How do aldosterone antagonist exert their effects?
Block the effects of aldosterone on the distal convoluted tubule and collecting duct.
Aldosterone
It is a steroid hormone produced by the adrenal cortex when stimulated by Angiotensin II.
It helps control the balance of water and salts in the kidney by keeping sodium and releasing potassium from the body.
What are the effects of chronic exposure to aldosterone?
Induces vascular remodeling in the glomerulus to retain sodium and water resulting in systemic hypertension.
Aldosterone also exerts proinflammatory effects promoting fibrosis.
What is a primary indication for use of spironolactone?
Hyperaldosteronism
When is it reasonable to suspect hyperaldosteronism in cats?
hypertension
hypernatremia
hypokalemia
mostly in chronic kidney disease
What is a potential adverse effect of spironolactone?
development of hyperkalemia. However, this is unlikely unless used with ACEi, ARBs or Beta blocker
Dihydropyridines
Dihydropyridines are a type of calcium channel blocker (CCB) that block calcium channels located in the muscle cells of the heart and arterial blood vessels, thereby reducing the entry of calcium ions into the cells. By blocking these channels, CCBs promote:
vasodilation
increase strength in contractility
minimal effect on cardiac conduction though the decrease in blood pressure may trigger a reflex tachycardia.
E.g. Amlodipine and Nicardipine
What is first line treatment for antihypertensives in cats?
Amlodipine because it has shown to be more effective than ACEi.
If the cat is refractory to amlodipine, then it may require an addition of ACEi or ARB
Side effects of CCBs
Reflex tachycardia
weakness, lethargy and decrease in appetite
intrarenal hemodynamics –> CCB promotes preferential afferent arteriolar dilation over the efferent arteriole, which may result in increased intraglomerular pressure, resulting in damage to the glomerulus and worsening proteinuria.
Adrenergic Antagonist
It can help manage SHT, especially if the underlying mechanism is sympathetically driven.
Prazosin
Selective alpha 1 antagonist to promote smooth muscle vascular relaxation.
Acepromazine
Dopamine antagonist with the potential to cause hypotension and GI upset
Atenolol
Beta 1 selective antagonist
Decreases heart rate and contractility
Reduces renin release and peripheral vascular resistance
Used more in cats with SHT and hypethyroidism
Used in dogs as adjunct for refractory SHT with reflex tachycardia
Propanolol
Non-selective beta antagonist
Decreases heart rate and contractility
Reduces renin release and peripheral vascular resistance
What is an adverse side effect of atenolol
Excessive bradycardia
Labetalol
Injectable mix of alpha and beta antagonists.
Used to manage severe acute hypertension
promotes vasodilation and prevents associated tachycardia
The use has been explored in dogs undergoing craniotomy or adrenalectomy
Hydralazine
Promotes vasodilation by altering smooth muscle intracellular metabolism.
works primarily on arteries
Causes vasodilation, afterload reduction and lowering of blood pressure
The mechanism is not entirely understood but the end result is smooth muscle relaxation and decrease in peripheral vascular resistance.
It is not used as a first-line drug but used as an adjunct in chronic management.
Injectable form used in urgent/emergent treatment due to its potent vasodilatory effects, and rapid onset.
What are adverse side effects to hydralazine?
Arteriolar vasodilator
excessive or irreversible hypotension
reflex tachycardia
sodium and water retention
GI upset
Sodium nitroprusside (SNP)
Arteriolar vasodilator
promotes potent vasodilation through release of nitric oxide.
Nitric oxide diffuses to vascular smooth muscle
decrease influx of calcium, activation of actin/myosin chains and overall contractile forces
Effects: smooth muscle relaxation and decreased vascular tone and peripheral vascular resistance
The injectable form has a short half-life and is easy to titrate, so it is ideally used for hypertensive crises. Administer as CRI.
Used to treat acute hypertensive crises or fulminant CHF
Contraindicated in hypotensive patients
IV nitroglycerine
promotes potent vasodilation through release of nitric oxide.
Nitric oxide diffuses to vascular smooth muscle
decrease influx of calcium, activation of actin/myosin chains and overall contractile forces
Effects: smooth muscle relaxation and decreased vascular tone and peripheral vascular resistance
The injectable form has a short half-life and is easy to titrate, so it is ideally used for hypertensive crises.
