Cardiovascular Pharmacology Flashcards
What are the P wave, QRS complex and T wave representations on the ECG for?
P wave = Depolarisation of the Atria
QRS complex = Depolarisation of the ventricles
T wave = Repolarisation of the ventricles
In a Ventricular Action Potential there are 5 phases (0-4). What are they? (Contractile Myocytes)
0 = Depolarisation 1 = Rapid Repolarisation 2 = Plateau 3 = Repolarisation 4 = Baseline Potential
Pacemaker cells have a different Action Potential sequence to contractile myocytes. Highlight the action potential they go through.
0 = depolarisation
3 = repolarisation
4 = baseline potential
repeat
Membrane depolarisation and repolarisation is a results of ion flows across the membrane of the cell. What ion channels are responsible for depolarisation and repolarisation?
Depolarisation:
Sodium INFLUX, Calcium INFLUX
Repolarisation:
Potassium EFFLUX, Active Na+-K+-ATPase
What do the following in the ECG represent? PR Segment PR Interval ST Segment QT Interval
PR Segment = AV Delay
PR Interval = Atrial Systole
ST Segment = Ventricular Plateau
QT Interval = Ventricular Depolarisation & Repolarisation
What are the ion mechanisms for a contractile myocyte action potential? Describe with the 5 phases (0-4)
0 = Rapid Na+ influx via Voltage Activated Sodium Channels (iNa) 1 = Transient K+ efflux (iTO1) 2 = Ca2+ influx via L-Type Voltage Activated Calcium Channels (iCa(L)) 3 = K+ efflux via: slow (iKs) & rapid (iKe) delayed rectifier potassium channels, also via iK1 4 = K+ efflux via iK1
What is absolute/effective refractory period?
The refractory period when the generation of the next action potential is not even possible at the strongest stimulus.
What is relative refractory period?
When the generation of the next action potential is possible, but requires a stronger stimulus.
Describe the mechanism of refractoriness
- Depolarisation stimulus opens Voltage Gated Sodium Channels
- They are rapidly INACTIVATED. If depolarisation is maintained (plateau), channels cannot be reopened until…
- Repolarisation below the threshold voltage (-65mV) recovers Na+ channels from inactivation moving them into the closed state.
Why does prolonging refractoriness in the heart a problem?
Causes a long QT interval which can promote cardiac dysrhythmias.
Describe the ion mechanisms that occur in a Pacemaker Potential.
4 = Pacemaker current 4 = Voltage gated T-type Calcium influx, iCa(T) 0 = Voltage Activated L-Type Calcium influx, iCa(L) 3 = Voltage Activated K+ Channels efflux, iK
What 2 ways activate iF (funny current)?
Membrane repolarisation (hyperpolarisation) Directly by cAMP (kinase dependent phosphorylation)
How is the iF current modulated by the Peripheral Nervous System?
Sympathetic: STIMULATION via β1 adrenoceptors; increases current.
Parasympathetic: INHIBITION via Muscarinic M2 receptors; decreases current
What functions does the iF current have?
Cardiac Automaticity
Heart Rate control by the PNS and Adrenaline
What drug will inhibit the iF current?
Ivabradine
Describe the Ion Mechanisms for the modulation of the Pacemaker potential via the Peripheral Nervous System.
Sympathetic: 1) β1 Adrenoceptor is stimulated 2) Increase Adenylyl Cyclase 3) Increase Cellular cAMP 4) Increase iF current 5) Increase the rate of pacemaker depolarisation 6) Increase conduction velocity RESULT: INCREASED HEART RATE
Parasympathetic: 1) M2 receptor is stimulated 2) Decrease Adenylyl Cyclase 3) Decrease Cellular cAMP 4) Decrease iF current 5) Decrease the rate of pacemaker depolarisation 6) Decrease conduction velocity RESULT: DECREASED HEART RATE
What are the 3 major pathways and 1 minor pathway of contraction through calcium entry and release?
MAJOR PATHWAYS:
1) Activation of L-VACC (Voltage Activated Calcium Channels) - responsible for phase 2 plateau - provides the influx of Ca++ ions.
