Download Calcium channel blockers

CALCIUM CHANNEL BLOCKERS
Calcium channel blockers (CCB) prevent calcium from entering cells (mainly of the heart
and blood vessel walls). Calcium channel blockers, also called calcium antagonists, are
used to treat various conditions, including high blood pressure, angina, Raynaud's
phenomenon and some arrhythmias. They are also used to try to stop premature labour
in pregnancy.
• DIHYDROPYRIDINES of I (nifedipine) and II (amlodipine) generation
• BENZOTHIAZEPINE (diltiazem)
• PHENYLALKYLAMINES (verapamil)
• PIPERAZINE (flunarizine)
NIFEDIPINE
VERAPAMIL
AMLODIPINE
DILTIAZEM
Voltage-operated Ca++ CHANNELS (VOCCs)
TYPE
L-TYPE CALCIUM CHANNEL
("LONG-LASTING" AKA "DHP
RECEPTOR")
P-TYPE CALCIUM CHANNEL
("PURKINJE") /Q-TYPE
CALCIUM CHANNEL
N-TYPE CALCIUM CHANNEL
("NEURAL"/"NON-L")
R-TYPE CALCIUM CHANNEL
("RESIDUAL")
T-TYPE CALCIUM CHANNEL
("TRANSIENT")
VOLTAGE
MOST OFTEN FOUND IN
HVA
(high voltage
activated)
Skeletal muscle, smooth muscle, bone
(osteoblasts), ventricular myocytes (responsible
for prolonged action potential in cardiac cell;
also termed DHP receptors), dendrites and
dendritic spines of cortical neurones
L-Type channel blockers are used as
antihypertensive and antiarrhythmic drugs
HVA
Purkinje neurons in the cerebellum / Cerebellar
(high voltage
granule cells
activated)
HVA
Throughout the brain and peripheral nervous
(high-voltagesystem.
activated)
intermediatevoltageCerebellar granule cells, other neurons
activated
neurons, cells that have pacemaker activity,
bone (osteocytes)
low-voltageT-Type channel blockers are used as
activated
antiepileptic and neuropathic painkiller drugs
L-TYPE CALCIUM CHANNEL 1 SUBUNIT
DIHYDROPYRIDINE
PHENYLALKYLAMINE
BENZOTHIAZEPINE
PHENYLALKYILAMINE bind to intracellular IV6 segment.
DIHYDROPYRIDINE bind to extracellular site on III5-III6 loop
BENZOTHIAZEPINE bind in between III and IV transmembrane segment
CALCIUM CHANNEL BLOCKERS
DIHYDROPYRIDINES
bind on extracellular
portion
PHENYLALKYLAMINES
and BENZOTHIAZEPINES
Bind on intracellular site
LIPOPHILICITY
IMPLICATIONS
DIHYDROPYRIDINES CAN BIND
AT CHANNEL RESTING STATE
VASCULAR EFFECT
PREVALENT ACTIVITY ON
PRECAPILLARY RESISTANCE
ARTERIES
PHENYLALKYLAMINES
AND
BENZOTHIAZEPINES
BIND
preferentially
after
channel
activation (opening) DURING
INACTIVE STATE. Therefore their
binding is USE-DEPENDENT
CARDIAC EFFECT
ON CONDUCTANCE FIBERS
CALCIUM CHANNEL BLOCKERS - NOMENCLATURE
•
•
•
•
•
•
•
•
•
•
•
amlodipine (NORVASC, ANTACAL, MONOPINA) 5mg & 10mg
felodipine (FELODAY, PLENDIL, PREVEX) 5mg & 10mg
barnidipine (LIBRADIN, OSIPINE, VASEXTEN) 10mg & 20mg
isradipine (LOMIR SRO, CLIVOTEN, ESRADIN) 5mg
lacidipine (LACIPIL, LACIREX) 4mg & 6mg
lercanidipine (ZANEDIP, LERCADIP, CARDIOVASC) 10mg & 20mg
manidipine (IPERTEN, VASCOMAN) 20mg
nicardipine (NICARDAL, NIMICOR, PERDIPINA, ecc.) 20mg & 40mg
nifedipine (ADALAT, NIFEDICOR, generico) 20mg, 30mg, 60mg «CRONO»
nisoldipine (SYSCOR) 10mg
nitrendipine (BAYPRESS, DEITEN) 20mg
•
dilthiazem (TILDIEM, generic)
•
•
verapamil (ISOPTIN, generic)
gallopamil (PROCORUM, ALGOCOR) 50mg & 100mg
MAIN PK FEATURES OF CCBs
DOSE
NIFEDIPINE
VERAPAMIL
Oral
Intravenous
10-40 mg 8 h-1
5-15 mg kg-1
80-160 mg 8 h-1
100-200 mg kg-1
Plasma concentrations
10-75 ng ml-1
50-250 ng ml-1
Protein binding
95
