Verapamil
Encyclopedia
Verapamil is an L-type calcium channel blocker
of the phenylalkylamine class. It has been used in the treatment of hypertension
, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine
. Verapamil has also been used as a vasodilator during cryopreservation of blood vessels. It is a class IV antiarrhythmic, more effective than digoxin
in controlling ventricular rate, and was approved by the U.S. Food and Drug Administration
(FDA) in March 1982.
in all cases is to block voltage-dependent calcium channel
s.
In cardiac pharmacology, calcium channel blockers are considered class IV antiarrhythmic agents. Since calcium channels are especially concentrated in the sinoatrial and atrio-ventricular nodes, these agents can be used to decrease impulse conduction through the AV node, thus protecting the ventricles from atrial tachyarrhythmias.
Calcium channels are also present in the smooth muscle that lines blood vessels. By relaxing the tone of this smooth muscle, calcium-channel blockers dilate the blood vessels. This has led to their use in treating hypertension
and angina pectoris.
The pain of angina is caused by a deficit in oxygen supply to the heart. Calcium channel blockers like Verapamil will dilate blood vessels, which increases the supply of blood and oxygen to the heart. This controls chest pain, but only when used regularly. It does not stop chest pain once it starts. A more powerful vasodilator such as nitroglycerin may be needed to control pain once it starts.
Verapamil is also used intra-arterially to treat cerebral vasospasm. Verapamil has been used to treat cluster headache
s, but it can also cause headaches as a side effect.
is much lower (10–35%). It is 90% bound to plasma proteins
and has a volume of distribution
of 3–5 L/kg. It is metabolized in the liver to at least 12 inactive metabolites (though one metabolite, norverapamil, retains 20% of the vasodilating activity of the parent drug). As its metabolites, 70% is excreted in the urine and 16% in feces; 3–4% is excreted unchanged in urine. This is a non-linear dependence between plasma concentration and dosage. Onset of action is 1–2 hours after oral dosage. Half-life is 5–12 hours (with chronic dosages). It is not cleared by hemodialysis.
Verapamil has been reported to be effective in both short-term and long-term treatment of mania and hypomania. Addition of magnesium oxide
to the verapamil treatment protocol enhances the antimanic effect. It has on occasion been used to control mania
in pregnant patients, especially in the first 3 months. It does not appear to be significantly teratogenic. For this reason, when one wants to avoid taking valproic acid (which is high in teratogenicity) or lithium
(which has a small but significant incidence of causing cardiac malformation), Verapamil is usable as an alternative, albeit presumably a less effective one.
s, facial flushing, dizziness
, swelling
, increased urination, fatigue, nausea, ecchymosis
, lightheadedness, and constipation
.
Along with other calcium channel blockers, verapamil is known to induce gingival hyperplasia.
as an inhibitor
of drug efflux pump proteins such as P-glycoprotein
. This is useful as many tumor
cell lines overexpress drug efflux pumps, limiting the effectiveness of cytotoxic drugs or fluorescent tag
s. It is also used in fluorescent cell sorting for DNA
content, as it blocks efflux of a variety of DNA-binding fluorophore
s such as Hoechst 33342. Radioactively-labelled
verapamil and positron emission tomography
can be used with to measure P-glycoprotein function.
has hindered the treatment of malaria
in Southeast Asia, South America and Africa. Resistance to chloroquine is caused by the parasite cell's ability to expel the drug outside of its digestive vacuole. It has been shown that verapamil, when used in combination with chloroquine, enhances the accumulation of chloroquine within a parasitic cell's digestive vacuole, rendering it incapable of detoxifying itself and making it more susceptible to death.
Calcium channel blocker
A calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with...
of the phenylalkylamine class. It has been used in the treatment of hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
. Verapamil has also been used as a vasodilator during cryopreservation of blood vessels. It is a class IV antiarrhythmic, more effective than digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
in controlling ventricular rate, and was approved by the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) in March 1982.
Mechanism and uses
Verapamil's mechanismMechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
in all cases is to block voltage-dependent calcium channel
Voltage-dependent calcium channel
Voltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+...
s.
In cardiac pharmacology, calcium channel blockers are considered class IV antiarrhythmic agents. Since calcium channels are especially concentrated in the sinoatrial and atrio-ventricular nodes, these agents can be used to decrease impulse conduction through the AV node, thus protecting the ventricles from atrial tachyarrhythmias.
Calcium channels are also present in the smooth muscle that lines blood vessels. By relaxing the tone of this smooth muscle, calcium-channel blockers dilate the blood vessels. This has led to their use in treating hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and angina pectoris.
The pain of angina is caused by a deficit in oxygen supply to the heart. Calcium channel blockers like Verapamil will dilate blood vessels, which increases the supply of blood and oxygen to the heart. This controls chest pain, but only when used regularly. It does not stop chest pain once it starts. A more powerful vasodilator such as nitroglycerin may be needed to control pain once it starts.
