Angina pectoris and Calcium Channel Blockers

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Transcript Angina pectoris and Calcium Channel Blockers

Calcium Channel Blockers
October 3, 2007
Frank F. Vincenzi
Ca signalling and Ca channel blockers: The
fundamental information
intracellular
Ca
2+ =
10
-7
M
extracellular
Ca 2+ = 10
-3
M
Calcium
• The FIRST second messenger
fundamental intracellular messenger for
a wide variety of physiological responses
in essentially all cell types (muscle tension,
neurotransmitter/hormone release, production
of inflammatory mediators)
• The LAST second messenger
accumulation of intracellular Ca2+ is a final
common pathway in both apoptotic and
necrotic cell death
Ca signalling: Two fundamental mechanisms
• Influx of Ca across the plasma membrane
– voltage-operated Ca channels (VOCs)
– receptor-operated Ca channels (ROCs)
• Internal release of Ca from intracellular stores
(sarcoplasmic/endoplasmic reticulum) (SER)
– Ca-induced Ca release (‘trigger Ca’)
– Inositol tris-phosphate( IP3) induced Ca release
• Combinations of the above mechanisms
Intracellular Calcium Release
• Inositol tris-phosphate (IP3)
– Present in almost all cells. IP3 acts on
sarcoplasmic/endoplasmic reticulum receptors (IP3Rs)
– IP3 may sensitize Ca-induced Ca release
• Calcium-induced calcium release
– Mainly in striated muscle
– Ryanodine receptors (RyRs)
• RyR1 (predominantly in skeletal muscle)
– [Mutation associated with malignant hyperthermia]
• RyR2 (predominantly in cardiac muscle)
• RyR3 (predominantly in brain & non-muscle)
Ca2+
2+
+
Ca2+ Na Ca
Ca2+
sarcolemma
R
O
C
ATP
Ca2+
Ca2+
Ca2+
R
O
C
Ca2+
RyR
Receptor operated
Ca channels mediate
some agonist actions
Agonist
Ca2+
Ca2+
Ca2+
SR
Ca2+
Ca2+
Ca2+
Ca2+
Ca signalling: Three examples
• Histamine on H-1 receptor activates phospholipase C and
releases inositol trisphosphate (IP3), IP3 acts on SR/ER IP3
receptors causing Ca release (CHEMICAL)
• Norepinephrine on beta-1 receptors in heart couple to G
protein and activate adenylyl cyclase; increase cAMP, activate
protein kinase A (PKA), phophorylate a cytoplasmic domain
of the Ca channel, increase Ca current; PKA also
phosphorylates phospholamban, an SR protein and increases
the activity of the SERCA pump; increase Ca storage and
release (CHEMICAL/ELECTRICAL)
• Cell depolarization activates voltage operated Ca channels
(VOCs) in the plasma membrane, promoting influx of Ca into
the cell cytoplasm, may be amplified by Ca induced Ca release
(ELECTRICAL)
Ca2+
+ Ca2+
2+
Na
Ca
Ca2+
sarcolemma
ATP
PLC
Ca2+
Ca2+
Ca2+
RyR
Phospholipase C and
inositol tris phosphate
mediate some agonist
actions by promoting
intracellular Ca release
histamine
Ca2+
Ca2+
Ca2+
SR
IP3
IP3 R
DAG
Ca2+
+ Ca2+
2+
Na
Ca
Ca2+
Ca2+
sarcolemma
V
O
C
ATP
V
O
C
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
RyR
Ca2+
2+
Ca2+ Ca
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
AC
Beta-1 Receptor
G
+ Ca2+
2+
Na
Ca
Ca2+
norepinephrine
Ca2+
sarcolemma
V
O
C
ATP
V
O
C
Ca2+
Ca2+
AC
P
Ca2+
Ca2+
Ca2+
Ca2+
RyR
Ca2+
Ca2+
P
G
cAMP
Ca2+
2+
Ca2+ Ca
Ca2+
Ca2+
Ca2+
Ca2+
Beta-1 Receptor
PKA
cAMP and protein
kinase A mediate some
of the positive inotropic
effects of catecholamines
by increasing Ca influx
and intracellular Ca storage
and release
Ca regulation of muscle tension:
different in different types of muscle
• Reversible ionic binding of Ca to the Ca binding
protein, troponin C
(Ca/TNC disinhibits actin/myosin ATPase)
– skeletal myo (force varied by recruitment)
– cardiac myo (force varied by cellular regulation)
• Covalent modification of myosin light chain
(Ca binds to the Ca binding protein, calmodulin
CaM, CaM binds to MLCK, MLCK
phosphorylates MLC, activates ATPase - tension)
– smooth myo (force varied by level of MLC
phosphorylation)
The
calcium
cycle in
HEART
muscle
Ca2+
+ Ca2+
2+
Na
Ca
Ca2+
sarcolemma
V
O
C
ATP
Ca2+
Ca2+
Ca2+
Ca2+
V
O Ca channel, DHPR
C
Ca2+
RyR
Ca2+
Ca2+
Ca2+
SR
Ca2+
The
calcium
cycle in
SMOOTH
muscle
The calcium
cycle in
SKELETAL
muscle
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Ca “channel”, DHPR
sarcolemma
Ca2+
T-tubule
Ca2+
RyR
Ca2+
Ca2+Ca2+
Ca2+
Ca2+
Ca2+
SR
Ca2+
Ca regulation in muscle: variations on a few themes
VOC
ROC
PMCA
SR
Na/Ca
exchange
Ca2+
Na +
actin
myosin
mitochondria
Na/K
pump
K
+
Muscle control: differential sensitivity to Ca
channel blockers (CEBs)
Overview of Plasma Membrane Ca Channels
• Voltage operated channels (VOCs)
L-type, N-type, T-type….etc.