90
Liver metabolism 1° passage
40-60 %
75-85 %
Half-life (t1/2)
3-5 h
5-10 h
MEDICAL USE FOR CCBs
DHP - SELECTIVE VASODILATORS
NON- DHP: EQUIPOTENT FOR CARDIAC
TISSUE AND VASCULATURE
MEDICAL USE FOR CCBs
• HYPERTENSION
By causing vascular smooth muscle relaxation, CCBs (DHP) decrease systemic
vascular resistance, which lowers arterial blood pressure. These drugs primarily
affect arterial resistance vessels, with only minimal effects on venous capacitance
vessels.
Reducing peripheral vascular
resistance,
however,
is
accompanied by compensatory
mechanism increasing heart
rate, inotropic stimulation, and
renin release.
These common effects of DHP,
especially at the beginning of
treatment, tend to reduce
during the first two weeks for
baroreceptor adjustments
MEDICAL USE FOR CCBs
• ANGINA
The anti-anginal effects of CCBs are derived from their vasodilator and
cardiodepressant actions. Systemic vasodilation reduces arterial pressure, which
reduces ventricular afterload (wall stress) thereby decreasing oxygen demand.
The more cardioselective CCBs
(verapamil
and
diltiazem)
decrease
heart
rate
and
contractility, which leads to a
reduction in myocardial oxygen
demand, which makes them
excellent antianginal drugs.
CCBs can also dilate coronary
arteries and prevent or reverse
coronary vasospasm (as occurs in
Printzmetal's variant angina),
thereby increasing oxygen supply
to the myocardium.
MEDICAL USE FOR CCBs
• ARRHYTHMIA
The antiarrhythmic properties (Class IV antiarrhythmics) of CCBs are related to
their ability to decrease the firing rate of aberrant pacemaker sites within the
heart, but more importantly are related to their ability to decrease conduction
velocity and prolong repolarization, especially at the atrioventricular node.
This latter action at the
atrioventricular
node
helps to block reentry
mechanisms, which can
cause supraventricular
tachycardia.
MEDICAL USE FOR CCBs
• CEREBRAL VASOSPASM
Some CCBs may be used to treat migraine headaches or vertigo. They may also
prevent cerebral ischemic damage from reactive vasospasm after subarachnoid
hemorrhage by dilating cerebral vessels and increasing blood flow.
MOST COMMON SIDE EFFECTS OF CCBS
• DIHYDROPIRYDINE - Nifedipine (18%)
–
–
–
–
–
–
–
Distal edema
Headache
Vertigo
Fatigue, dizziness
Postural hypotension/ reflex tachycardia
Palpitation
Aggravamento dell’angina
• PHENYLALKYLAMINE - Verapamil (10%)
–
–
–
–
Constipation
AV Block, bradicardia
Insufficienza cardiaca
Vertigo, headache, dizziness
• BENZOTHIAZEPINE
- Diltiazem (5%)
– AV Block,
bradycardia
– Vertigo, dizziness
– Rashes
– Headache
ATP-sensitive K+-channels OPENERS
These drugs hyperpolarize the smooth muscle, which closes voltage-gated
calcium channels and decreases intracellular calcium. With less calcium available
to combine with calmodulin, there is less activation of myosin light chain kinase
and phosphorylation of myosin light chains. This leads to relaxation and
vasodilation. Because small arteries and arterioles normally have a high degree
of smooth muscle tone, these drugs are particular effective in dilating these
resistance vessels, decreasing systemic vascular resistance, and lowering
arterial pressure. The fall in arterial pressure leads to reflex cardiac stimulation
(baroreceptor-mediated tachycardia).