2) Activation of RyRs on the Sarcoplasmic Reticulum (SR)
3) Calcium-Induced Calcium release from the Sarcoplasmic Reticulum
MINOR PATHWAY:
4) Ca++ influx via Ca++/Na+ Exchanger (NCX)
What are the activators and inhibitors of RyR2 (cardiac Ryanodine Receptors)?
Activators:
Ca++ ions
Ryanodine (at nanomolar concs)
Inhibitors:
Ryanodine (At micromolar concs)
What are the sensitisers for RyR2?
Caffeine
Halothane
CATECHOLAMINES
What are the MAJOR and MINOR calcium pathways for cardiac muscle relaxation?
- Ca++ REUPTAKE into the Sarcoplasmic Reticulum via SERCA (Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase) (70-80%)
- Ca++ extrusion by Na+-Ca++ exchanger (NCX) (20-30%)
- Ca++ extrusion by Ca++-ATPase (Ca++-pump) ~1% Ca++ removal
- Ca++ uptake into mitochondria via mitochondrial Ca++ uniporter (~1% Ca++ removal)
What regulates the Cardiac Isoform of SERCA (SERCA2a)?
Phospholamban (PLB)
How does PLB regulate Ca++ reuptake?
RE-UPTAKE
1) β1 adrenoceptors are stimulated from catecholamines
2) PKA is activated.
3) PKA promotes the phosphorylation of PLB
4) Phosphorylated-PLB promotes faster re-uptake and therefore faster relaxation
The Sodium-Calcium Exchanger (NCX) has two different modes. What are they and how do they work?
1) Forward (Normal) Mode - Responsible for repolarisation in phase 3 of AP.
Activated by a build up of cytosolic Ca++ during the cardiac AP
Extrude 1 Ca++ ion in exchange for 3 Na+ ions.
2) Reverse Mode - Responsible for the depolarisation in phase 0 of AP
Activated by a build up of cytosolic Na+
Exclude 3Na+ ions for 1 Ca++ ion
Increase in cytosolic [Ca++] (MINOR ROLE)
Sympathetic stimulation has the effects of both increasing AND decreasing the concentration of cytosolic Calcium. Why?
Increase in [Ca++]:
1) increase in calcium influx via L-voltage activated calcium channels activation
2) Increase in calcium release via RyR2 activation
3) Increase in calcium sensitisation via Tropinin I phosphorylation
Decrease in [Ca++]:
1) Increase in calcium reuptake via increase in SERCA activity (PLB-mediated)
What drug binds to the Ca++-TNC complex to prolong systole action?
Levosimendan
Describe the ion mechanism in cardiac glycosides (eg. Digoxin)
Digoxin will inhibit the Na+/K+-ATPase by binding to the extracellular K+ binding site of the ATPase.
There will be an indirect activation of the REVERSE MODE of the NCX as a result of the accumulation of the intracellular Na+, thus resulting in an increase in cytosolic Ca++.
What is digoxin used for?
Congestive Heart Failure
Antidysrhythmic: Atrial Fibrillation & Atrial Flutter
In terms of coronary circulation, what are the roles of the left and right coronary artery?
Left Coronary Artery: supplies the left and right sides of th heart (about 85% of CBF)
Right Coronary Artery: Supplies the SA node, AV node and right side of the heart
What cardiac metabolites will cause vasodilation of the coronary arteries?
Adenosine
Potassium
Hypoxia (decreased tissue partial oxygen)
In an emergency with heart block, what drugs are used?
Atropine (IV), or Isoprenaline (IV)
There are several mechanisms behind tachydysrhythmias, what are they?
Automaticity:
Enhanced (Sympathetic overreactivity)
Abnormal (Ectopic pacemaker)
Triggered:
Early after depolarisation (EAD) - TORSADES DE POINTES
Delayed After Depolarisation (DAD)
Reentry
There are three types of Re-entry. What are they?
AV Node and Atria (AVNRT) Purkinje Fibres (VT) Accessory Pathways (AVRT)
Re-entry causes what on an ECG?
An atrial echo
What is the common cause of Atrial Fibrillation?
