CHAPTER ONE

1.0  INTRODUCTION

1.1  BACKGROUND OF STUDY

Sildenafil citrate is a potent, competitive phosphodiesterase type 5 isoenzyme inhibitor, it was the first in a class of effective oral treatment for erectile dysfunction(ED) of varying etiologies including erectile dysfunction associated with drugs, diabetes, other general medical conditions and spinal cord injury (Giulinao et al). Sildenafil citrate was initially studied for use in hypertension and angina pectoris but since it induced penile erection to patients who took the drug in clinical trials (ABM), Pfizer decided to market it for erectile dysfunction rather than Angina, and was approved for use for erectile dysfunction by the FDA on March 27th 1998. Sildenafil popularity with young adults has increased over the years (Peterson, 2001). The availability of sildenafil has changed the view of ED management, as well as increased patient access to disease management resources.(Boyce et.al 2001). A significant portion of the literature describing the use of sildenafil in recreational settings comes from Great Britain. The authors of one British review in 2000 reported that the PDE5 inhibitor was supplied via the Internet, as well as from street sources.(Downie et.al 2000) Opioid abusers were seeking the drug to improve sexual performance that might be adversely affected by long-term opiate use. Healthy menwere also seeking the drug in the belief that it would improve their sexual performance. The perceived risks of obtaining sildenafil via such online sources were assessed in 1999. Ten virtual pharmacies that sold sildenafil pursuant to an online prescription issued by an affiliated physician were assessed for their extent of dispensing the drug despite evident patient contraindications.(Eysenbach et.al1999)  Investigators posed as a 69-year-old obese woman with coronary artery disease and hypertension who complained of having “no orgasm.” Concomitant medications that were listed on the patient’s request form were captopril, pravastatin, atenolol, and erythromycin. One pharmacy offered to supply cimetidine tablets to be used in conjunction with sildenafil, with the explanation that concomitant use would lead to a “56% increase in plasma sildenafil concentrations…increased effectiveness would be noted with the same dose of Viagra taken with 800 mg of cimetidine.”(Eysenbachet al 1999) Three companies provided the requested drug, one of which sent an e-mail message advising the patient to discontinue the use of her other medications when taking sildenafil. Of those that failed to ship the product, two cited importation restrictions, three unknown benefits of the drug in women, and one cardiovascular concerns. The mean purchase cost per tablet was approximately twice that of prescription sildenafil obtained from a U.S. community pharmacy.

Erectile dysfunction is defined as the inability to achieve and sustain an erection of adequate rigidity for satisfactory sexual intercourse during sexual activity of humans. Penile erection is the hydraulic effect of blood entering and being retained in sponge-like bodies within the penis. The process is most often initiated as a result of sexual arousal,when signals are transmitted from the brain to nerves in the penis. The most important organic causes are cardiovascular disease,diabetes , neurological problems(for example,trauma from prostatectomy surgery), hormonal insufficiency (hypogonadism) and the drug side effects.

Psychological impotence is where erection or penetration fails due to thoughts or feeling (psychological reasons) rather than physical impossibility;this is somewhat less frequent but can often be helped. Notably in psychological impotence there is a strong response to placebo treatment. Erectile dysfunction can have severe psychological consequences as it can be tied to relationship difficulties and masculine self-image.

Besides treating the underlying causes such as potassium deficiency or arsenic contamination of drinking water, the first line treatment of erectile dysfunction consist of a trial of PDE5 inhibitors drugs(the first of which was sildenafil ) .In some cases treatment involves prostaglandin tablets in the urethra ,injections into the penis ,a penile prosthesis ,a penis pump or vascular  reconstructive surgery.

