Cardiac drugs - Australian National University

THE AUSTRALIAN NATIONAL UNIVERSITY
Pharmacokinetics and -dynamics
of Commonly Used Cardiac Drugs
Christian Stricker
Associate Professor for Systems Physiology
ANUMS/JCSMR - ANU
[email protected]
http://stricker.jcsmr.anu.edu.au/Cardiac_drugs.pptx
CS 2016
CS 2016
Aims
At the end of this lecture students should be able to
•
list at least 3 classes of antiarrhythmics and describe their molecular
targets and mechanisms of action;
•
explain how β-AR agonists and antagonists affect the ICS and the
cardiac myocyte;
•
give details how Ca2+ channel blockers influence the heart and
peripheral vessels;
• illustrate how cardiac glycosides increase contractility and lower HR
and list some drug interactions that may lead to increased toxicity;
• outline how phosphodiesterase inhibitors increase contractility; and
• demonstrate how NO releasing drugs cause vasodilation and how
that temporarily improves O2 demand.
CS 2016
Contents
1. Rhythm – antiarrhythmics
– Partial & “specific” block of ion channels
• Sodium channel blockers
• β-adrenoreceptor (β-AR) blockers
• Calcium channel blockers (CCB)
2. Cardiac contractility
– Hypertension / cardiac remodelling
– Heart failure
• Cardiac glycosides
• β-adrenoreceptor agonists
3. Improvement in cardiac O2 consumption
– Vasodilators
• NO releasing compounds
CS 2016
1. Antiarrhythmics
• Classification
• Classes
• Unclassified antiarrhythics
CS 2016
Classification of AR Drugs
• Based on physiological effect.
• Four classes
– Class I: Na+ channel blockers
– Class II: β-adrenoreceptor blockers
– Class III: Drugs prolonging AP
– Class IV: Ca2+ channel blockers
• Unclassified antiarrhythmic drugs
• Antiarrhythmics can cause arrhythmias.
CS 2016
Class I –
+
Na
Channel Blockers
Modified from Golan et al, Principles of Pharmacology, 2005
•
Effective on cells with Na+ currents : myocardial/Purkinje cells – not nodal
cells (affect phase 0 of AP).
• Subdivided into subclasses IA, IB, IC
• Lidocaine (local anaesthetic) blocks Nav1.5 not as well as “neuronal” Nav
– used to block ventricular tachycardia (i.v. injection/infusion).
•
Na+ channel block IC > IA > IB – due to nature & kinetics of block.
CS 2016
!9*44#QQ#V P6\9.-/2+4
a2R0-/`#b3) 25D`#$%&%
L _882-34#K.3)#.1#Q!"#*15#,7.-7324
V ->@(e
L Q!"G#>]#529*7f#Z(C#0132+R*9g[
V ,-e#h#52-*7#.8#(@(e#h#TCeG#(C#
42=,213f#W#TCe#6 12=D#-)+.1.6`#
5+.,.6 W#K*3),.3+.F0-D
V ,./01&h#TCeD
V !*1#K2#4221#*15#R2+08025#O03)#_!dD
L @7.-732G#12=D#01.6 W#9<4.3+.F0Z*94.#9*32+[D
!"#$%&'
Class II – Properties of β-Blockers
Generation
Examples
1st
2nd
3rd
Propranolol
Metoprolol
Bisoprolol
Carvediol
β1 > β2
Selectivity
β1 ≈ β2
β1 > β2
Also cause
vasodilation
(antag. α-AR)
•
Bronchospasm, cold extremities, impotence (central β2-AR).
•
Excessive β1-AR blockade: heart block, bradycardia, heart failure.
•
Insomnia, depression.
•
Different generations produce different side effects.
•
More on β-AR blockers in one of the next pharmacology lectures.
CS 2016
Class IV
2+
Ca
•
Channel Blockers
Verapamil, diltiazem
– Dose-dependent block of ICaL in clinically
relevant doses.
Hirth et al., J Mol Cell Cardiol 15(1983):799
• Verapamil, diltiazem better on cardiac tissue.
• …pines better on vessels (vary, nifedipine).
•
SAN
– Prolongs PMP decay and amplitude↓
(small): HR↓ - neg. chrono-, bathmotropic.
•
AVN
– Reduces amplitude and shortens AP:
currents↓ for depolarisation of surrounding
cells: neg. dromotropic.
•
Cardiac myocyte
– Shoulder↓ and amplitude↓ (small): ICaL↓ →
– Force↓: neg. ino- , lusotropic.
