L17 Ca2+ and NO

Vascular tissue vs cardiac cells Ca2+ function

Ca2+ works on SR and Myosin LCK in vascular tissue

Cardiac cell is much faster, just bind to troponin C and myosin for contraction

Heart rate change of verapamil, diltiazem and dihydropyridines

Decrease/no effect for V and D

Increase for dihydro though cause of compensation for Bp decrease

Peripheral vasodilation of verapamil, diltiazem and dihydropyridines

Increase both

Blood pressure change of verapamil, diltiazem and dihydropyridines

Decrease both

Av node conduction of verapamil, diltiazem and dihydropyridines

Decrease for V and D

Dihydro has no effect

Cardiac contractility of verapamil, diltiazem and dihydropyridines

Decrease for V and D

Dihydro has no effect/slight increase

Verapamil vs diltiazem vs dihydros binding and abilities

Bind different sites within a1 subunit of L type Ca2+ channel

Differ in ability to modulate channel states

Dihydropyridine for Angina

Dilate peripheral blood vessels to decrease HR and contractility

Reflex stimulation due to BP can increase heart rate though

Antianginal effect can follow from afterload reduction

PRIMARILY FOR HYPERTENSION THOUGH (NOT FOR ANGINA)

Verapamil and diltiazem for angina

Verapamil is NON SELECTIVE, decrease Hr and contractility at similar concentrations

Reflex stim due to lower BP is offset by cardiac suppression (NICE)

Antianginal from reduced peripheral resitstance, lower BP (All with minimal change to heart rate nice)

Lead to reduced myocardial O2 demand

diltiazem is similar

Verapamil therapeutic use and warnings (2+4)

For managing chronic and prinzmetal angina

Also for cardiac arrhythmia and hypertension

CI for CHF, and ventricular dysfunction

Can worsen AFib and cardiomyopathy

CAN INDUCE BRADYCARDIA/hypotension

acute liver injury but rare

Phenylalkylamine

Verapamil ade and DDIs

ADE: Monitor liver dysfunction patients for overdosage

DDIs: MORE IMPORTANT THAN DILTIAZEM

Caution with bblockers, antihypertensive and anti arrhythmia drugs

Verapamil exposure can be increased if given with CYP3A4 inhib

Verapamil is strong inhibitor of CYP3A, can lead to increased plasma level of drugs metabolized by CYp3A4

Verapamil structure and ADME and brand names

Bad bioavailability and t1/2 but got a SR version for longer

Depend on CYp3A4 oxidation to norverapamil (active metab)

Calan is brand name

To metabolize turn the CH3 on the middle plain nitrogen to just a H

Diltiazem Therapeutic use and Warnings (2+3)

For managing chronic and prinzmetal angina

Also for cardiac arrhythmia and hypertension

CI with other agents that slow cardiac conduction and for use in patients with CHF

can cause hypotension and very rare liver injury

Is a benzothiazepine

Diltiazem HCl ADE and DDIS

ADE: well tolerated but can cause edema, headache, nausea, dizziness, rash

DDIs: MODERATE CYP3A4 inhibitor (not that bad compared to verapamil)

Diltiazem ADME and brand name and structure

Benzothiazepine

Ok F, bad t1/2 but have a LA formulation

Metabolized in liver by CYp3A4 into active metabolite (2 METABOLITES)

Metabolites are des methyl and des acetyl

Has S+N

Is metabolized on the plain nitrogen or remove the ester underneath the bunny ear Os.

Brand name is Cardizem

Endogenous NO production

Produced by vascular endothelium, works on platelets, immune, GI and CNS

Productio of NO is important for blood flow (increase it)

Formed by NOS(nitric oxide synthase) and L-arginine

NOS is ca2+ and calmodulin dependent (Up increase NOS)

NO produced by cutting l arginine into L citruline and NO

NO effects and transport

Can bind to hemoglobin in blood to deactivate as NO3

Also deactivated by intracellular oxidants like O2

Diffuses to smooth muscle cells where it binds to guanlyl cyclase, which then turns GTP to cGMP that causes vascular relaxation (inhibits Ca2+ entry)

Half life of NO is only 5 seconds or less

cGMP metabolism

Metabolized by phosphodiesterase enzymes

GMP just has a lot more phosphate groups (that are not ring fashioned)

Vascular relaxation enhancement in relation to NO and cGMP (3 things)

Increase NO F

Directly work on GC

Inhibit cGMP breakdown by phosphodiesterase

Organic nitrate vasodilators, and GC activators and PDE5

Increase NO F, used to treat angina

GC activators more for hypertension and PDE5 more for hypertension and erectile dysfunction