Verapamil is also used intra-arterially to treat cerebral vasospasm. Verapamil has been used to treat cluster headache
Cluster headache
Cluster headache, nicknamed "suicide headache", is a neurological disease that involves, as its most prominent feature, an immense degree of pain in the head. Cluster headaches occur periodically: spontaneous remissions interrupt active periods of pain. The cause of the disease is currently unknown...
s, but it can also cause headaches as a side effect.
Pharmacokinetic details
Given orally, 90–100% of Verapamil is absorbed, but due to high first-pass metabolism, bioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
is much lower (10–35%). It is 90% bound to plasma proteins
Plasma protein binding
A drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, β‚ and γ...
and has a volume of distribution
Volume of distribution
The volume of distribution , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing...
of 3–5 L/kg. It is metabolized in the liver to at least 12 inactive metabolites (though one metabolite, norverapamil, retains 20% of the vasodilating activity of the parent drug). As its metabolites, 70% is excreted in the urine and 16% in feces; 3–4% is excreted unchanged in urine. This is a non-linear dependence between plasma concentration and dosage. Onset of action is 1–2 hours after oral dosage. Half-life is 5–12 hours (with chronic dosages). It is not cleared by hemodialysis.
Verapamil has been reported to be effective in both short-term and long-term treatment of mania and hypomania. Addition of magnesium oxide
Magnesium oxide
Magnesium oxide , or magnesia, is a white hygroscopic solid mineral that occurs naturally as periclase and is a source of magnesium . It has an empirical formula of and consists of a lattice of Mg2+ ions and O2– ions held together by ionic bonds...
to the verapamil treatment protocol enhances the antimanic effect. It has on occasion been used to control mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
in pregnant patients, especially in the first 3 months. It does not appear to be significantly teratogenic. For this reason, when one wants to avoid taking valproic acid (which is high in teratogenicity) or lithium
Lithium carbonate
Lithium carbonate is a chemical compound of lithium, carbon, and oxygen with the formula Li2CO3. This colorless salt is widely used in the processing of metal oxides and has received attention for its use in psychiatry. It is found in nature as the rare mineral zabuyelite.-Properties:Like almost...
(which has a small but significant incidence of causing cardiac malformation), Verapamil is usable as an alternative, albeit presumably a less effective one.
Side effects
Some possible side effects of the drug are headacheHeadache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s, facial flushing, dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, swelling
Swelling (medical)
In medical parlance, swelling is the transient enlargement or protuberance in the body and may include tumors. According to cause, it may be congenital, traumatic, inflammatory, neoplastic or miscellaneous....
, increased urination, fatigue, nausea, ecchymosis
Ecchymosis
An ecchymosis is the medical term for a subcutaneous purpura larger than 1 centimeter or a hematoma, commonly called a bruise. It can be located in the skin or in a mucous membrane.-Presentation:...
, lightheadedness, and constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
.
Along with other calcium channel blockers, verapamil is known to induce gingival hyperplasia.
Overdose
Acute overdose is often manifested by nausea, asthenia, bradycardia, dizziness, hypotension and cardiac arrhythmia. Plasma, serum or blood concentrations of verapamil and norverapamil, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. Blood or plasma verapamil concentrations are usually in a range of 50-500 μg/L in persons on therapy with the drug, but may rise to 1–4 mg/L in acute overdose patients and are often at levels of 5–10 mg/L in fatal poisonings.Uses in cell biology
Verapamil is also used in cell biologyCell biology
Cell biology is a scientific discipline that studies cells – their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division and death. This is done both on a microscopic and molecular level...
as an inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of drug efflux pump proteins such as P-glycoprotein
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
. This is useful as many tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
cell lines overexpress drug efflux pumps, limiting the effectiveness of cytotoxic drugs or fluorescent tag
Fluorescent tag
In molecular biology and biotechnology, a fluorescent tag is a part of a molecule that researchers have attached chemically to aid in detection of the molecule to which it has been attached. The tag is some kind of fluorescent molecule...
s. It is also used in fluorescent cell sorting for DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
content, as it blocks efflux of a variety of DNA-binding fluorophore
Fluorophore
A fluorophore, in analogy to a chromophore, is a component of a molecule which causes a molecule to be fluorescent. It is a functional group in a molecule which will absorb energy of a specific wavelength and re-emit energy at a different wavelength...
s such as Hoechst 33342. Radioactively-labelled
Isotopic labeling
Isotopic labeling is a technique for tracking the passage of a sample of substance through a system. The substance is 'labeled' by including unusual isotopes in its chemical composition...
verapamil and positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
can be used with to measure P-glycoprotein function.
Veterinary use
Intra-abdominal adhesions are common in rabbits following surgery. Verapamil can be given post-operatively in rabbits who have suffered trauma to abdominal organs to prevent formation of these intra-abdominal adhesions.Potential use in the treatment of malaria
Recent resistance to the anti-malarial drug chloroquineChloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
has hindered the treatment of malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
in Southeast Asia, South America and Africa. Resistance to chloroquine is caused by the parasite cell's ability to expel the drug outside of its digestive vacuole. It has been shown that verapamil, when used in combination with chloroquine, enhances the accumulation of chloroquine within a parasitic cell's digestive vacuole, rendering it incapable of detoxifying itself and making it more susceptible to death.