• Receptor operated channels (ROCs)
coupled to diverse receptors in the same cell
• Mechanically operated channels (MOCs)
not widely appreciated (yet)
Voltage operated Ca Channels
• L-type
(‘long’, important in heart & smooth muscle)
• N-type
(‘nerve’, important in conduction & synaptic
transmission)
• T-type
(‘transient’, heart & smooth muscle)
Calcium Channel Blockers
• Currently marketed Ca channel blockers all block
L-type channels.
• Other terminology for these drugs:
Calcium entry blockers (CEBs)
Slow channel blockers
“Calcium antagonists” (ugh!)
(why NO T call them calcium antagonists?)
Chemical classifications of Ca channel blockers
• dihydropyridines
e.g., nifedipine (Procardia®)
(have given the name to voltage operated Ca
signaling proteins - ‘the dihydropyridine receptor’
• benzothiazepines
e.g., diltiazem (Cardizem®)
• phenylalkylamines
e.g., verapamil (Isoptin®, Calan®)
In General Calcium Channel Blockers Are:
• Lipid soluble
• Rapidly absorbed
• Largely protein bound
• Of low bioavailability
• Metabolized by the liver
Calcium Channel Blockers: Site and
Mechanism of Action
• L-type voltage operated channels (VOCs) and
receptor operated channels (ROCs)
• Binding to Ca channel protein
(slightly different site for each class):
– inhibits ionophoric activity of affected channels (all
agents)
– delays recovery of the affected voltage operated
channels (verapamil > diltiazem >> nifedipine)
Calcium Channel Blockers:
Frequency Dependence
• Verapamil (and to some extent, diltiazem)
selectively inhibits rapid cardiac rhythms by
delaying recovery of calcium channels
• Dihydropyridines, such as nifedipine, have little or
no effect on cardiac Ca channels in vivo
Calcium channel blockers: potencies for
different tissues compared
• Smooth muscle
dihydropyridines (e.g., nifedipine) >>
verapamil ~ diltiazem
• Heart
– SA & AV nodes
verapamil ~ diltiazem >> nifedipine
– myocardium
verapamil > diltiazem >> nifedipine
Clinical Effects of Ca Channel Blockers
• Relax arteriolar smooth muscle, little or no
venodilation
• Verapamil & diltiazem also depress SA and AV
nodes and depress myocardial contractility to
some extent.
• Dihydropyridines do not affect heart in vivo in
normal doses
• Note: little or no effect on nervous system or
skeletal muscle (no block of N-type Ca channels,
and internal cycling of Ca, respectively)
Calcium Channel Blockers: Indications
• Angina (multiple mechanisms)
• Atrial arrhythmias (AV node conduction depends on
‘Ca action potentials’ - some Ca channel blockers
increase AV node refractory period)
• Hypertension (decrease vascular resistance)
( ± nifedipine for malignant hypertension)
(sodium nitroprusside is a drug of choice here)
(Raynaud’s syndrome?, asthma?, atherosclerosis?,
reperfusion injury?)
