NITRATES AND

NEWER ANTI-ANGINALS

Dr.Mrunalini
PGDCC
ANGINA
THIS PAIN OFTEN
RADIATES TO THE
NECK, JAW, ARMS,
BACK, OR EVEN THE
TEETH.
ANGINA IS USUALLY FELT
AS:
-PRESSURE, 
-HEAVINESS, 
-TIGHTENING, 
-SQUEEZING, OR 
-ACHING ACROSS THE CHEST,
PARTICULARLY BEHIND THE
BREASTBONE.
TYPES OF ANGINA

1. Stable Angina.

2. Unstable Angina.

3. Variant Angina.
STABLE ANGINA:CLASSIFICATION

• Exertional
• Variant
• Anginal Equivalent Syndrome
• Prinzmetal’s Angina
• Syndrome-X
• Silent Ischemia
CCSC ANGINA CLASSIFICATION
• Angina
Class I only with extreme exertion
• Angina with walking
• Class
1 to 2IIblocks
• Angina with walking
• Class
1 block
III
• Angina with minimal activity
• Class IV
CURRENT ANTIANGINAL STRATEGIES
TMR

EECP Chelation
therapy
Exercise training
Non pharmacologic SCS

Current anti-anginal strategies

Pharmacologic EECP-ENHANCED
EXTERNAL COUNTER
Fasudil Nicorandil
PULSATION
TMR-TRANS
Trimetazidine Ivabradine MYOCARDIAL
REVASCULARIZATIO
Ranolazine N
SCS-SPINAL CORD
STIMULATION
ANTI ANGINALS
1. NITRATES
2. BETA BLOCKERS
3. CALCIUM CHANNEL BLOCKERS
4. METABOLIC MODULATORS: Ranolazine ,
Trimetazidine , Perhexiline
5. POTASSIUM CHANNEL ACTIVATOR: Nicorandil
6. OTHERS:IVABRADINE
 MYOCARDIAL ISCHEMIA:
SITES OF ACTION OF ANTI-ISCHEMIA MEDICATION

Development of ischemia Consequences of ischemia

O2 demand
• Electrical instability
• Heart rate • Myocardial dysfunction
• Blood pressure
Ischemia (↓ systolic function/
• Preload
↑ diastolic stiffness)
• Contractility (Ca2+ overload)

↓O2 supply
Ranolazine
Conventional
anti-ischemic
medications Compression
of nutritive
 ß blockers
 Nitrates blood vessels
 Ca++ blockers
NITRATES
NITRATES
MECHANISM OF NITRATES ACTION IN ANGINA:

 Nitrates provide an exogenous source of

vasodilator NO(a very short lived free
radical)coronary vasodilation.
 Chronic use of nitrates produce tolerance-a
significant clinical problem.
 Unlike Endogenous NO radicals(role in vagal
neuro transmission)exogenous NO radical share
only vasodilatory effect.
MECHANISM OF ACTION
 Vasodilatory effects;coronary and peripheral

 Reduced oxygen demand

 Endothelium and vascular mechanisms

Compound Route Preperation and dosage Duration of effects & comments
PHARMACOKINETICS
Amyl nitrate inhalation 2-5mg
OF NITRATES
10sec-10min;For Δsis of LVoutflow
obstruction in HCM
NTG(Glyceryl a. S/L • 0.3-0.6mg upt 1.5mg • T1/2=7min,peak levels=2min;given
Trinitrate) b. Ointmnt • 2% 7.5-40mg acutely for rest angina
c. Spray • 0.4mg metered dose • Apply twice daily;6hr interval;effect
d. Trans • 0.2-0.8mg/hr on for 12hrs upto 7hrs
dermal off for 12hrs. • Similar to tablet
patch • 2.5-13mg;1-2tab TID • Effect within min &lasts 3-5hrs
e. Oral:SR • 1-3mg tab TID • 4-8hrs after 1st dose
f. Buccal • 5-200mcg/min infusion • Similar to TDpatch
g. IV • In UA,↑sing dose needed to
overcome tolerance