Erectile dysfunction affects approximately 10% of men and higher percentages of men of advanced age.(Krenzelok et al 2000). In 1998, the Food and Drug Administration (FDA) approved sildenafil (Viagra®—Pfizer), the first drug in the  phosphodiesterase (PDE) 5 inhibitor class, for the treatment of male erectile dysfunction (ED). As of 2002, the drug was marketed in more than 110 countries, and more than 100 million prescriptions had been issued for the agent.( Padma-Nathan  et al,2002) The availability of sildenafil has changed the view of ED management, as well as increased patient access to disease management resources.( Boyce  et al 2001) Along with the more recently marketed tadalafil (Cialis®—Lilly ICOS) and vardenafil Levitra®—Bayer HealthCare/ GlaxoSmithKline), sildenafil is now considered a first-line agent for treatment of ED, surpassing the use of intracavernosal or intraurethral prostaglandins, oral androgens, and vacuum devices. When used so widely, safety of medications is a particular concern, as even rare adverse effects affect substantial numbers of patients.

Erectile dysfunction is estimated to affect up to 30million men in the United States (Aytac et.al 1999). The disorder is age associated (Goldstein  et.al 1998) with estimated prevalence rates of 39 percent among men 40 years old and 67 percent among those 70 years old (Data on file  2005) .

1.2    PHARMACOLOGY OF SILDENAFIL

Sildenafil protects cyclic guanosine monophosphate (cGMP) from degradation by cyclic guanosine monophosphate specific phosphodiasterase type 5 (PDES) in the corpus cavernosum. Nitric oxide in the corpus cavernosum of the penis binds to guanylatecyclase receptors, which results in increased levels of cyclic guanosine monophosphate, leading to smooth muscle relaxation vasodialation) of the intimal cushions of the helicine arteries. This smooth muscle relaxation leads to vasodialation and increased inflow of blood into the spongy tissue of the penis causing an erection (Webb et al ,1999).

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate specific phosphodiesterase type 5 (PDES), which is responsible for degradation of cGMP in the corpus cavernosum. The molecular structure of sildenafil is similar to that of cyclic guanosine monophosphate and acts as a competitive binding agent of PDES in the corpus cavernosum resulting in more cyclic guanosine monophosphate and better erections (Allen et al,1999).

 1.2.1   Mode of Action

Sildenafil protects cyclic guanosine monophosphate (cGMP) from degradation by cyclic guanosine monophosphate specific phosphodiesterase type5 (PDE5) in the corpus cavernosum. Nitric oxide in the corpus cavernosum of the penis binds to guanylatecyclase receptors, which results in increased level of cGMP,leading to smooth muscle relaxation(vasodialation) of the intimal cushions of the helicine arteries. This smooth muscle relaxation leads to vasodialationand increased inflow of blood into the spongy tissue of the penis causing erection (Webb et.al,1999).

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate specific phosphodiesterase type5 (PDE5),which is responsible for degradation of cGMP in the corpus cavernosum. The molecular structure o sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum resulting in more cyclic guanosine monophosphate and better erections(Allen et.al ,1999)

1.2.2 Pharmacodynamics

Erections are controlled by the parasympathetic nervous system upon sexual stimulation, a decrease in vascular resistance is mediated by acetylcholine and nitric oxide resulting in vasodilatation. The hemodynamic mechanism of an erection is comprised of five stages. During the latent  stage arterial and cavernous smooth muscle relaxation occurs.  Vasodilatation results in high levels of blood flow causing the penis to grow to it’s full size. This stage is called tumescence. During the full-erection stage blood flow fills penis sinusoids and outflow is restricted. This is followed by the rigid erection phase during which the cavernosum muscles contract causing the penis to become rigid. Little blood flow occurs during this stage. During the final stage, detumescence, the cavernous muscles relax and blood flows out of the penis. Erectile dysfunction may occur when there is insufficient blood supply to the penis or when the penis unable to prevent out flow of blood from the penis. Sildenafil is a specific inhibitor of PDES, an enzyme responsible for the breakdown of CGMP to 5’GMP. Increased levels of CGMP stimulate vasodilatation and facilitate the generation and maintenance of erections. These vasodialatory effects also help reduce symptoms of pulmonary arterial hypertension. Sildenafil also exhibits some activity against PDE6 (10 times less potency compared to PDE5), PDE isoform found predominantly in the retina. This activity is responsible for the blue tinged vision experienced by users of sildenafil. (Boolell M et.al 1996 June)

(Cheiflin MD et. Al Jan 1999) (friesR et.al Nov. 2005)

1.2.3    Pharmacokinetics

Sildenafil is rapidly absorbed after oral administration with greater than 90% absorbed with up to 40% reaching systemic circulation unchanged following first pass metabolism. The volume of distribution of sildenafil is 105L and has a protein binding of 96%.

