CAM201 Cardiovascular Drugs Flashcards
Describe the cellular mechanisms of CCBs
Calcium channel blockers are L-type calcium channel antagonists. They inhibit calcium entry into the cell.
As antagonists, they prevent the normal intracellular pathways from occurring, resulting in relaxation of smooth and cardiac muscle.
Normal Smooth muscle cells: Normally, Ca++ enters the cell, and binds to calmodulin. Calmodulin then activates MLCK, which phosphorylates the myosin heads. This causes cross-bridge cycling and consequent contraction.
CCBs inhibit this pathway by blocking L-type Ca++ channels.
Normal Cardiac Muscle Cells: Normally, Ca++ enters the cardiac cell, and binds to troponin, which is attached to tropomyosin. When Ca++ binds to troponin, this results in a conformational change in troponin’s position, which reveals the myosin binding site on actin. Thus, cross-bradige cycling can occur, and contraction occurs.
CCBs inhibit this pathway by blocking L-type Ca++ channels
What are the types of CCBs and how do they differ?
How does this affect their indications?
CCBs are also Class IV Anti-arrhythmics (Verapamil is chiefly used for arrhythmias)
Dihydropyridines (Nifedipine, Felodipine, Amlodipine) act mainly on vascular smooth muscle (Angina, HTN)
Phenylalkylamines (Verapamil) acts mainly on cardiac tissues, primarily at the SA and AV nodes (thus good for supraventrilular arrhythmias).
Benzothyazapines (Diltiazem) act on both smooth and cardiac muscle, but do not affect cardiac muscle to the same extent as Verapamil. Angina, HTN, Arrhythmias.
CCBs: Chronotrope and Inotropes?
Negative inotrope:
- Reduced Ca++ entry into the cell results in engagement of fewer fibres, and thus reduced contractility
Negative chronotrope:
By delaying the ‘plateau’ phase (phase 2) of depolarisation, CCBs slow HR
CCB: Effect on the cardiac cycle
By inhibiting (slowing) the intake of Ca++ into smooth muscle and cardiac cells, CCBs extend the ‘plateau’ (phase 2) phase, effectively slowing re-polarisation and increasing the refractory period. This is how phenylalkylamines aid arrhythmias.
Describe the cellular mechanisms of BBs
BBs antagonise SNS activity by acting as competitive antagonists of B1 and B2 receptors on cardiac and smooth muscle, respectively. They prevent the binding of NA/A.
The net effect is a reversal of normal sympathetic activity. Thus, BBs cause contraction in smooth muscle, and relaxation in cardiac muscles.
Normal Smooth Muscle Cells: When A or NA binds to B2, this activates Adenylate Cyclase, which converts ATP to cAMP. cAMP up-regulates PKA, which consequentially inhibits the action of MLCK. Thus, myosin heads are not phosphorylated, cross-bridge cycling does not occur, and the smooth muscle relaxes.
BBs prevent this intracellular pathway by preventing NA and A from binding to B2. Thus, causing smooth muscle contraction.
Normal Cardiac Muscle Cells: When A or NA bind to B1, this activates Adenylate Cyclase, which converts ATP to cAMP. cAMP then up-regulates PKA. In cardiac cells, PKA increases Ca++ entry into the cell, resulting in contraction.
BBs prevent this intracellular cascade by preventing NA/A from binding to B1. Thus, causing Cardiac Muscle Relaxation.
What are the different types of BBs?
How does this affect their indications?
Non-specific BBs bind B1 and B2 equally: Propanolol, Carveidilol (which is also an alpha 1 antagonist), Sotalol (also a Class III).
Cardio-specific: bind B1 preferentially: Metoprolol, Atenolol, Bisoprolol, Nebivolol.
*At high doses, even B1-selective BBs will start to bind B2 as well
Generally speaking, non-selective BBs are contra-indicated in asthma, although all BBs should be used with caution.
BBs Effect on the cardiac Cycle:
As BBs decrease the rate of Ca++ into the cell by inhibiting SNS output, they slow the ‘pacemaker potential’ phase (phase 4) of the cardiac cycle. Thus they can also be used in arrhythmias - chiefly affect at SA and AV nodes.
