hale exam 2 lecture 2 part 2 [start angina drug deck] and also lecture 3

Verapamil HCl (Isoptin, Calan, Verelen) therapeutic use

- sustained-release, oral formulations for the treatment of HTN,

- management of chronic stable angina & Prinzmetal's angina

- treatment of AV node dependent supraventricular tachyarrhythmias [PSVT]

Verapamil PK

- significant first-pass metabolism via CYP3A4 oxidation to norverapamil

- norverapamil is active metabolite that contributes to efficacy despite the short half life and poor oral bioavailability of the verapamil

- mostly excreted through kidney and liver as metabolites

- extended release formulation delays time to peak plasma concentration [2 hours to 7 hours]

Verapamil contraindications

- avoid use in patients with severe left ventricular dysfunction

Verapamil warnings/precautions

- can cause or worsen cardiac hypertrophy, heart failure and/or pulmonary edema

Verapamil adverse effects

- patients with liver dysfunction should be monitored for signs of overdosage

Verapamil DDIs

- more significant than those of diltiazem

- caution when co-administering with beta-blockers, antihypertensive drugs, anti-arrhythmia agents

- is a strong inhibitor of CYP3A, so it can cause an increase in plasma levels of other drugs that are significantly metabolized by CYP3A4

Diltiazem HCl (Cardizem)

- sustained release oral formulations for HTN treatment

- management of chronic stable angina

- Prinzmetal's angina

- treatment of AV node dependent supraventricular tachyarrhythmias

diltiazem PK

- significant first-pass metabolism CYP3A4 oxidation to des-acetyl diltiazem, which is an active metabolite that contributes to efficacy

- extended release formulation delays time to peak plasma concentration

diltiazem contraindications

- avoid use in patients following acute MI with pulmonary congestion

diltiazem warnings, precautions and adverse effects

- same as verapamil:

• can cause or worsen cardiac hypertrophy, heart failure and/or pulmonary edema

• patients with liver dysfunction should be monitored for signs of overdosage

diltiazem DDI

- considered to be less significant than those of verapamil

- exposure can be increased if coadministered with CYP3A4 inhibitors

- moderate inhibitor of CYP3A, so it can cause an increase in plasma levels of other drugs that are significantly metabolized by CYP3A4

dihydropyridine in antianginal therapy

- "vasoselective"

- dilate peripheral blood vessels at concentrations below those that decrease hr and contractility

- reflex stimulation [from lowering BP] can lead to an increased hr

- antianginal effect primarily follows afterload reduction

- generally preferred for treating stable angina when only vasodilation desired: treating concurrent htn or if beta blocker co-administered

phenylalkylamines and benzothiazepines [verapamil and diltiazem] in antianginal therapy

- "non-selective"

- dilate peripheral blood vessel and decrease hr and contractility at similar concentrations

- reflex stimulation from lowering BP is offset by cardiac effects

- used to treat stable angina or 1st line of therapy for Prinzmetal's angina

- caution needed if B-blocker co-administered due to potential additive cardiac effects that could lead to risk of bradycardia/conduction block

verapamil/diltiazem antianginal effect primarily follows from...

- afterload reduction

- reduction of myocardial oxygen demand

- reduction of coronary vasospasm

beta-blockers considerations as antianginals

- are 1st line treatments for stable angina

- clinically demonstrated to reduce the severity and frequency of attacks of stable angina and also improve survival post-myocardial infarction

- selective B1-antagonists/blockers are effective additive therapy for unstable angina/angina

why are beta-blockers effective in angina

- decrease in heart rate and systolic bp prolongs myocardial perfusion and increases blood supply to ischemic regions of the heart

why are selective B1-blockers effective additive therapy for unstable angina

- lower myocardial oxygen demand reduces the chance that transient coronary obstruction will trigger ischemia

- buys time for antiplatelet and anti-thrombotic therapies to address underlying plaque/thrombus

why are selective B1-blockers effective additive therapy for angina

- B2 antagonism can drive bronchoconstriction and vascular smooth muscle constriction

- ion channels and specific coupling to receptors in vascular smooth muscle cells could lead to increase in calcium concentrations inside the cell

B2 agonism leads to

- increased cAMP, which decreases myosin phosphorylation and ultimately results in smooth muscle relaxation

beta blockers in angina

- metoprolol, atenolol, bisoprolol, carvedilol

metoprolol in angina

- most commonly used B1 antagonist in the US

- excreted as metabolite through kidney

- may mask tachycardia due to some metabolic disorders, like hypoglycemia and hyperthyroidism

- with prolonged use of beta blockers, your sympathetic nervous system tone goes up and you will have slightly higher basal activity, so if you abruptly stop beta-blocker it can cause rebound hypertension and result in angina pectoris

second most commonly used beta blocker for angina

- bisoprolol

- high selectivity

carvedilol in angina

- nonselective for beta, but also blocks a1 and CCB

- provides stronger BP lowering and moderately potent

NO production and function in vascular tissue

- produced by many cells in the body, including vascular endothelium

- important roles in regulation of blood flow, platelets, immune, GI regulation, as well as CNS signaling

- formed via action of nitric oxide synthase [NOS] on L-arginine

NOS on L-arginine

- activity of NOS is Ca and calmodulin dependent

- NO diffuses to smooth muscle cells where it binds to guanylyl cyclase

- NO can also binds to hemoglobin in the blood, where it is deactivated as nitrate

