Understanding Benign Prostatic Hyperplasia (BPH)

Also called an enlarged prostate, benign prostatic hyperplasia (BPH) is a condition that becomes more common with age. Basically, in this condition, the prostate enlarges and leads to other complications such as urinary tract, bladder or kidney problems. BPH is an essential topic for your Pharmacology preparation.
Read this blog post till the end to ace your NEET PG exam preparation.

Definition

• In BPH, the prostate gland gets enlarged and presses against the urethra.
• Thus, the patient isn't able to pass the urine properly.
• The residual urine remaining in the bladder leads to an increased frequency and urgency of urination. It is commonly seen in elderly patients. Drugs are given to patients who do not wish to undergo surgery.

Drugs used in Benign Prostatic Hyperplasia (BPH)

• Fast acting component: α-Blockers. These further include the α1 selective blockers and α1A selective blocker (for bladder).
  • The α1 selective blockers are useful for both BPH and hypertension (HTN) e.g., Prazosin, Terazosin, and Doxazosin. Terazosin and Doxazosin have a quinazoline moiety, which is effective in prostate smooth muscle apoptosis. Alfuzosin is useful only in the management of BPH alone. The disadvantage of α1 blockers is that the patient may develop hypotension repeatedly.
  • α1A selective blockers are only useful for BPH and have no effect on HTN or BP, e.g., Tamsulosin and Silodosin. An important complication (adverse effect) of Tamsulosin is floppy iris syndrome, which is an intraoperative complication. Tamsulosin and silodosin are the drugs of choice for BPH. They don't affect the BP.
• Slow-acting component: These take months to show their effect. They are called 5α-reductase inhibitors.

5α Reductase Inhibitors

• Testosterone is converted into dihydrotestosterone (DTH).
• This conversion is done by an enzyme called 5α reductase inhibitor. Increased DTH can lead to BHP, androgenic alopecia, and hirsutism.  These can be treated with 5α reductase inhibitors, e.g., Finasteride. Thus, the mechanism of action of finasteride is type 2 5α reductase inhibition. Dutasteride inhibits both type 1 and type 2 5α reductases. It is approved only for BPH treatment. These drugs have shown to decrease the size of the prostate in prolonged use.

Drugs used in the Management of Erectile Dysfunction

Oral Drugs

• Oral drugs are phosphodiesterase (PDE) V inhibitors, e.g., Avanafil, Sildenafil, Vardenafil, and Tadalafil (ASVT). Avanafil is a short-acting drug, while tadalafil is a longer-acting drug.
• Mechanism of action of sildenafil:
  • Penile nerve stimulation can release nitrous oxide (NO). This stimulates an enzyme called soluble guanylyl cyclase (SGC), which in turn converts the guanosine triphosphate (GTP) to guanosine 3',5'-cyclic monophosphate (cGMP). 
  • The cGMP activates protein kinase G (PKG), which causes vasodilation (VD). This is responsible for penile erection.
  • In erectile dysfunction, the cGMP is broken down into 5'-GMP. The enzyme responsible for this breakdown is PDE V.
  • Thus, to increase the penile erection duration, the cGMP level should be increased. This is done by inhibiting the PDE V enzyme. This increases the vasodilation period and the duration of the erection. This is the mechanism of action of sildenafil.

Q. Can sildenafil and nitrates be combined?

Ans: Both drugs increase cGMP. This leads to a severe fall in BP, resulting in severe hypotension. Thus, any PDE V inhibitor given with nitrate has a risk of severe hypotension.

• Pharmacokinetics of PDE V inhibitors:
  • These are not aphrodisiacs. They only prolong the duration of the erection. These should be given 1-2 hours before sexual intercourse. Any PDE V inhibitor given with nitrate has a risk of severe hypotension.
• Adverse effects of PDE V inhibitors: 
  • Decrease in BP
  • Increased heart rate (HR)
  • Blue or green tinted vision (due to PDE 6 inhibition in the retina). 
  • Sometimes there is a prolonged erection.

