Doxazosin: The Past Drug

Doxazosin is a drug developed to help with mild to severe hypertension as well as to ease prostate muscle contractions. Both problems are an indirect effect of over stimulation of one or multiple of the three α₁-adrenoceptors. To solve this problem a synthetic or natural, synthetic in this case, compound had to be developed that would inhibit the activity of the α₁-adrenoceptors. The process to make the specific antagonist is outlined in a span of nine pages which boils down to an extensive synthesis of minimally twelve steps. These steps utilize several of the same compounds with varying R-groups branched off them that change the structure of the base compound. Several methods including HPLC, LC-MS, UV spectrophotometry and HPTLC3,4,5,6 were used to determine the final pharmaceutical formulation. UV spectrophotometry was the main determinate in dosage for pharmaceutical use. Absorbance values for several dosages were observed in human liver cells and half-lives helped to determine the dosage that would stay in the body for the correct amount of time.

Three alpha-blockers or antagonists were developed and FDA-approved prior to doxazosin. They mostly were targeted for the first of the three receptors as this is accepted as the primary receptor associated with prostate smooth muscle contraction. These included the nonselective phenoxybenzamine (which inhibited all of the α₁-adrenoceptors), short-acting selective prazosin, and lastly the long-lasting and selective terazosin. Comparatively to the last of these, doxazosin has a significantly longer half-life while keeping the selectivity of terazosin as well. Similarly, all of these drugs were developed as a drug to be used with several others as well to work together. Doxazosin before being replaced also went through extensive clinical trials in order to develop a way to orally take the compound. The polymer that was found suitable to coat the tablet was Eudragit powdered E-100. However, a major flaw with the doxazosin drug is that it has little to no feedback control. This means that because it is an antagonistic drug, it does not produce any product that will go back and limit the effect of the drug. This coupled with the fact it has a long half-life means that even though the needed effects stay for a long time so do adverse effects. These include low blood pressure, dizziness, shortness of breath, tiredness, abdominal pain, diarrhea, headache, and swelling caused by the inhibition of the α₁-adrenoceptors. Doxazosin had less of a correlation with these side effects than the first two inhibitors developed however was more likely to cause these than terazosin and therefore was not used long.

The regulation and testing of doxazosin is very minimal in information because it is the fifth alpha blocker developed in its class. This means that the developers of this drug did not need to go through most of the  beginning trials as long as they could prove that this drug has the same effects and target as the previous drugs developed. However, many later clinical trials and some animal testing had to be conducted in order to prove the viability of this advanced version. Also, due to stricter laws in foreign countries regarding the distribution of pharmaceuticals, places such as the European Union are still continuing clinical trials for the base line drug combined with other medications and with slight modifications. Trials conducted using animal test subjects such as dogs and rats resulted in the formation of myocardial fibrosis within months of administering the drug. Nothing similar to these results was proven to happen in human trials. Pregnant women are advised to be cautious and consult a doctor before taking doxazosin, but trials show that radioactivity passed through the placenta with no adverse effects. Trials were not conducted on children below the age of 12 and therefore they are cautioned against taking the drug. The largest concern through all human trials was the result of BPH or benign prostate hyperplasia and slight concerns over increased hypertension. No overdoses occurred during any trial and therefore max doses were not determined prior to prescribing only a correct dosage.

The drug was originally manufactured, patented and distributed by Pfizer pharmaceuticals. They still today sell the synthetic compound under the name of Cardura and Cardura XL. These titles are both copyrighted to the Pfizer company and there are several general names for the pharmaceutical. The first patent was developed in 1985 by Edwards K David under the administration of Pfizer. Today there have been over 208 patents using doxazosin whether by itself or with other compounds and 9 of them belong to Pfizer, and 7 to David.

After the drug completed clinical trials its sales reached a peak point around the end of 1999 leading into the first two quarters of the 2000 financial year. They then soon declined to $552 million from $795 million between the single year following into 2001. This is shown by a 22% decrease of all alpha-blocker sales in the most previous years.

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https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019668s021lbl.pdf