organic nitrates

use: ischemic heart dz

1) Prevent angina attack: use

a. isosorbide dintrate
b. nitropatch/nitropaste: slow release formulations of Nitroglycerin. Extensive 1 st pass-
metabolism in liver
2) Abort attack already in progress
a. Terminate using sublingual nitroglycerin: rich vascular supply under tongue, avoid
hepatic metabolism. Could be ppt. by exercise or stress
- Look out for tolerance, greatest w/ frequent high doses.
o Result from inhibition of mitochondrial aldehyde dehydrogenase by ROS generated from
NO/generated during the production of NO
o Terminate drug action by inactivation of enzyme terminaiting NO production.
o Angina might rebound if interrupt therapy for 8-12/day to curb tolerance

MOA

NO activate Guanylate Cyclase  inc. cGMP in cytoplasm  act. PKG (protein kinase) 
1)phosphorylate + act. Ca2+-ATPase in SR membrane  remove Ca2+ from cytoplasm  reduce
contractile state of vascular smooth msucel.

2) phosphorylate myosine -> dec. sensitivyt of contractile apparatus to Ca2+

Benefit: reduce myocardial oxygen demand

- Dilate both vein and arteries

- Low dose: venodilatation dominates; preload << afterload. Dec. ventricular wall tension (reduce
preload) and increase pressure gradient for perfusion across the ventricular wall. Latter favors
subendocardial perfusion.
- Decrease peripheral artierolar resistance reduce impedance gainst which ventricles ejects, and
reduce cardiac work.
- Don’t increase total coronary BF
- Cuase redistribution of blood toward ischemic myocardial region, restore ischemic areas to
normal BF

Invariant angina or advanced unstable angina: use organic nitrates at HIGH does to relax smooth
muscle of coronary arteries to coutnerct vasospasm.

Toxic Side Effects:

High dose: reduce diastolic BP xs, compromise conronary flow.

Systemic hypotension  reflex sympathetic discharge  inc. HR and contractility (inc. Myocardial O2
demand and counteract benefits.

Major side effects: headache and orthostatic hypotension

Ca Channel blockers: work on vascular. for outpatient therapy to prevent recurrence of anginal attacks.

- Prevent attack of stable and unstable angina by reducing myocardial oxygen demand through
arterial vasodilation
- Sometimes treat stable/exertional angina
- Work wel compared to L-type Ca2+ channels

Verapamil (not assoc. w/ inc. HR and contractility) and Diltiazem (don’t block cardiac Ca2+ strong enof
to elicit reflex sympathetic discharge) : block cardiac and vascular channels =.

- Clear negative inotropic and chronotropic effect to reduce myocardial oxygen demand
- Strongly block cardiac L=type Ca2+ chnannels, redue the magnitude of inward Ca current, slow
rate of SA node PM + conduction velocity thru AV node
- Reduce rate of recovery of Ca2+ from inactivated state
- Reduce HR and force of contraction  reduce Myocardial oxygen demand
- Vasodilators and and cardiodepressants
- Cardiodepressant, reduce BP
- Bind to 1 site

Side effect: Cardiac depression  produces transient asystole, bradycardia, reduced ventricular
function

dihydropyridine (bind separate site), more strongly block vascular Ca2+ channels, produce greater
vasodilation, greater reduction of afterload, and larger drp in BP.

- Has lots of toxic effects as it can increase myocardial o2 demand due to sympathetic discharge
to pt. that compromised coronary circulation cant meet.
- Prevents attack of vasospasm thru arterial vasodilation

Almodipine: (long acting) more effective vasodilator, no affect HR or force of contraction

- Selectively for vascular channels

- Not cardiodepressant; reduce BP; don’t provoke sympathetic discharge  safer

Nifedipinemore systemic)

o Rapid acting, inc. HR and cardiac contractility due to reflex sympathetic discharge

Nicardipine:

MOA:
 - Reduce afterload, no effect on preload.
- act upon the vascular L-type Ca2+ channel much like local anesthetics act upon the Na + channel.
- cross the plasma membrane, enter the channel from the inside of the cell when it is in the open
state, and prevent ion flux
- bind to the channel in the inactivated state and delay the transition to the closed state

Side Effects:

- hypotension and aggravation of MI

- aggravate MI
1. reduced coronary perfusion due to xs low diastolic BP
2. Selective vasodilation of coronary arteries in non-ischemic regions of heart.
Conronary arteires in ischemic region of heart already maximally dilated,
dilateion of remaining coronary arteries steal bloodfrom tehn = “coronary
steal”
**coronary vasodilation is actuallyharmful for ppl w/ stable or unstable angina
3. Inc. myocardial O2 demand due to reflex sympathetic discharge that inc. HR
and force of contraction. (rapid-acting dihydropyridine)

 Blockers
- Almost all exert cardioprotecctive effects
- 1 vs. 2 receptors, multifunctional receptor antagonism
- Reduce recurrent episodes of MI: mainstay therapy for un/stable angina
- Ineffective in variant angina as they don’t relax arterial smooth muscle
- = or > to Ca+ channel blockers for long term
- Reduces morbidity and mortality in persons who has
-

Non-selective  blockers:

- Reduce afterload somewhat w/ 1n2 mechanisms

- Assoc. w. troubling SE
- Don’t use in diabetics, asthmatics coz it inhibits b2 (used for bronchodilation)

1

- Atenolol, metoprolol
o Don’t reduce peripheral resistance significant – no reduction of afterload
o Few side effects

clinical use is very much toward the use of 1-selective drugs and, increasingly, toward the use of multi-
functional β blockers.

Labetalol – given IV
Propranolol – don’t cause vasodilation

Beta2: endogenous comes out

Beta blocker that blocks beta2, periphery resistance will increase

MOA

- Fall in myocardial oxygen consumption at rest and during exertion

- Reduced thru
1. Reduce HR, esp. during exeercise
2. Reduce inotropy
3. Reduce arterial pressure (esp. systolic pressure) during exercise

Scca have little cytoplasm (where cytoskeleton is found) make them very weak and easily
squashed if u see the black line must suspect small cell CA, aggressive dz, id early n treat it.

Von hippel-lindau dz: affects adrenal glands, kidneys and pancreas. Usually a tumor in BV
(hemanigioblastoma)  form in brain, retina, CNS, eye, other CNS areas. Very rare.