No risk of cyanide poisoning
What are the adverse side effects associated with sodium nitroprusside?
generation of cyanide and thiocyanate at high doses and prolonged use.
Patients with kidney and liver disease have decreased metabolism, therefore greater risk of cyanide toxicity.
Clinical signs of toxicosis: metabolic acidosis, depression, stupor, seizures
Fenoldopam
Selective agonist of dopamine 1 receptor. Promotes peripheral and renal vasodilation and natriuresis
Increases glomerular filtration rate
Injectable has a short half life.
Good potential for application in hypertensive crisis, but needs further investigation in vet med.
Class 1 Antiarrhythmics
Sodium channel blockers
Interferes intracellularly with sodium conduction through sodium channels
Subclassification determined by potency of effects on sodium channel, activated/inactivated blockade and effects on other channel receptors.
Class 1A antiarrhythmic agents
Quinidine and procainamide
Effective against ventricular and supraventricular arrhythmias.
fast sodium channel blocking effects and moderate blockade of rapid component of the delayed rectifier potassium current resulting in action potential elongation.
Procainamide
Class 1 A antiarrhythmic
Sodium channel blocker
Depresses conduction velocity and prolongs refractory period in a variety of tissues, including atrial and ventricular myocardium
Administer slowly IV over 5-10 minutes to prevent hypotension
Adverse effects more commonly associated with cats and humans; include anorexia, nausea, and vomiting
Class IB Antiarrhythmic
Inhibits fast sodium channels, primarily in the open and inactivated state, with rapid onset.
Sodium current is also inhibited, resulting in the shortening of action potential in normal myocardial tissue
Lidocaine and mexiletine
Lidocaine
Class IB antiarrhythmic
Sodium channel blocker.
The ability of lidocaine to block sodium currents is better during acidosis.
Benefit: minimal hemodynamic, SA, AVN affect at standard doses
Hepatic clearance determines serum concentration
Heart failure, hypotension, and severe hepatic disease can decrease lidocaine metabolism and predispose patients to lidocaine toxicity.
Adverse effects: higher incidence in cats
Nausea, vomiting, lethargy, tremors, seizure activity (usually symptoms stop when lidocaine is discontinued)
Dosing: Bolus 2mg/kg over 20-30 seconds; bolus can be repeated up to 8mg/kg within 10 minute period barring adverse effects
CRI: 25-75mcg/kg/min
Mexiletine
Class 1B antiarrhythmic
most common oral class in dogs
Highly protein-bound and excreted by the kidneys
Use and adverse effects similar to Lidocaine (rarely used in cats because of adverse effects)
Tocainide
Class 1B antiarrhythmic
Similar to lidocaine, rarely used in small animals because of high incidence of serious adverse effects including renal failure and corneal dystrophy
Class 1C Antiarrhythmic
Potent blockade of the open state fast sodium channel with greater effects as the depolarization rate increases
These agents prolong the refractory period in atrial and ventricular tissues
Propafenone and Flecainide
Propafenone
Class 1C antiarrhythmic
used to treat narrow complex tachyarrhythmias
usually combined with diltiazem
also has mild beta blocking properties
Flecainide
Class 1C antiarrhythmic
potent negative inotropic properties
Side effects include GI, but not commonly seen
Rarely used in veterinary medicine
Monitor heart rate, blood pressure and ECG when administering
Class II antiarrhythmic
Beta-adrenergic antagonists or beta-blockers are the most used cardiovascular drugs.
Must be cognizant of animals’ underlying disease when prescribing.
Beta-blockers contraindicated in patients with evidence of sinus nodal dysfunction, AVN conduction disturbances, pulmonary disease or CHF (must be evaluated for fluid retention and condition must be stabilized before implementing beta-blockade).
Reduces heart rate and myocardial oxygen demand and increases atrioventricular conduction time.
Inhibits pacemaker current I(f) that promotes proarrhythmic depolarization in damaged cardiomyocytes
Inhibits calcium current by decreasing tissue cyclic adenosine monophosphate levels ; the magnitude of effects depends on the sympathetic state. Greater effect with higher adrenergic states
Beta-adrenergic antagonists slow AVN conduction in SVT by slowing sinus discharge rate in inappropriate sinus tachycardia and suppresses ventricular tachycardia that may be exacerbated by increased sympathetic tone.