Iso Sorbide Di a. S/L • 2.5mg-15mg • Onset 5-10min;effect upto 60min

Nitrate b. Oral • 5-80mg 2-3*daily • Upto 8hrs
c. Spray • 1.25mg on tongue • Rapid action (2-3min)
d. Chewable • 5mg as single dose • Exercise time↑sed for 2min-2 ½ hrs
e. SR • 40mg once or2ˣdaily • Upto 8hrs
f. IV • 1.25-5mg/hr • May need ↑sing dose in UA
g. Ointment • 100mg/24hrs • Not much effective

Isosobide-5- Oral 20mg BD(7hrs apart) 12-14hr after chronic therapy 2wks
mononitrate 120-240mg OD (slow release) Efficacy upto 12hrs after 6wks
Pentaerythrito S/L 10mg as needed No efficacy data
l Tetra Nitrate
DRUG INTERACTIONS
 Selective PDE-5 inhibitors like sildenafil and CCBs
cause serious hypotension when combined with
Nitrates.
Sildenafil ↓ses BP by 8.4/5.5mmHg and much
more in patients taking Nitrates.
 Beneficial interaction with Hydralazine
 Infusion rate of NTG required to produce Heparin
resistance is relatively high(>350mcg/min) and such
dose is not ordinarily infused.
 NITRATES preparations

Short acting nitrates for  Long Acting Nitrates

effort angina: For Angina
Prophylaxis:
-Sublingual Nitroglycerine(0.3- Isosorbide Dinitrate(oral
0.6mg) 15-120mg)
-Nitroglycerine Spray
-Mononitrates(30-
-Isosorbide Dinitrate(s/l 5mg)
240mg)
-ointments
-Transdermal Nitrate
Patches
 Adverse Reactions :
1- Postural Hypotension & 2- Tachycardia
Syncope

3- Drug Rash

4- Facial Flushing

6- Prolonged high dose

5- Throbbing Headache Methaemoglobinaemia
PRECAUTIONS Tablets should be kept in air tight containers.NTG sprays are inflammable
Common side • Headache frequently
effeccts • Facial flushing,S/L nitrates Halitosis
SERIOUS side • Syncope and hypotension
effects • Tachy cardia but unexplained bradycardia may occur in acute MI
• Prolonged high dose methemoglobinemia(treat with i.v. methylene blue 1-
2mg/kgbwt
• High nitrate doses induce heparin resistance.

CONTRAINDICATNS • In HCM,nitrates may exaggerate outflow obstruction

• Acute inferior MI with RV extension(here fall in filling pressure may lead to
hemodynamic and clinical deterioration)

RELATIVE CIs • In Cor Pulmonale and Arterial hypoxemia(nitrates↓se arterial o₂ tension by venous
admixture)
• Glaucoma
• Cardiac tamponade/Constrictive pericarditis/tight MS
• Already compromised diastolic filling may be aggravated.
TOLERANCE • Continuous therapy and frequent high dose lead to tolerance that eccentric dose
may avoid
• Cross tolerance occurs btwn various formulations
WITHDRAWL • In some withdrawl may ppt symptoms and sudden cardiac death may occur
SYMPTOMS • Recurrence of anginal pain in nitrate free intervals during sustained therapy(less
common with β-blocker co-therapy)
THERAPEUTIC EFFECTS:
 Nitrates for Acute Coronary Syndrome:
Initial dose 5mcg/min(2.5mcg/min in borderline
BP)uptitrated as needed.
 Acute Heart Failure and Acute Pulmonary Edema: In
Acute Pulmonary edema s/l NTG 0.8-2.4mg every 5-
10min can relieve dyspnoea within 15-20min,and fall
in LV filling pressure and rise in cardiac output.
 Congestive Heart Failure: High dose of
dinitrate(60mg 4times daily)-hydralazine may be
added to ACE inhibitors.
 *NITRATE TOLERANCE AND NITRIC OXIDE RESISTANCE:-

• Impaired Bio Conversion Of Nitrates To Active form:-

• impairment of the bio conversion of NTG to dinitrate with ↓sed
release of NO* radical.
Mitochondrial enzyme:
• NTG aldehyde dehydrogenase(or CYP 450)
NO*(bio-tranformatn)

• Free Radical Hypothesis and Endothelial

Dysfunction:- prolonged nitrate administration can lead to
formation of superoxides and peroxynitrite.
• ↓sed vasodilatory effects by inhibition of guanylase cyclase with
↓sed formatn of cGMP;impaired endothelial dysfunction and
↓sed activity mitochondrial enzyme.
PREVENTION AND LIMITATION OF NITRATE
TOLERANCE:

Nitrate Cross Tolerance:-

Nitrate Pseudotolerance and Rebound:-

Nitric Oxide Resistance:-

NEWER ANTI-ANGINALS

1) Ranolazine
2) Trimetazidine
3) Perhexiline
4) Fasudil
5) Nicorandil
6) Ivabradine
NEWER ANTI
ANGINALS AND THEIR
SITE OF ACTION
RANOLAZINE
 Ranolazine represents a new class of antianginal drugs.
 It is a compound with a structure similar to
trimetazidine.
 Ranolazine is a partial inhibitor of fatty acid oxidation
[ pFOX ].
 Ranolazine has also been shown to be capable of :
 Inhibiting the late inward sodium entry, thus
 Decreasing the calcium overload, thus
 Reducing diastolic stiffness, and
 Improving myocardial perfusion.
 CONSEQUENCES ASSOCIATED WITH
DYSFUNCTION OF LATE SODIUM CURRENT

• Diseases
(eg, ischemia, heart
failure) Na+ channel

• Pathological milieu
(Gating
(reactive O2 species,
mechanism
ischemic metabolites) malfunction)
• Toxins and drugs
(eg, ATX-II, etc.)

Mechanical Oxygen supply Electrical

dysfunction and demand instability

• Abnormal contraction • Increase ATP

• Early after potentials
and relaxation consumption
• ↑ diastolic tension • Decrease ATP • Beat-to-beat ΔAPD
(↑LV wall stiffness) formation• Arrhythmias (VT)
 RANOLAZINE: MECHANISM OF ACTION
Ischemia Ranolazine
inhibits the late inward
Ranolazine prevents Na current
diastolic stiffness there ↑ Late INa
by preserves Myocardial
blood flow
Na+ overload

Ca2+ overload

Diastolic relaxation failure

(increased diastolic tension)
Extravascular compression
BASIS OF pFOX 
1. Myocardial ischemia is associated with sudden increase in fatty acid
levels resulting in enhanced oxidation of long chain fatty acids 

 2. Oxidation of fatty acids needs more  3. Moreover this may lead to
ATPs and also an increased oxygen accumulation of free fatty acids and lactic
demand for their breakdown than acid increasing the acidosis and affecting
oxidation of carbohydrates  heart performance. 

 4. These mechanisms have harmful effects on the contractility and efficiency of the
heart.

 5. Treatment must aim to shift myocardial substrate utilisation to glucose metabolism as
this will then provide benefits to ischemic patients.

6. This is achieved by drugs which suppress fatty acid oxidation. Trimetazidine Ranolazine
RANOLAZINE:DRUG INTERACTIONS
Inhibitors of CYP3A ↑se ranolazine levels in
plasma and cause QTc prolongation so should not
be co-administered with ranolazine.
• Diltiazem
• Verapamil
• Ketoconazole and azole derivatives
• Macrolide antibiotics
• HIV protease inhibitors
• Grape juice or grape fruit containing products.
 Metabolic modulation
Additional, well-tolerated
antianginal efficacy in patients who
remain symptomatic despite Reduces late Na+ current 
maximal anti-anginal therapy

Ranolazine
Reduces nitrate Does not affect BP
consumption summary

Does Not Affect Heart Rate

Reduces angina frequency

Extends Exercise ability

TRIMETAZIDINE

• Trimetazidine, a new antianginal drug that

selectively inhibits fatty acid beta oxidation and is
devoid of any direct hemodynamic effects
• Unique in its ability to decrease symptoms of
angina when used in patients resistant to
hemodynamic treatment
 METABOLISM IN MYOCARDIUM:
 In the normal myocardium,
 Fatty acid is a major source of ATP production in the heart
 Acetyl CoA from FA oxidation competes with glucose oxidation as
a source of acetyl CoA for the Kreb’s cycle.
 The reduced FAD and NAD from beta oxidation further inhibits
glucose oxidation and glycolysis
 Ischemic myocardium:
 The contribution of anaerobic glycolysis to ATP production
becomes more important
 If the heart relies on fatty acid beta oxidation, cardiac efficiency
decreases further
 Optimize energy metabolism in the ischemic heart
 Inhibiting FA oxidation which will indirectly stimulate glucose utilization
 Stimulate glucose oxidation directly
MODE OF ACTION:
 Anginal patients accumulate FFAs, which the cardiac
muscles oxidise for their energy requirements,
 LCFA oxidation demands more ATP to break down
the FFAs than glucose oxidation.
 This demands more O2 and more blood supply from
the anginal heart, adding to the load on the
compromised heart.
 This is prevented by trimetazidine which shifts
metabolism from LCFAs to glucose.
METABOLIC MODULATION (PFOX): TRIMETAZIDINE