Random ectopic activity from the pulmonary vein in the left atrium
Classify antidyrhythmic drugs according to the Vuaghan-Williams Classification
Class I: Na+ Channel Blockers
Class II: β-Blockers
Class III: Drugs that prolong the action potential duration
Class IV: Calcium Channel Blockers
What is the main mechanism of Class I antidysrhythmics?
Blockage of FAST voltage activated Na+ Channels
Class I antidysrhythmics are classified based on their dissociation rate and are therefore classified into three sub-types. What are they?
Class Ia: Intermediate Dissociation Rate
Class Ib: Fast Dissociation Rate
Class Ic: Slow Dissociation Rate
What are the drugs in each subtype of Class I Antidysrhythmics?
Ia: Disopyramide, Procainamide, Quinidine
Ib: Lignocaine, Mexilitine
Ic: Flecainide, Propafenone, Moricizine
Class Ia drugs have what effects on the Cardiac Action Potential and what effects on the ECG?
Cardiac Action Potential: decreases Vmax, increases duration
ECG: increases QRS duration, increases QT interval
Class Ib drugs have what effects on the Cardiac Action Potential and what effects on the ECG?
Cardiac Action Potential: No effect on Vmax, Decrease in duration
ECG: QRS duration unchanged, but a modest decrease in the QT interval
NB Blocks extra heart beats
Class Ic drugs have what effects on the Cardiac Action Potential and what effects on the ECG?
Cardiac Action Potential: Decrease in Vmax, Small increase/no effect on Action Potential
ECG: Increase in QRS duration
modest increase in QT interval
From each Class I antidysrhythmic subtypes, list the most relevant drug, and its therapeutic use.
Class Ia: Disopyramide - Atrial Fibrillation - Ventricular Tachycardia Class Ib: Lidocaine -Ventricular Tachycardia & Ventricular Fibrillation Class Ic: Flecainide -Paroxysmal Supraventricular Tachycardia (due to AVNRT) -Atrial Fib. & Flutter -WPW syndrome
What are the clinical uses of Class II Antidysrhythmics (β-Blockers)?
Rate control in Supraventricular Tachycardias (due to increased sympathetic activity)
Rate and rhythm control in Atrial Fibrillation & Flutter
Ventricular Fibrillation
What are the drugs that are classified under Class III antidysrhythmics?
Amiodarone, Sotalol, Bretylium
What is the common mechanism behind Class III antidysrhythmics?
Blocking voltage-activated K+ channels & prolonging the repolarisation (phase 3)
What are the side effects of Amiodarone?
Dysrhythmias Thyroid Abnormalities Corneal Deposits Pulmonary Disorders Skin Pigmentation
What are the drugs under the Class IV antidysrhythmics?
Verapamil, Diltiazem
What is the mechanism Class IV antidysrhythmics undergo?
They block voltage-activated L-type Calcium channels
What is the main effect of a Class IV antidysrhythmic?
Slows down conduction at the Atrio-Ventricular node
What are they main side-effects of a Class IV antidysrhythmic?
Bradycardia
Negative inotropic effect
Constipation (Verapamil)
Hypotension (more with Diltiazem)
What main drug interaction does Verapamil have with, and what is it?
with Digoxin, and it increases Digoxin toxicity.
There are certain antidysrhythmic drugs that fall out of the Vaughan-Williams classification. What are they and what are their therapeutic indications?
-Atropine (IV route) for Sinus Bradycardia (β-Blocker overdose)
-Isoprenaline (IV route) for heart block
-Adrenaline for cardiac arrest
Adenosine (IV route) for PSVT (Paroxysmal Supraventricular Tachycardia)
-Digoxin for rapid Atrial Fibrillation (rate controlling)
What is the blood pressure equation?
Blood Pressure = Cardiac Output x Total Peripheral Resistance
(Cardiac Output = Heart Rate x Stroke Volume)
What factors affect contractile activity?
1) Spontaneous electrical activity in the plasma membrane of the muscle fibre
2) Neurotransmitters released by automatic neurons
3) Hormones
4) Locally induced charges in the chemical composition of the extracellular fluid surrounding the fibre
5) Stretch
How does a SMOOTH muscle contract?