nifedipine: indications
• Angina, variant angina
• Hypertension
• Off label
aortic regurgitation, diabetic nephropathy, hiccups,
hypertensive emergency/urgency, prophylaxis of migraine,
premature labor (FDA-use-in-pregnancy C)
nifedipine: selected adverse reactions
• Hypotension
• Peripheral edema
• Flushing, headache
diltiazem: indications
•
•
•
•
Angina, variant angina
Atrial flutter, atrial fibrillation
Paroxysmal supraventricular tachycardia
Hypertension - slow release formulations only
• Off label
Cardiomyopathy, diabetic nephropathy, proteinuria,
prophylaxis of migraine
diltiazem: selected adverse reactions
•
•
•
•
•
Depression of cardiac muscle
AV nodal blockade
Hypotension
Peripheral edema
Flushing, headache
verapamil: indications
•
•
•
•
Angina, unstable angina, variant angina
Atrial flutter, atrial fibrillation
Paroxysmal atrial tachycardia (prevent and Tx)
Hypertension
• Off label
claudication, prophylaxis of migraine, mania
verapamil: selected adverse reactions
•
•
•
•
•
•
Depression of cardiac muscle
AV nodal blockade
Hypotension
Peripheral edema
Flushing, headache
Constipation
Psaty et al., (1995)* Use of
short acting (emphasis
added) Ca channel blockers,
especially in high doses,
and particularly when
combined with diuretics,
was associated with an
increased risk of myocardial
infarction.
(None of the therapies
monitored decreased MI
risk significantly)
Cochrane, different result
with long acting CEBs
*JAMA 274: 620-625, 1995
Scarlett O’Brian
• Scarlett O’Brian is a 38 year old female who was
diagnosed with mild hypertension. She was given
a prescription for verapamil (80 mg, TID, #100).
• Two days later she called her boyfriend (a
prominent [married] business executive) to an
urgent meeting to ‘sort out their relationship’.
• The boyfriend later testified that they had a
‘couple of drinks’ while he explained that he was
not going to leave his wife.
Scarlett O’Brian collapses
• As they continued to talk, Scarlett began to feel
poorly. She fainted, but appeared to be breathing
adequately. Over the course of the next hour,
while lying down, she became worse with a
pounding headache, profound ‘weakness’ and
inability to stand.
• The boyfriend delayed calling 911 for fear of
making their relationship public. When she
became unconscious, he finally called. By the
time EMTs arrived she was in complete heart
block. Efforts to restore an effective cardiac
rhythm failed.
Scarlett O’Brian, what happened?
• Did she die of some underlying disease?
• Did she die of alcohol poisoning?
• Did she die because of verapamil?
Scarlett O’Brian, Autopsy
• Body is that of a well developed, well nourished
female (60 kg).
• No structural cause of death could be identified.
• Gastric contents contained partially disintegrated
tablets (yellow)
• Toxicology (blood) identified:
caffeine - trace
ethanol - 350 mg/l (0.035 BAC)
verapamil - 23 mg/L
If taken as prescribed, what was the predicted
average steady state concentration of
verapamil in Scarlett?
• CL verapamil = 15 mL/kg/min = 54 L/h in 60 kg pt.
• Rx: 80 mg TID = 240 mg/24 h = 10 mg/h
• Css = (10 mg/h) * (0.22) / (54 L/h) = 0.04 mg/L
(equivalent to 40 ng/mL)
Verapamil, some useful numbers
• NORMALLY, a large first-pass effect, 22%
bioavailability
(metabolized in the liver to norverapamil)
• Urinary excretion < 3%
• Plasma binding = 90%
• CL = ‘15 mL/min/kg’ (15 mL*min-1*kg-1)
• Vd = 5 L/kg
• Half life = 4 hours
• Effective concs. = 120 ng/mL
• Toxic concs. ?
Scarlett, more questions
• Was Scarlett a poor metabolizer?
• Suppose she had metabolized none of the
verapamil, how much should be in her body?
3 days * 240 mg/day = 720 mg
• How much verapamil was in the prescription?
• 100 tablets * 80 mg/tab = 8000 mg
• Even if Scarlett had taken all 100 tablets at once,
if the drug was absorbed and metabolized
normally only about 1600 mg should have been
present.
Scarlett, the numbers tell the story
• How much verapamil should she have taken?
(three days time 240 mg/day = 720 mg)
• Theoretical Vd of verapamil in Scarlett’s body?
(60 kg * 5 L/kg = 300 L total Vd)*
• Blood conc at autopsy = 23 mg/L
• IF distributed in total Vd, then the total verapamil
in Scarlett’s body:
• 300 L * 23 mg/L = 6900 mg.
Scarlett O’Brian: A suicide gesture gone bad
• Scarlett probably took most or all of the
prescription of verapamil shortly before her
boyfriend arrived.
• The drug was rapidly absorbed and saturated first
pass mechanisms (bioavailability approached 1).
• Hypotension and heart block were produced as the
concentration of verapamil increased.
• The delay in calling 911 probably turned a suicide
gesture into a suicide.