Used to treat supraventricular and ventricular arrhythmias.
Also used in HCM to control heart rate and decrease myocardial oxygen demand
Can cause hypotension due to decreased heart output.
Extremely low dosages must be used with patients with systolic myocardial dysfunction. Because of that, beta blockers are not generally first choice for acute anti-arrhythmic therapy because the amount required is not well tolerated.
Propranolol
Non-selective beta receptor antagonist (targets both beta-1 and 2 receptors).
Function: decrease heart rate and contractility. Decrease renin release and peripheral vascular resistance
Esmolol
Class II Antiarrhythmic
Short-acting Beta-1 blocker that can help control sympathetically driving ventricular tachycardia . Administered as a CRI on telemetry.
Side effects: Negative inotropic effects may be too pronounced in some patients and cause cardiovascular collapse. Requires blood pressure monitoring.
Atenolol
Class II antiarrhythmic.
The most common oral beta blocker in small animals.
Relative beta 1 selectivity and long half-life compared to propranolol.
Water soluble and eliminated by the kidney.
Metoprolol
Class II antiarrhythmic.
Common oral beta blocker in small animals.
Long half-life compared to propranolol.
Metabolized and eliminated through the liver.
Class III Antiarrhythmic agents
Block the repolarization of I(k) resulting in prolongation of action potential durations and effective refractory period.
Blocks rapid component of I(k) instead of the slow component – therefore effects are accentuated at slower heart rates rather than at the problematic tachyarrhythmic rates.
Puts patients at risk of early afterdepolarization (accounts of proarrhythmic effects of class III AA drugs) - risk is increased in patients with hypokalemia, bradycardia, intact females, increasing age, macrolide antibiotic therapy/other drug therapies
Amiodarone
Class III Antiarrhythmic
Alpha and Beta blocking properties.
Effects on sodium, potassium, and calcium channels.
Broadest spectrum exhibiting properties of all 4 AA classes.
Makes action potential durations more uniform throughout the myocardium and has the least reported proarrhythmic activity of any of the class III agents.
Used for refractory tachyarrhythmias, both atrial and ventricular
Significant side effects in dogs, including hepatopathy and anaphylaxis.
Monitor heart rate, blood pressure and ECG with administer.
Available as oral or injectable.
Major drawback: associated with a host of multi-systemic adverse side effects that do not occur with sotalol.
Adverse side effects (more common with higher maintenance doses): vomiting, anorexia, hepatopathies, thrombocytopenia
Two brands:
Cardarone IV, Nextarone
Cardarone IV
IV formulation of amiodarone
Serious side effects attributed to vasoactive solvents in the formulation.
Side effects include life-threatening hypotension, anaphylaxis, bradycardia, acute hepatic necrosis, and death.
Nexterone
Premixed aqueous solution of IV amiodarone.
No adverse hemodynamic effects of other adverse cllinical effects in healthy research dogs.
Class IV antiarrhythmic agents
Calcium channel antagonist
Slow AVN conduction and prolong the effective refractory period of nodal tissue
Effects are more notable at faster stimulation rates and in depolarized fibers.
Effective in slowing the ventricular response rate to atrial tachyarrhythmias and can prolong AVN’s effective refractory period to terminate AVN-dependent tachyarrhythmia.
It is mainly indicated to reduce the rate of arrhythmias passing through the AV node, such as supraventricular arrhythmias.
Major negative inotropic effects due to interactions with calcium in the smooth muscles.
Causes vasodilation
Limit amount of calcium available in cardiac contractility.
Diltiazem is the most widely used IV antiarrhythmic drug
Diltiazem
Class IV antiarrhythmic
Calcium channel blocker.
Minimal negative inotropic effects.
Used in dogs to immediately terminate a severe AVN-dependent tachyarrhythmia or slow ventricular response rate to an atrial tachyarrhythmia.
Adverse side effects: hypotension and bradyarrhythmia.
Administer IV slowly over 2-3 minutes.
Oral diltiazem administered TID.
Digoxin
Class V anti-arrhythmic (other)
Effects occur indirectly through the autonomic nervous system by enhancing central and peripheral vagal tone.