1) Increase in cytosolic Ca++
2) Ca++ binds to calmodulin in cytosol
3) Ca++-Calmodulin complex binds to myosin light chain kinase (MLCK)
4) MLCK uses ATP to phosphorylate myosin cross bridges
5) Phosphorylated cross-bridges bind to actin filaments
6) Cross bridge cycle produces tension & shortening
This is a SLOW process
How does a SKELETAL muscle contract?
1) Increase in cytosolic Ca++
2) Ca++ binds to tropinin on thin filaments
3) Conformational change in tropinin moves tropomyosin out of position
4) Myosin cross bridges bind to actin
5) Cross-bridge cycle produces tension and shortening.
This is a FAST process
What are the main mechanisms in increasing cytosolic Ca++ in Smooth Muscle?
1) Agonist-induced IP3-mediated intracellular Ca++ release from the Sarcoplasmic-Reticulum (SR)
2) Extracellular Ca++ influx via vascular voltage-gated L-type calcium channels
How can we facilitate the relaxation of smooth muscle?
1) Inhibition of MLCK
2) Activation of MLCP
What are the two main vasodilators produced by endothelial cells?
1) Nitric Oxide (NO) or Endothelium-Dervied Relaxation Factor EDRF)
2) Prostaglandin I2 (PGI2)
There are three isoforms of Nitric Oxide Synthase. What are they, and where are they found (respectively)?
1) Endothelial NOS (eNOS) - abundant in endothelial cells
2) Neuronal NOS (nNOS) - in neurons (NANC transmitter)
3) Inducible NOS (iNOS) - upregulated in inflammation in macrophages
What are the typical symptoms of Angina Pectoris?
Chest in the front of the chest, often radiated to the neck, jaw, shoulders or arms
What are the first line treatments of Angina?
β-blockers - Atenolol, Acebutolol, Pindolol, Propanolol, Labetolol
Ca++ Channel Blockers - Nifedipine, Amlodipine, Diltaziem, Verapamil
What treatments are used as a 2nd line treatment in angina? (or when CCBs/β-blockers are contraindicated)
Organic Nitrate Vasodilators
Ivabradine (iF current inhibitor)
Nicorandil
Ranolazine
Isosorbide Mononitrate, Isosorbide Dinitrate, Glyceryl Trinitrate & Sodium Nitroprusside are example of what type of drugs?
Nitric Oxide Donors
How do Organic Nitrates work?
Dilation of collateral vessels which increases oxygen supply to ischaemic myocardium
Systemic Vasodilation dramatically decreases preload and slightly decreases afterload which ultimately decreases the cardiac oxygen demand
In stable angina, what are the treatments for: acute pain, and prevention?
Acute Pain: Short lasting GTN sublingual spray
Prevention: Long lasting isosorbides (orally)
What is the first line treatment in unstable angina?
GTN IV infusion
What is the first line treatment for variant angina?
Nitrate Vasodilator + Calcium channel blocker
What are the side effects or Ivabradine?
Blurred vision
Bradycardia
AV Block
Arrythmias
What the mechanisms behind the drug “Nicorandil”?
Activates vascular ATP-sensitive K+ channels
Release NO => increases cGMP
How does Ranozaline work?
Inhibits late Na+ channels
What are the therapeutic uses for Ranozaline?
In unstable angina
Protects cardiac muscles from ischaemic damage
What characterises a STEMI?
ST elevation on the ECG
There are two types of NSTEMI, what are they?
ST-depression
T-inversion
There are prophylaxis for unstable angina. What are they?
Aspirin: 300mg loading dose, and continue indefinitely
Fondaparinux: patients who do not have a high bleeding risk
Unfractioned heparin: if angiography is likely within 24 hours
What are the antiplatelet agents and what are their mechanism of action?
Aspirin: COX-1 Inhibitor
Clopidogrel: ADP Receptor antagonsist
Dipyramidole: Phosphodiesterase Inhibitors
ABCIXIMAB, Eptifibatide, Tirofiban: Glycoprotein IIb/IIIa inhibitors
What are the therapeutic indications of Aspirin?
Primary prevention of Acute Coronary Syndrome (ACS)
In unstable angina (300mg loading dose)
Secondary prevention of Myocardial Infarction
What is the mechanism for Clopidogrel?