Organic nitrate vasodilators CI with GC and PDe5 inhib cause too much hypotension

Organic nitrate vasodilators 3 effects

Vasodilation decrease pressure (Venous>arterial) in systemic vasculature

Decrease O2 demand and wall stress from less preload/afterload

Increase O2 supply and prevent vasospasms and vasodilate/improvement of perfusion

How to directly deliver NO? (2 drugs)

Nitroprusside

NO gas

Nitroglycerin brand name, metabolism and ADME and structure

Is GTN/nitrostat

Reduced to 1,2 glycerl dinitrate and Nitrite in mitochondria by ALDH-2 and then No2 to NO through respiratory chain or acidic disproportionation

reduced to dinitro and monitro in liver, RBC and vascular wall (ER but only at high doses)

Ok F, but VERY SHORT t1/2,

3NO3s around a carbon

Isosorbide mononitrate metabolism, brand name and ADME and structure

Activated by P450 in ER to make NO

Is ISMN/monoket

100%F, long t1/2, and excrete in kidney only

Has only one No3, has 2 hydrofuran rings

Isosorbide dinitrate metabolism, brand name and ADME and structure

Activated by P450 in ER to make NO

Is ISDN/Isordil titradose or dilatrate SR

Is only 25%F, and short t1/2 of 1h, metabolized and excreted through mononitro metabolites

Is 2 NO3s with 2 hydrofuran rings

GTN Dosage forms (4)

Oral given 2-4x a day

Spray and subliginual Prn and then buccal/3-5 hours

Transdermal for 12-16h/day

IV also

ISMN and ISDN dosage forms

ISMN given every 2-3 hours or 2x/day for ER

ISDN 2x/day or once daily with ER form

BOth are oral only

Chronic stable angina and organic nitrate vasodilators

GTN for rapid treatment or acute prophylaxis before exertion

ISMN, ER GTN and ISDN are for prophylaxis in patients with more occasional episodes

Variant angina and organic nitrate vasodilators

Long acting nitrates only and used in combo with other agnets

Organic nitrate vasodilators ADRs?

Very rare, come from vasodilators MoA

Headache, hypotension, syncope, rash, less common

Organic nitrate vasodilators tolerance description

Anginal effect decreases quickly if given continuously due to tolerance from reduced capacity of vascular cells to make NO (have increase in superoxide and other metabolizers, so decrease NOS, GC and ALDH2)

Also have neurohormonal activation of vasoconstrictors in response to increase in IV volume

How to prevent tolerance in organic nitrates (3)

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

GTN: no night doses for stable angina, use patches to treat nocturnal angina instead

ISD ISMN: manage tolerance through dose schedule

Ivabradine use and MOA

Used for stable angina in which b blockers are not tolerated, is a 2nd line agent FOR ANGINA

Oral and solution formulations reduce risk of heart failure with reduced ejection fraction(So is a 2nd line agent), no benefit in reducing all cause morbidity

MOA: block cardiac Na+ channels (hyperpolarization activated cyclic nucleotide gated) to reduce heart rate, BUT NOT CARDIAC CONTRACTILITY (lead to decreased O2 demand)

Ivabradine Structure and brand name and ADME

Looks like geometry dash with a block, and metabolized on the plain nitrogen (CH3 to simple hydrogen) into des methyl version that contributes to efficacy

Good F, and need to dose 2x a day cause 6 hrs t1/2

metabolized in kidney and liver

Is Corlanor

Ivabradine Warnings and CIs (3)

Visual changes from effecting Nucleotide channels in the eye

CI for cardiac conduction syndrome, bradycardia, pregnancy and HYPOTENSION

Can cause and/or be victom of CYp3A4 DDIs

Ranolazine use and MOA

2nd line agent for chronic angina

Can combine with lots of other cardiovascular drugs

MOA not rly understood, but know have reduction of heart rate and BP and change in coronary blood flow

Maybe from inhibition o=f cardiac anion fluxes to maintain Na and Ca homeostasis

Ranolazine Warnings and CIs (3)

Can cause and/or be victim of CYp3a4 DDIs

Most frequent ADE are dizziness, headache, nausea, constipation (CNS and GI effects), but pretty well tolerated

Ranolazine Structure and brand name and ADME

Looks like a beta blocker, but is not cause of the double rings ong

Is ranexa

Good F, 2x a day though cause 7 hr t1/2

Excreted changed and unchanged in liver and kidney

S and R enantiomers have the same ADME