Doxazosin: Mechanism of action, uses, side effects and interactions

What is doxazosin?

Doxazosin is included in a group of drugs which are called as alpha-adrenergic receptor blockers. The main purpose of these agents is that they relax the veins and arteries which allows blood to easily pass through them.

Therefore, doxazosin also has the ability to cause relaxation of the veins and arteries. It also causes the relaxation of the muscles which are situated in the prostate gland or even the muscles located in the urinary bladder neck which allows for easy urination.

Doxazosin is basically a non-selective alpha-1 adrenergic receptor antagonist which is used for the treatment of benign prostatic hyperplasia and hypertension.

It is manufactured by many pharmaceutical companies and is available under different brand names for example Cardura.

Doxazosin description, IUPAC name, molecular formula, weight, structure and drug class

Doxazosin is an antagonist of alpha-1 adrenergic receptors which are located in the smooth muscles of the urinary bladder neck and prostate gland and is chemically described as [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl)methanone;methanesulfonic acid. It is a quinazoline compound and has some smooth muscle relaxing properites.

IUPAC name: [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl)methanone

Molecular formula: C23H25N5O5

Molecular weight: 451.483 g/mol

Drug class: This compound belongs to the class of organic compounds known as n-arylpiperazines. These are organic compounds containing a piperazine ring where the nitrogen ring atom carries an aryl group.

Chemical structure

Doxazosin description, IUPAC name, molecular formula, weight, structure and drug class

Doxazosin identification

Doxazosin is available in the form of a white powder which is soluble in dimethylformamide while it is slightly soluble in ethanol, methanol and water. It is only slightly soluble in acetone and methylene chloride.

What is the mechanism of action of doxazosin?

Doxazosin is basically a quinazoline which shows antihypertensive and antineoplastic effects. The drug is an alpha-adrenergic receptor antagonist and it selectively binds to and inhibits the alpha-1 adrenergic receptors.

As these alpha-1 adrenergic receptors are blocked, their action on vascular smooth muscles is also inhibited which leads to a decrease in the peripheral vascular resistance and produces an antihypertensive effect.

The drug also shows high affinity for the alpha-1c receptors which are located in the prostate gland and function predominantly in the gland.

The effect on alpha-1c receptor explains the use of the drug in benign prostatic hyperplasia.

Moreover, doxazosin also causes the inhibition of protein kinase B (PKB)/Akt-signaling death receptor regulatory pathway which induces apoptosis in cancerous cells in the prostate gland due to which it can be used as an antineoplastic agent for the treatment of prostate cancer.

What are the indications of Doxazosin?

Doxazosin is a drug which is primarily used for the following indications:

  • Benign prostatic hyperplasia
  • Hypertension

Doxazosin may be used either alone or in combination with other antihypertensive drugs for the treatment of hypertension.

Doxazosin and Benign Prostatic Hyperplasia (BPH)

Benign prostatic hyperplasia is a condition associated with the enlargement of the prostate gland in males which causes symptoms such as urinary frequency, nocturia, weak stream, hesitancy and incomplete bladder emptying and these symptoms are related to the anatomic and functional components.

The anatomic component is associated with the increase in the size of the prostate which is primarily caused by the proliferation of the smooth muscle cells present in the prostate stroma.

However, the dynamic component is associated with the increase in the smooth muscle tone in the prostate and the urinary bladder neck.

Since alpha-1 receptors are present in high concentration in the prostatic stroma so they are responsible for the degree of smooth muscle tone in the prostatic capsule and bladder neck.

When these receptors are blocked, this leads to a decrease in the urethral resistance and relieves the symptoms of urinary obstruction and BPH and causes an improvement in the flow of urine.

Doxazosin and Hypertension

The primary action of doxazosin is the selective blockade of alpha-1 adrenergic receptors.

However, doxazosin has the ability to antagonize the pressor effects of phenylephrine which an alpha-1 agonist and also has the capability to antagonize the systolic pressor effects of norepinephrine.

Prazosin also has a similar activity to antagonize phenylephrine as doxazosin.

Since doxazosin selectively blocks the alpha-1 adrenergic receptors in the small arteries and veins, it causes a decrease in the peripheral vascular resistance and a decrease in the blood flow which ultimately leads to a reduced blood pressure.

