Calcium Channel blockers. Drugs acting on the RAAS. Flashcards
What are L-type calcium channels?
What are L-type voltage-gated calcium channels?
L-type voltage-gated calcium channels (VGCCs) are multisubunit membrane proteins that regulate calcium influx into excitable cells.
What do calcium channel blockers do?
Calcium channel blockers inhibit the influx of calcium in the cell through the L-type voltage-gated calcium channels.
L-type calcium channels are
typical for smooth muscle
(myocardial, vascular, and nonvascular) cells and neurons.
Calcium channel blockers:
Bind to the alpha1-subunit of
the of the L-type calcium
channels
What is the role of the transmembrane calcium influx on vascular smooth muscle?
Vascular smooth muscle:
Dependent on Ca2+
transmembrane flux for normal resting tone and contraction
Arterioles are more sensitive than veins
What is the role of the transmembrane calcium influx on cardiac muscle?
Cardiac muscle:
Calcium-dependent action potential
• Impulse generation
• AV conduction
Excitation-contraction coupling in cardiomyocytes
What is the role of the transmembrane calcium influx on non-vascular smooth muscle?
Non-vascular smooth muscle
Bronchial, GI, uterine
What is the role of the transmembrane calcium influx on skeletal muscle?
not dependent on calcium influx
How are calcium channel blockers classified?
Dihydropyridines: First generation Nifedipine Nitrendipine Nimodipine
Second generation
Felodipine
Prolonged-release forms of first-generation drugs
Third generation
Amlodipine
Lacidipine
Lercanidipine
Non-dihydropyridines:
Phenylalkylamines
Verapamil
Benzothiazepines
Diltiazem
What is the Pk of calcium channel blockers - routes of administration?
Routes of administration
Oral
IV: verapamil
What is the Pk of calcium channel blockers - oral bioavailability?
Oral bioavailability
Variable, but often low: from <20-25% (verapamil) to 65-90% (amlodipine)
First-pass metabolism
What is the Pk of calcium channel blockers - elimination routes?
Mostly extensive metabolism
What is the Pk of calcium channel blockers - plasma half-lives?
Relatively short (4-6 hrs): nifedipine, diltiazem, verapamil
Intermediate (8-16 hrs): felodipine
Relatively long (20-50 hrs): amlodipine
What are the pharmacological effects of calcium channel blockers?
(cardiac, vascular, and non-vascular smooth muscle)
Cardiac effects (verapamil, diltiazem)
Depression of the pace-maker activity in the SA node
(negative chronotropic effect)
Depression of AV conductance (negative dromotropic effect)
Depression of contractility (negative inotropic effect)
Vascular effects (mainly DHPs)
Arterial/arteriolar dilatation reduction of after-load and BP
Coronary vasodilatation useful in variant angina (due to
artery spasm)
Relaxation of non-vascular smooth muscle
Bronchial
GI
Uterus
What are the clinical uses of calcium channel blockers?
In cardiovascular diseases
Hypertension (all calcium channel blockers)
Angina pectoris (all calcium channel blockers, except I generation
DHP)
Supraventricular arrhythmias (verapamil, diltiazem)
Peripheral vascular diseases (Raynaud’s phenomenon) (DHP)
In neurologic diseases
Migraine prophylaxis (nifedipine, nimodipine, verapamil)
Ischemic brain disease (nimodipine)
In obstetrics
Prevention of premature labor
What are the adverse effects of calcium channel blockers?
Headache, flush, dizziness (nifedipine»_space; second
generation DHPs)
Reflex tachycardia (nifedipine»_space; second generation
DHPs)
Induction of ischemic pain (nifedipine in short-acting
forms)
Ankle edema (DHPs)
Hypotension
Constipation (verapamil)
AV conduction problems (verapamil, diltiazem)
Deterioration of CHF (verapamil, diltiazem)
Gingival hyperplasia
Taste disturbances
What are the drug interactions and contraindications of calcium channel blockers?
Drug interactions
Deleterious
• Verapamil with BABs
• Verapamil with digoxin ( plasma levels)
Beneficial
• DHPs with BABs
Contraindications
CHF
• Absolute: verapamil, diltiazem
• Relative: DHPs
What is the RAAS?
The renin–angiotensin–aldosterone system (RAAS) is a critical regulator of blood volume and systemic vascular resistance.
It does this by increasing sodium reabsorption, water reabsorption, and vascular tone.
How is the RAAS activated?
Increased renin activity through:
Low kidney perfusion
Beta1 stimulation
Increased levels of angiotensin II (AT-II)
Receptors
• AT1
(mediate most of the CV effects of AT II)
• AT2
(mainly expressed in brain during fetal life)
Effects of AT II
• Vasoconstriction
• Increased secretion of aldosterone
• Increased Na+
reabsorption in the proximal tubules
• Mitogenic factor in cardiac and vascular cells – cardio-vascular hypertrophy
Increased activity of aldosterone
Retention of sodium and water
Excretion of potassium
Growth factor activity
What is an angiotensin-converting enzyme (ACE) and where is it located?
ACE: a membrane-bound enzyme on
the surface of the endothelial cells
Location
Particularly abundant in the lung (vast
area)
Others: in the heart, kidney, brain, etc.
What are the functions of ACE?