CS 2016
2+
Ca
Channel Blocker Properties
•
Bind to α1C subunit of the L-type Ca2+ channel (but not any other!);
location of binding dependent on the class.
•
Chemically, 3 classes (functionally, Class II and III are similar)
– Class I: Dihydropyridines (”… pines”, like nifedipine, nimodipine, etc.)
– Class II: Phenylalkylamines (verapamil)
– Class III: Benzothiazepines (diltiazem)
•
Orally active (bioavailability …pines ~50%; verapamil 10 – 20%)
•
Extensively metabolised in liver (cytochrome P-450) ; high first-pass
effect (half-lives ≈ 1.5 – 6.0 h); metabolites renally excreted.
•
Highly plasma protein bound (> 80%)
•
Peak action: …pines 1 – 2 h; verapamil 3 – 4 h.
•
Effective as prophylactics (vasodilation).
•
In combination with β-AR blockers can cause heart block.
•
Can provoke MI upon withdrawal (like β-AR blockers).
CS 2016
Unclassified Antiarrhythmics
• Adenosine (natural nucleoside – ATP/ADP breakdown)
– Activates via Gi/o-protein GIRK channels: hyperpolarization; and
– directly inhibits ICa: suppresses SAN APs.
• Mg2+
– Can be antiarrhythmic at normal Mg2+ serum levels.
– Many proteins require Mg2+ as co-factor or for structural
stabilisation: Na+/K+-ATPase, Na+ and some K+ channels.
• K+ - restoration of normal K+ enough
– Hyperkalaemia: RMP↑ (EK↑) →
• Pos. bathmotropic → arrhythmia
• Inactivation of INa → APs resemble ICS
Berne & Levy, 2008
– Causes Ca2+ channel block (steric effect as ion larger than Ca2+).
– Hypokalaemia: RMP↓ (EK↓) →
• Neg. bathmotropic → pacing delayed → other pacemaker takes over → arrhythmia CS 2016
Summary of Antiarrhythmics
• Important to realise that antiarrhythmics can cause
arrhythmias.
• Do not cause specific channel blocks as partial block is
often functionally much preferred (like antiepileptics).
• Narrow margin between efficacy and side-effects.
• Application in the hands of specialists.
• But:
– These reduce mortality (β-blockers) under certain conditions, and
– side effects can be minimized with intelligent prescribing.
CS 2016
2. Cardiac Contractility
• Hypertension: reduce contractility
• Heart failure: increase contractility
CS 2016
Reduction of Contractility
• Both L-type Ca2+ channel and β-AR blockers
reduce contractility (see earlier):
– Negative ino- and lusotropic.
• In context of hypertension (see that lecture)
mostly in combination with
– diuretics (see later in the Block), and
– ACE / AT receptor blockers (see later in the Block).
CS 2016
Increased Contractility
• In context of heart failure (see lecture
on heart failure earlier this block).
• Classes causing increased contractility
1. Cardiac glycosides (Digitalis derivatives)
2. β-adrenoreceptor agonists
3. Phosphodiesterase inhibitors
CS 2016
1. Cardiac Glycosides
•
Foxglove (Digitalis purpurea; compounds
sourced also from other plants; toad skin).
•
One of the oldest medicinal plants
– Used by Egyptians, Romans and Chinese
– 1250 first writing by Welsh doctor
– 1542 Leonhard Fuchs recommends its use
– 1722 Listed in pharmacopoeia in London
– 1785 scientific report by William Withering
– 1799 John Ferrier identifies cardiac action
– Scientifically only established in the last 80 years
•
Glycosides have a
– sugar residue end (digitoxose),
Goodman &Gilman’s, 1996
– steroid nucleus (determines pharmacokinetics). &
– lactone ring (required for activity).
•
Examples: Digoxin, digitoxin, ouabain,
lanatoside C, etc.
CS 2016
Mechanism of Action
•
Block of Na+/K+-ATPase
→ Depolarisation and
[Na+]i↑ → NCX reverses
→ Ca2+ influx → [Ca2+]i↑
→ sarcoplasmic Ca2+↑:
Positive inotrope:
[Ca2+]i↑ → contractility↑.
•
•
Parasympathetic
activation: Negative
chrono-, dromo-,
bathmotrope: HR↓.
Goodman & Gilman, 1996
Experimental evidence (dog; i.v. digoxin into coronary):
– AP shape changes: QT shortening in ECG as AP duration↓.
