Cardiovascular pharmacology Flashcards
Treatment of heart failure
positive inotropes: cardiac glycosides, sympathomimetics, inodilators
vasodilators: pure and with additional properties
Neuroendocrine modulators
Negative inotropes
heart failure= heart no longer adequately perfusing the body
Positive inotropes
increase force of contraction- used for short term measures or emergency treatment
positive inotropes often combined with a vasodilator
if you increase contractility, you also increase myocardial oxygen consumption–>the more rational approach is to try to vasodilate the heart (i.e. reduce preload/afterload)
cardiac glycosides (more often used as AARDs)
Sympathomimetics: Beta agonists
Inodilators: PDE III inhibitors and calcium sensitizers
Beta 1 adrenergic agonists and Inodilators (PDE III inhibitors)
Mechanism of action is related
in the cardiac muscle cell: beta-1 agonists stimulate adenylate cyclase (AC) via a G-protein to form cAMP
PDE III inhibitors prevent breakdown of cAMP
nb: increasing cAMP in cardiac muscle cell leads to increasing contractility
Both B-1 agonist and PDE III inhibitors increase cAMP, which increases Ca2+, which increases contraction.
Beta-adrenergic agonists
All catecholamines stimulate Beta receptors–> they also stimulate alpha receptors–>vasconstriction, increased HR, pro-arrhythmic. Catecholamines should be used in resuscitation, not for heart failure
Dobutamine: synthetic B1 agonist–> potent positive inotrope, little effect on HR and BP (cf. non-specific action of catecholamines)
nb: Beta 2 adrenoceptors in VSM and bronchi. If you increase cAMP in these cells, see relaxation
Dobutamine
synthetic B1 agonist- potent positive inotrope
indicated in life threatening heart failure with severely impaired systolic function
Short term treatment- up to 3 days, but see residual benefits for several days to weeks after treatment.
Tx is short term because Dobutamine down-regulates beta receptors- the drug loses efficacy fairly quickly
clinical note: given IV due to half life of 2 minutes, monitor BP, HR. rhythm
PDE III inhibitors
e.g. Amrinon, Milrinone- used when dobutamine fails for treatment of acute HF
positive inotropes and vasodilators–>Inodilators
in VSM, cAMP causes relaxation due to inhibitory effect on myosin kinase. If you increase amount of cAMP using PDE III inhibitor–>relaxation.
Side effects: ventricular arrhythmia, ruptured chordae tendinae
Differences in cAMP action in VSM and cardiac muscle cell
in cardiac muscle cell: cAMP–>protein kinase A–> increase Ca2+–> increase contractility
PDE III inhibits cAMP–>5’AMP
therefore, beta 1 agonit, and PDE III both increase amount of cAMP in cardiac muscle cell.
In VSM: cAMP has inhibitory effect on myosin kinase. myosin kinase leads to contraction. therefore, if we’re inhibiting myosin kinase with cAMP, we get relaxation of the VSM.
PDE III inhibits cAMP–>5’AMP, which means there’s more cAMP, which means mysoin kinase is inhibited and we get relaxation of the smooth muscle.
Pimobendan (Calcium sensitizers)
Mechanism of action:
- calcium sensitiser: sensitizes myocardium to Ca2+. Increased force of contraction without an increase in Ca2+ concentration; Pimobendan enhances Ca2+/troponin interaction by increasing the affinity of Ca2+ for the binding site.
