Drugs

Question 1

Angiotensin-Converting Enzyme Inhibitors (ACEIs)

Answer 1

• Inhibitors of the angiotensin-converting enzyme (ACE)
• Prototype: ramipril
  INDICATIONS:
• Hypertension (HTN)
• Chronic congestive heart failure (CHF)
• After myocardial infarction (MI)

Question 2

MOA of ACEIs

Answer 2

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).

Question 3

Angiotensin Receptor Blockers (ARBs)

Answer 3

• 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

Question 4

MOA of ARBs

Answer 4

• 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

Question 5

Direct Renin Inhibitors

Answer 5

• Agents that directly inhibit renin, an enzyme in the RAS
• Prototype: aliskiren
  INDICATIONS:
• HTN
• Chronic congestive heart failure (currently being investigated)

Question 6

MOA of Direct Renin Inhibitors

Answer 6

• 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.

Question 7

Sodium Channel Blockers (Class I Antiarrhythmics)

Answer 7

- 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

Question 8

MOA of Sodium Channel Blockers

Answer 8

• 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.

Question 9

β Antagonists (β-Blockers)

Answer 9

• 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.

Question 10

MOA of β-Blockers for HTN

Answer 10

• 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.

Question 11

MOA of β-Blockers for Tachycardia and Arrhythmia

Answer 11

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.

Question 12

MOA of β-Blockers for Myocardial Ischemia and Infarction

Answer 12

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

Question 13

MOA of β-Blockers for Chronic Congestive Heart Failure

Answer 13

• 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.

Question 14

Potassium Channel Blockers (Class III Antiarrhythmics)

Answer 14

• 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

Question 15

MOA of K channel blockers

Answer 15

• 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.

Question 16

Calcium Channel Blockers 
(non-DHPs ,but not the DHPs, are class IV antiarrhythmics)

Answer 16

• 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

Question 17

MOA of CCBs on HTN

Answer 17

• 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.

Question 18

MOA of CCBs on Tachycardia and Arrhythmia

Answer 18

• 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.

Question 19

Anticholinergics

Answer 19

• Prototype: Atropine
  INDICATIONS
  Cardiovascular
• Sinus bradycardia with hypotension
• May be useful in second-degree heart block causing bradycardia
• Usually not effective in third-degree heart block, but can be tried
• Treatment of anticholinesterase side effects (common) or poisoning (rare)

Noncardiovascular

• To dry oral and bronchial secretions (for bronchoscopy)
• To relax the bladder (see also section on anticholinergics and overactive bladder)

Question 20

MOA of Anticholinergics

Answer 20

• Anticholinergics block the activity of ACh of the parasympathetic system at muscarinic receptors (M).
• With respect to the CV system, this effect is most pronounced on the SA node and AV node, resulting in increased pacemaker rates of the SA node and sometimes increased conduction through the AV node.
• The primary result is a faster HR. The effect of AV node conduction is not clinically important unless a conduction block such as first-, second-, or third-degree AV block is present.
• Atropine does not preferentially act on cardiovascular tissues.

Question 21

Adenosine

Answer 21

• Adenosine is an antiarrhythmic that does not fall into the Vaughan Williams classification (class I to IV) scheme.
  INDICATIONS
• Adenosine is used for the diagnosis and treatment of supraventricular tachycardias (SVTs).

Question 22

MOA of Adenosine

Answer 22

• Adenosine stimulates adenosine A1 receptors in the AV node, which results in:
  ▴ Increased outward K+ currents
  ▴ Decreased inward Ca+2 currents
  ▴ Decreased inward Na+ currents (If)
• These ionic actions hyperpolarize the cell (i.e., make the inside of the cell more negative because there are fewer positive ions inside the cell) and render it refractory for a prolonged period (a few seconds or more).
• Essentially, the AV node is completely turned off for a brief period of time, creating a third-degree heart block for a few seconds. Through this action, tachycardias that originate in the atria can be diagnosed more easily because all the QRSs are absent from the ECG for a few seconds.
• Because the AV node is turned off, any reentry circuit that was originating inside or travelling through the AV node will be terminated.

Question 23

Digoxin

Answer 23

• Digoxin is classified as a cardiac glycoside. It is an inotrope that does not have its effects mediated through β receptors.
• Digoxin is also loosely classified as an antidysrhythmic.
  INDICATIONS
• CHF (third-line drug in adults, first-line drug in children)
  ▴ Digoxin increases contractility.
• Atrial fibrillation
  ▴ Digoxin decreases AV node conduction and slows the ventricular rate.

Question 24

MOA of Digoxin

Answer 24

Digoxin has two mechanisms of action:
1. Inotropic action:
▴ Through the action of Na/K/ATP ion pump blockade, the following sequence of ionic events occurs:
↓ Na exits the cell
↑ Intracellular Na
↓ Na electrochemical gradient for Na-Ca exchanger
↓ Ca exits the cell
↑ Intracellular Ca
▴ The increase in intracellular calcium results in increased contractility, SV, and CO.
▴ In heart failure, sympathetic tone is increased as a compensatory mechanism to increase CO. Digoxin increases contractility and hence SV and CO, therefore reducing the need for sympathetic compensation; thus digoxin reduces the sympathetic tone in heart failure.
2. Increased parasympathetic nervous system activity:
▴ Digoxin sensitizes arterial baroreceptors in the carotid sinus and activates the vagal nuclei (in the brainstem). These baroreceptors induce a response via the vagus nerve that decreases HR and causes vasodilation when the receptors are stretched. HR decreases owing to increased parasympathetic tone of the SA and AV nodes. By this mechanism on the AV node, digoxin is useful in patients with atrial fibrillation.

