Men's Health Education: Analysis of the Effects and Side Effects of Commonly Used Antihypertensive Drugs on Sexual Function

Effects of Drugs on Male Sexual Function

Any drug that alters the body's hormonal environment, the conduction of somatic nerves, or blood flow to the reproductive organs may lead to decreased libido and affect the normal physiological functions of penile erection or ejaculation.

Antihypertensive Drugs

1. Clonidine
Clonidine, also known as clonidine, is an alpha-receptor agonist. Its chemical structure contains an imidazoline ring, making it a dichloroaniline imidazoline. Its chemical structure is similar to that of the adrenergic receptor blocker benzylzoline and the adrenergic mimic naphazoline, hence it is used as a centrally acting antihypertensive drug. Its mechanism of action is generally believed to be through central action, activating alpha receptors in inhibitory neurons of the medulla oblongata and hypothalamus, reducing sympathetic efferent transmission, leading to inhibition of peripheral sympathetic nerve function, decreased cardiac output, and decreased peripheral vascular resistance, thus exhibiting a hypotensive effect. The corpora cavernosa of the penis contain adrenergic and cholestatic nerve fibers; the sympathetic nervous system plays a promoting role in penile erection; and the brain contains the ejaculation activation system—the catecholamine system. Approximately 10%–20% of male patients may experience impotence or decreased libido after taking clonidine. One study of 28 men who used clonidine in combination with chlorothiazide diuretics found that 5 (17.9%) experienced impotence and 4 (14.3%) experienced decreased libido. Experimental studies have shown that clonidine can affect α-adrenergic receptors, thus strongly inhibiting the effects of catecholamines and insulin in plasma, leading to hyperglycemia and impaired glucose tolerance. Clonidine excites postsynaptic α receptors in the central nervous system, activating inhibitory neurons and reducing peripheral sympathetic nerve activity, thereby lowering blood pressure. Due to the negative feedback caused by the excitation of presynaptic α receptors in the periphery, the release of norepinephrine is reduced, which, while lowering blood pressure, also causes impotence. 2. Methyldopa

Methyldopa, also known as α-methyldopa or Aldomet, is formed by replacing the hydrogen atom at the α-position of dopa (dihydroxyphenylalanine) with a methyl group. Due to its central hypotensive mechanism similar to clonidine, methyldopa exhibits a weaker anti-adrenergic effect through important enzymatic metabolic pathways in the brain and peripheral tissues. Therefore, while exerting its hypotensive effect, methyldopa also inhibits sexual function. If the daily dose is less than 1.0g, 10%–15% of male patients may experience decreased libido and impotence; 10%–15% of female patients may also experience decreased libido or impaired sexual arousal. If the daily dose reaches 1.0–1.5g, 20%–25% of both male and female patients may experience sexual dysfunction after taking this drug. When the daily dose reaches 2.0g or more, 50% of patients may experience significant sexual dysfunction. Further increases in dosage may cause loss of orgasm and decreased sexual arousal in some women, while some men may experience delayed ejaculation.

Methyldopa does not affect testosterone levels in the male bloodstream. Decreased libido is partly due to drowsiness and fatigue, a common side effect of this drug, and may also be a result of the indirect impact of methyldopa on sexual function. Sexual side effects usually resolve rapidly within 1-2 weeks after discontinuation of this class of drugs.

3. Reserpine Reserpine, also known as snake root alkaloid, is an alkaloid originally extracted from the Indian snake root rauwort. Reserpine's antihypertensive effect is characterized by a slow onset of action, mild but long-lasting effects. Its antihypertensive mechanism is closely related to the depletion of the neurotransmitter norepinephrine in the vesicles of central and peripheral adrenergic nerve endings. The mechanism by which reserpine depletes neurotransmitters includes: binding to vesicle membranes, inhibiting the amine pumps on the vesicle membranes that actively take up neurotransmitters, thereby hindering the reuptake of neurotransmitters and causing them to be destroyed by monoamine oxidases in the cytoplasm; it also hinders dopamine from entering the vesicles, thus reducing neurotransmitter synthesis. Due to vesicle membrane dysfunction (or damage), stored neurotransmitters gradually diffuse into the cytoplasm and are destroyed and inactivated by MAO. Because all three stages of neurotransmitter uptake, synthesis, and storage are disrupted, neurotransmitter depletion at nerve endings leads to a decrease in sympathetic nerve activity. Reserpine has a weak central sedative effect, and prolonged use often produces adverse reactions such as drowsiness and depression. Its mechanism of action may be closely related to the depletion of central catecholamines and serotonin.

Reserpine and its antihypertensive agents can deplete catecholamines in many tissues (including the brain), thus producing a significant sedative effect. This sedative effect can be very strong, indirectly reducing a patient's libido. Because many hypertensive patients clinically exhibit significant depressive symptoms, even small doses can reduce libido. Once a patient experiences depression, the percentage of those with sexual dysfunction and decreased libido is quite high. Both it and methyldopa have the property of increasing prolactin levels, sometimes leading to gynecomastia and galactorrhea in men, and can also cause impotence or ejaculatory dysfunction.

4. Guanethidine

Guanethidine is a synthetic guanidine antihypertensive drug and a representative adrenergic neuron blocking agent. In retrograde ejaculation caused by abnormal nerve innervation, guanethidine induces a so-called chemical sympathectomy effect.

Guanethidine has a strong and sustained antihypertensive effect, dilating both resistance and volume vessels, slowing the heart rate, leading to decreased peripheral resistance, reduced venous return, and decreased cardiac output, thus exhibiting a strong antihypertensive effect. Guanethidine's antagonistic effect on adrenergic mediators has been clinically reported. Its main effect on sexual function is the inhibition of ejaculation in men, the degree of which is often related to the dosage. For example, at daily doses above 25 mg, approximately 50%–60% of male patients may experience delayed or absent ejaculation. Guanethidine can persistently prevent the release of neurotransmitters from adrenergic neurons, significantly reducing norepinephrine levels, which may cause erectile dysfunction in patients with hypertension, a fact confirmed by clinical observations. A small number of men taking this drug may indeed experience erectile dysfunction. In a group of 22 male patients taking guanethidine and chlorothiazide diuretics to control blood pressure, 3 (13.6%) experienced impotence, and another 13 (59.1%) experienced decreased libido. Its mechanism of action likely reflects the drug's inhibitory effect on sexual response, or perhaps the ejaculation disorder is simply due to psychological factors. Pretchard et al. (1986) reported that guanethidine caused erectile dysfunction in 40%–67% of cases and ejaculatory dysfunction in 40%–70% of cases.

Among antisympathetic drugs, guanethidine is more likely to cause impotence than clonidine, which may be related to the fact that guanethidine cannot enter the central nervous system and mainly exerts its effects in the periphery.