Used as an antiarrhythmic due to its ability to slow AV conduction time and have parasympathomimetic effects
Treats SVT to slow AV nodal conduction and reduce ventricular rate
Positive inotrope that will increase cardiac contractility in systolic disease
The risk of toxicity manifests as neurological, GI, and cardiac involvement.
Predisposed to toxicity if the patient has renal dysfunction, hypokalemia, elderly, chronic lung disease, hypothyroidism.
Magnesium Sulfate
1st line treatment for torsades de pointes
Used to treat hypomagnesemia
Administer slowly IV @ 30mg/kg over 5-10 minutes
Adverse effects: CNS depress, weakness, bradycardia, hypotension, hypocalcemia and QT prolongation
Adenosine
Used in humans to terminate AVN dependent tachyarrhythmias.
No study to date has shown effectiveness in dogs and cats.
Antiarrhythmic devices/procedures
Transvenous radiofrequency catheter ablation
Permanent pacemaker implantation
Implantable cardioverter defibrillators
Transverse radiofrequency catheter ablation
Identify reentrant circuit or automatic focus for ablation
Deliver radiofrequency energy via electrode causing thermal desiccation of small volume tissue to interrupt tachycardia circuit
Permanent pacemaker implantation
Manage bradyarrhythmias
Implantable cardioverter defibrillators
experimental in dogs
Anticholinergics
class of drugs taht block the action of acetylcholine (ACh), a neurotransmitter that sends signals between cells that affect a bodily function.
By blocking ACh at synapses in the central and peripheral nervous system, anticholinergics inhibit the parasympathetic nervous system.
Atropine
Anticholinergic
inhibit acetylcholine at muscarinic receptors
Clinical effects include increasing heart rate, resolving vagally mediated bradycardia, decreasing GI motility, pupillary dilation, bronchodilation, urinary retention and drying or secretion
Most commonly used to treat vagal-mediated bradycardias and toxicities
Able to pass the placental barrier.
Glycopyrrolate
Anticholinergic
inhibit acetylcholine at muscarinic receptors
Clinical effects include increasing heart rate, resolving vagally mediated bradycardia, decreasing GI motility, pupillary dilation, bronchodilation, urinary retention and drying or secretion
Most commonly used to treat vagal-mediated bradycardias and toxicities
Glycopyrrolate is associated with more stable cardiovascular system with fewer arrhythmias
Glycopyrrolate has a stronger anti-saliva secretion effect than atropine
It does not pass the placental barrier and, therefore, is the agent of choice for pregnant animals.
Diuretics (7 classes)
Loop diuretics
Osmotic Diuretics
Potassium sparing diuretics
Thiazide diuretics
Carbonic anhydrase inhibitors
Aldosterone Antagonist
Aquaretics (new)
Goals for diuretic therapy
Enhanced excretion of retained water, solutes and toxins
Promote urine flow
decrease urine concentration of solutes and toxins
Common indications for diuretic use
Oligoanuric acute renal failure
decompensated kidney disease
Congestive heart failure
ascites from liver failure
other fluid and electrolyte disorders
When it is justified to use diuretics to treat edema?
Only when fluid retention is caused by an increase in hydrostatic pressure.
When vascular permeability is increased, further depletion of vascular volume with diuretics is rarely indicated and often detrimental
Adverse effect of exaggerated diuresis
May activate RAAS by reducing intravascular volume and ventricular filling and may subsequently decrease tissue perfusion.
Therefore, diuresis requires therapeutic monitoring
Pathologic conditions that contribute to diuresis
pressure natriuresis
osmotic diuresis
pressure natriuresis
A negative feedback in hypervolemic hypertensive states
Diuretics operating on which part of the nephron is most effective and why?
Diuretics at the loop of Henle are the most effective because of the large amount of filtrate delivered to this site and the lack of efficient distal reabsorption region.
What triggers an increase to antidiuretic production?
Elevated plasma osmolality
hypovolemia
hypotension
(lesser extent) nausea
increased concentration of angiotensin II
Osmotic diuresis
passive mechanism due to abnormal urine concentration of osmotically active solutes such as glucose and sodium
What is required for antidiuretic hormone to function?
functional renal tubular system
medullary concentration gradient of sodium and urea
functional ADH receptor system
without any one of these factors will result in inappropriate diuresis
What may affect function of diuretics that work on proximal tubule?
