Glyceryl trinitrate is the most commonly used nitrate. It has a half-life of only a few minutes. Extensive removal by the liver makes oral administration ineffective. It is therefore given sublingually, intravenously or for prolonged action due to continued absorption, transdermally. Glyceryl trinitrate tablets deteriorate on storage and it is recommended that tablets should be kept in their original bottle and kept for no more than 3 months after opening. This problem does not occur with the isosorbide nitrates or the glyceryl trinitrate sublingual spray.

Isosorbide mononitrate is 100% bioavailable after oral administration and has a half-life of about 5 hours. Sustained-release formulations permit once-daily dosing.

Isosorbide dinitrate has low bioavailability of about 25% given orally but sublingual absorption is satisfactory. It has a half-life of about 45 minutes. Many of isosorbide dinitrate’s effects are due to the presence of isosorbide mononitrate, one of its active metabolites.

Precautions and adverse effects: Tolerance to nitrates occurs with frequent or continuous exposure and may develop within 24 hours. Whatever the agent or route of administration it is important to ensure a nitrate-free interval of 10 to 12 hours each day. Patients should be advised to apply or take their nitrate at the time of the day when angina is most frequent (eg at night for nocturnal angina or in the morning for diurnal angina). Major dose-related adverse effects of nitrates include headache and hypotension.

Interactions: Phosphodiesterase type 5 inhibitors—sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra)—must not be used concomitantly with nitrates because they potentiate the vasodilatory effect of circulating nitric oxide, resulting in significant hypotension. Nitrates should not be administered within 3 to 5 days of tadalafil, and within 24 hours of sildenafil or vardenafil.

Constituents
Limited chemical information is available for black horehound. Documented constituents include diterpenes (e.g. ballotenol, ballotinone, preleosibirin), flavonoids, and volatile oil.

Food Use
Black horehound is listed by the Council of Europe as a natural source of food flavouring (category N3). This category indicates that black horehound can be added to foodstuffs in the traditionally accepted manner, although insufficient information is available for an adequate assessment of potential toxicity.

Herbal Use
Black horehound is stated to possess anti–emetic, sedative and mild astringent properties. Traditionally, it has been used for nausea, vomiting, nervous dyspepsia, and specifically for vomiting of central origin.

Contra–Indications and Warnings
None documented.

Pregnancy and lactation
Black horehound is reputed to affect the menstrual cycle. In view of the lack of phytochemical, pharmacological and toxicity data, the use of black horehound during pregnancy and lactation should be avoided.

Pharmaceutical Comment
Limited phytochemical or pharmacological information is available for black horehound to justify its use as a herbal remedy. In view of the lack of toxicity data, excessive use should be avoided.

Artichoke is stated to possess diuretic, choleretic, hypocholesterolaemic, hypolipidaemic, and hepato stimulating properties. Modern use of artichoke is focused on its use in the treatment of hyperlipidaemia, hyperlipoproteinaemia, non–ulcer dyspepsia and conditions requiring an increase in choleresis. There is also interest in the potential hepatoprotective properties of globe artichoke, although this has not yet been tested in controlled clinical trials.

Pharmacological Properties

Several pharmacological properties have been documented for artichoke leaf, including inhibition of cholesterol biosynthesis, hypolipidaemic, anti oxidant and hepatoprotective activity. It remains unclear which of the constituents of artichoke are responsible for its pharmacological activities. The dicaffeoylquinic acids, which include cynarin, are likely to be an important group of constituents in this respect. The sesquiterpene lactones, such as cynaropicrin, and flavonoids, such as luteolin glycoside, may also exert biological effects.

Sildenafil is predominantly metabolized by hepatic cytochrome P450 (CYP) enzymes. CYP3A4 is the major metabolizing enzyme and CYP2C9 the minor one. One active metabolite with properties similar to the parent drug has been identified and is formed by N-desmethylation of sildenafil. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil and accounts for about 20% of the pharmacologic effects of sildenafil. The metabolite is further metabolized to inactive compounds.