Question 25

Statins

Answer 25

- Statins are designed to reduce low-density-lipoprotein (LDL) cholesterol and raise HDL cholesterol. -Prototype: atorvastatin, simvastatin INDICATIONS -Used as first-line agents in the management of hyperlipidemia

Question 26

MOA of Statins

Answer 26

- These drugs are HMG-CoA reductase inhibitors. HMG-CoA reductase mediates the first step in the biosynthesis of cholesterol. - Reduced biosynthesis of cholesterol causes an increase in the number of LDL receptors, through the actions of sterol regulatory element binding proteins (SREBPs). Additional LDL receptors increase the catabolic rate of LDL, and the liver's extraction of LDL precursors. These actions reduce the plasma pool of LDL. - Other effects of statins include the following: ▴ Small increase in plasma HDL (approximately 5%) ▴ Reduction in plasma triglycerides by 10% to 25%

Question 27

Inotropes and Pressors

Answer 27

``` - An inotrope is a drug that results in an increase in inotropy (contractility). Pressors are drugs that primarily cause vasoconstriction. Both drugs are given to increase BP in an attempt to maintain adequate organ perfusion. COMMON DRUGS: - Dopamine - Dobutamine - Norepinephrine - Epinephrine - Phenylephrine ```

Question 28

MOA of Inotropes and Pressors

Answer 28

- These drugs all exert their actions via the autonomic nervous system α and β receptors. In addition to these receptors, dopamine acts via dopaminergic (DA) receptors. - Drugs that are β1 agonists are inotropes; drugs that are α1 agonists are pressors. Activation of DA receptors results in mesenteric and renal vasodilation. β2 agonists are vasodilators on skeletal muscle. - β1 agonists increase CO - α1 agonists cause SM contraction leading to vasoconstriction - dobutamine is an inotrope; Norepinephrine and phenylephrine are primarily pressors; Epinephrine and dopamine are both pressors and inotropes.

Question 29

Nitrates

Answer 29

- Nitrates are agents that release nitric oxide (NO). - Prototype: nitroglycerin (NTG) INDICATIONS - Stable angina: treatment and prevention - Acute coronary syndromes: ▴ Unstable angina ▴ Acute MI - CHF - Hypertensive emergency - To decrease uterine muscle tone (a less common use): ▴ To treat premature labor ▴ To treat fetal distress caused by high uterine contraction

Question 30

MOA of Nitrates

Answer 30

- NO, also known as endothelium-derived relaxing factor (EDRF), induces vasodilation primarily on the venous side of the circulation (venodilation). It does this by activating guanylyl cyclase, an enzyme that produces cGMP, which decreases Ca+ entry into cells and causes relaxation of vascular smooth muscle. - This venodilatory effect produces a pooling of blood in the venous capacitance vessels, resulting in a reduction in venous return, preload, and end diastolic pressure, which: ▴ Lowers ventricular wall tension and reduces oxygen demand ▴ Improves the coronary pressure gradient ▴ These two mechanisms improve the supply-demand balance of the myocardium and are the primary mechanisms by which NTG relieves angina

Question 31

Vasodilators

Answer 31

- Vasodilators cause dilation of arterioles and, to a lesser extent, veins. - Prototype: Hydralazine INDICATIONS - HTN

Question 32

MOA of Vasodilators

Answer 32

- The underlying mechanism of vasodilation of arteriolar smooth muscle by the direct vasodilators is still not confirmed, but theories include interference with the release of Ca+2 from the SR and activation of potassium channels. - Hydralazine is not a coronary artery dilator and is not a venodilator; Hence, it will have no effect on preload. For this reason it is not a very useful drug for treatment of chronic heart failure.

Question 33

Natriuretic Peptides

Answer 33

- Also called natriuretic factors, natriuretic peptides are endogenous hormones that are used to treat heart failure. The drug is recombinant human brain natriuretic peptide (BNP). - Prototype: Nesiritide INDICATION - Advanced decompensated acute heart failure

Question 34

MOA of Natriuretic Peptides

Answer 34

- Endogenous natriuretic factors are increased during heart failure in response to atrial stretch and ventricular stretch, when the chambers are volume overloaded because of heart failure. - BNP binds to BNP receptors on blood vessels and kidneys, which activates the cGMP system, resulting in the following effects: ▴ Blood vessels: vasodilation ▴ Kidneys: natriuresis and diuresis ▴ Kidneys: inhibition of renin and aldosterone - Through these effects, the abnormally high preload of the heart is reduced and abnormally high afterload (vasoconstriction) is also reduced. Both reduction of preload and reduction of afterload are important components of treating patients with heart failure

Question 35

Ramipril

Answer 35

Angiotensin-Converting Enzyme Inhibitors (ACEIs)

Question 36

Losartan

Answer 36

Angiotensin Receptor Blockers (ARBs)

Question 37

Aliskiren

Answer 37

Direct Renin Inhibitors

Question 38

Propranolol

Answer 38

β Antagonists (β-Blockers)

Question 39

Amiodarone

Answer 39

Potassium Channel Blockers (Class III Antiarrhythmics)

Question 40

Amlodipine

Answer 40

Calcium Channel Blockers

Question 41

Atropine

Answer 41

Anticholinergics

Question 42

Adenosine

Answer 42

Antiarrhythmic

Question 43

Digoxin

Answer 43

Inotrope

Question 44

atorvastatin/simvastatin

Answer 44

Statins

Question 45

Nitroglycerin

Answer 45

Nitrates

Question 46

Hydralazine

Answer 46

Vasodilators