Diuretics that work on proximal tubule can modulate a greater bulk of sodium, but their efficacy may be overcome by distal compensatory increases in sodium reabsorption.
What may limit efficacy of diuretics operating on distal tubule?
Diuretics operating on distal tubule may be limited by small amount of sodium reaching distal tubule
Osmotic Diuretics
hyperosmolality causes water shift from the intracellular fluid compartment to extracellular space, causing ECF expansion
Used to contract ICF in cases with cerebral edema associated with an increase in ICF and elevated intracranial pressure
Contraindicated for patients in or at risk of heart failure.
Effective in patients with anuric or oliguric rental disease, cerebral edema and increased intraocular pressure
eg. Mannitol
Mannitol
osmotically active non reabsorbed sugar alcohol
filtered by the glomerulus; does not undergo tubular reabsorption, thereby increasing tubular flow rate and osmotic diuresis
An increase in tubular flow rate reduces urea absorption, resulting in increased urinary clearance and serum urea concentration.
Potential benefits of mannitol:
Prostaglandin-induced renal vasodilation
reduced tendency of erythrocytes to aggregate
reduced renal vascular congestion
reduced hypoxic cellular edema
protection of mitochondrial function
reduced oxidative damage
renoprotectant when administered before toxic or ischemic event
*No data supports above benefits in renal failure cases
At high doses, mannitol can cause renal vasoconstriction and tubular vacuolization
Use cautiously with oliguric animals to avoid volume overload, hyperosmolality and further renal damage.
Carbonic Anhydrase Inhibitors
Clinical application of carbonic anhydrase inhibitors - mainly used to treat elevated intraocular pressure in glaucoma.
Work by suppressing the activity of carbonic anhydrase, an enzyme in red blood cells that converts carbon dioxide into carbonic acid and bicarbonate ions. CAIs can reduce secretion of H+ ions by the kidney tubule and can also impair the reabsorption of sodium, chloride and bicarbonate.
eg. Acetazolamide
Carbonic anhydrase also located on other organs.
Blockade of ocular and brain CA decreases the production of aqueous humor and CSF.
Blockade of red blood cell CA hampers carbon dioxide transport
Gastric CA - minimally affected by inhibitors.
Acetazolamide
Carbonic anhydrase inhibitor
Function: diuretic
Inhibits mostly the type II (cytoplasmic) and IV(membrane) proximal tubular carbonic anhydrases, decreasing the reabsorption of sodium bicarbonate.
Results in metabolic acidosis and natriuresis - minimal and self-limiting because progressively less bicarbonate is filtered as the proximal tubule becomes less responsive to carbonic anhydrase inhibition and the distal sodium reabsorption increases to compensate for the proximal losses.
Loop Diuretics
Binds to and inhibits Na+-K+-2Cl- cotransporters on the apical membrane of epithelial cells of the thick ascending loop of Henle.
Inhibition of reabsorption of both Na and Cl, ions remain in the tubular lumen and
water follows, resulting in diuresis and increased Na secretion
○ High sodium concentration later in the nephron results in increased sodium and
potassium exchange, which leads to increased potassium secretion as well
○ Increased calcium secretion also occurs
○ Also believed to decrease renal vascular resistance and increase renal blood
flow
Prototypical loop diuretic: furosemide
Torsemide
Furosemide
Loop diuretic
Improves renal parenchymal oxygenation by decreasing the energy expenditure of the secondary active Na-K-2Cl transporter
Mannitol + furosemide > synergistic in inducing diuresis in dogs with acute renal failure
Relative short half-life: 1-1.5 hours in dogs > can result in intermittent rebound sodium retention with loss of efficacy.
most commonly used in patients in heart failure.
Torsemide
potent loop diuretic of pyridine-sulfonylurea class
longer half-life (8 hours)
higher bioavailability (80%-100%)
strong diuretic effect than furosemide
Large scale study - effective in dogs with mitral valve disease, but high rate of renal adverse events.
Additional benefits observed in other species: vasodilation, improved cardiac function, reduction of myocardial remodeling, mineralocorticoid-receptor blockade with anti-aldosterone effect - has not been shown in small animals
Thiazide diuretics
exert their action by inhibiting the NaCl cotransporter on distal tubule.
