11.12 pharm of angina pectoris

Question 1

what is Angina Pectoris?

Answer 1

Chronic disease, intermittent attacks of chest pain, radiate through chest, shoulder & arm

Question 2

what are the four types of angina?

Answer 2

A: typical (stable, effort) angina (major type)
B. Variant (Prinzmetal’s) angina:
- ↓ O2 supply - unchanged demand - ie. at rest, coronary spasm (PGs?)
C. Unstable angina: (most dangerous)
- ↓ O2 supply, plaque, platelets, clot
D. Microvascular angina (Syndrome X):
- atherosclerosis in small coronary a.

Question 3

Typical (Stable, Effort) angina:

Answer 3

• ↑ O2 demand - fixed supply

Question 4

Variant (Prinzmetal’s) angina:

Answer 4

• ↓ O2 supply - unchanged demand - ie. at rest, coronary spasm (PGs?)

Question 5

Unstable angina:

Answer 5

• ↓ O2 supply, plaque, platelets, clot

Question 6

Microvascular angina (Syndrome X):

Answer 6

• atherosclerosis in small coronary a.

Question 7

what are the main mechanisms to treat angina (basic)

Answer 7

-angina is a supply vs demand problem, so either increase the oxygen supply or decrease the oxygen demand

Question 8

The primary determinants of myocardial O2 supply:

Answer 8

a. Coronary blood flow (major determinant)
b. O2 content of the blood
c. O2 extraction by the myocardium

Question 9

The primary determinants of myocardial O2 consumption:

Answer 9

a. Ventricular systolic pressure (afterload)
b. Heart size (preload)
c. Heart rate
d. Myocardial contractility

Question 10

Improving supply/demand ratio:

Answer 10

a. Relaxation of resistance vessels (small arteries and arterioles) ↓TPR → ↓BP → ↓Afterload, ↓O2 demand
(Nitrates, calcium channel blockers and beta-blockers)
b. Relaxation of capacitance vessels (veins and venules) ↓Venous return, ↓heart size, ↓Preload, ↓O2 demand (Nitrates)
c. Blockade or attenuation of sympathetic influence on the heart ↓Contactility, ↓HR, ↓O2 demand
(Beta-blockers)
d. Coronary vessel dilation
- Important mechanism for relieving vasospastic angina - ↑O2 supply
(Nitrates)

Question 11

Relaxation of resistance vessels (small arteries and arterioles) ↓TPR → ↓BP → ↓Afterload, ↓O2 demand

Answer 11

Nitrates, calcium channel blockers and beta-blockers)

Question 12

Relaxation of capacitance vessels (veins and venules) ↓Venous return, ↓heart size, ↓Preload, ↓O2 demand

Answer 12

nitrates

Question 13

Blockade or attenuation of sympathetic influence on the heart ↓Contactility, ↓HR, ↓O2 demand

Answer 13

beta-blockers

Question 14

Coronary vessel dilation

- Important mechanism for relieving vasospastic angina - ↑O2 supply

Answer 14

nitrates

Question 15

nitrates mechanism of action:

Answer 15

• Direct smooth m. relaxation
• High specificity vascular sm
• Vasodilation: veins > arteries
• ↓Preload > ↓Afterload
  a. Formation of NO in endothelial cells involving sulfhydral (SH) groups
  b. Interaction between NO and thiols in smooth mus. to form nitrosothiols
  c. Nitrosothiol activates guanylate cyclase and increased formation of cGMP
  this leads to vasodilation

Question 16

continual use of nitrates leads to ….

Answer 16

Tolerance (formation of disulfide bonds)
oxidation of SH groups and formation of disulfide bonds - develops fast and recovers fast ie. “Monday syndrome or Head”
-So individuals need abstinence periods

Question 17

Nitrates and Nitrites MOA

Answer 17

• Formation of Nitric oxide (NO) → activation of guanylate cyclase
• ↑ Ca++ uptake SR, dephosphorylation of myosin-LC
  Tolerance: frequency / dose dependence (absence periods)
  Absorption and disposition: well absorbed, first-pass metabolism with oral administration (10-20%)

Question 18

adverse actions of nitrates and nitrites

Answer 18

Adverse actions: headache, flushing, hypotension, reflex tachycardia, possible circulatory collapse CI: PDE5 inhibitors (ie. Viagra)

Question 19

when are nitrates and nitrites contraindicated?

