CALCIUM CHANNEL BLOCKERS AND CARDIOVASCULAR SAFETY.pptx

1. CALCIUM CHANNEL BLOCKERS
WITH CARDIOVASCULAR
SAFETY

2. 2
CURRENT ANTIHYPERTENSIVE
ARMAMENTARIUM
Antihypertensives
CCBs
ACE-I
ARBs
Diuretics
Beta Blockers
Alpha
Blockers
Central
Sympatholytics
Vasodilators
More than 40 years have passed since the development of CCB as
a promising antihypertensive agent.

3.  CCBs are potent anti-hypertensive agents.
 Favored in management of hypertension as
monotherapy/combination therapy.
 Gaps remain in therapy with CCBs in terms of
end organ protection & incidence of distressing
adverse effects.
3
JNC VIII RECOMMENDS CCBS AS FIRST LINE
ANTIHYPERTENSIVE AGENTS
JAMA. 2014;311(5):507-520.

4. • Amlodipine: Evidence based CCB
Trial
ALLHAT
ASCOT -
BPLA
ACCOMPL
ISH
VALUE
No of
Patients
42,000
19,257
11,506
15245
Follow up
(years)
4.9
5.5
3
4.2
Results
Amlodipine >
ACEI
Amlodipine > B
Blockers
Amlodipine >
Diuretics
Amlodipine
>ARB
Amlodipine has proven its CV efficacy and safety against all
other 1st line antihypertensive.
Among CCBs, amlodipine is widely evaluated for improvement of CV
outcomes in hypertensive in multiple large randomized clinical trials

5. GAPS IN THERAPY OF HYPERTENSION
WITH CCBS
Inadequate Cardiac Protection:
1. Vasodilatation induced Reflex Tachycardia
2. Inadequate correction of myocardial ischaemia
3. Persistent Risk of Arrhythmia
4. Hypertrophy & Remodeling of cardiac myocytes
5. No anti-platelet action
5

6. GAPS IN THERAPY OF HYPERTENSION
WITH CCBS
Inadequate Vascular Protection:
1. Progressive Endothelial Dysfunction
2. Accelerated atherosclerosis
3. Reactive Oxygen Species mediated vascular damage
Inadequate Cerebrovascular Protection:
1. Increased risk of stroke
2. No protection from progressive decline of cognition
Distressing Side Effects:
1. Peripheral oedema
2. Constipation
3. Flushing
4. Palpitations & Tachycardia
6

7. NEWER CCB BRIDGES THE
GAPS
7
Dual & triple blockade of calcium channels may offer additional benefits.

8. DRUG PROFILE OF A NOVEL CCB
8
Drugs Blocking activity
L-type N-type T-type
Nifedipine + - -
Amlodipine + - -
Cilnidipine + + -
Efonidipine + - +
Azelnidipine + - +
Benedipine + + +
Keio J Med. September 2010 ; 59 (3) : 84－95.

9. NEGLIGIBLE PEDAL OEDEMA
**International Prescribing Informations
SIDE EFFECT** Efonidipine Amlodipine Cilnidipine Benidipine
PEDAL
OEDEMA <0.1% 5-16% Up to 5% Up to 5%
 Pedal oedema is the most frequently
encountered side effect with CCBs
 Responsible for therapy discontinuation in
significant number of patients
 Conventional CCBs produce pedal oedema by
predominant pre-capillary dilatation
 “Incidence of pedal oedema with
Efonidipine is negligible due to its
balanced dilatation of pre & post-capillary
vessels”

10. AZELNIDIPINE
• Azelnidipine is a new dihydropyridine calcium channel
antagonist.
• It is L and T type of calcium channel blocker.
• Composed of a racemic mixture containing a 1:1 ratio of
the active R-enantiomer and the inactive S-enantiomer.
Drugs 2003; 63 (23): 2613-2621

11. MECHANISM OF ACTION OF AZELNIDIPINE
 Blocks L-Type calcium channel in blood vessel and T-type
Calcium channel in heart.
 Results in vasodilation and reduced heart rate.
 Thus continues to produce long-term antihypertensive
effect.
 It shows gradual fall in BP, hence does not induce reflex
tachycardia.
Drugs 2003; 63 (23): 2613-2621

12. DOSAGE AND INDICATIONS
 Azelnidipine tablets 16 mg.
 For the treatment of Essential Hypertension.
CDSCO site
Approved by
DCGI
USE IN SPECIFIC POPULATION
 Severe renal Impairment: Efficacy have not been established
 Severe hepatic impairment: Efficacy have not been established
 Pediatric Use: Efficacy have not been established
 Elderly Use: Low dose (8 mg once daily) is recommended
 Pregnancy: Not recommended
 Nursing mother: Not recommended