Myocytes
FFA Glucose • O2 requirement of
glucose pathway is
Acyl-CoA Pyruvate lower than FFA pathway
β-oxidation
• During ischemia,
Trimetazidine

Acetyl-CoA oxidized FFA levels rise,

blunting the glucose
Energy for contraction
pathway

pFOX = partial fatty acid oxidation

FFA = free fatty acid
TRIMETAZIDINE:
• Newer antianginal agent
• Inhibits mitochondrial 3-ketoacyl coA thiolase (3-KAT)
• This shifts substrate utilization from FA to glucose
metabolism
• By decreasing the intracellular concentrations of
protons, trimetazidine prevents calcium and sodium
overload
• It protects the heart from the destructive effects of
fatty acid accumulation and increased protons
INDICATIONS AND CONTRAINDICATIONS

Indications:
• Angina pectoris and IHD

• Myocardial ischemia sequale.

Precautions and CIs:

• Pregnancy and lactation

• Children

• Impaired renal and hepatic function

• Hypersensitivity reactions
Dosage:
20mg tab thrice a day after food.
Side effects:
Headache
Vertigo ,Nausea and GI discomfort
Pharmacokinetics
Trimetazidine is absorbed through the intestinal mucosa
with a Tmax (time to reach maximum concentration) of
5.4 hours.
Bioavailability:
87%, slightly inferior with trimetazidine modified release
than with the immediate-release formulation, explaining
the increase in the dose of trimetazidine (35 mg
compared with 20 mg for the immediate-release tablet).
PERHEXILINE

Mechanism of Action:
• Perhexiline binds to the mitochondrial enzyme
carnitine palmitoyltransferase (CPT)-1 and CPT-2.
• It acts by shifting myocardial substrate utilization
from long chain fatty acids to carbohydrates
through inhibition of CPT-1 and, to a lesser
extent, CPT-2, resulting in increased glucose and
lactate utilization.
FASUDIL
 Rho kinase inhibitor.
 Bio-availability: well absorbed
 Metabolism: metabolized quickly to
hydroxyfasudil
 Half life: 0.76 hours. Active metabolite
(hydroxyfasudil) 4.66 hours.
 MODE OF ACTION
 Rho kinase triggers vasoconstriction through
accumulation of phosphorylated myosin
Ca2+ Ca2+ Agonist

PLC Receptor

IP3 = inositol PIP2

triphosphate VOC ROC
PIP2 =
Rho
IP3 Fasudil
phosphatidylinositol
biphosphate Rho kinase
PLC = phospholipase
SR Ca2+ Myosin
C
ROC = receptor- MLCK Myosin phosphatase
operated channel
SR = sarcoplasmic Ca2+ Myosin-P
Calmodulin
reticulum
VOC = voltage-
operated channel
MODE OF ACTION :
• The role of Ca2+ in activating myosin light chain kinase (MLCK)
and phosphorylating myosin to cause contraction is well known.
• Dephosphorylation by myosin phosphatase causes subsequent
dilation.
• More recently, the involvement of Rho kinase has been
identified.
• In the absence of increases in intracellular Ca2+, Rho (a member
of the Ras superfamily of small G proteins) activates Rho kinase,
which in turn deactivates myosin phosphatase. This causes
accumulation of phosphorylated myosin.
USES
 It has been used for the treatment of cerebral
vasospasm, which is often due to subarachnoid
hemorrhage as well as to improve the cognitive
decline seen in stroke victims.
 It has been found to be effective for the
treatment of pulmonary hypertension
NICORANDIL