- inodilator: PDE III inhibitor effects
Less arrhythmogenic than PDE III inhibitors
-mild positive chronotropic effect; decreased sympathetic drive
Absorption impaired by presence of food
Other effects of Pimobendan (calcium sensitizers)
inhibition of PDE V (pulmonary)- similar to PDE III but present in the lung blood vessels. PDE V leads to breakdown of cGMP leading to increased contractility of the lung vessels. If you inhibit PDE V, can help alleviate arteriolar pulmonary hypertension
decrease cytokines
decrease aggregation of platelets
positive lusitropic effects–> diastolic relaxation of ventricles–>greater relaxation, better cardiac filling, better CO.
nb: pimobendan has very good safety record, well-tolerated
Vasodilators
preferred clinical approach ot HF; also used for tx of systemic hypertension
Pure: calcium channel blockers; hydralazine; prazosin; nitrates
Vasodilators with additional properites: inodilators; ACE inhibitors; PDE V inhibitors
Aims of vasodilators
decrease pre-load and after-load; essentially unloading the failing heart
Overall, reduce cardiac work load.
Arteriodilators, balanced vasodilators, venodilators
Average pre-load= 100mmHg
can get good perfusion at 70-80mmHg
*BP reserve= 20-30mmHg–> reduce BP without significantly reducing perfusion.
Calcium channel blockers (vasodilators)
Treatment: systemic hypertension and HF
voltage operated Ca2+ channels that allow Ca2+ during depolarization–>triggers Ca2+ release from SR to cause contraction
e.g. Amlodipine (Nifedipine)
Mechanism of action: block L-type calcium channels- Some cardio-selective, others vascular-selective
Phenylalkamines e.g. verapamil (class 4 AARD)–>cardio
Dihydropyridines e.g. Amlodipine–> vascular
Benzothiazepines e.g. Diltiazem (class 4 AARD)–> intermediate
Amlodipine primarily arteriolar dilation–> little cardiac effect
Amlodipine pharmacokinetics
90% bioavailability (cf. 65% in humans)
extensive metabolism
Long half-life (30 hours)
High Vd- use SID- appealing in terms of at home sustainable treatment
Good safety profile
Hydralazine-vasodilator
not used much therapeutically
potent, but not totally sure how it works–> suggestion that is has direct relaxant action on VSM
Side effects: hypotension/tachycardia/renin-angiotensin-aldosterone activation
Indication: severe mitral regurgitation
Prazosin- vasodilator
alpha 1-adrenoceptor antagonist
nb: alpha 1 is main contractile stimulus of VSM
mechanism of action: non-selective alpha 1 antagonist
Pharmacokinetics: well absorbed, half life 3-4 hours; hypotensive effect is prolonged
Side effects: hypotension and syncope
Indication: anti-hypertensive
Nitrovasodilators (Nitrates)
Short term anti-hypertensive therapy- useful in acute situations
Mechanism of action: Nitrates act as donors of nitric oxide (NO); mimic endogenous system
nb: very extensive 1st pass metabolism; no oral administration–can give sublingual or IV
Mechanism of nitrates as vasodilators
Nitrates act like endogenous system of vasodilation i.e. mimicking endothelium derived nitric oxide (NO).
Primary stimulus for production of NO is shearing force generated by blood flow. Shearing force simtulus endothelium nitric oxide synthase to convert L-arg to NO.
NO stimulates guanylate cylcase to convert to cGMP. cGMP results in relaxation of smooth mucle.
Nitrates are v. lipid soluble and rapidly distributed–> spontaneously donate NO, which diffuses and causing relaxation.
Nitrovasodilators (Nitrates) drugs and side effects
Short term therapy: Isosorbide dinitrate
Glyceryl trinitrate
sodium nitroprusside
Side effects: hypotension
Cautions: glyceryl trinitrate can be administered topically–> rapid absorption–> wear gloves to administer
Sildenafil- PDE V inhibitor (vasodilator)
Sildenafil aka viagra
PDE V- high concentrations in pulmonary arteries and erectile tissue
Sildenafil: used for tx of erectile dysfunction, pulmonary hypertension
Selectively prevent pulmonary hypertension
Improves exercise tolerance
Neuroendocrine modulators
vasodilate and improve maladaptive changes
- ACE inhibitors (and antagonists)
- Beta blockers
- Aldosterone antagonists
- (Digoxin)
Inhibitors of angiotensin II
angiotensin converting enzyme inhibitors (ACE inhibitors)
angiotensin II receptor antagonists
Rate limiting step: renin release from juxtaglomerular cells
ACE inhibitors: prevent conversion of angiotensin 1 to angiotensin 2
Angiotensin II receptor antagonists block AT 1 receptors
ACE Inhibitors-Mechanism of action
ACE: predominant in vasculature of respiratory system
ACE inhibitor blocks formation of AT II.