ACE works on angiotensin I to form angiotensin II
it also breaks down bradykinin.
Consequences of ACE inhibition :
• Reduced plasma levels of ATII
• Increased plasma levels of bradykinin
https://cvpharmacology.com/vasodilator/ACE
What are the drugs acting on the RAAS?
АСЕ inhibitors
Blockers of angiotensin II
(AT1) receptors
Direct renin inhibitors
Aldosterone antagonists
What are the pharmacokinetics of ACE- I?
ACEI are pro-drugs (except captopril and
lisinopril): they are hydrolyzed by hepatic
esterases to the active drugs, e.g. enalaprilat.
PK:
Adequate but incomplete absorption following
oral administration
Variable oral bioavailability – from 11%
(trandolapril) to 75 % (captopril)
Elimination
The majority of ACEI have predominantly renal
excretion (except fosinopril, moexipril)
Half-lives – variable: from ~ 2 hrs (captopril)
to ~ 50 hrs (ramipril)
What are the pharmacodynamics of ACE-i? (vascular effects, renal effects, organ-protective effects)
Vascular effects:
-Vasodilation
• Reduce peripheral resistance
• Reduce venous tone
Renal effects
- Increased excretion of Na+
- Mechanism: hemodynamic and through
aldosterone inhibition
Organ-protective effects (with long-term
therapy)
- Reduced LV hypertrophy (heart)
- Reduced media/lumen ratio (kidney, retina)
What are the clinical uses of ACE-I?
In CHF: first-line drugs:
All patients with systolic LV dysfunction (class I-IV)
should receive an ACEI
Documented evidence of reduced morbidity and
mortality
In arterial hypertension:
ACEI are amongst the first-line drugs for initial
monotherapy
Preferred in patients with diabetes
In diabetic nephropathy:
ACEI delay the development of the end-stage renal
failure
In myocardial infarction:
ACEI reduce the overall mortality
What are the adverse effects, contraindications, and drug interactions with ACE-I?
Adverse effects:
Dry, non-productive, permanent cough (5-20 %)
Allergic reactions (angioedema, skin rash)
Hyperkalemia
Hypotension (when used to treat conditions other
than arterial hypertension)
Contraindications:
Bilateral renal artery stenosis (acute renal failure)
Pregnancy (ACEI fetopathy – renal impairment)
Drug interactions:
With K+ sparing diuretics (risk of hyperkalemia)
What is the PK of angiotensin receptor blockers?
PK:
Rapid absorption following oral administration
Bioavailability – variable: from ~13%
(eprosartan) to ~80% (irbesartan)
Highly bound to plasma proteins (95-99%)
Metabolism:
• Active metabolite (losatran)
• Inactive metabolites (the rest)
Plasma half-lives: long enough to allow
once-a-day dosing
What is the PD of angiotensin receptor blockers (ARBs), adverse effects, and clinical use?
PD
Similar to ACEI
Vascular effects:
-Vasodilation
• Reduce peripheral resistance
• Reduce venous tone
Renal effects
- Increased excretion of Na+
- Mechanism: hemodynamic and through
aldosterone inhibition
Organ-protective effects (with long-term
therapy)
- Reduced LV hypertrophy (heart)
- Reduced media/lumen ratio (kidney, retina)
Adverse effects:
Similar to those of ACEI (but no cough)
Others: headache, muscle cramps, infections of
the upper respiratory tract, dizziness, fatigue
Clinical use – as alternatives to ACEI in:
Arterial hypertension
CHF
What is the pK of direct renin inhibitors?
Aliskiren
PK:
Oral application: low bioavailability, not influenced by food
t1/2 ~ 40 h; 1 x daily
What is the PD of direct renin inhibitors?
PD
Directly inhibits renin and decreases its activity
What are the indications for direct renin inhibitors?
Indications
Arterial hypertension; especially in patients with diabetes (renal
protection)
What are the ADR of direct renin inhibitors?
Adverse drug reactions:
Diarrhea (the most common adverse reaction)
Angioneurotic edema
Hyperkalemia (especially in combination with ACE-I in diabetic patients)
What are the contraindications of direct renin inhibitors?
Contraindications:
Pregnancy – because of the lack of clinical studies it should not be
used by pregnant women and by women planning pregnancy
What are aldosterone antagonists?
Drugs
Nonselective: Spironolactone
Selective (II generation): Eplerenone
What is the PK of aldosterone antagonists?
PK:
Orally active Metabolism • To active metabolites (Spironolactone) • To inactive metabolites (Eplerenone) Plasma half-lives • Long with Spironolactone (due to the active metabolites) • Shorter with Eplerenone
What is the PD of aldosterone antagonists?
PD
Prevent salt retention: weak to moderate diuretic effect
Inhibit myocardial and vascular hypertrophy and fibrosis
Prevent hypokalemia
What are the ADRs of aldosterone antagonists?
Adverse effects
Hyperkalemia
Endocrine abnormalities: gynecomastia, menstrual irregularities,
decreased libido (Spironolactone)
What are the clinical uses of aldosterone antagonists?
Clinical use:
In hypertension – in conjunction with potassium-depleting
diuretics
In CHF
In primary hyperaldosteronism
In secondary hyperaldosteronism
• Cirrhosis with ascites
• Nephrotic syndrome
• CHF