Sildenafil appears to be completely metabolized in the liver to it metabolizes. It’s metabolism is mediated mainly by cytochromeP450 microsonalisozymes 3A4 (major route) and 2c9 (minor route). The major circulating metabolite N-demethylatedmetablitie, has PDE selectivity similar to the parent drug and 50-% of it’s in vitro potency-the N- dealkylated metabolite sildenafil also undergoes N-dealklyation followed by N-demethylation of the piperazine ring.  Sildenafil is cleared predominantly by the CYP3A (major route) and Cytrochome P450 2Cg (CYP2C9, minor route) hepatic microsomal isoenzymes. After either oral or intravenous administration, sildenafil is excreted on metabolites predominantly in the faeces (approximately 80% of the administered oral dose) and to a lesser extent in urine (approximately 13% of the administered oral dose). (Boolell et al 1996) (Fries R et al No. 2005) (Cheitlin et al ,1999).

1.2.4    Adverse Effects

In clinical trials, the most common adverse effects of sildenafil use included headache, flushing, indigestion, nasal congestion and impaired vision, including photophobia and blurred vision (abcviagra prescribing information, 2007). Some sildenafil users have complained of seeing everything tinted blue (cyanopsia) (Viagra and Vision Web, 2001). Some complained of blurriness and loss of peripheral vision. In July 2005, the FDA found that sildenafil could lead to vision impairment in rare cases (FDA updates labelling for Viagra,2005) and a number of studies have linked sildenafil use with non artericanterior ischemic optic neuropathy (Laties , 2009) . Rare but serious adverse effects found through post marketing surveillance included prolonged erections, severe low blood pressure, myocardial infarction (heart attack) ventricular arrhythmias, stroke, increased intraocular pressure and sudden hearing loss (ABC Viagra prescribing information, 2007). In October 2007, the FDA announced that the labelling for all PDE 5 inhibitors, including sildenafil required a more prominent warning of the potential risk of sudden hearing loss (FDA Annomies revistris to label for Viagra on July 2007).