Mainly used for anticalciuretic properties to prevent calcium-containing uroliths
Managing CHF in conjunction with other diuretics
treating ascites associated with right-sided heart failure
also used for treating polyuria of diabetes insipidus by inducing a mild hypovolemia and increasing proximal sodium conservation.
eg. Hydrochlorothiazide
Aldosterone Antagonist
Antagonize aldosterone by binding to its receptor in the late distal tubule and the collecting duct
increases sodium, calcium and water excretion and decreases potassium loss
e.g. Spironolactone and eplerenone
When to suspect hyperaldosteronism
concurrent hypernatremia, severe hypokalemia
Spironolactone
Aldosterone antagonist
potassium sparing diuretic
Best used in cases of hyperaldosteronism
Main clinical applications in liver and heart failure.
Also used as an antihypertensive in hyperaldosteron cases.
Usually, it is in combination with a more efficient loop diuretic.
Also seems to have a positive effect on myocardial remodeling and the reduction of cardiac fibrosis
Commonly added to other diuretics to reduce their potassium-wasting effects
Main adverse effect: development of hyperkalemia
potassium-sparing diuretics
Inhibit sodium reabsorption in the distal tubule and the collecting duct; suppressing the driving force for potassium secretion.
Only weak diuretic and natriuretic properties
Mostly used to counterbalance potassium-wasting effects of proximal diuretics.
e.g. Amiloride and triamterene
Aquaretics
New class of diuretics that antagonize the vasopressin V2 receptor in the kidney and promote solute-free water clearance
Vaptans - vasopressin receptor antagonist
Clinical use: free water rention in hypervolemic hyponatremia or normovolemic hyponatremic
drugs: conivaptan, tolvaptan and mozavaptan
Not used in small animals
Pimobendan
Function: positive inotropic and vasodilatory effects
Phosphodiesterase III inhibitor
Calcium sensitization
Used to treat congestive heart failure
Mechanism of Pimobendan via calcium sensitization
increase contractility via increasing binding affinity to the regulatory site on troponin C for calcium
sensitizes the myocyte contractile apparatus to calcium without increasing the amount of calcium within the cell.
Pimobendan is not dependent on catecholamines
Mechanism of pimobendan via phosphodiesterase III inhibition
increase contractility by increasing intracellular calcium levels.
PDE III inhibition increases cyclic adenosine monophosphate (cAMP), which in turn increases cAMP-dependent protein kinase.
Increase in calcium sequestration during diastole and increase in calcium influx during systole - both contribute to positive inotropy
PDE III and PDE V are found in vascular smooth muscle. Inhibition of PDE III and PDE V increases intracellular cAMP and cGMP - which facilitates calcium update through intracellular storage sites. Results in reduction of available calcium for contraction > greater vascular smooth muscle relaxation.
Elimination of Pimobendan
undergoes hepatic demethylation
bioavailability and duration of affect of Pimobendan
Pimobendan is highly protein bound with greater than 90% bioavailability.
Maximal cardiac effects at 2-4 hours following oral administration and persists up to 8 hours.
Clinical use of pimobendan
FDA approved to treat CHF with myxomatous mitral valve degeneration or DCM
Adverse effects of pimobendan
generally well tolerated but may cause GI upset - inappetence, vomiting, diarrhea and lethargy
Anti-hypertensives (7 mechanisms of action)
Angiotensin-converting enzyme inhibitor
Angiotensin receptor blocker
aldosterone antagonist
calcium channel blocker
alpha 1 antagonist
beta antagonist
arteriolar vasodilator
Angiotensin-converting enzyme inhibitor (ACE inhibitor)
Family of drugs designed to disrupt the renin-angiotensin-aldosterone system (RAAS).
Medications function by inhibiting the conversion of angiotensin I to angiotensin II.
ACE inhibitors can decrease proteinuria
promote vasodilation, venodilation and reduction in plasma volume with reduction in systolic blood pressure
ACE inhibitors can cause decreased metabolism of vasodilatory agent bradykinin –> further reduction in vascular tone
Clinical application of ACE inhibitors where systemic hypertension is caused by known or suspected increase in RAAS - most commonly related to chronic kidney disease and or glomerular disease.
Most commonly considered 1st line treatment for dogs (not cats).