Irreversible block of Gi-coupled P2Y12 receptors
How does Dipyramidole work?
Decreased platelet activation and aggregation.
Vasodilation
What are the different anticoagulants?
Heparin and LMWHs Fondaparinux Rivaroxaban Huridin Dabigatran Etexilate Warfarin
What are the side effects of Heparin?
Bleeding
Immune Thrombocytopenia
Osteoporosis
Hypersensitivity
What is the antidote for Heparin?
Protamine Sulfate
What is Fondaparinux used for?
Acute Coronary Syndromes (eg. STEMI, NSTEMI, Unstable Angina)
Stroke
Deep Vein Thrombosis
Pulmonary Embolism
Used as a prophylaxis of venous thromboembolism
How does Rivaroxaban work?
Selective factor Xa inhibitor
What are the direct thrombin inhibitors?
Huridin
Dabigatran
Etexilate
What therapeutic uses do direct thrombin inhibitors have?
Prevention of stroke and embolism
Prophylaxis of venous thromboembolism
How to Warfarin work?
Inhibits Vitamin K reductase which prevents clotting.
What is the antidote to Warfarin
Vitamin K
What are the drugs used to lower lipid concentrations in the body?
Statins Ezetimibe Fibrates Bile Acid Binding resins Nicotinic Acid
What are the NET effects of statins?
Significantly reduce LDLs
Increases HDLs
Give three example of statins.
Simvastatin
Atorvastatin
Pravastatin
How does Ezetimibe work?
Decreases cholesterol absorption
What are the NET effects of Fibrates?
Increase in lipoprotein lipase activity
Increased in HDL synthesis
Increase in β-oxidation of fatty acids
Give two examples of Fibrates.
Fenofibrate
Gemfibrozil
What are the bile acid binding resins?
Colestyramine
Cholesterol
What are the benefits and drawbacks of bile acid binding resins?
Benefit: Decrease LDL
Drawbacks: No increase in HDL
Increase in triglycerides
What are the effects of nicotinic acid?
Decrease LDL
Increase HDL
What are the three stages of clinic blood pressure?
Stage 1: 140/90 mmHg
Stage 2: 160/100 mmHg
Stage 3: 180/110 mmHg
According to the NICE Hypertension guidelines, what is the first line treatment for a non-black, younger than 55 year old person suffering from hypertension?
ACE Inhibitor
According to the NICE Hypertension guidelines, what is the first line treatment for a black OR older than 55 year old person suffering from hypertension?
Calcium Channel Blocker
Activation of the Renin-Angiotensinogen-Angiotensin-System (RAAS) causes what physical changes in the body?
Vasoconstriction Salt Retention (Increased Aldosterone = Increased Na+ Absorption)
Give two examples of ACE Inhibitors
Captopril and Enalapril
What is the most common ADR from taking ACE Inhibitors?
Dry Cough
Give two examples of Angiotensin Receptor (AT1) Blockers
Losartan
Candesartan
Give an example of a Renin Inhibitor
Aliskiren
What are the selectivities of the Calcium Channel Blockers?
Nifedipine & Amlodipine - VASCULAR
Verapimil - CARDIAC
Diltaziem - INTERMEDIATE
Thiazides used alongside ACE Inhibitors and Calcium Channel Blockers are used as second-line treatment for what?
Hypertension (according to the NICE guidelines)
How do β-blockers act to treat hypertension?
Reduces the sympathetic drive to the heart which lowers the heart rate
Blocks juxtaglomerular β-adrenoceptors which reduces renin secretion
What is different about Nebivolol in comparison to the other β-blockers?
Uniquely stimulates Nitrous Oxide in the endothelium
How do α-adrenoceptor antagonists act to treat hypertension?
Dilates the arteries which causes the reduction in total peripheral resistance
Dilates the venous capacitance vessels which ultimately decreases preload
How do the ‘Directly-Acting Vasodilators’: Minoxidil and Diazoxide work?
They activate the ATP-sensitive K+ channels
This causes membrane hyperpolarisation which will close off the L-VDCCs.
Closure of said channels causes vasorelaxation and thus a decrease in Total Peripheral Resistance meaning a lower blood pressure.
