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Pharmacology > Calcium Channel blockers. Drugs acting on the RAAS. > Flashcards

Calcium Channel blockers. Drugs acting on the RAAS. Flashcards

1
Q

What are L-type calcium channels?

A

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.

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2
Q

What do calcium channel blockers do?

A 
 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

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3
Q

What is the role of the transmembrane calcium influx on vascular smooth muscle?

A

Vascular smooth muscle:

 Dependent on Ca2+
transmembrane flux for normal resting tone and contraction
 Arterioles are more sensitive than veins

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4
Q

What is the role of the transmembrane calcium influx on cardiac muscle?

A

Cardiac muscle:

 Calcium-dependent action potential
• Impulse generation
• AV conduction
 Excitation-contraction coupling in cardiomyocytes

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5
Q

What is the role of the transmembrane calcium influx on non-vascular smooth muscle?

A

Non-vascular smooth muscle

 Bronchial, GI, uterine

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6
Q

What is the role of the transmembrane calcium influx on skeletal muscle?

A

not dependent on calcium influx

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7
Q

How are calcium channel blockers classified?

A 
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

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8
Q

What is the Pk of calcium channel blockers - routes of administration?

A

Routes of administration
 Oral
 IV: verapamil

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9
Q

What is the Pk of calcium channel blockers - oral bioavailability?

A

Oral bioavailability
 Variable, but often low: from <20-25% (verapamil) to 65-90% (amlodipine)
 First-pass metabolism

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10
Q

What is the Pk of calcium channel blockers - elimination routes?

A

Mostly extensive metabolism

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11
Q

What is the Pk of calcium channel blockers - plasma half-lives?

A

Relatively short (4-6 hrs): nifedipine, diltiazem, verapamil

 Intermediate (8-16 hrs): felodipine

 Relatively long (20-50 hrs): amlodipine

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12
Q

What are the pharmacological effects of calcium channel blockers?
(cardiac, vascular, and non-vascular smooth muscle)

A

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

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13
Q

What are the clinical uses of calcium channel blockers?

A

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

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14
Q

What are the adverse effects of calcium channel blockers?

A

Headache, flush, dizziness (nifedipine&raquo_space; second
generation DHPs)

 Reflex tachycardia (nifedipine&raquo_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

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15
Q

What are the drug interactions and contraindications of calcium channel blockers?

A

Drug interactions
 Deleterious
• Verapamil with BABs
• Verapamil with digoxin ( plasma levels)

 Beneficial
• DHPs with BABs

 Contraindications
CHF
• Absolute: verapamil, diltiazem
• Relative: DHPs

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16
Q

What is the RAAS?

A

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.

17
Q

How is the RAAS activated?

A

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

18
Q

What is an angiotensin-converting enzyme (ACE) and where is it located?

A

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.

19
Q

What are the functions of ACE?

A

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

20
Q

What are the drugs acting on the RAAS?

A

 АСЕ inhibitors

 Blockers of angiotensin II
(AT1) receptors

 Direct renin inhibitors

 Aldosterone antagonists

21
Q

What are the pharmacokinetics of ACE- I?

A

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)

22
Q

What are the pharmacodynamics of ACE-i? (vascular effects, renal effects, organ-protective effects)

A

 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)

23
Q

What are the clinical uses of ACE-I?

A

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

24
Q

What are the adverse effects, contraindications, and drug interactions with ACE-I?

A

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)

25
Q

What is the PK of angiotensin receptor blockers?

A

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

26
Q

What is the PD of angiotensin receptor blockers (ARBs), adverse effects, and clinical use?

A

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

27
Q

What is the pK of direct renin inhibitors?

A

Aliskiren
PK:
 Oral application: low bioavailability, not influenced by food
 t1/2 ~ 40 h; 1 x daily

28
Q

What is the PD of direct renin inhibitors?

A

PD

 Directly inhibits renin and decreases its activity

29
Q

What are the indications for direct renin inhibitors?

A

Indications
 Arterial hypertension; especially in patients with diabetes (renal
protection)

30
Q

What are the ADR of direct renin inhibitors?

A

Adverse drug reactions:

 Diarrhea (the most common adverse reaction)
 Angioneurotic edema
 Hyperkalemia (especially in combination with ACE-I in diabetic patients)

31
Q

What are the contraindications of direct renin inhibitors?

A

Contraindications:

 Pregnancy – because of the lack of clinical studies it should not be
used by pregnant women and by women planning pregnancy

32
Q

What are aldosterone antagonists?

A

Drugs
 Nonselective: Spironolactone
 Selective (II generation): Eplerenone

33
Q

What is the PK of aldosterone antagonists?

A

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
34
Q

What is the PD of aldosterone antagonists?

A

PD
 Prevent salt retention: weak to moderate diuretic effect
 Inhibit myocardial and vascular hypertrophy and fibrosis
 Prevent hypokalemia

35
Q

What are the ADRs of aldosterone antagonists?

A

Adverse effects
 Hyperkalemia
 Endocrine abnormalities: gynecomastia, menstrual irregularities,
decreased libido (Spironolactone)

36
Q

What are the clinical uses of aldosterone antagonists?

A

Clinical use:

 In hypertension – in conjunction with potassium-depleting
diuretics

 In CHF

 In primary hyperaldosteronism

 In secondary hyperaldosteronism
• Cirrhosis with ascites
• Nephrotic syndrome
• CHF

Pharmacology (35 decks)

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