– Increase in Ca2+ liberation → tension increases (inotropism).
•
Slow onset (i.v. 30 min; practically over days; urine output ↑).
CS 2016
Pharmacokinetics / -dynamics
Goodman & Gilman, 1996
•
•
Drug interactions with verapamil,
quinidine, etc.
–
Renal failure: reduction in clearance and
volume of distribution.
–
Antibiotics: increase bioavailability by killing
enteric bacteria.
–
Hypokalaemia: increased binding to Na+/K+ATPase (diuretics…)
Signs of toxicity:
– Gastrointestinal: Emesis, vomiting,
diarrhoea
– Cardiac: Extrasystole, AV-block,
tachycardia
– Neurological: Headache, xanthopsia,
insomnia, hallucinations, etc.
•
Oral bioavailability: 75%
•
Long τ1/2: 36 h
•
Elimination: 90% renal via GFR
•
Volume of distribution: 640 L / 70 kg →
binds to a lot of other membranes.
•
Small therapeutic window.
•
Requires regular monitoring.
CS 2016
2. β-Adrenoreceptor Agonists
• Isoprenaline, dobutamine
Levick, 5th ed., 2010
• Sympathomimetic effect on
ICS (positive chrono-,
bathmo-, dromotrope) and
myocyte (positive ino- and
lusotrope).
• Clinical use reserved for
short-term support of failing
circulation (ICU):
dobutamine continuous i.v.;
τ1/2 = 2.5 min.
CS 2016
3. Phosphodiesterase Inhibitors
Levick, 5th ed., 2010
• Milrinone, amrinone,
vesnarinone, (caffeine)
• Indirect sympathomimetic
effect on ICS (positive chrono-, bathmo-, dromotrope)
and myocyte (positive inoand lusotrope)
• associated with increased
mortality in long-term use.
• Only used for short-term
(~48 h) support of a failing
circulation.
CS 2016
3. Improving O2 Consumption
• Overview
• Organic nitrates
• Ca channel blockers
CS 2016
After Goodman & Gilman, 2011
Overview
• O2 demand vs. O2 supply issue
• In any instance, two leavers to pull:
– Agents decreasing O2 demand and
• Organic nitrates
• Ca2+ channel blockers
– Agents increasing O2 supply.
• Vasodilators (Ca2+ channel blockers)
CS 2016
Organic Nitrates
•
Nitroglycerin, nitroprusside, isosorbide
nitrate: release NO at different rates.
•
NO causes VSMC relaxation both on
venous (preload) and arterial (coronary;
afterload) side: SV↓ → wall tension↓
– mildly negative inotropic
– increased ventricular fibrillation threshold
– decreased platelet aggregation
•
Kinetics of nitroglycerine:
– Large first pass effect (bioavailability < 10 –
20%): → sublingual appl.
– τ1/2 = 2.8 min; volume of distribution: 3 L/kg
– Short duration action: 15 – 30 min
– Can be given orally (sustained release
tablets) or transdermally (patch)
Shah et al., Int J Cardiol 50 (1995):225–231
– Cannot be stored for long (instability)
CS 2016
Take-Home Messages
• Antiarrhythmics block specific ion channels with a narrow margin
between efficacy and side-effects but they can also induce arrhythmias.
• β-AR blockers and Ca2+ channel blockers have similar actions on the
heart but the latter also affect vessels directly.
• Cardiac glycosides block Na/K-ATPase to revert NCX to raise [Ca2+]
resulting in improved contractility and increased vagal activity.
• Glycosides have a narrow therapeutic window and interactions with
many drugs can result in increased toxicity.
• Temporarily, both β-AR blockers and phosphodiesterase inhibitors can
be used to improve cardiac function.
• Ischaemia is ameliorated either by increasing O2 supply (vasodilation;
Ca2+ channel blockers) or demand (preload, afterload, HR, contractility).
• NO releasing drugs cause fast (venous) vasodilation resulting preload↓.
CS 2016
MCQ
Mike Denning, a 58 year-old has intermittent angina and uses
sublingual nitroglycerin during attacks. He reports tachycardia
whenever he takes the drug. Which of the following statements
would you use to best explain this observation to the patient?
A. It causes a decrease in intracranial pressure.
B. It immediately activates the cardiopulmonary reflex.
C. It has a direct positive chronotropic effect on nodal cells.
D. It facilitates noradrenaline release from sympathetic nerve
endings.
E. It causes increased sympathetic activity due to a fall in
systemic blood pressure.
CS 2016