DIAZOXIDE
MINOXIDIL
ATP-sensitive K+-channels
These channels are directly linked to the metabolic cell state.
• Channel is CLOSED when intracellular ATP concentration is HIGH (100 µM).
• Channel is OPEN when intracellular ATP concentration is LOW (less than 100 µM).
PANCREAS:
When glycemia is high, glucose
enters the cell by GluT2, ATP
increases and the K-channel
closes.
K-channel
closing
depolarizes the cell, allowing
opening of Calcium-channels
and subsequent release of
insulin
from
intracellular
vescicles.
NEURONs:
K-channels
control
depolarization
frequency, reducing it
when
intracellular
energy is low.
CV SYSTEM:
K-channel opening results in
cell
hyperpolarization,
therefore inhibiting Cachannel
opening
and
subsequent cell activation.
DIAZOXIDE
•
EMERGENCY TREATMENT
on
HYPERTENSION
(no pheocromocytoma)
• EV ADMINISTRATION
• Fast-induced effect
• Binds plasma proteins (90%),
• Liver metabolism, renal excretion
•
EMERGENCY TREATMENT
on HYPOGLYCEMIC STATE
(insulinoma)
• ORAL ADMINISTRATION (PROGLICEM®)
• 25 o 100 mg.
• Bioavailability > 80%
• Variable half-life (20 – 40 h)
MINOXIDIL
Common side effects to minoxidil include headaches, flushing and reflex tachycardia.
The potent vasodilator actions of minoxidil can lead to fluid retention and edema
formation. Reflex cardiac stimulation can precipitate angina in patients with coronary
artery disease. Minoxidil produces T wave changes in a high percentage (~60%) of
patients under chronic treatment.
One of the most noted side effects of minoxidil is hypertrichosis, a thickening and
enhanced pigmentation of body hair, and therefore this drug is more commonly used
for treating baldness.
ENDOTHELIN-1 RECEPTOR ANTAGONISTS
• Endothelin-1 (ET-1) is produced mainly by
vascular endothelial cells and exerts both
vasoconstriction and vascular smooth muscle
cells proliferation.
• ET-1 biological activity depends on activation
of ETA and ETB receptor subtypes.
• ETA receptors are prevalently expressed on
vascular smooth muscle cells, and are
particularly important on pulmunar arteries.
• ETB receptors sare ubiquitously expressed on
endothelial cells and their activation results in
increased release of NO and prostacyclin (with
subsequent vasodilatant effects).
Their role on pulmunary arteries includes also
clearing of circulating ET-1.
ENDOTHELIN-1 EFFECTS, RECEPTORS and ANTAGONISTS
ENDOTHELIN-1 RECEPTOR BLOCKERS
BOSENTAN
Bosentan is a competitive antagonist of ET-A and ET-B receptors, with a slightly higher
affinity for ET-A than ET-B.
Bosentan is indicated mainly for the treatment of pulmonary hypertension. In Europe,
bosentan is also approved for reducing the number of new digital ulcers in patients with
systemic sclerosis .
Due to potential hepatotoxicity and onset of anemia, bosentan requires a monthly
monitoring of liver function and hematocrit.
Due to a pharmacokinetic interaction, hormone-based contraception is not possible in
women taking bosentan, therefore other highly reliable forms of contraception should
be used instead. Bosentan is contraindicated in pregnancy because of its teratogenicity
SITAXENTAN, AMBRISENTAN, ATRASENTAN
are selective ETA receptor antagonists with similar medical use and comparable side
effects (including teratogenicity)