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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
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:
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
3- Drug Rash
4- Facial Flushing
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:-
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.)
Ca2+ overload
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
Myocytes
FFA Glucose • O2 requirement of
glucose pathway is
Acyl-CoA Pyruvate lower than FFA pathway
β-oxidation
• During ischemia,
Trimetazidine
Indications:
• Angina pectoris and IHD
• Children
• 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
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
DOSAGE
Start with 5 mg twice daily
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 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????
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