Also, ACE breaksdown bradykinin, which is a vasodilator . ACE inhibitors results in increased amounts of bradykinin, thereby increasing vasodilation.
Bradykinin is involved in the autoregulation of renal perfusion.
ACE inhibitors- pharmacodynamic effects
Arteriolar and venodilation
decrease plasma aldosterone
enhanced Na+ and water excretion
reduced oedema
Consequences: improve clinical signs and quality of life
Pimobendan + ACE inhibitors= complementary effects and even better improvement with combination
ACE inhibitors and the kidneys
ACE inhibitors can off-set renal hypertension.
Angiotensin II has a much greater constriction effect on efferent arterioles, which results in increased GFR. ACE inhibitors can help decrease GFR.
Side effects of ACE inhibitors
Hypotension: particularly if combined with diuretic
Renal impairment: interferes with autoregulation of the kidney, although in general, ACE inhibitors are beneficial to the kidneys
Hyperkalemia: increased K+ esp in combo with diuretic
(Anorexia, vomiting, diarrhea- pretty uncommon)
(cough)- well documented in humans (due to increased secretion of bradykinin)- in animals, this side effect may be masked by fact that cough is a symptom of HF in dogs.
Bradykinin causes contraction of non-vascular smooth muscles of bronchus and gut, but vasodilation of VSM
ACE inhibitors- pharmokinetics
Administered as pro-drugs
Enalapril–>enalaprilat
Benazepril–>benazeprilat
Ramipril–>ramiprilat
Imidapril–>imidaprilat
renal/hepatic elimination
food can decrease bioavailability (enalapril- only eliminated by the kidneys, avoid with significant renal dz)
Angiotensin II receptor antagonists
Direct action at angiotensin II receptors.
Used in human cardiology
Differences from ACE inhibitors: block angiotensin II formed by other routes; doesn’t prevent breakdown of bradykinin
Angiotensin II receptor antagonist- Telmisartan (semintra)
Telmisartan not indicated for HF
mechanism: competitive antagonist at the angiotensin I receptor
decreased BP, decreased proteinuria
side effects: hypotension, decrease red blood cell count (generally well tolerated)
Pharmacokinetics: oral solution, high plasma protein binding
Glucuronidation occurs (even in the cat) but mainly excreted unchanged in the feces.
Use: treat poteinuria in cats with renal disease–> decrease GFR, decrease proteinuria
Aldosterone antagonists
Spirolactone (diuretic)
used to deal with aldosterone escape
Aldosterone may increase due to incomplete inhibition of ACE, or other factors.
Can block aldosterone escape using concurrent aldosterone antagonism (see diuretics)
nb: beware hyperkalemia
Negative inotropes
Beta blockers: e.g. atenolol, carvedilol (see class 2 AARDs)
Calcium channel blockers: Diltiazem (see class 4 AARDs).
Anti-arrhythmic drugs (AARDs)
treatment of tachyarrhythmias: vaughn william’s classification; digoxin
treatment of bradyarrhythmias: muscarinic antagonists, beta-agonists, methylxanthines
nb: arrhythmia=dysrrhythmia
biggest side effect of AARDs=arrythmia due to interference with autonomic regulation.