Classical alpha blockers also block the alpha-2 receptors which cause an excessive release of norepinephrine resulting in rapid heart rate, palpitations and increased renin release.

However, doxazosin limits this excessive release by selectively blocking the alpha-1 receptors causing less cardiac stimulation and less renin activity. In the majority of the patients, doxazosin alone is used to control the blood pressure.

However, if this monotherapy is unable to control the blood pressure, doxazosin may be combined with other antihypertensive agents such as thiazide diuretics, beta blockers, calcium channel blockers or angiotensin converting enzyme inhibitors.

Doxazosin for the management of hypertension

Doxazosin pharmacokinetics

Doxazosin is administered orally in the form of tablets. The drug is well absorbed upon oral administration.

Although the drug undergoes first-pass metabolism, almost two third of the dose if available which indicates that the drug is not extensively metabolized as a result of the first pass effect.

The bioavailability of the drug is 65% and it takes 2 to 3 hours for the drug to reach peak plasma concentration when administered orally.

The volume of distribution of the drug is 1 to 3.4 L/kg.The drug is metabolized primarily by the liver either by O-demethylation of the quinazoline nucleus or by hydroxylation of the benzodioxan moiety.

The drug is also extensively bound to plasma protein and about 98% of the drug is bound to the plasma proteins. Doxazosin has an elimination half-life of about 22 hours which accounts for the once daily dosing of the drug.

The drug is excreted primarily in the faeces while only a small amount of the drug is excreted in urine. It has been estimated that 63% of the administered dose is excreted in faeces while only 9% of the dose is excreted in urine.

However, only 4.8% of the administered dose is excreted as unchanged drug in faeces.

What are the contraindications of doxazosin?

Doxazosin is a drug which is contraindicated in the following conditions:

  • If a person is allergic or hypersensitive to any type of quinazolines such as prazosin, terazosin, or doxazosin so in such conditions a severe hypersensitivity reaction can occur so the drug should not be used.
  • Patients who have a history of orthostatic hypotension or who are suffering from orthostatic hypotension.
  • Patients suffering from benign prostatic hyperplasia and having concomitant upper urinary tract congestion, chronic urinary tract congestion or those having stones in the urinary bladder.
  • In hypertensive lactating mothers where the drug is intended to be used for the treatment of hypertension.
  • Patients suffering from hypotension when using the drug for benign prostatic hyperplasia are contraindicated to use the drug.
  • Those patients who use the doxazosin as monotherapy and are suffering from either bladder overflow or anuria with or without progressive renal insufficiency should stop using it.

Doxazosin and postural hypotension / syncope

Doxazosin, being an alpha-adrenergic blocking agents has the tendency to cause drastic hypotension especially when the patient is in the upright position.

This is also known as postural hypotension which is also associated with syncope and other postural symptoms which include dizziness.

These orthostatic effects are common with the first dose of the drug due to which it is also known as the “First-dose” effect. Moreover, this effect can also occur if the dosage of the drug is increased or if the therapy is interrupted for some days.

To prevent excessive hypotension and syncope the starting dose of the drug should be kept low and patients are given 1 mg dose at the start of the therapy. The patient should be promptly given supportive treatment and should be placed in recumbent position if syncope occurs.

Doxazosin and priapism

The drug has rarely been associated with priapism which is characterized by painful penile erections which remain sustained for hours and remain unrelieved even after masturbation or sexual intercourse.

This is a very serious condition and can lead to permanent impotence so the patient should be advised about the seriousness of the condition and to seek prompt medical attention if such symptoms appear.

Doxazosin use in patients with acute cardiac conditions

Since doxazosin in a vasodilatory antihypertensive agent, therefore it should be used with caution in patients having the following acute cardiac conditions:

  • Pulmonary oedema due to aortic or mitral stenosis
  • High output cardiac failure
  • Right sided heart failure due to pulmonary embolism or pericardial effusion
  • Left ventricular heart failure with low filling pressure

Doxazosin use in patients with hepatic impairment

Since the drug is metabolized primarily in the liver therefore the drug should be used with caution in patients having hepatic impairment.

Those patients suffering from such diseases which affect the normal functioning of the liver should also use the drug with caution.

Doxazosin use with phosphodiesterase-5-inhibitors

Drugs characterized as phosphosphodiesterase-5-inhibitors exhibit vasodilating effects therefore the concomitant use of these drugs with doxazosin can cause symptomatic hypotension in some patients.