BBs: Chronotropes and Inotropes
Negative Inotrope (decreased contractility)
Negative Chronotrope
Because they decrease Ca++ entry into the cell, there is less cytoplasmic Ca++, and thus less fibres are engaged - this reduces contractility.
Because they slow the development of pacemaker potential, they also slow HR.
Describe the cellular mechanism of Alpha Agents
Alpha Agents antagonise SNS activity. They cause relaxation of smooth muscle.
Alpha 1 receptors are located in the walls of Smooth Muscle Cells. Under Normal Conditions, NA/A bind to A1. This results in activation of Phospholipase C, which activates Inosistol Triphosphase and Diacyglycerol. This results in an increase in intracellular Ca++ and contraction occurs.
Alpha 1 antagonists inhibit this intracellular pathway by blocking A1 receptors. This results in smooth muscle relaxation.
Alpha 2 receptors are located on the walls of pre-synaptic terminals. Under normal conditions, NA/A bind to A2, and inhibit Adenylate cyclase, thus ATP is not converted to cAMP, and PKA is not up-regulated. This results in inhibition of Ca++ intake. Decreased intracellular Ca++ results in decreased exocytosis of NA and A.
Alpha 2 Agonists mimmic this effect, to reduce the amount of NA/A exocytosis, to further ensure smooth muscle relaxation.
What are the types of Alpha Agents?
Alpha 1 Antagonists: Prazosin (Also Carveidilol which is a non-selective BB)
Alpha 2 Agents: Methyldopa, Clonidine, Monoxidine
What are the effects of Alpha Agents?
By causing smooth muscle relaxation, Alpha Agents cause systemic vasodilation, thus lowering blood pressure.
Because they are specific for A1 and A2 (not B1 and B2), they do this without causing cardiac interference.
Describe the systemic effects of Nitrates
Nitrates cause relaxation of smooth muscle. Thus, they are used for HTN but chiefly for Angina.
By relaxing smooth muscle, nitrates cause vasodilation. Low doses of nitrates cause venous vasodilation and high doses of nitrates cause venous and arterial vasodilation.
Vasodilation results in increased pooling in circulation, resulting in decreased return to the heart - reduced preload.
Vasodilation also results in decreased peripheral resistance (lowers BP) - reduces afterload.
Thus, the heart does not have to contract as hard, and myocardial O2 demand is reduced.
Concurrently, nitrates also cause dilation of coronary arteries, increasing blood flow to the myocardium.
Thus, nitrates can be used for Angina and HTN
Describe the Cellular Mechanisms of Nitrates
Nitrates are metabolised into NO, which enters smooth muscle cells.
Within the SMC, NO activates Guannylate Cyclase, which converts GTP to cGMP
cGMP then up-regulates PKG, which causes decreased Ca++ entry into the cell
PKG also causes dephosporylation of myosin heads, so that cross-bridge cycling cannot occur
Overall, this results in smooth muscle relaxation
Types of Nitrates and their indications
GTN: sublingual spray or tablet.
GTN is rapidly inactivated by first-pass hepatic metabolism, thus it is administered as a sublingual spray or tablet.
Tablets are more volatile, and thus the sublingual spray is more commonly used.
GTN is most commonly used to relive symptoms of Angina.
Regular GTN use can lead to a build of NO in the body, and subsequent desensitisation to the effects of GTN. A 12-hour free period is required to rectify this.
Isosobide Mononitrate/Dinatrate are administered as tablets, mainly for angina prophylaxis. They are metabolised into active compunds, thus are longer lasting and can be used as prophylaxis.
Types of Renin-Angiotensin System Inhibitors and their indications
RAS inhibitors = ACE Inhibitors, and Angiotensin II Receptor Blockers
Under normal conditions the RAS synergises with the SNS to increase BP
Evidence suggests that HTN often arises from inappropriate RAS activity, raising BP
ACEI and ARBS result in decreased circulating blood volume, vasodilation, and inhibition of mediators that lead to heart and vasculature hypertrophy and hyperplasia
They are first-line for HF, and are also commonly used in HTN
Describe the Cellular Mechanisms of RAS Inhibitors
Under normal conditions, the RAS acts (in synergy with the SNS) to increase BP
In response to decreased filtration in the kidneys (ideally, secondarily to decreased BP), the juxtaglomerular cells in the kidneys release Renin
In the blood, Renin converts Angiotensinogen into Angiotensin I
In the lungs, ACE converts Angiotensin I into Angiotensin II
Angiotensin then binds to AT1 and AT2 receptors to cause systemic effects:
1) Increased production and secretion of Aldosterone from the Adrenal gland, which results in increased Na+ resorption (increasing blood volume), and the secretion of ADH which causes thirst.
