Drugs Flashcards
Angiotensin-Converting Enzyme Inhibitors (ACEIs)
- Inhibitors of the angiotensin-converting enzyme (ACE)
- Prototype: ramipril
INDICATIONS: - Hypertension (HTN)
- Chronic congestive heart failure (CHF)
- After myocardial infarction (MI)
MOA of ACEIs
Through inhibition of ACE with an ACEI, the following effects occur:
1. Lower levels of angiotensin II are produced.
- Angiotensin II is a direct vasoconstrictor.
- Angiotensin II results in aldosterone secretion, which causes Na and water reabsorption in the kidney.
2. Higher levels of bradykinin are produced.
- Bradykinin is a vasodilator.
Net result: Because AII levels are lower and bradykinin levels are higher, there is more vasodilation; SVR (systemic vascular resistance) and afterload are lowered. Because aldosterone levels are lower, less Na and water are reabsorbed in the kidney; therefore preload is reduced (Figure 11-1).
Angiotensin Receptor Blockers (ARBs)
- ARBs antagonize the angiotensin receptor
- Prototype: losartan
INDICATIONS: - Hypertension (HTN)
- Chronic congestive heart failure (CHF)
- For patients who require an ACEI but cannot tolerate it because of cough
MOA of ARBs
- ARBs are antagonists of the angiotensin-1 (AT1) receptor. Therefore they block the actions of AII.
- AII is a vasoactive hormone that induces vasoconstriction and stimulates the secretion of aldosterone by the adrenal cortex, which results in sodium and water retention.
- Blocking AT1 results in vasodilation, natriuresis (renal loss of sodium), and diuresis (renal loss of water).
- Effects of ARBs are downstream of ACE.
- ARBs have no effect on bradykinin levels. Because bradykinins are vasodilators, ARBs might not produce as much vasodilation as ACEIs.
- Conversely, ACE is not the only enzyme that forms angiotensin II. Thus ARBs might provide more complete inhibition of the vasopressor activity of AII compared with ACEIs
Direct Renin Inhibitors
- Agents that directly inhibit renin, an enzyme in the RAS
- Prototype: aliskiren
INDICATIONS: - HTN
- Chronic congestive heart failure (currently being investigated)
MOA of Direct Renin Inhibitors
- Renin is an enzyme released from the kidneys that converts angiotensinogen to angiotensin I. Considered the rate-limiting step in the formation of AII.
- Renin and its inactive precursor, prorenin, are stored in the juxtaglomerular cells of the kidney. Renin is released in response to three different stimuli:
▴ Change in Na and Cl reabsorption at the macula densa
▴ Change in BP (via the baroreceptor pathway)
▴ β1-receptor stimulation - AII performs two main functions via the AT1 receptor:
▴ Direct vasoconstriction
▴ Stimulation of aldosterone secretion which leads to Na+ and H2O reabsorption - Other agents that target the RAS, such as the ACEIs and ARBs, elicit a compensatory increase in plasma renin activity, resulting in increased binding of AII to AT1 receptors and other AT receptors.
Sodium Channel Blockers (Class I Antiarrhythmics)
- Na channel blockers are Vaughan Williams class I antiarrhythmics. There are three subclasses: Ia, Ib, and Ic. Prototypes: Class Ia: procainamide, disopyramide, and quinidine Class Ib: lidocaine Class Ic: propafenone and flecainide
MOA of Sodium Channel Blockers
- Na channels are blocked, so Na+ movement during phase 0 of action potential is inhibited. Results in “slow” phase 0, causing a wider (and slower) QRS wave on the electrocardiogram (ECG). The net result is slower conduction.
- Phase 3 can be longer or shorter, depending on the subclass (a, b, or c).
- Changing the duration of the action potential influences the QT interval (distance from the QRS to the T wave). This distance is the refractory period of the ECG. Therefore changing the action potential durations will change the refractory times of atrial, Purkinje or ventricular tissues.
- Because abnormal electrical circuits require a delicate balance between conduction speed and refractory times, changing these parameters will sometimes terminate dysrhythmias or create new ones.
β Antagonists (β-Blockers)
- β-Blockers antagonize β receptors of the SNS.
Prototype: Propranolol - β-Blockers are a heterogeneous family and can be subclassified according to the receptors they antagonize (it is important to know which are β1 selective):
▴ Cardioselective (β1): atenolol, metoprolol, nebivolol, esmolol
▴ Noncardioselective (β1, β2): propranolol, nadolol, timolol
▴ Mixed α and β: labetolol, carvedolol
▴ Partial agonists (stimulate mildly when receptor is inactive, inhibit when active): pindolol, acebutolol - Selectivity is relative. This means that β1-selective blockers will block β2 receptors, but to a much lower degree than nonselective β-blockers.
