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Pharmacology > Cardiovascular pharmacology > Flashcards

Cardiovascular pharmacology Flashcards

1
Q

Treatment of heart failure

A

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

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2
Q

Positive inotropes

A

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

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3
Q

Beta 1 adrenergic agonists and Inodilators (PDE III inhibitors)

A

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.

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4
Q

Beta-adrenergic agonists

A

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

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5
Q

Dobutamine

A

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

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6
Q

PDE III inhibitors

A

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

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7
Q

Differences in cAMP action in VSM and cardiac muscle cell

A

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.

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8
Q

Pimobendan (Calcium sensitizers)

A

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

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9
Q

Other effects of Pimobendan (calcium sensitizers)

A

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

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10
Q

Vasodilators

A

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

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11
Q

Aims of vasodilators

A

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.

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12
Q

Calcium channel blockers (vasodilators)

A

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

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13
Q

Amlodipine pharmacokinetics

A

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

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14
Q

Hydralazine-vasodilator

A

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

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15
Q

Prazosin- vasodilator

A

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

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16
Q

Nitrovasodilators (Nitrates)

A

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

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17
Q

Mechanism of nitrates as vasodilators

A

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.

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18
Q

Nitrovasodilators (Nitrates) drugs and side effects

A

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

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19
Q

Sildenafil- PDE V inhibitor (vasodilator)

A

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

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20
Q

Neuroendocrine modulators

A

vasodilate and improve maladaptive changes

  • ACE inhibitors (and antagonists)
  • Beta blockers
  • Aldosterone antagonists
  • (Digoxin)
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21
Q

Inhibitors of angiotensin II

A

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

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22
Q

ACE Inhibitors-Mechanism of action

A

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.

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23
Q

ACE inhibitors- pharmacodynamic effects

A

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

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24
Q

ACE inhibitors and the kidneys

A

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.

25
Q

Side effects of ACE inhibitors

A

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

26
Q

ACE inhibitors- pharmokinetics

A

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)

27
Q

Angiotensin II receptor antagonists

A

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

28
Q

Angiotensin II receptor antagonist- Telmisartan (semintra)

A

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

29
Q

Aldosterone antagonists

A

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

30
Q

Negative inotropes

A

Beta blockers: e.g. atenolol, carvedilol (see class 2 AARDs)

Calcium channel blockers: Diltiazem (see class 4 AARDs).

31
Q

Anti-arrhythmic drugs (AARDs)

A

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.

32
Q

Class 1 AARDs

A

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

33
Q

Class 1 AARD examples

A

Class 1a: quinidine; procainamide

Class 1b: lidocaine (lignocaine); mexilitine; tocainide; phenytoin

Class 1c: flecainide; encainide

34
Q

Class 1 AARD mechanisms

A

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

35
Q

Class 1a AARD indications and side effects

A

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

36
Q

Class 1b AARD indications and side effects

A

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.

37
Q

Class 2 AARD

A

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.

38
Q

Class 2 AARD mechanisms

A

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

39
Q

Class 2 AARD indications and side effects

A

Major indications: arrhyrhmias (both Supraventricular and ventricular)

  • hypertrophic cardiomyopathy
  • heart failure

Side effects: worsening CHF, negative inotropy, lethargy, depression; bradycardia; bronchospasm

40
Q

Class 2 AARD dosing

A

Variable response between individuals

Titrate to effect–> start with low dose

Withdraw drug gradually

41
Q

Class 3 AARD

A

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.

42
Q

Class 3 AARD pharmacokinetics and side effects

A

Long half-life: can give SID

Lipophilic: good distribution, achieve good steady state

Side effects: elevated liver enzymes, GI disturbances, pulmonary fibrosis, thyroid effects

43
Q

Class 4 AARD

A

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.

44
Q

Class 4 AARD indications and side effects

A

Indications: supraventricular arrhythmias; hypertrophic cardiomyopathy; dogs with atrial fibrillation (added to digoxin); systemic hypertension (amlodipine)

Side effects:

cardiac: negative inotrope, bradycardia
vascular: hypotension

45
Q

Cardiac glycosides- chemistry

A

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.

46
Q

Cardiac glycoside- effects

A

Antiarrhythmic effects

Baroreceptor/neuroendocrine effects

positive inotropic effects

diuretic effects

47
Q

Cardiac glycosides- antiarrhythmic effects

A

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

48
Q

Cardiac glycosides- Baroreceptor and neuroendocrine modulatory effects

A

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.

49
Q

Cardiac glycosides- positive inotropic effects

A

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

50
Q

Cardiac glycoside-diuretic effects

A

Na+/K+ ATPase on basolateral aspect of renal tubular epithelial cells–> promote tubular absorption of sodium

Inhibition of this results in diuresis.

51
Q

Pharmacokinetics of Cardiac Glycosides

A

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

52
Q

Cardiac glycoside- adverse effects

A

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

53
Q

Cardiac glycosides- predisposed to toxicity

A

thin, cachexic

obese

ascites

hypoproteinemia

hypothyroidism

impaired renal function

electrolyte disturbance

other drugs

dobermans

54
Q

Cardiac glycosides- preventing toxicity

A

start on low dose; dose by body surface area

avoid loading doses

reduce dose if predisposed to toxicity

check serum level after 7 days

55
Q

Cardiac glycosides- dealing with toxicity

A

Stop for 3-5 days

Start again at lower dose

check electrolytes, acid-base balance

treat arrhythmias

overdose: activated charcoal/cholestyramine resin; digibind

56
Q

Treatment of bradyarrhythmias

A

More likely to use pacemaker for chronic bradyarrhythmias

  • muscarinic antagonists
  • beta agonists
  • methylxanthines
57
Q

Muscarinic antagonists

A

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.

58
Q

Beta agonists

A

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

59
Q

Methylxanthine

A

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

Pharmacology (12 decks)

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