Other Drugs in the Treatment of Erectile Dysfunction

• Androgen replacement: In cases of libido loss due to low testosterone, these can be used.
• Injectables: These are given into the penis before the intercourse. The issue with injectables is that they cause pain. Examples of injectables are Phentolamine, Papaverine, and Alprostadil.

Drugs Used in the Management of Premature Ejaculation

• Premature ejaculation is a condition where the person ejaculates early. 
• Selective serotonin reuptake inhibitors (SSRIs): which delay the ejaculation process, e.g., Dapoxetine (FDA-approved drug) and Paroxetine (off-label use).
• Tricyclic antidepressants (TCAs): These are another class of drugs to treat premature ejaculation, e.g., Clomipramine (serotonergic property).

Hormonal Therapy of Prostate Cancer

• Prostate cancer is usually treated by surgery, but it might not always be feasible.
• Prostate cancer is a testosterone dependent cancer.
• The drugs used in its treatment include the following:
  • Androgen receptor blockers- Flutamide, Bicalutamide, Enzalutamide, and Nilutamide. All of these are approved for prostate cancer. Flutamide is also approved for acne and hirsutism.
  • Gonadotropin-releasing hormone (GnRH) agonists- Leuprolide and Goserelin. These are given as a continuous treatment.
  • GnRH antagonist- Abarelix and Degarelix.
  • Abiraterone: It acts by inhibiting the 17 α hydroxylase enzyme.
• The continuous use of GnRH agonists will increase the levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH). This in turn will increase the testosterone levels. This can lead to a cancer flare-up. Later, the receptors are desensitized, which decreases FSH, LH, and testosterone. To prevent the cancer flare-up, flutamide is given three days before GnRH agonists. This is called combined androgen blockade.

Q. Can flutamide be given alone? Ans:

• Whenever testosterone levels increase, it causes a negative feedback mechanism in the hypothalamus. Flutamide blocks the testosterone receptors in the hypothalamus and the pituitary gland. In the absence of negative feedback, there's an increase in testosterone production. This will replace the flutamide from the prostate, causing prostate cancer flare-up. Thus, flutamide cannot be given alone. GnRH agonists are continuously given along with flutamide. This desensitizes the testosterone receptors in the pituitary gland. Thus, testosterone won't be released.

Drugs Causing Gynecomastia

• The drugs causing gynecomastia are: (Mnemonic- "In moving a dashing car SKODA")
  • In- Isoniazid (INH).
  • Moving- Methyldopa and Metoclopramide.
  • Dashing- Domperidone.
  • Car- Cimetidine.
  • S- Spironolactone.
  • K- Ketoconazole.
  • O- Oestrogen.
  • D- Digoxin.
  • A- Anti-androgens.

Summary

• Two important drugs used in the treatment of BPH:  α blockers (faster acting). Tamsulosin and Silodosin are the drugs of choice in the treatment of BPH, as they don't produce hypotension. The slower-acting drugs are α reductase inhibitors. They inhibit the conversion of testosterone to DTH. They decrease the size of the prostate.
• Drugs to treat erectile dysfunction are PDE V inhibitors. They increase the cGMP and cause vasodilation and increase of penile erection. They are to be avoided with nitrates as they can cause a severe drop in blood pressure. The injections include Phentolamine, Papaverine, and Alprostadil. Androgen replacement therapy can also be done.
• The SSRI of choice for premature ejaculation is Dapoxetine.
• Prostate cancer is treated with androgen receptor blockers like flutamide. It is also used to treat acne and hirsutism. The GnRH agonists are used continuously, but flutamide is added to avoid flare-ups. Flutamide isn't given alone to avoid blocking the negative feedback of testosterone. Other drugs used in the treatment of prostate cancer include GnRH antagonists (Abarelix and Degarelix) and Abiraterone (17 α hydroxylase enzyme inhibitor).

And that is everything you need to know about benign prostatic hyperplasia (BPH) for Pharmacology paper and ace your NEET PG preparation. For more informative and engaging posts like these, download the PrepLadder App and keep following our blog!