MOA of β-Blockers for HTN
- Antagonism of β1 receptors results in reductions in heart rate (HR) and stroke volume (SV). Cardiac output (CO) is therefore reduced, which leads to a reduction in BP.
- In addition, β1 antagonism leads to a reduction in renin secretion, which in turn reduces production of AII.
- β-Blockers also have direct inhibitory effects on the SNS.
MOA of β-Blockers for Tachycardia and Arrhythmia
Depression of the sinoatrial (SA) node (slows automaticity) slowing the SA pacemaker rate.
▴ This mechanism is useful in sinus tachycardia only.
Depression of the AV node (prolongs the refractory period). This mechanism may be able to terminate a reentry circuit that involves the AV node.
MOA of β-Blockers for Myocardial Ischemia and Infarction
Increases oxygen supply to and decreases oxygen demand of the myocardium.
β-Blockers result in the following:
▴ Slower HR = less work = lower oxygen demand
▴ Slower HR = longer diastolic time = more time for myocardial perfusion (which occurs only during diastole)
▴ Lower contractility = less work = lower oxygen demand
▴ Lower BP = less work = lower oxygen demand
MOA of β-Blockers for Chronic Congestive Heart Failure
- Patients with CHF have an inefficient system and thus require extra support such as increased levels of SNS activation, renin-angiotensin activity, endothelin activity, and many other compensatory mechanisms.
- Sustained activation of the SNS results in fibrosis and apoptosis of myocytes.
- Through low level blockade of the SNS, the fibrosis and apoptosis (and other damaging mechanisms) are slowed or inhibited.
- Unfortunately, the long-term (years) gain of using β-blockers in heart failure is often counterbalanced by the short-term (months) worsening of symptoms, and therefore β-blocker titration in CHF must be made carefully and judiciously.
Potassium Channel Blockers (Class III Antiarrhythmics)
- K channel blockers are Vaughan Williams class III antiarrhythmics.
- Prototype: Amiodarone
INDICATIONS - Acute treatment and prevention of atrial fibrillation and flutter
- Acute treatment and prevention of ventricular fibrillation and ventricular tachycardia
MOA of K channel blockers
- Blocking K channels in phase 3 of the action potential slows the efflux of K back out of the myocyte, which slows the rate at which the cell repolarizes and therefore lengthens the plateau phase of the action potential. This increases the refractory period of atrial, ventricular, and Purkinje cells. This also increases the QT interval on the ECG (Figure 11-5).
- Amiodarone contains multiple antiarrhythmic properties and is an Na blocker, a K blocker, a Ca blocker, and β-blocker, all rolled into one chemical. However, it is primarily referred to as a class III drug.
Calcium Channel Blockers (non-DHPs ,but not the DHPs, are class IV antiarrhythmics)
- CCBs are agents that act by blocking calcium channels, either in the heart or on blood vessels. There are two major classes within CCBs: dihydropyridine (DHP) and non-DHP.
PROTOTYPE AND COMMON DRUGS
Dihydropyridines:
Prototype: amlodipine
Nondihydropyridines:
Prototypes: diltiazem, verapamil
MOA of CCBs on HTN
- Calcium channels are designated as L-, T-, P/Q-, N-, and R-type. L means long duration, and T means transient.
- L-type calcium channels are located on the heart, skeletal muscle, neurons, vascular smooth muscle, and uterus.
- All CCBs are antagonists of L-type calcium channels. By blocking the influx of calcium through L-type channels, these agents inhibit contraction of smooth muscle.
- The DHP CCBs have greater selectivity for the vasculature than either diltiazem or verapamil, the non-DHP CCBs.
- DHPs have little effect on the recovery of the calcium channel and thus minimal effects on cardiac Ca channels involved with automaticity (HR), conduction speed, and refractory periods (important with regard to the AV node).
- As a result DHPs have a greater vasodilatory effect than non-DHPs and essentially no direct clinical effect on the heart.
- In other words, DHPs are vasodilators, and non-DHPs are cardiac depressants with some vasodilator activity.
MOA of CCBs on Tachycardia and Arrhythmia
- Non-DHPs are also class IV antiarrhythmics.
- Blocking Ca+2 channels in phase 0 of the action potential lengthens the depolarizing current in SA and AV nodal cells. This results in more time before the next action potential. In the SA node, the result is a slower pacemaker. In the AV node, the result is a longer refractory period.