Pharmacology - Cardiac & Arrythmias Flashcards
Cell membrane potential - 3
- Electrical events in cells are created by movement of charged ions across a semipermeable cell membrane.
- There are more negative charges inside the cell compared to the cell exterior.
- Hence, when voltage is measured inside the cell, it displays negative values measured in mV, & is commonly referred to as a cell membrane potential.
About ion driving forces - 5
- electrical negativity inside the cell that attracts positive ions
- Chemical [gradient] for a given ion between the cell interior & the exterior.
- The [gradients] for K+ & for Na+ & Ca++ oppose one another
- Efflux of K+ outside the cell is opposed by intracellular electronegativity.
- Influx of Na+ & Ca++ is assisted by intracellular electronegativity.
Ions transport - 3
- through ion channels (driven by both [gradient] for an ion & degree of cell electronegativity)
- By active transport (by ATP-driven pumps against [ion] gradients)
- by ion transporters & ion exchangers (driven by [ion[ gradients)
Selective vs non-selective Ion channels
- selective (permeable to only one ion, e.g. sodium channels, potassium channels, calcium channels)
- non-selective (permeable to more than one ion, e.g. Na+/K+)
Ion channels can be controlled by - 6
- Neurotransmitters (ligand-gated ion channels, e.g. nicotinic cholinergic receptor)
- Membrane voltage (voltage-activated ion channels)
- Receptor-coupled (metabotropic ion channels)
- Various ligands (e.g. cAMP, ATP, intracellular calcium ions)
- Other factors (e.g. mechanical stretch)
- Constitutively active (e.g. background potassium channels)
Cell resting potential - 9
- At rest cell membrane is mostly permeable to K+ ions
- K+ leaves via potassium channels [down] gradient, increasing electronegativity
- K+ efflux aided by [K+] gradient, oppose to electronegativity
- Na-pump maintain K+ & Na+ [gradients]
- Na-pump is electrogenic & maintains electrical negativity inside cells by removing excess Na+
- At rest, K+ efflux through K+ channels, maintains electronegativity
- Hence a negative basal membrane potential in majority of cells
- Many cells also permeable to Na+ at rest. Na+ influx reduces electronegativity inside the cell
- Results in less negative resting potential
Membrane depolarisation - 5
1, Activation (opening) of fast sodium channels by a stimulus
2. causes rapid Na+ influx (assisted by gradient & cell electronegativity).
3. Build-up of Na+ reduces electrical negativity inside the cell.
4. Membrane potential becomes less negative, & the cell becomes depolarised.
5. At the peak of the AP cell interior can become even more positive than the cell exterior (AP overshoot).
Membrane repolarisation - 5
- In most AP depolarisation is short-lived & followed by repolarization
Two processes are involved, both stimulated by membrane depolarisation: - Increased K+ efflux through voltage-activated potassium channels
- Decreased Na+ influx due to closure of fast Na+ channels (inactivation) whilst depolarised.
- Cell is repolarised, & basal membrane potential is restored
- Na+ & K+ gradients restored by activity of the Na-pump
Define Refractoriness
Refractoriness: inability to generate 2nd AP in response to next stimulus
Two types of refractoriness
Two types of refractoriness:
1. Absolute (no AP will occur)
- Relative (a stronger stimulus can evoke the 2nd AP before cell is fully repolarised)
Refractoriness: Main mechanistic - 3
- Inactivation of fast sodium channels triggered by depolarisation.
- Inactivated sodium channels cannot be re-opened the 2nd depolarising stimulus.
- Sodium channels should recover from inactivation (occurs during repolarisation phase).
Partial Refractoriness - 3
1.Most Na channels are inactivated (absolute refractoriness)
2. Na channels are partly recovered (relative refractoriness)
3. Na channels are fully recovered (no refractoriness)
Functional relevance of Refractoriness - 5
- Refractoriness determines AP duration, hence regulating the frequency of Aps
- Longer the refractoriness, slower rate of AP generation.
- In skeletal muscles & heart, refractoriness determines rate of muscle contractions.
