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