Answer 19

with PDE5 inhibitors (ic Viagra)

Question 20

Viagra

Sildenafil

Answer 20

• phosphodiesterase type 5 inhibitor
• ↑NO release
• leads to ↑cGMP
• initially developed for angina
• CI with nitrates, alpha-blockers

Question 21

Nitroglycerin - Routes of administration

Answer 21

1. Sublingual tablet (for an acute attack)
   • Avoids first-pass effect
   • Onset: 30 sec, Duration: 30 min
2. Buccal tablet
   • Tablet placed in buccal cavity
   • Adheres to mouth’s mucosal surface, NG released for 3-6 hrs
3. Oral
   • Translingual spray – Duration 30 min
   • Oral tablet – Duration 6 hrs, subject to first-pass effect
4. Topical
   a) ointment (paste)
   • Duration: 3-4 hrs, used in acute care setting
   • Inconvenient, messy, largely replaced by patch
   b) Transdermal system (patch)
   • Delivers nitroglycerin over 24 hr period
   • Avoid continuous use to prevent tolerance (remove at night)

Question 22

Sublingual tablet (Nitroglycerin)

Answer 22

Avoids first-pass effect

• Onset: 30 sec, Duration: 30 min

Question 23

Buccal tablet (nitroglycerin)

Answer 23

• Tablet placed in buccal cavity

* Adheres to mouth’s mucosal surface, NG released for 3-6 hrs

Question 24

Oral (nitroglycerin)

Answer 24

• Translingual spray – Duration 30 min

* Oral tablet – Duration 6 hrs, subject to first-pass effect

Question 25

Topical nitroglycerin

Answer 25

a) ointment (paste) • Duration: 3-4 hrs, used in acute care setting • Inconvenient, messy, largely replaced by patch b) Transdermal system (patch) • Delivers nitroglycerin over 24 hr period • Avoid continuous use to prevent tolerance (remove at night)

Question 26

acute onset/attack angina use which nitroglycerin route of admin?

Answer 26

-sublingual tablet or translingual spray

Question 27

Isosorbide dinitrate [ISDN] – converted to ISMN c. Isosorbide mononitrate [ISMN]

Answer 27

• Active metabolite of ISDN • Not subject to first-pass metabolism • Greater bioavailability (100%) • Clinical efficacy not greater than ISDN Both forms have: 30 min onset, 6 hr duration

Question 28

Calcium Channel Blockers and use for angina

Answer 28

- frontline class, oral and generally well absorbed - bind to L-type calcium channels in cardiac and vascular smooth muscle - inhibition of calcium influx into cardiac and arterial smooth muscle cells - minimal effect on venous capacitance vessels. - dilate arterioles →↓TPR →↓ BP (less verapamil, more nifedipine), ↓ afterload - negative inotropic action on heart (more verapamil, less nifedipine), →↓ oxygen demand - T1⁄2: most 2-5 hrs, bepridil 42 hrs, amlodipine 30-50- hrs - CHRONIC TXT

Question 29

Nifedipine: (DHP)

Answer 29

- mainly arteriole vasodilation, little cardiac effect - reflex tachycardia, flushing, peripheral edema

Question 30

Verapamil:

Answer 30

- significant cardiac depression, constipation - caution in digitalized patients (↑ digoxin levels) - incr renal blood flow (CCBs tend to incr renal blood flow)

Question 31

Diltiazem:

Answer 31

- similar to Verapamil / Nifedipine (less) - actions on cardiac and vascular beds - INCR. RENAL BLOOD FLOW

Question 32

examples of Non-dihydropyridines (non-DHPs):

Answer 32

verapamil, diltiazem

Question 33

examples of Dihydropyridines (DHPs):

Answer 33

Nifedipine, or anything with [-dipine]

Question 34

Calcium-Blockers: Adverse effects

Answer 34

- constipation (more likely with non-DHPs) - non-DHPs: cardiac depression, bradycardia, AV block - non-DHPs are contraindicated with beta-blockers - mostly DHPs: hypotension, reflex tachycardia, flushing, headache, edema - hypotension (more likely with DHPs) - gingival hyperplasia (nifedipine, 10%) - CHF non-DHPs contraindicated, DHPs not recommended - CYP3A4 inhibitors: grapefruit, verapamil, diltiazem - CYP3A4 substrates: amlodipine, verapamil

Question 35

Drug Choices in Angina: Effort angina

Answer 35

nitrates, calcium-blockers, beta-blockers, aspirin

Question 36

Drug Choices in Angina: variant angina:

Answer 36

nitrates, ccbs

Question 37

drug choices for unstable angina

Answer 37

nitrates, calcium-blockers, beta-blockers,

Question 38

Aims in the use of antianginal drugs:

Answer 38

a. Treatment of acute attack - nitroglycerin very effective (i.v., sublingual, oral spray) b. Short term prophylaxis - taking nitroglycerin prior to physical or emotional stress to prevent attack c. Long term prophylaxis - objective is to reduce frequency of angina attacks. Many options are now available ie. long-acting nitrates, Ca++-blockers, β- blockers, aspirin, anticoagulants, thrombolytics

Question 39

Treatment of acute attack

Answer 39

nitroglycerin very effective (i.v., sublingual, oral spray)

Question 40

Short term prophylaxis

Answer 40

taking nitroglycerin prior to physical or emotional stress to prevent attack

Question 41

Long term prophylaxis

Answer 41

objective is to reduce frequency of angina attacks. Many options are now available ie. long-acting nitrates, Ca++-blockers, β- blockers,