- In skeletal muscles, AP are short & at high AP rate individual contractions add together causing a sustained contraction of muscle.
- In the heart, cardiac AP has a plateau phase that increases AP duration, hence increases refractoriness of the heart.
Cardiac AP: 2
Cardiac AP:
1. In contractile atrial & ventricular myocytes & Purkinje fibers
2. Defines heart rhythm, regulates heart rate, controls force of the heartbeat
Pacemaker AP: 3
Pacemaker AP:
1. In pacemaker cells of the SA & AV Nodes
2. Sets heart rate (SAN)
3. Controls the rate of heartbeat (AVN)
The Cardiac AP is divided into 5 phases.
Phase 0: Rapid depolarisation
Phase 1: Rapid repolarization
Phase 2: Plateau
Phase 3: Repolarisation
Phase 4: Baseline
Main types of ion channels which contribute to different phases of the Cardiac AP include - 5
- Phase 0: Rapid depolarization: Fast voltage-activated sodium influx
- Phase 1: Rapid repolarization: Transient potassium efflux & chloride influx (increase electronegativity)
- Phase 2: Plateau: A slower L-type voltage-activated calcium influx is balanced by voltage-activated potassium efflux thus maintaining the plateau
- Phase 3: Repolarisation: Several voltage-activated potassium channels
- Phase 4: Baseline (stable): Active background potassium efflux
Refractoriness: Therapeutics - 3
- Block voltage-activated potassium channels in repolarisation phase 3, hence a longer AP duration (e.g. anti-arrhythmic Class III drugs);
- Reduce a number of available voltage-activated sodium channels, hence slowing down the rate of depolarisation phase 0 (termed Vmax) (e.g. anti-arrhythmic Class I drugs)
- Refractoriness can be reduced by drugs that block:
Voltage-activated calcium channels during plateau phase 2 (e.g. anti-arrhythmic Class IV drugs)
Phases of the Pacemaker AP: 0,3,4
Phase 0: Slow depolarisation: Slow onset of the AP
No phase 1 or plateau present
Phase 3: Repolarisation
Phase 4: Baseline (unstable): Spontaneous depolarisation
Ion fluxes in the Pacemaker AP:
0, 3, 4
Phase 0: Slow depolarisation: Slow voltage-activated L-type calcium influx
Phase 3: Repolarisation: Voltage-activated potassium efflux
Phase 4: Pacemaker potential: Most important is sodium influx via non-selective cation channels (‘funny’ current). Little background potassium efflux.
SINUS RHYTHM & NORMAL HEART RATE ON ELECTROCARDIOGRAM (ECG)
Sinus rhythm- a regular heart beat driven by the SAN with rate 60-100 bpm
Normal HR 60-100 bpm at a glance on ECG: the R-R interval should be within (0.6-1 sec).
Conduction System of the Heart and ECG
- 7
- P-wave: depolarisation of the atria
- PR interval: (Atrial depolarisation & AV delay)
- PR-segment: (AV delay)
- QRS complex: depolarisation of the ventricles
- ST-segment: (Ventricular plateau)
- T-wave: repolarisation of the ventricles.