To prevent this effect, it is recommendedto keep a gap of atleast 6 hours between the administration of doxazosin and a phosphodiesterase-5-inhibitor and the treatment with phosphodiesterase-5-inhibitor with the lowest possible dose.

Doxazosin use in patients undergoing cataract surgery

During cataract surgery, the intraoperative floppy iris syndrome has been observed in some patients who were or had been using alpha-1 blockers therefore the use of such medications should be brought into the notice of the ophthalmic surgeon prior to surgery.

Use of doxazosin during pregnancy and breastfeeding

There is not enough evidence of the safety of the drug in pregnant women because of the lack of well controlled studies. However, the drug should only be used during pregnancy if the benefits of the drug outweigh the risks.

The pregnant women can be at a risk if their hypertension is kept untreated and it is the duty of the healthcare provider to provide proper counselling to the pregnant women regarding the use of the drug.

The drug should be used with caution by mother who is breastfeeding the new-borns. There is not enough evidence to support that the drug causes serious effects in infants but many sources reveal the presence of the drug in breast milk but not causing any serious effects.

What are the side effects associated with doxazosin

Doxazosin can cause a variety of side effects. It can cause common as well serious side effects. Some common side effects occurring by the use of the drug incudes:

  • Dizziness
  • Lightheadedness
  • Fatigue
  • Feeling of tiredness
  • Drowsiness
  • Shortness of breath
  • Nausea
  • A runny nose
  • Abdominal pain
  • Swelling of hands, feet, ankles or lower leg
  • Weight gain
  • Hypotension
  • Muscle or joint pain

The drug can also cause some serious side effects including:

  • Fast or pounding heartbeats
  • Fluttering in the chest
  • Shortness of breath
  • Fainting
  • Pruritus
  • Skin rash
  • Yellowing of eyes or skin
  • Dark urine
  • Easy bleeding or bruising
  • Fever
  • A persistent sore throat
  • Vertigo
  • Sweating
  • Painful or prolonged erection of the penis

Doxazosin and leukopenia/neutropenia

Decreases in mean white blood cell (WBC) and mean neutrophil count were observed in controlled clinical trials of hypertensive patients receiving doxazosin.

In cases where follow-up was available, WBC and neutrophil counts returned to normal after discontinuation of doxazosin. No patients became symptomatic as a result of the low WBC or neutrophil counts.

What if I overdose doxazosin?

If the drug has overdosed, it can lead to severe hypotension. This can be treated by placing the patient in a supine, head-down position and performing shock treatments on the patient.

For this purpose, plasma volume increasing agents can be used and after that such medications can be given which increase the blood pressure.

The patient should be continually monitored and should be given supportive and symptomatic treatment.

The fluid and electrolytes of the patient should also be monitored. Haemodialysis is not recommended as the drug is extensively bound to plasma proteins.

What are the precautions needed with doxazosin?

You should always talk to your doctor or pharmacist if you are allergic to the drug or even if you are allergic to other alpha receptor blockers.

You should also tell your healthcare provider about any other allergies which could include the pharmaceutical excipients.

You should also discuss your medical history with your doctor or pharmacist especially a history of any heart disease such as congestive heart failure, angina, heart attack in the last 6 months, history of any liver disease or certain eye problems such as cataracts or glaucoma.

Since the drug causes dizziness and drowsiness so you should avoid driving, using machinery or doing activities which require alertness. Alcoholic beverages should also be avoided.

During pregnancy, the drug should be used with caution and should be consulted with the doctor or pharmacist before using. As the drug passes into breast milk so mothers should consult with the doctor before breast feeding.

What is the dosage and administration of doxazosin?

Doxazosin administered orally and is available in the form of tablets. It is available in different strengths which include 1 mg, 2 mg, 4 mg, and 8 mg tablets. However, the dose of the drug varies according to the condition of the patient.

Dose in hypertension:

The initial dose which is given to the adult patients is 1 mg and is administered once in a day. As the drug may cause orthostatic hypotension so it is important to monitor the blood pressure in upright position especially during the duration of the first dose and whenever the dose is increased.

Where the blood pressure is not adequately being controlled with a dose of 1 mg daily, the dose can be increased to 2 mg in a single day.