13. EFFECTS PROVEN IN PRE-CLINICAL STUDIES
 Negative chronotropic effect 1
 Inhibit Aldosterone synthesis and secretion 2
 Dilate efferent arterioles 3
 Preserves insulin signaling and glucose uptake 3
1. Journal of Hypertension 2014, 32:1898–1904
2. Eur J Pharmacol. 2009 Mar 1;605(1-3):49-52
3. Drugs R D (2013) 13:63–73
4. Endocrine Journal 2015, 62 (8), 741-747

14. Kozo Yao ,et al. Journal of pharmacological sciences: 2006: 100 (4) : 243-61
Triple calcium channel blocking effect
Benidipine inhibits not only the L-type Ca2+ channel, but also especially
inhibits the N-type and T-type Ca2+ channels.
Its triple Ca2+-channel blocking effects, are involved in the
pharmacological actions of this drug, such as its renoprotective
effect.
BENEDIPINE
Dose 4-8 mg BD

15. Cardio-protective & anti-atherosclerotic effects of Benidipine
Kozo Yao ,et al. Journal of pharmacological
Benidipine has anti-oxidative activity
Stimulates NO production
Suppresses the expression of adhesion
molecules
Suppresses the proliferation of vascular
smooth muscles
Suppresses the proliferation of mesangial cells
Protects the myocardium

16. CILINIDIPINE
 Demonstrates significant sympatholytic action.
 Attenuates platelet activation (and consequent arterial
thrombosis), tachycardia, oxidative stress, and also inhibits
activation of renin-angiotensin system in blood vessels.

17. •Cilnidipine improves the ambulatory BP and HR profile.
•Significant suppression of LVH in hypertensive CKD
patients.
Dose 5-10 mg OD, Maximum dose
20mg

18. EFONIDIPINE
Dose 20-40 mg OD

19. NEGATIVE CHRONOTROPIC EFFECT
 Efonidipine regulate heart rate
(HR) by inhibiting T-type
calcium channels, which are
localized primarily in SA node &
are involved in pacemaker
mechanism of heart.
Cardiovasculnr Drug Reviews, Vol. 12, No. 2, 1994
Antihypertensive effect by blocking L-type calcium channels causes
reflex tachycardia by  sympathetic drive
Reduces SNS activity & enhances PNS activity

20. ANTIANGINAL ACTION
 Efonidipine reduces myocardial oxygen demand &
improves coronary blood supply:
 T-type Ca2+ channel blockade in SA Node reduces heart rate
 Reduction in heart rate lowers myocardial oxygen demand
 T-type Ca2+ channel blockade in coronary vasculature dilates
coronary blood vessels &  coronary blood flow
 Increased coronary blood flow ameliorates myocardial ischaemia
1.Curr Ther Res Clin Exp. 2003 Nov;64(9):707-14 2.Journal of Human Hypertension.2002);16: 539-547
LONG TERM CARDIOPROTECTION
• Efonidipine lowers circulating Aldosterone levels by
blocking T-type Ca2+ channels in the adrenal cortex
• Prevents Aldosterone induced cardiac hypertrophy &
remodeling

21. ANTI-ARRHYTHMOGENIC ACTION
 Efonidipine  the risk of SVTs and
prevents AF from becoming
permanent by blocking T-type
channels
. J Atheroscler Thromb. 2009 Oct; 16(5): 568-75.

22. ROLE IN ENDOTHELIAL PROTECTION &
ANTI-OXIDANT ACTIVITY
 Efonidipine  8-hydroxy-2`-
deoxy Guanosine (8-OH-dG) &
Malondialdehyde-modified LDL
(markers of oxidative damage)
and improves endothelial
function
Diabetes Care.2007 Jun;30(6):1605-7.

23. ANTI-ATHEROGENIC ACTION
 Prevention of
platelet/monocyte
activation & release of
cell adhesion molecules
 Reduces atherosclerotic
plaque size by
preventing cholesterol
ester deposition in them
 Prevents proliferation of
smooth muscle cells in
the arteries
. J Atheroscler Thromb. 2009 Oct; 16(5): 568-75.

24. ANTI-PLATELET ACTION
 Efonidipine therapy
significantly reduces
markers of platelet
activation.
 Efonidipine prevents
platelet activation and
reduces the risk of
vascular injury and
atherosclerosis.
J Hum Hypertens. 2002 Aug;16(8):539-47.

25. REDUCES INSULIN RESISTANCE
• Efonidipine lowers Insulin
Resistance by blocking the T-
type channels
• Improves glycemic control
Springer Vienna. 2015; 137-150.

26. TAKE HOME POINTS
 Unique novel CCB (L,N & T-type) with potent anti-
hypertensive action & myriad of Pleiotropic Effects
• Superior renoprotective action by blockade of T-type calcium channels in
the kidneys & adrenal glands.
• Enhanced cardioprotective action & significant anti-anginal effect.
• Superior vasculoprotection with pronounced anti-oxidant & anti-atherogenic
activity.
• Offers cerebroprotection & prevents decline in cognitive function.
• Unique anti-platelet activity & improves insulin resistance.
• Unmatched safety profile: Least incidence of
 Pedal oedema
 Constipation
 Palpitation
 Flushing