Class 1 AARDs
Mechanism of action: block sodium channels
reduce rate of depolarization during Phase 0: block fast inward Na+ current to decrease rate of depolarization of cardiac AP
use-dependent channel block (i.e. at higher heart rate, block increases; at slower heart rate, block decreases)
Class 1 includes local anaesthetics
Further subdivided into:
Class 1a- intermediate dissociation from channel
Class 1b- fast dissociation
Class 1c- slow dissocation
Class 1 AARD examples
Class 1a: quinidine; procainamide
Class 1b: lidocaine (lignocaine); mexilitine; tocainide; phenytoin
Class 1c: flecainide; encainide
Class 1 AARD mechanisms
Inhibit fast Na+ channels
reduce slope of phase 0, rate of depolarization
Class 1a: prolong AP duration, prolong refractory period
Class 1b: slightly decrease AP duration and refractory period
Class 1c: no effect on AP duration or refractory period
Class 1a AARD indications and side effects
Major indication: hemodynamically significant or life threatening ventricular arrhythmias
to convert atrial fibrillation to sinus rhythm (quinidine in horses)
Side effects: hypotension; increased QRS duration, QT interval; ventricular tachycardia
nb: quinidine is also anticholinergic
Class 1b AARD indications and side effects
Major indication: hemodynamically significant or life threatening ventricular arrhythmias
lidocaine effective in recent onset arrhythmia in dogs
Side effects: muscle fasiculations; tremor, shivering; seizures
Class 1c not used in vet med.
Class 2 AARD
Beta blockers:
- B1 and B2 receptors e.g. Propanolol, Sotalol
- B1 receptors e.g. Atenolol
- B1, B2, and alpha 1 receptors, e.g. Carvedilol
Receptor distribution: B1 in heart; B2 in bronchial and VSM, also nodal tissue
Few arrhythmias are CAUSED by excessive sympathetic stimulation, but can be exacerbated by it. Beta blockers can help decrease tachyarrhythmias.
Class 2 AARD mechanisms
Beta blockers:
- reduce sympathetic drive: slow AB node conduction; negative inotropes (decrease force of contraction, decrease O2 consumption, offset any hypoxia that may be contributing- nb: hypoxia is common cause of arrhythmias).
- reduce O2 consumption–> improved oxygenation
Don’t use beta-blockers until heart failure is controlled
Class 2 AARD indications and side effects
Major indications: arrhyrhmias (both Supraventricular and ventricular)
- hypertrophic cardiomyopathy
- heart failure
Side effects: worsening CHF, negative inotropy, lethargy, depression; bradycardia; bronchospasm
Class 2 AARD dosing
Variable response between individuals
Titrate to effect–> start with low dose
Withdraw drug gradually
Class 3 AARD
e.g. amiodarone, sotalol, bretylium
Block outward K+ channels (responsible for repolarization)
Markedly increases AP duration and refractory period (extended hyperpolarization)
Effects in other classes e.g. Amiodarone is a sodium channel blocker (class 1), alpha and beta blocker (class 2), caclium channel blocker (class 4)
Sotalol also has Beta blocking actions.
Class 3 AARD pharmacokinetics and side effects
Long half-life: can give SID
Lipophilic: good distribution, achieve good steady state
Side effects: elevated liver enzymes, GI disturbances, pulmonary fibrosis, thyroid effects
Class 4 AARD
calcium channel blockers
e.g. verapamil, diltiazem
Mechanism of action: block L-type calcium channels
profound effect on nodal tissue: reduce AP height, prolong AP
shorten AP at cardiomyocytes
Negative inotropes- decrease force of contraction
Positive lusitropes- diastolic relaxation of ventricles–>greater relaxation, better cardiac filling, better CO.
Class 4 AARD indications and side effects
Indications: supraventricular arrhythmias; hypertrophic cardiomyopathy; dogs with atrial fibrillation (added to digoxin); systemic hypertension (amlodipine)
Side effects:
cardiac: negative inotrope, bradycardia
vascular: hypotension
Cardiac glycosides- chemistry
From foxgloves and related plants
e.g. digoxin, oubain
3 components: sugar, steroid, lactone. In the body, the sugar moiety is knocked off and the cardiac glycoside becomes activated.