- QT-interval: (Ventricular depolarisation & repolarisation)
Cardiac AP: Key summary points
Phase 0,1,2,3
Rapid depolarisation: Phase 0
Ion mechanism: Fast sodium influx via voltage-activated sodium channels
Roles: Rapid conduction of the AP via ventricles (Bundle of His & Purkinje fibres)
Rapid excitation of atrial and ventricular myocytes
Pharmacology: Target for Class I anti-arrhythmic drugs (discussed in Heart-2)
Plateau Phase 2
Ion Mechanisms: Slow calcium influx via L-type voltage-activated calcium channels balanced by potassium efflux via voltage-activated potassium channels (IKs & IKr)
Roles: Determine the duration of the cardiac AP and refractoriness of the heart
Determine the force of cardiac contraction
Repolarisation Phase 3
Ion Mechanisms: Increased potassium efflux via voltage-activated potassium channels
Roles: Repolarisation of the cell membrane, Determine the duration of the cardiac AP and refractoriness of the heart
Pharmacology: Target for Class III anti-arrhythmic drugs
Pacemaker AP of the SA and AV nodes: Summary points:
0,2,3,4
Slow depolarisation Phase 0
Ion mechanism: Mainly L-type voltage-activated calcium channels (with assistance of T-type VACCs at the beginning of phase 0)
Roles: Lead pacemaker (in the SAN) & gating between the atria and ventricles (in the AVN)
Pharmacology: Target for Class IV anti-arrhythmic drugs
Plateau Phase 2: Absent
Repolarisation Phase 3:
Ion Mechanisms: Increased potassium efflux via voltage-activated potassium channels
Roles: Repolarisation of the AP
Pharmacology: Not currently targeted therapeutically
Phase 4: No true baseline; instead a slow depolarising (pacemaker) potential
Ion Mechanisms: Sodium influx via hyperpolarisation-activated, cAMP-gated non-selective channels (If “ funny” current)
Pharmacology: Target for Class II anti-arrhythmic drugs (discussed in Heart-2). IVABRADINE
Key features of If “funny” current:
- 4
- Hyperpolarization-activated Cyclic Nucleotide-Gated (HCN) channel is a non-selective cation channel, primarily permeable to Na, but can K+ to pass.
- It plays a crucial role in regulating heart rate by controlling cardiac automaticity, allows modulation via ANS & adrenaline.
- Sympathetic activation (via β1- and β2-adrenergic receptors) increases cAMP, stimulating the channel.
- Parasympathetic activation (via muscarinic M2 receptors) decreases cAMP, inhibiting the current.
Key features of If “funny” current:
Clinical relevance - 4
Clinical Relevance:
1. Beta-adrenoceptor activation increases the pacemaker current, accelerating heart rate.
2. Muscarinic receptor activation decreases the current, slowing heart rate.
3. Drugs like ivabradine block this current to reduce heart rate, especially in conditions like angina.
4. Cardiac glycosides can have both positive and negative effects on heart rate, influencing vagal tone.
MODULATION OF THE PACEMAKER POTENTIAL BY Sympathetic & Parasympathetic STIMULATION
- 4
- Increase in sympathetic stimulation increases the magnitude of the inward directed If current, speeding up depolarisation.
- The larger the If current, the less time is required to reach the threshold for phase 0 AP, hence an increase in HR
- Parasympathetic stimulation slows the current, more time is required to reach the threshold. The frequency of AP is reduced, reducing HR
- Ivabradine slows the diastolic depolarization slope by blocking the If current, leading to HR reduction.
Classification of arrhythmias
Dysrhythmia - “abnormal rhythm”
Arrhythmia - “no rhythm”
Bradycardia - slow HR
Tachycardia - fast HR
Regular vs Irregular - based on effect of Heart rhythm
By the site of origin:
Supraventricular (SAN, atria & AVN)
Ventricular (His Bundles, Purkinje fibres & ventricles)
Type of QRS complex:
Narrow complex
Broad complex
Signs & symptoms of arrhythmias - 6
- Palpitations
- Shortness of breath & fatigue
- Chest pain
- Dizziness, feeling faint (pre-syncope)
- Blackouts
- Cardiac arrest
Types of Pathological Bradycardia: AV Block - 4
- First-degree: a slower AV conduction
- Second-degree: Missed beats to the ventricles
- Third-degree (complete block): No conduction to ventricles (P waves & QRS complexes randomly separated).