Sildenafil is excreted as metabolites primarily in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Both sildenafil and its active metabolite have terminal half-lives of about 4 hours. Sildenafil levels at 24 hours post a single 100 mg oral dose average 2 ng/ml (compared to peak plasma levels of approximately 440 ng/ml). Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, with free plasma concentrations approximately 40% greater than those seen in healthy younger volunteers (18—45 years). In volunteers with mild (CrCl = 50—80 mL/min) and moderate (CrCl = 30—49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) were not altered. In volunteers with severe (CrCl <= 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment.

As reported by the manufacturer, the pharmacodynamic response to sildenafil was assessed in eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction. In these studies sexual stimulation resulted in improved erections, as assessed by penile plethysmography, after sildenafil administration compared with placebo. Most studies evaluated the efficacy of sildenafil approximately 60 minutes post dose. The erectile response, as determined by penile plethysmography, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study. The effects of sildenafil were evident for up to 4 hours but the response was diminished compared to 2 hours.

Sildenafil can inhibit PDE5 present in esophageal smooth muscle, lung tissue, and brain tissue. Inhibition of PDE5 in lung tissue results in relaxation of pulmonary vascular smooth muscle and subsequently pulmonary vasodilation, thereby making sildenafil an effective agent in treating pulmonary hypertension. Inhibition of PDE5 present in esophageal smooth muscle can cause a marked inhibition of esophageal motility as well as a reduction in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD).  Sildenafil has been shown to cross the blood-brain barrier and inhibit PDE5 in cerebral blood vessels. The areas of the brain that have the highest activity of PDE5 are the hippocampus, cerebral cortex, and basal ganglia. Although clinical studies have not proven this effect, inhibition of PDE5 by sildenafil in the brain may result in emotional, neurological, and psychological effects.

Brief History of Viagra: Sildenafil was originally developed as an antianginal agent but was found to be more effective in treating ED and subsequently PAH. In regards to ED, sildenafil (Viagra®) was the first drug with this mechanism of action to be marketed; it is not a prostaglandin inhibitor. As opposed to other therapies for impotence which require direct injection into the penis or insertion of a urethral suppository, sildenafil is given orally. The drug was tested in more than 4000 men in 21 clinical trials. The average age of these men was 55 years and they had erectile dysfunction for an average of 5 years before entering the study. Sildenafil was effective in roughly 70% of subjects. Response rates of 90% have been achieved in trials of male patients with psychogenic impotence. Sildenafil may also be effective in male patients with impotence related to diabetes mellitus or due to pelvic fracture urethral disruption. In a study comparing oral sildenafil to sublingual apomorphine, an investigational ED drug, sildenafil was significantly more effective than apomorphine. Sildenafil has been shown to be effective and well tolerated in patients on multidrug antihypertensive regimens and not associated with additional safety risks in these patients.
Final FDA approval for sildenafil (Viagra®) for the treatment of erectile dysfunction (ED) in men was granted on March 27, 1998.

Not Just for Erectile Dysfunction: Sildenafil continues to be studied clinically to assess its utility in treating sexual dysfunction in females, but initial studies have found sildenafil to provide results similar to placebo in women. Shortly after approval for ED, studies showed sildenafil was effective in treating patients with PAH. Sildenafil improved exercise capacity as well as mean pulmonary artery pressure and other measures of cardiac function in patients with PAH. Sildenafil is the first oral therapy approved for treating early stages of PAH. Sildenafil has also shown efficacy in treating altitude sickness. Due to a risk of cardiovascular adverse events, this drug should not be used in patients taking nitrate therapy such as GTN.

Final FDA approval for sildenafil (Revatio™) for treatment of pulmonary arterial hypertension (PAH) was granted June 3, 2005.

In conclusion, Jenny McCarthy needs to be educated on this disorder before she can go around advocating to anybody.