Prazosin

Clinical data
Trade names	Minipress, Vasoflex, Lentopres, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682245
License data	US DailyMed: Prazosin US FDA: Prazosin
Pregnancy category	AU: B2[1]
Routes of administration	By mouth
Drug class	α1 blocker
ATC code	C02CA01 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	~60%
Protein binding	97%[2]
Onset of action	30–90 minutes[3]
Elimination half-life	2–3 hours[2]
Duration of action	10–24 hours[2]
Identifiers
IUPAC name (2-furyl)methanone
CAS Number	19216-56-9 Y
PubChem CID	4893
IUPHAR/BPS	503
DrugBank	DB00457 Y
ChemSpider	4724 Y
UNII	XM03YJ541D
KEGG	D08411 Y
ChEBI	CHEBI:8364 Y
ChEMBL	ChEMBL2 Y
CompTox Dashboard (EPA)	DTXSID4049082
ECHA InfoCard	100.038.971
Chemical and physical data
Formula	C19H21N5O4
Molar mass	383.408 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(N3CCN(c2nc1cc(OC)c(OC)cc1c(n2)N)CC3)c4occc4
InChI InChI=1S/C19H21N5O4/c1-26-15-10-12-13(11-16(15)27-2)21-19(22-17(12)20)24-7-5-23(6-8-24)18(25)14-4-3-9-28-14/h3-4,9-11H,5-8H2,1-2H3,(H2,20,21,22) Y Key:IENZQIKPVFGBNW-UHFFFAOYSA-N Y
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Prazosin is an α₁ blocker medication primarily used to treat high blood pressure, symptoms of an enlarged prostate, and nightmares related to post-traumatic stress disorder (PTSD).^[4] It is a less preferred treatment of high blood pressure.^[4] Other uses may include heart failure and Raynaud syndrome.^[5] It is taken by mouth.^[4]

Common side effects include dizziness, sleepiness, nausea, and heart palpitations.^[4] Serious side effects may include low blood pressure with standing and depression.^[4][5] Prazosin is a non-selective inverse agonist of the α₁-adrenergic receptors.^[4] It works to decrease blood pressure by dilating blood vessels and helps with an enlarged prostate by relaxing the outflow of the bladder.^[4] How it works in PTSD is not entirely clear.^[4]

Prazosin was patented in 1965 and came into medical use in 1974.^[6] It is available as a generic medication.^[4] In 2020, it was the 190th most commonly prescribed medication in the United States, with more than 2 million prescriptions.^[7][8]

Medical uses

Prazosin is active after oral administration and has a minimal effect on cardiac function due to its α₁-adrenergic receptor selectivity. When prazosin is started, however, heart rate and contractility can increase in order to maintain the pre-treatment blood pressures because the body has reached homeostasis at its abnormally high blood pressure. The blood pressure lowering effect becomes apparent when prazosin is taken for longer periods of time. The heart rate and contractility go back down over time and blood pressure decreases.

The antihypertensive characteristics of prazosin make it a second-line choice for the treatment of high blood pressure.^[9]

Prazosin is also useful in treating urinary hesitancy associated with benign prostatic hyperplasia, blocking α₁-adrenergic receptors, which control constriction of both the prostate and urethra. Although not a first-line choice for either hypertension or benign prostatic hyperplasia, it is a choice for people who present with both problems concomitantly.^[9]

During its use for urinary hesitancy in military veterans in the 1990s, Murray A. Raskind and colleagues discovered that prazosin appeared to be effective in reducing nightmares. Subsequent reviews indicate prazosin is effective in improving sleep quality and treating nightmares related to post-traumatic stress disorder (PTSD).^[10][11]

Prazosin is used off-label in the treatment of insomnia and can produce sedative effects.^[12][13] It has been said to be the only selective α₁-adrenergic receptor antagonist which has been used in the treatment of insomnia to any significant degree.^[12] It is used at doses of 1 to 12 mg for this purpose.^[12] The combination of prazosin and the beta blocker timolol may produce greater sedative effects than either of them alone.^[13]