However, the maximum dose that can be given in a day should not exceed 16 mg as it may lead to overdose and cause deleterious effects.

Dose of benign prostatic hyperplasia:

The initial dose which is given to the patients with the condition is also 1 mg per day. In order to achieve the desired results the dose may be increased in steps from 1mg to 2 mg to 4 mg and then to 8 mg per day as may be required.

The maximum dose that can be given in this condition cannot be exceeded more than 8 mg per day.

Any special dosing considerations to be made?

Doxazosin is extensively metabolized by the liver. Those patients who are suffering from any kind of hepatic disease, they should be prescribed the lowest possible adult dose.

Can I take doxazosin and alfuzosin?

Alfuzosin is an α-blocker. The drug-drug interaction between two different alpha blockers is reported to be severe.

Even though the pharmacokinetic and pharmacodynamics of using two alpha-blockers for the treatment of benign prostate hyperplasia and hypertension is still under study but according to Food and Drug Administration (FDA), the interaction between these two drugs has adversely affected the patient.

Dizziness, syncope, and hypotension are commonly seen with worse intensity.

Can I take doxazosin and dalfopristin or quinapristin?

When doxazosin is used concomitantly with any of these two drugs, a moderate level of drug-drug interactions takes place. The patient may suffer from hypotension thus is recommended to monitor the blood pressure at regular intervals.

Dalfopristin/ quinupristin increases the serum concentrations of doxazosin this is because of the fact that dalfopristin/ quinupristin is a potent inhibitor of CYP3A4 metabolic enzymes and doxazosin is the substrate for these enzymes.

Concomitant administration of doxazosin with these drugs has shown an increase of about 10% in the value of mean AUC and a slight rise in the mean Cmax value and elimination half-life of doxazosin.

Can I take doxazosin and dopamine?

Dopamine: when the patient is on a dopamine infusion, care should be taken off not to administer doxazosin or any other alpha-blocker. If such combination is given to the patient, unwanted peripheral vasoconstriction is observed.

This occurs especially when dopamine is being administered at a slightly higher dose. The peripheral vasoconstriction is opposed by the action of an alpha-blocker.

However, no effect of doxazosin is seen to counteract on the vasodilation of mesenteric, cerebral or renal arteries.

Can I take doxazosin and iloperidone?

When iloperidone is administered to the patient along with doxazosin, a moderate degree of drug-drug interactions take place.

In addition to the effect produced by doxazosin blockage, iloperidone is also responsible for producing vasodilatory effects in the body. This has contributed to a significant reduction in blood pressure and lead to orthostatic hypotension.

Other signs which are linked with hypotension include dizziness, syncope and in some cases tachycardia is also seen.

In cases where these both drugs are to be used by the patient for the purpose of treating hypertension, they should be counseled on how to take measures in order to prevent any harm occurring due to syncope.

Till the complete effects of the combined therapy are not known, regular monitoring of blood pressure is recommended.

Can I take doxazosin and telithromycin?

According to the guidelines, it is advised to monitor the blood pressure regularly when telithromycin is given in combination with doxazosin.

It has been observed that because of the inhibiting ability of CYP3A4 isozymes by telithromycin have contributed to the plasma levels of doxazosin as it acts as the CYP3A4 substrate.

A rise in mean AUC value was seen by 10% when both the drugs are given together to the patient. Along with this the Cmax and mean half-life value for doxazosin was also increased.

How to administer doxazosin?

For taking the drug orally, it is recommended that after taking the drug especially the first dose, one should carefully observe for orthostatic hypotension and its associated symptoms.

  • For taking immediate-release tablets: it can be administered to the patient without consideration of the meals.
  • For extended-release tablets: a single dose should be administered in the morning with breakfast.
  • Before starting the treatment with these tablets, the last dose of immediate release dose at the evening time a day before should be avoided. Otherwise patient will suffer from syncope.

How to store doxazosin?

The medication should be kept in the container in which it is supplied. The container should be closed tightly and should be kept out of the reach of children.

The drug should be stored ideally at room temperature and the temperature should not exceed 30°C. it should not be stored in the bathroom as it can get contaminated and should be kept away from excessive heat and moisture.

The drug should be located at a safe place to keep it out of the reach of children as it may lead to poisoning if they consume it.

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