Cardiac glycoside- effects
Antiarrhythmic effects
Baroreceptor/neuroendocrine effects
positive inotropic effects
diuretic effects
Cardiac glycosides- antiarrhythmic effects
Increased parasympathetic activity– decreased sinus rate
local effect: decrease speed of AV node conduction, prolong refractory period
slow ventricular response to atrial flutter/fibrillation–> prevents transmission of fibrillation down to ventricles
Cardiac glycosides- Baroreceptor and neuroendocrine modulatory effects
Baroreceptor function is decreased in HF–> glycosides increase baroreceptor function
decrease sympathetic activity
decrease concentration of catecholamines
significant side effects–> narrow therapeutic index- we have better alternatives for treatment of heart failure.
Cardiac glycosides- positive inotropic effects
Inhibition of Na+/K+ ATPase
increase intracellular Na+ concentration–> negative impact on passive exchanger which exchanges Ca2+ moving out and Na+ moving in
Slows extrusion of Ca2+ via Na+/Ca2+ exchange transporter
increased intracellular Ca2+ stored in SR
Increased Ca2+ released by each AP
Consequences: mild positive inotrope
Cardiac glycoside-diuretic effects
Na+/K+ ATPase on basolateral aspect of renal tubular epithelial cells–> promote tubular absorption of sodium
Inhibition of this results in diuresis.
Pharmacokinetics of Cardiac Glycosides
Digoxin: oral admin=60-75% bioavailability
25% plasma protein bound
Large Vd (skeletal muscle reservoir)
half life in dog 24-30 hours; in cat 36 hours
Approx 7 days to steady state
Renal excretion
Cardiac glycoside- adverse effects
Disturbances of rhythm: block of AV conduction; increased ectopic pacemaker activity
Effect of potassium: effects of glycosides increased if plasma concentration of K+ decreases
Narrow therapeutic index
Digoxin toxicity: excessive borborygmi, depression, anorexia, vomiting and diarrhea, cardiac arrhythmia
Cardiac glycosides- predisposed to toxicity
thin, cachexic
obese
ascites
hypoproteinemia
hypothyroidism
impaired renal function
electrolyte disturbance
other drugs
dobermans
Cardiac glycosides- preventing toxicity
start on low dose; dose by body surface area
avoid loading doses
reduce dose if predisposed to toxicity
check serum level after 7 days
Cardiac glycosides- dealing with toxicity
Stop for 3-5 days
Start again at lower dose
check electrolytes, acid-base balance
treat arrhythmias
overdose: activated charcoal/cholestyramine resin; digibind
Treatment of bradyarrhythmias
More likely to use pacemaker for chronic bradyarrhythmias
- muscarinic antagonists
- beta agonists
- methylxanthines
Muscarinic antagonists
Mechanism: antagonism of muscarinic ACh receptors–> +ve chronotropes
Indications: bradyarrhythmias associated with high vagal tone
Side effects: constipation, sinus tachycardia, urinary retention, dry mucous membranes
e.g. atropine- can be used diagnostically (atropine response test to determine is bradyarrhythmias caused by high vagal tone)
Propanthaline- fewer side effects than atropine and better for oral dose.
Beta agonists
e.g. isoprenaline (B1), terbutaline (B2)
Mechanism: stimulation of beta-adrenergic receptors
Indications: sinus arrest, AV block; bronchodilatory (more likely therapeutic use)
Side effects: Isoprenaline- ventricular arrhythmia
terbutaline: tremor, tachycardia, hypotension
Methylxanthine
e.g. theophylline, aminophylline, etamiphylline
Mechanism of action: Mild PDE inhbition- not specific to III or V
enhanced sympathetic drive–> mild positive inotropic and chronotropic effects
Indications: widely used in past for HF, now more for bronchodilation