 Nicotinamide derivative.
 Nicorandil possesses a nitrate moiety and,
therefore, produces hemodynamic effects
similar to those of long-acting nitrates.
 This is a potassium channel activator
inaddition.
NICORANDIL: Mode
of action

NITRATE associated effects:

Vasodilation of coronary epicardial arteries
NICORANDIL : MODE OF ACTION

Nicorandil dual action

Nitrate-like action K+ channel opener ATP

Dilates epicardial Venodilatation Dilates peripheral Dilates coronary

Coronary arteries arterioles Resistance
vessels
Decreased Decreased
Preload afterload

↑ coronary ↓ Myocardial O2 ↓ Myocardial O2 ↑ coronary

blood flow requirement requirement blood flow
 MODE OF ACTION
 Sustained dilation of both arterial,resistance and
conductive vessels that leads to ↓se in both
preload & afterload thus ↑se coronary blood flow
as well as balanced peripheral action.
 ↑se c-GMP ;Hyperpolarization of smooth muscle.

 In a patient with normal LV function,↓se in preload

was apparent from a ↓se in LVEDP from 7.4±1.7 to
3.2±1.5mmHg further produce marked ↓se in
TPR&Ao.pressure with ↓se in DBP/SBP.
 Its strong spasmolytic effect : relieves dynamic
coronary obstruction.
 PHARMACOKINETICS
 Well absorbed.
No significant first-pass metabolism.
 Bioavailability:aprx 75%,Cmax achieved in 30 to 60 min
 Metabolism mainly by de-nitration with less than 20%
of an administered dose being excreted in the urine.
 Elimination half-life of about 1 hour.

DOSAGE
 Start with 5 mg twice daily

 Upward titration : 10 – 20 mg twice daily

 Maximum : 40 mg/ day

SIDE EFFECTS
 Headache ,nausea,vomitings,dizziness
 Rectal ulcerrs/bleeding

 High doses: Hypotension and Tachycardia

 Inflammation or damage to liver

 Ulceration – mouth,skin,genitals,stomach/GIT
 Ulcers in GITperforation
CONTRAINDICATIONS

 Hypotension
 Recent MI with heart failure and low filling
pressure.
 Cardiogenic shock
 Pregnancy
 Breast feeding
DRUG INTERACTIONS
 CCBs,antihypertensives,TCAs and MAOIs when
administered along with nicorandil cause
dizziness/giddiness
 When administered with Corticosteroids ↑se risk
of bleeding/GI ulcers
 Should not be given with sildenafil(drugs for
impotence)/vasodilators
IVABRADINE
• Ivabradine selectively targets the Na+/K+
current (If current) in pacemaker cells of the
sinoatrial node.
• Channels that carry the If current are unique
to the sinoatrial node.
• If is an inward Na+/k+ current that activates
pacemaker cells of SA node.
•IVABRADINE :
•Selectively blocks If in a
current-dependent
fashion.
•Reduces slope of
diastolic depolarization ,
slowing HR.
 DOSE
• Starting dose of Ivabradine is 5 mg twice daily.
• After 3-4weeks of treatment, the dose may be ↑sed to
7.5 mg twice daily depending on the therapeutic
response.
• If, during treatment, heart rate ↓ses persistently below
50 bpm at rest or the patient experiences symptoms
related to bradycardia such as dizziness, fatigue or
hypotension, the dose must be titrated downward
including the possible dose of 2.5 mg twice daily (one
half 5 mg tablet twice daily).
• Treatment must be discontinued if heart rate below 50
bpm or symptoms of bradycardia persist. 
ADVERSE EFFECTS:
• 14.5% of all patients taking ivabradine
experience Luminous phenomena (by patients described
as sensations of enhanced brightness in a fully maintained
visual field). This is probably due to blockage of I h ion
channels in the retina which are very similar to cardiac If.
• Dizziness,headaches and blurred vision
• Bradycardia
• Ventricular Extra systoles
• AV block.
CONTRAINDICATIONS
• Sick sinus syndrome
DRUG INTERACTIONS:
• Cannot be used concominantly with  CYP3A4
inhibitors such as Azole Antifungals(such as
ketoconazole)
•  Macrolide Antibiotics, nefazodone
• The Anti-hiv Drugs nelfinavir and ritonavir
QUERIES????
?