2) Causes vasocontriction
3) Causes hypertrophy and hyperplasia of the heart and vasculature
ACEI are competitive inhibitors of ACE. They have a higher affinity for ACE than Angiotensin I. Thus, they bind to ACE and prevent it from converting Angiotensin I into Angiotensin II - this prevents all sequential occurrences in the RAS.
ARBS bind to AT1 and AT2 receptors, preventing Angiotensin II from binding. This prevents the occurrence of all systemic effects resulting from the binding of Angiotensin II and AT1/AT2.
Diuretics: Cellular mechanisms
Diuretics decrease the reabsorption of Na+ and Cl- in the kidney, leading to increased Na+ and Cl- excretion in the urine.
By extension, this causes increased water excretion, as water follows down an osmotic gradient.
There are three main types of Diuretics:
Thiazides, Loop Diuretics and K-sparing Diuretics
Describe the Cellular Mechanisms of Thiazides
Thiazides act by binding to the Cl-/Na+ co-transporter proteins in kidney epithelial cells.
They inhibit Na+ movement back into the bloodstream.
By affecting Na+ movement, Thiazides also indirectly affect the Na+/K+ pump, leading to increased K+ excretion.
Increased ionic excretion leads to increased fluid excretion (osmotic gradient)
Thiazides also have a vasodilatory effect which isn’t quite understood
Can cause hypokalaemia
Often best to use Thiazides with K-sparing diuretics, which decrease K+ excretion at the distal nephron
Describe the Cellular Mechanism of Loop Diuretics
Loop diuretics are High-ceiling diuretics. They are the most powerful, causing a 15-25% excretion of filtered Na+.
Loop Diuretics Bind to the Cl- binding site on Cl-/Na+/K+ transport pumps, preventing the reabsorption of Na+ and Cl-
Also best used with K-sparing diuretics which decrease K+ excretion at the distal nephron
*Also cause massive loss of Ca+ and Mg
Loop Diuretics are the diuretic of choice for HTN treatment
Describe the cellular mechanisms of K-Sparing Diuretics
K-sparing diuretics block Na+ reabsorption at the distal nephron, resulting in increased Na+ excretion.
K-sparing diuretics decrease K+ excretion
K-sparing diuretics have much less diuretic affect than Loops or Thiazides, as they only act on the distal nephron.
They are often used in conjunction with Loops and Thiazides to prevent Hypokalaemia
Diuretics: Types and Indications
Thiazides:
Chlorthalidone, Hydrochlorothiazide, Indapamide, Bendrofluazide
Loop Diuretics: Frusemide, Piretenide, Etharynic Acid, Bumetanide
K-Sparing: Spironalactone, Amiloride, Triamterene
Used in HTN (Loops = first line) and careful use of diuretics is also implicated in HF
How do Class I Anti-arrhythmics work?
Class I Anti-arrhythmics bind to (and block) Na+ voltage-gated ion channels during phase 0 (depolarisation).
Thus, they prolong AP, and also increase refractory period.
Depending on the specific drug, they bind Na+ voltage gated channels in their open (lignocaine) or closed (Quinidine, Flecainide) states.
There are 3 subclasses: 1a, 1b, 1c.
Class 1a cellular mechanism
Quinidine binds to voltage-gated Na+ channels in their open state, thus slowing phase 0 (depolarisation). By remaining attached to Na+ for a given time, Quinidine also increases refractory period.
Does not differentiate between healthy and diseased tissue - has pro-arrhythmic effect, like all anti-arrhythmics
Class 1b cellular mechanism
Lignocaine binds to voltage-gated Na+ channels in their open and closed states. Lignocaine has a rapid dissociation time, thus it manages to differentiate between normal and diseased tissue: Lignocaine dissociates within the timeframe of a normal heartbeat, thus it only prevents abnormal beats.
Lignocaine increased AP time and Refractory period.
Relatively low pro-arrhythmic effect due to rapid dissociation.