Generally well tolerated.
Biggest concern: potential to worsen glomerular filtration rate and renal function through preferential dilation of the efferent arteriole (thereby reducing glomerular filtration pressure)
e.g. Enalapril, benazepril, lisinopril
Enalapril
Angiotensin Converting Enzyme Inhibitor
Benazepril
Angiotensin Converting Enzyme Inhibitor
Lisinopril
Angiotensin Converting Enzyme Inhibitor
Angiotensin receptor blockers (ARBs)
Class of drugs that block angiotensin II from its receptor.
Does not affect the metabolism of bradykinin
ARBs can decrease proteinuria
promote vasodilation, vasodilation and reduction in plasma volume with a reduction in systolic blood pressure
Side effects: similar side effects as ACEi; avoided or cautiously used in patients with severe dehydration or azotemia.
e.g. Telmisartan, losartan
Telmisartan
Angiotensin receptor blocker
Calcium channel blockers
decrease calcium influx into cardiac tissues (antiarrhythmic properties) and vascular smooth muscles (antihypertensive properties)
May cause reflex bradycardia
Other side effects could include weakness, lethargy, decreased appetite
CCBs promote preferential afferent arteriolar dilation over the efferent arteriole, which increases intraglomerular pressure, which could damage the glomerulus and worsen proteinuria.
Amlodipine
Belongs to the dihydropyridines family
Calcium channel blocker
Relative selectivity for vascular smooth muscles so promotes vasorelaxation and reduces systemic vascular resistance
An associated decrease in blood pressure may trigger reflex tachycardia.
First-line antihypertensive of choice for managing SHT in cats
Phentolamine
Alpha 1 adrenergic antagonist
used in hypertensive crisis, specifically as rescue therapy during pheochromocytoma surgery
phenoxybenzamine
Alpha 1 adrenergic antagonist
commonly used to stabilize patients with pheochromocytoma prior to surgical intervention
Vasopressor
Any drug specifically used to cause constriction to blood vessels
increase cardiac afterload, produce vasoconstriction, increase vasomotor tone and systemic vascular resistance
most common pathway is alpha 1 adrenergic agonism
positive inotrope
Any drug specifically used to increase cardiac contractility
most common pathway to achieve this is beta 1 adrenergic agonistm
Negative inotrope
decrease cardiac contractility
Dopamine
Catecholamine and sympathomimetic
Primary receptors: dopaminergic, beta-1 and alpha 1 adrenergic agonist
different doses = different effects
Low range - stimulate urine production in oliguiric or anuric AKI
Intermediate range: predominantly positive inotropic effects
High doses: vasoconstriction/increase in vascular resistance
Effects: increases renal blood flow
improves inotropy
increases heart rate
increases systemic vascular resistance
increases blood pressure
increases cardiac out put
Deliver as a CRI
Side effect: arrhythmias, tachycardia, hypertension
Continuous ECG, BP monitoring recommended
Dobutamine
Sympathomimetic
receptors: Beta-1 and Adrenergic-2 agonist
Effects: improves inotropy
+/- increase in heart rate
Increase in cardiac output
+/- increase in blood pressure
decrease systemic vascular resistance
Deliver as a CRI
Side effects: arrhythmias, tachycardia, hypertension, bradycardia
Monitoring: ECG/BP continuous
Norepinephrine
catecholamine and sympathomimetic
Receptors: Alpha-1 and beta 1 adrenergic agonist
Effects: increase in inotropy
decrease in heart rate
increase in systemic vascular resistance
increase in blood pressure
Deliver as a CRI
Side effects: arrhythmias, hypertension, bradycardia, excessive vasoconstriction
Epinephrine
Catecholamine
Receptors: alpha 1 and beta 1 adrenergic agonist
Lower doses have predominantly beta agonist effect: vasodilation, bronchodilation, increased cardiac contractility and cardiac output, increased heart rate
higher doses: more alpha 1 adrenergic effects: vasoconstriction
Used to treat anaphylaxis
Side effects: arrhythmia
Monitoring: continuous ECG/BP
Deliver as IV bolus, CRI, IM or intratracheally
Phenylephrine
sympathomimetic
receptor: alpha-1 adrenergic agonist
Effects: decrease in heart rate
increase in systemic vascular resistance (marked vasoconstriction) increase in blood pressure
May improve blood pressure, but the increase in cardiac afterload may decrease stroke volume and cardiac output
Deliver as a bolus or CRI
Side effects: arrhythmia, hypertension, bradycardia, excessive vasoconstriction
Ephedrine
Sympathomimetic
receptors: beta-1 agonist, and alpha 1 adrenergic agonist
effects: increase inotropy
increase in blood pressure
increase in cardiac output
+/- Heart rate
increase in systemic vascular resistance
deliver as a bolus (short duration of effect) or CRI
Side Effects: arrhythmias, tachyphylaxis (reduced sensitivity after repeated administration), hypertension, bradycardia, tachycardia
Vasopressin
receptors?