- NO also deactivated by intracellular oxidants

- net half life of NO is <5 secs

Guanylyl cyclase

- catalyzes the conversion of GTP to cGMP, which regulates vascular relaxation

- exact mechanism unclear, but it involves inhibition of Ca2+ entry into smooth muscle cells

cGMP deactivated by

- phosphodiesterase enzymes

cGMP and vascular relaxation enhancement

- increasing NO availability

- directly activating or enhancing activity of GC

- inhibiting breakdown of cGMP by phosphodiesterases

organic nitrate vasodilators function

- increase NO bioavailability, which is useful to treat angina

- GC stimulators have more utility for treating pulmonary arterial hypertension

- PDE5-is used to treat PAH and erectile dysfunction

contraindications with organic nitrate vasodilators

- both sGC stimulators or PDE5-i due to potential for severe hypotension

organic nitrate esters

- prodrugs that are sources for exogenous NO

- sodium nitroprusside and NO gas can also be used to directly deliver NO

- main effect is preload and afterload remember

Primary cardiovascular effects of organic nitrates on systemic vasculature

- vasodilation affords decrease in pressure [venous > arterial]

Primary cardiovascular effects of organic nitrates on cardiac cells

- decrease in wall stress from reduced preload and afterload

- decrease in O2 demand

Primary cardiovascular effects of organic nitrates on coronary arteries

- prevention/reversal of vasospasm

- vasodilation and improvement of subendocardial perfusion

- increase in O2 supply

organic nitrate prodrugs

- nitroglycerin [GTN, Nitrostat]

- isosorbide mononitrate [ISMN, Monoket]

- isosorbide dinitrate [ISDN]

nitroglycerin [GTN, Nitrostat] metabolism in vascular cells

- GTN is reduced to 1,2-glyceryl dinitrate and nitrite NO2- in the mitochondria by ALDH2

- NO2- requires further bioactivation by either reduction by the respiratory chain or by acidic disproportionation to yield NO

- bioactivated in smooth ER at higher doses

ISMN and ISDN metabolism in vascular cells

- bioactivated by p450 enzymes in the smooth ER directly yielding NO

nitroglycerin

- lots of formulations, but SL is most common

- extremely short half life

- reduced to less vasoactive dinitro- and mononitro metabolites in the liver, RBCs and vascular wall

ISMN (isosorbide mononitrate)

- has extended release formulation to make dosing 2x day instead of every 2-3 hours

- 100% OBA

- longest half life of the organic nitrate vasodilators

- kidney excretes 100% of single dose over 5 days

ISDN (Isosorbide dinitrate)

- when metabolized, there is increased duration of action with NO coming from this compound

- extended release oral capsule extended dosing from 2xday to once daily

- low OBA and somewhat decent half life

- metabolized and excreted via formation of active mononitro metabolites

organic nitrate vasodilators in chronic stable angina

- GTN preferred for rapid treatment or acute prophylaxis before exertion/exercise

- long acting nitrates [ISMN, er-GTN, ISDN] used for prophylaxis in patients with more occasional episodes

organic nitrate vasodilators in variant [Prinzmetal's] angina

- long-acting nitrates used in combination with other agents, like CCBs

organic nitrate vasodilators toxicity and adverse effects

- rare and exclusively follow from vasodilatory MOA

- headache, hypotension, syncope, rash

tolerance to organic nitrate vasodilators

- the antianginal efficacy of organic nitrate rapidly diminishes with frequent continuous administration

- organic nitrate antianginal therapy should be designed to prevent tolerance

the antianginal efficacy of organic nitrate rapidly diminishes with frequent continuous administration

- Vascular tolerance follows from the reduced capacity of vascular cells to produce NO from nitrate vasodilators

- Increase in superoxide and peroxynitrite production contributes to vascular tolerance by decreasing NOS activity & inhibition of GC, ALDH2

- Pseudo-tolerance follows from acute neurohormonal activation of vasoconstrictor signals and the response to an increase intravascular volume

organic nitrate antianginal therapy should be designed to prevent tolerance

- Avoid high doses and interrupt therapy for 8-12 h daily

- with GTN, omit night doses with stable angina and use patches to treat nocturnal angina

- with ISDN ad ISMN, manage tolerance via dose schedule

Ivabradine therapeutic uses

- 2nd line agent for Oral and solution formulations for the treatment of stable angina in patients in whom B-blockers are not tolerated or are not sufficiently efficacious

- Oral and solution formulations to reduce morbidity and mortality risks of HFrEF as 2nd line agent

Ivabradine MOA

- selective block of HCN [Hyperpolarization-activated Cyclic Nucleotide-gated) channels to reduce heart rate, but not contractility which leads to decreased O2 demand

Ivabradine PK

- not the best oral bioavailability and extensively metabolized, so excreted through kidneys and liver

Ivabradine warnings and contraindications

- Visual changes ("phosphenes") can follow from effect on retinal HCN channels

- Contraindicated vs. cardiac conduction syndromes, bradycardia, hypotension & use during pregnancy

- Can cause and/or be a victim of CYP3A4-based drug-drug interactions

Ranolazine therapeutic uses

- Oral (extended-release) formulation for treatment of stable angina as 2nd line therapy

- May be combined with many other cardiovascular drugs (e.g., beta blockers, Ca++ channel blockers, ACE inhibitors, AT1 blockers, lipid lowering agents, anti-thrombotics)

Ranolazine antianginal mode of action

- Independent from reductions in heart rate and arterial blood pressure or changes in coronary blood flow

- Follows in part from the inhibition of several cardiac ion fluxes -> maintains Na, Ca homeostasis

Ranolazine ADME

- similar for both R and S enantiomers

- extensively metabolized and both this and parent excreted through liver and kidneys

Ranolazine warnings and contraindications

- Can cause and/or be a victim of CYP3A4-based drug-drug interactions

- Most frequent adverse effects are dizziness, headache, nausea, constipation