Best choice for ventricular arrhythmias.
Class 1 c cellular mechanism
Flecainide binds to voltage-gated Na+ channels, slowing AP and increasing refractory period.
Flecainide has a very slow dissociation timeframe: 3-5 normal heartbeats. Thus, has an extreme pro-arrhythmic effect.
Class III actions, and which drugs
The Class III action is the delaying of phase 3 of the AP (repolarisation) by inhibiting K+ influx into the cell.
This results in an extended refractory period.
Amiodarone = also posesses characteristics of Class I, Class II (BB) and Class IV (CCB) drugs
Sotalol = which is also a non-selective BB
Cellular Mechanisms of Amiodarone
Class III action: Prolongs refractory period by prolonging phase 3 of AP - repolarisation. Does this by inhibiting K+ influx into the cell. Affects all cardiac tissues.
Class I action: Prolongs phase 0 of action potential - depolarisation - by blocking Na+ voltage-gated channels, thus slowing the rate of depolarisation.
Class II action: Blocks B receptors
Class IV action: Decreases Ca++ influx via blocking l-type Ca++ channels, thus relaxing both smooth and cardiac muscle
Overall effects:
1) Prolongs AP and refractory period - negative chronotrope
2) Decreases contractility - Negative Inotrope
3) Relaxes smooth muscle, causing vasodilation
Serious Adverse Side effects:
Lung fibrosis: amiodarone complexes are deposited in lung, which leads to antigen-antibody reactions resulting in fibro-collagenous healing - lung fobrosis.
Remember Amiodarone also requires loading dose due to its very long half-life. Thi is also a risk - as amiodarone stays in the body for so long, serious adverse effects can occur long-term after very few doses.
Cellular Mechanisms of Sotalol (in light of its Class III effects)
Solatlol is a non-selective BB as well as a Class III.
Thus, it antagonises SNS activity by blocking B1 and B2 receptors. It also prolongs AP/refractory period in all cardiac tissues via its Class III effect: inhibiting influx of K+ during phase 3, thus prolonging repolarisation.
Describe the cellular mechanisms of Digoxin
Digoxin = Class V (un-classed) Anti-arrhythmic
Has a positive inotrope and negative chronotrope effect. Thus fewer, but more forceful, contractions.
Digoxin competes with K+ for the K+ binding spot on the Na+/K+ ATPase pump in cardiac muscles.
This results in an increase in intracellular Na+, which causes a decrease in Na+/Ca++ exchange, resulting in increased intracellular Ca++ levels.
Increased Ca++ levels gives Digoxin its’ Positive Inotrope effect.
Digoxin is also, however, a negative chronotrope via indirectly increasing vagal tone.
Thus, there are fewer, but more forceful, contractions.
Digoxin is good for rate control in AF
Describe the cellular mechanisms of Adenosine
Adenosine is a Class V (Un-classed) Anti-arrhythmic.
Adenosine acts on A1-adrenergic and M2 receptors at the AV node
Adenosine reduces K+ efflux from the cell, resulting in a decrease in cAMP-induced Ca++ influx
By this mechanism, Adenosine slows conduction at the AV node
Adenosine is thus useful in treatment of Acute Supraventricular Tachycardia
Describe the cellular mechanisms of Isoprenaline
Isoprenaline is a Class V (un-classed) Anti-arrhythmic.
Isoprenaline is a potent B1 and B2 Agonist - i.e. it increases SNS activity
It has a positive inotropic and positive chronotropic effect.
Isoprenaline is used in shock, bradycardia and heart block
In Smooth Muscle: Isoprenaline binds to B2 receptor and mimics the normal effect of NA/A. Activation of Adenylate cyclase, which converts ATP and cAMP, which up-regulates PKA, which blocks MLCK from phosphorylating myosin heads, thus inhibiting cross-bridge cycling. Causes smooth muscle cell relaxation - vasodilation
In cardiac cells: Isoprenaline binds to B1 receptors and mimics the normal effects of NA/A. Activation of Adenylate Cyclase, which converts ATP to cAMP, which up-regulates PKA, which increases Ca++ entry to cell. This causes cardiac muscle contraction. The increased amount of Ca++ into the cell also causes a positive inotrope effect as more fibres are engaged.