Effects?
Delivery method?
side effects?
Non-adrenergic hormone AKA anti-diuretic hormone
receptors: V1 vasopressin Agonist
effects: increase systemic vascular resistance
increase blood pressure
Increase in cardiac afterload may decrease stroke volume and cardiac output, resulting in decrease oxygen delivery to tissue
Alternative or conjunctive therapy to epinephrine in CPCR
More effective than epinephrine when patient in acidosis.
deliver as a bolus or CRI
Side effects: arrhythmias, hypertension, bradycardia, excessive vasoconstriction
What stimulates the release of vasopressin?
by which mechanisms?
- increases in plasma osmolality - central chemoreceptors detect systemic osmolality. Peripheral chemoreceptors in mesenteric and portal veins detect changes in osmolality of ingesta. Afferent impulses ascend via vagus nerve to stimulate vasopressin release. Plasma tonicity sened by hypothalamus to stimulate more vasopressin release.
- decreases in blood pressure - shifts osmolality. Baroreceptors in left atrium, aortic arch and carotid sinus sense drops in blood pressure and circulating blood volume. Allows for release of disinhibition of vasopressin release.
- drop in circulating blood volume
Vasopressin release can be inhibited by which drugs?
glucocorticoids
low dose opioids
atrial natriuretic factor
GABA neurotransmitter
Vasopressin receptors:
V1 receptor
location and mechanism of action
found primarily on smooth muscle cells
Activation of voltage gated calcium channels, increases intracellular calcium levels allowing for vasoconstriction.
V1-R in platelets - facilitates thrombosis because of intracellular calcium
V1-R in kidneys decrease blood flow to inner medulla and limit anti-diuretic effects; selective cause contraction of efferent arterials to increase GFR
There are species variations in V1R locations.
Vasopressin receptors:
V2 receptor
location and mechanism of action
Found primarily on basolateral membrane of distal tubule and principle cells of cortical and medullary rental collecting duct
triggers fusion of aquaporins with plasma membrane of collecting duct –> increasing water absorption.
stimulates release of platelets from bone marrow and enhances release of Von Willebrand’s factor and Factor VIII from endothelial cells
Role of vasopressin in homeostasis
regulating fast shuttling of aquaporin-2 to cell surface
stimulates synthesis of RNA encoding aquaporin 2
hereditary nephrogenic diabetes insipidus have V2-R gene mutations
Vasopressin metabolism and excretion
half life is 24 minutes
cleared by renal excretion and metabolized by tissue peptidases
Adverse effects of Vasopressin
contraction of bladder and gallbladder smooth muscles
increase peristalsis
decrease in gastric secretions
increase in GI sphincter pressure
Local irritation at injection site.
If extravasated, may cause skin necrosis
May increase liver enzymes and bilirubin levels
decrease platelet count
hyponatremia
anaphylaxis/urticaria
bronchospams
abdominal pain
hematuria
water intoxication reported with high dose treatment of diabetes
Terlipressin
selective for V1R
prolong duration - 6 hours half life
Used to manage hemorrhagic gastroenteritis
increase adverse effects - peripheral cyanosis/ischemia (use with caution)
Selepressin
V1R agonist
found to reduce risk of coronary ischemia
less adverse effects on mesenteric blood flow and gastric mucosal perfusion
effective substitute for maintaining MAP, reducing vascular leak, edema formation and shortening duration of shock.
Comparative study with norepi -> no improved outcome
Desmopressin acetate
synthetic vasopressin
intranasal and injectable form
binds primarily to V2R
more potent antidiuretic and procoagulant