The drug is usually recommended for severe stings from the Indian red scorpion.^[14][15][16]

Adverse effects

Common (4–10% frequency) side effects of prazosin include dizziness, headache, drowsiness, lack of energy, weakness, palpitations, and nausea.^[17] Less frequent (1–4%) side effects include vomiting, diarrhea, constipation, edema, orthostatic hypotension, dyspnea, syncope, vertigo, depression, nervousness, and rash.^[17] A very rare side effect of prazosin is priapism.^[17][18] One phenomenon associated with prazosin is known as the "first dose response", in which the side effects of the drug – specifically orthostatic hypotension, dizziness, and drowsiness – are especially pronounced in the first dose.^[17]

Orthostatic hypotension and syncope are associated with the body's poor ability to control blood pressure without active α-adrenergic receptors. People on prazosin should be told to rise to stand up slowly, since their poor baroreflex may cause them to faint if their blood pressure is not adequately maintained during standing. The nasal congestion is due to dilation of vessels in the nasal mucosa.^{[medical citation needed]}

Pharmacology

Pharmacodynamics

Prazosin is an α₁-blocker that acts as a non-selective inverse agonist at α₁-adrenergic receptors, including of the α_1A-, α_1B-, and α_1D-adrenergic receptor subtypes.^[19] It binds to these receptors with affinity (K_i) values of 0.13 to 1.0 nM for the α_1Α-adrenergic receptor, 0.06 to 0.62 nM for the α_1B-adrenergic receptor, and 0.06 to 0.38 nM for the α_1D-adrenergic receptor.^[20][21] It has much lower affinity for the α₂-adrenergic receptors (K_i = 210–5,012 nM for the α_2A-adrenergic receptor, 13–398 nM for the α_2B-adrenergic receptor, and 10–200 nM for the α_2C-adrenergic receptor).^[20][21] The α₁-adrenergic receptors are found in vascular smooth muscle, where they are responsible for the vasoconstrictive action of norepinephrine.^[22] They are also found throughout the central nervous system.^[23] α₁-Adrenergic receptors have additionally been found on immune cells, where catecholamine binding can stimulate and enhance cytokine production.^[24][25]

Pharmacokinetics

Prazosin has an onset of action of 30 to 90 minutes,^[3] the elimination half-life of prazosin is 2 to 3 hours,^[2] and its duration of action is 10 to 24 hours.^[2]

Research

Prazosin has been shown to prevent death in animal models of cytokine storm.^[26] As a repurposed drug, prazosin is being investigated for the prevention of cytokine storm syndrome and complications of COVID-19 where it is thought to decrease cytokine dysregulation.^[27][25][28]

Synthesis

Thieme Synthesis:^[29] Patents:^[30][31] Revised:^[32][33]

Nitration of verataldehyde (1) afforded 6-nitroveratraldehyde (2). Oxidation to 6-nitroveratric acid (3). Primary amide formation gave 4,5-dimethoxy-2-nitrobenzamide (4). The reduction of the nitro group led to 2-amino-4,5-dimethoxybenzamide (5). Condensation with urea (not the more dangerous phosgene although ethyl chloroformate is less reactive) gave 6,7-dimethoxyquinazoline-2,4-dione (6). Halogenation with phosphorus oxychloride led to 2,4-Dichloro-6,7-dimethoxyquinazoline (7). Reaction with one equivalent of ammonia appeared to occur with apparent selectivity giving 2-chloro-6,7-dimethoxyquinazolin-4-amine (8). Displacement of the remaining halogen is achieved with piperazine under more strenuous conditions afforded 6,7-dimethoxy-2-piperazin-1-ylquinazolin-4-amine (9). Reaction with 2-furoyl chloride completed the synthesis of Prazoin (10).

Alternatively, react with 1-(2-Furoyl)Piperazine directly.

References

External links

• "Prazosin". Drug Information Portal. U.S. National Library of Medicine.