- Treatment: Pacemaker
Causes of Bradycardia - 8
Physiological causes:
1. Increased vagal tone
2. In trained athletes
Non-cardiac causes:
3. Endocrine disorders (hypothyroidism)
4. An electrolyte imbalance (hyperkalaemia, hypo- & hyper- calcaemia)
5. Drugs: anti-arrhythmic (beta-blockers, CCBs, digoxin); antihypertensive (clonidine)
6. Hypothermia
Degeneration & diseases of SAN, atrium & AVN):
7. Sick Sinus Syndrome, pause on ECG
(ischaemia & infarction of the SAN)
- Atrioventricular blockade or heart block (ischaemia; fibrosis, congenital heart defects; infections & inflammations such as myocarditis, diphtheria, rheumatic fever)
Anti-arrhythmic drugs: The Vaughan Williams Classification
Class I
Sodium channel blockers
Disopyramide (Ia), Lidocaine (1b);
Flecainide (1c)
Class II:
Beta-blockers:
Propranolol, Atenolol, Esmolol
Class III: Drugs that prolong the AP duration
Amiodarone, Sotalol
Class IV: Calcium channel blockers:
Verapamil, Diltiazem
Anti-arrhythmic drugs: Class I
Sodium channel blockers
Disopyramide (Ia), Lidocaine (1b);
Flecainide (1c)
- Block the fast voltage-activated sodium channels (rapid depolarisation phase 0).
- Slow down the upstroke of the cardiac AP, hence slow down AP conduction (Ia & Ic).
- Most effective in ventricular myocytes, Purkinje fibres and in the atria.
- The block is use-dependent (i.e. it increased with increased HR, thus reducing AP frequency
ADR
Disopyramide - Cadriogenic shock
Lidocaine - CNS effects e.g. drowsiness
Flecainide - sudden death in patients with MI
Anti-arrhythmic drugs:
Class II: Beta-blockers –
Propranolol, non-selective b-blocker
Atenolol, b1-selective
Block cardiac b1-adrenoceptors
Slow down conduction at the AVN
e.g.
Propranolol, a long-acting non-selective b-blocker
Atenolol, b1-selective
ADR
Bradycardia, myocardial depression
Anti-arrhythmic drugs:
Class III. Drugs that prolong the AP duration: e.g. Amiodarone
Main mechanism:
Block of voltage-activated potassium channels in repolarisation phase 3 of the action potential.
Effects:
Prolong the duration of the cardiac AP
Prolong the QT interval
Increase refractoriness of the heart
ADR
Thyroid abnormalities
Corneal fat deposits
Anti-arrhythmic drugs: Class IV. Calcium Channel Blockers
Verapamil (Phenylalkamines)
Diltiazem (Benzothiapenes)
Mechanism
Block L-type voltage-activated calcium channels
Slow down conduction at the AV node
ADR
Bradycardia
Constipation
Hypotension
Common Tachyarrhythmias
& causes
Supraventricular tachycardia (SVT):
1. Paroxysmal SVT (PVST)
2. Atrial Fibrillation (AF)
3. Atrial Flutter (“Flutter”)
Ventricular:
Ventricular Tachycardia (VT)
Ventricular Fibrillation (VF)
Genetic disorders
Congenital heart defects
Hyperthyroidism
Hypokalaemia
Some drugs e.g. Inhalers, Antibiotics
Atrial Fibrillation (AF):
& Atrial Flutter:
Atrial Fibrillation (AF):
Characterized by a fast, irregularly irregular heartbeat.
Cause: Random ectopic activity from pulmonary veins in the left atrium.
Atrial Flutter:
Characterized by a fast, regular heartbeat.
Cause: One or more foci of re-entrant excitation in the atria. It may eventually evolve into AF.
Danger: Both AF and flutter increase stroke risk due to blood stasis and thrombi formation in the atria.
Pharmacological Treatment for Atrial Fibrillation (AF) and Atrial Flutter:
Treatment Strategies:
Rhythm Control (restoring normal rhythm):
Electrical cardioversion (often first choice)
Pharmacological cardioversion:
Class Ic: Flecainide
Class III: Amiodarone
Rate Control (slowing down heart rate without restoring normal rhythm):
Class II (Beta-blockers)
Class IV (Diltiazem, Verapamil is not recommended due to its negative inotropic effects)
Digoxin (used traditionally for its negative chronotropic and positive inotropic effects)
Atrial Flutter treatment options include:
Catheter ablation
Electrical cardioversion
Pharmacological cardioversion using drugs like:
Class 1c (e.g., Flecainide)
Class IV (e.g., Diltiazem)
Amiodarone
