NITRATES AND NEWER ANTI-ANGINALS

Dr.MrunaliniPGDCC

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

• Class I

• Class II

• Class III

• Class IV

• Angina only with extreme exertion• Angina with walking

1 to 2 blocks• Angina with walking

1 block• Angina with minimal activity

CURRENT ANTIANGINAL STRATEGIES

Current anti-anginal strategies

Non pharmacologic

Pharmacologic

Trimetazidine

Fasudil Nicorandil

Ivabradine

Ranolazine

Exercise training

EECP Chelationtherapy

SCS

TMR

EECP-ENHANCED EXTERNAL COUNTER PULSATIONTMR-TRANS MYOCARDIAL REVASCULARIZATIONSCS-SPINAL CORD STIMULATION

ANTI ANGINALS

1. NITRATES2. BETA BLOCKERS3. CALCIUM CHANNEL BLOCKERS4. METABOLIC MODULATORS: Ranolazine ,

Trimetazidine , Perhexiline 5. POTASSIUM CHANNEL ACTIVATOR: Nicorandil6. OTHERS:IVABRADINE

MYOCARDIAL ISCHEMIA:SITES OF ACTION OF ANTI-ISCHEMIA MEDICATION

Ranolazine

Consequences of ischemia

• Electrical instability• Myocardial dysfunction (↓ systolic function/ ↑ diastolic stiffness)

Conventionalanti-ischemicmedications ß blockers Nitrates Ca++ blockers

Compressionof nutritive

blood vessels

Ischemia(Ca2+ overload)

O2 demand• Heart rate• Blood pressure• Preload• Contractility

↓O2 supply

Development of ischemia

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

PHARMACOKINETICS OF NITRATESCompound Route Preperation and dosage Duration of effects & commentsAmyl nitrate inhalation 2-5mg 10sec-10min;For Δsis of LVoutflow

obstruction in HCMNTG(Glyceryl Trinitrate)

a. S/Lb. Ointmntc. Spray d. Trans

dermal patch

e. Oral:SRf. Buccalg. IV

• 0.3-0.6mg upt 1.5mg• 2% 7.5-40mg• 0.4mg metered dose• 0.2-0.8mg/hr on for 12hrs

off for 12hrs.• 2.5-13mg;1-2tab TID• 1-3mg tab TID• 5-200mcg/min infusion

• T1/2=7min,peak levels=2min;given acutely for rest angina

• Apply twice daily;6hr interval;effect upto 7hrs

• Similar to tablet• Effect within min &lasts 3-5hrs• 4-8hrs after 1st dose• Similar to TDpatch• In UA,↑sing dose needed to

overcome tolerance

Iso Sorbide Di Nitrate

a. S/Lb. Oralc. Sprayd. Chewablee. SRf. IVg. Ointment

• 2.5mg-15mg• 5-80mg 2-3*daily• 1.25mg on tongue• 5mg as single dose• 40mg once or2ˣdaily• 1.25-5mg/hr • 100mg/24hrs

• Onset 5-10min;effect upto 60min• Upto 8hrs• Rapid action (2-3min)• Exercise time↑sed for 2min-2 ½ hrs• Upto 8hrs• May need ↑sing dose in UA• Not much effective

Isosobide-5-mononitrate

Oral 20mg BD(7hrs apart)120-240mg OD (slow release)

12-14hr after chronic therapy 2wksEfficacy upto 12hrs after 6wks

Pentaerythritol Tetra Nitrate

S/L 10mg as needed No efficacy data

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 effort angina:

-Sublingual Nitroglycerine(0.3-0.6mg)-Nitroglycerine Spray-Isosorbide Dinitrate(s/l 5mg)

Long Acting Nitrates For Angina Prophylaxis:

Isosorbide Dinitrate(oral 15-120mg)

-Mononitrates(30-240mg)

-ointments-Transdermal Nitrate

Patches

Adverse Reactions :1- Postural Hypotension &

Syncope2- Tachycardia

5- Throbbing Headache

4- Facial Flushing

3- Drug Rash

6- Prolonged high dose Methaemoglobinaemia

PRECAUTIONS Tablets should be kept in air tight containers.NTG sprays are inflammableCommon side effeccts

• Headache frequently• Facial flushing,S/L nitrates Halitosis

SERIOUS side effects

• Syncope and hypotension• 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 SYMPTOMS

• In some withdrawl may ppt symptoms and sudden cardiac death may occur• 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.• NTG 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.

Mitochondrial enzyme:aldehyde dehydrogenase(or CYP 450)

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) Fasudil5) Nicorandil6) 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)

• Pathological milieu(reactive O2 species,ischemic metabolites)

• Toxins and drugs(eg, ATX-II, etc.)

Na+ channel

(Gating mechanism malfunction)

• Increase ATP consumption• Decrease ATP

formation

Oxygen supply and demand

• Abnormal contraction and relaxation

• ↑ diastolic tension(↑LV wall stiffness)

Mechanicaldysfunction

• Early after potentials

• Beat-to-beat ΔAPD• Arrhythmias (VT)

Electricalinstability

RANOLAZINE: MECHANISM OF ACTION

Ischemia

↑ Late INa

Na+ overload

Diastolic relaxation failure(increased diastolic tension)Extravascular compression

Ca2+ overload

Ranolazineinhibits the late inward

Na currentRanolazine prevents diastolic stiffness there by preserves Myocardial blood flow

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 ATPs and also an increased oxygen demand for their breakdown than oxidation of carbohydrates

3. Moreover this may lead to accumulation of free fatty acids and lactic acid increasing the acidosis and affecting 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.

Ranolazine summary

Metabolic modulation

Reduces late Na+ current

Does not affect BP

Does Not Affect Heart Rate

Extends Exercise ability

Reduces angina frequency

Reduces nitrate consumption

Additional, well-tolerated antianginal efficacy in patients who remain symptomatic despite maximal anti-anginal therapy

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

• O2 requirement of glucose pathway is lower than FFA pathway

• During ischemia, oxidized FFA levels rise, blunting the glucose pathway

FFA Glucose

Acyl-CoA

Acetyl-CoA

Pyruvate

Energy for contraction

Myocytes

β-oxidation

Trimetazidine

pFOX = partial fatty acid oxidationFFA = 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 discomfortPharmacokinetics 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 myosinCa2+

Ca2+

PLC

SR Ca2+

Receptor

Agonist

Myosin

Myosin-P

Myosin phosphatase

PIP2

IP3

MLCK

VOC ROC

Ca2+

Calmodulin

Rho

Rho kinase

Fasudil

• IP3 = inositol triphosphate

• PIP2 = phosphatidylinositol biphosphate

• PLC = phospholipase C

• ROC = receptor-operated channel

• SR = sarcoplasmic 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.

NITRATE associated effects:Vasodilation of coronary epicardial arteries

NICORANDIL: Mode of action

NICORANDIL : MODE OF ACTION

Nitrate-like action K+ channel opener ATP

Dilates epicardial Coronary arteries

Venodilatation Dilates peripheral arterioles

Dilates coronaryResistance vessels

DecreasedPreload

Decreased afterload

↑ coronary blood flow

↓ Myocardial O2

requirement↓ Myocardial O2

requirement

↑ coronary blood flow

Nicorandil dual action

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 GITperforation

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 syndromeDRUG 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?????