The most common adverse effects of sildenafil therapy are headache (16%), flushing (10%), and dyspepsia (7%). Abnormal vision, including light sensitivity and color impairment (e.g., blue tints of vision), may be experienced by up to 3% of patients, particularly those receiving doses in excess of 100 mg.(Cheitlin MD et al 1999) Such experiences are more  characteristic of sildenafil’s weak inhibitory effect on PDE6. Prolonged erections, sometimes to the extent of at least6 hours ( priapism), have also been reported with the agent. These adverse effects are similarly noted with the two newer agents. However, tadalafil’s lesser affinity for PDE6 theoretically diminishes the likelihood of visual changes. This agent does, however, have increased affinity for PDE11, commonly found in skeletal muscle and other organs. Patient complaints of myalgia and back pain may be related to this mechanism.(Hussar et al,2003) Inhibition of PDE5, a substance present throughout the vasculature produces hypotension. (Cheitlin et al, 1999)  Systolic and diastolic pressures may be diminished by 8–10 mm Hg and 5–6 mm Hg, respectively, following sildenafil administration. The drug potentiates the decrease in blood pressure resulting from nitrates, and concurrent use with such agents is contraindicated. Caution should be exercised with concomitant administration of alpha-adrenergic receptor blockers, and sildenafil doses should not exceed 25 mg within 4 hours of alpha-blocker administration. The agent should also not be initiated in men for whom sexual activity is not recommended due to underlying cardiovascular conditions that place them at risk if hypotension develops. No direct comparison of the three marketed agents has been conducted, particularly with regard to efficacy measures. One potentially significant difference among the drugs, however, is sildenafil potential for prolongation of the QTc interval, a phenomenon associated with ventricular dysrhythmias and sudden cardiac death.(Levitra et al.2003) Although reports of this problem  which have been published are scarce, patients should be carefully screened and monitored. Sildenafil should not be administered to patients with congenital lQTc prolongation or those receiving Class IA or III anti-arrhythmic agents. Cardiac conduction disorders are also more likely when thePDE5 inhibitor is used concomitantly with CYP 3A4 inhibitors(e.g., itraconazole, ketoconazole, erythromycin). Sildenafil is also contraindicated for use in patients receiving alpha-adrenergic receptor antagonists, medications commonly administered for the management of benign prostatic hyperplasia are  yet to be published. Despite sildenafil’s relatively benign adverse effect profile, a number of cases of morbidity andmortality related to cardiovascular events have been reported sincethe drug’s introduction. A 1999 summary of post marketing surveillance revealed that 77 of 130 verified deaths possibly associated with sildenafil were cardiovascular in nature (Kloner et al.1999), these deaths included 41 cases of definite or suspected myocardial infarction(MI). Some investigators have speculated that these deaths were related to increased sexual exertion or the concurrent use of nitroglycerin products. Researchers from FDA investigated deaths in men prescribed sildenafil in the first 11 months of its availability in the United States.(Wysowski et al 2002).  Domestic reports submitted via the FDA Adverse Event Reporting System were analyzed, and MIs occurring in sildenafil users up to 24 hours following drug administration were assessed. This group included a total of 130 men in the United States who died following sildenafil use. Two cases—ruled as homicide and drowning—were excluded. Cardiovascular events potentially involving MI occurred in 77 patients, while stroke occurred in 3; the cause of death was unknown in 48. Death occurred within 4 to 5 hours of sildenafil administration in 43 men, 29 of whom died during or shortly after intercourse. The median age of all patients was 64 years (range, 29–87; n = 104). Concomitant nitrate use could not be excluded in 12% of patients. Additionally, three patients had nitroglycerin in their possession at the time of death, but their exposure to the drug was uncertain. At least one risk factor for cardiovascular or coronary artery disease was noted in 73% (128) of patients. Forty-six patients ingested sildenafil doses within the normal daily range, while one received more than 100 mg and another experienced an “overdose.” Doses consumed were not documented in the remaining 68 cases. The authors concluded that the number of deaths due to MI was no greater than that expected, based upon the number of sildenafil prescriptions dispensed during the study period. The analysis was limited by a number of factors, including the voluntary nature of the reporting system, the significant publicity shortly after its marketing regarding potential cardiovascular effects of the drug, and the retrospective nature of data collection and analysis. No comparator groups or formal tools were used to assess suspected adverse reaction causality.

1.2.5    Indications

In the United States, sildenafil,  is approved for the treatment of erectile dysfunction.(Kloneret al 1999). In addition to facilitating tumescence, these drugs shorten the refractory period associated with subsequent ejaculation. They are also effective in both Iatrogenic and disease-related ED, including that resulting from diabetes or  prostatectomy.(Boyce  et al, 2001) Most men (35%–91%) respond to a single 50 mg dose of sildenafil; however, as little as 25 mg may be effective in some patients (<18%), while others may require up to 100 mg (1%–69%).The usual dose of sildenafil administered for ED is 50 mg approximately 1 hour before anticipated sexual activity, up to a maximum of 100 mg.(Viagra prescribing information) The drug is not recommended to be administered more frequently than once daily. Starting doses of 25 mg should be considered in elderly patients or those with hepaticor severe renal impairment (i.e., creatinine clearances less than 30mL/minute). Because of sildenafil’s metabolic route, drug interactions are a concern. Concurrent use of CYP 3A4 inhibitors— including itraconazole (Sporanox—Janssen), ketoconazole, and erythromycin—requires sildenafil dosage adjustment. In general, use with CYP 3A4 inhibitors necessitates the administration of no more than 25 mg of sildenafil in a 24-hour period. A single dose of 25 mg should not be exceeded in a 48-hour period in patients receiving ritonavir, as the combination resulted in an 11-fold increase in sildenafil’s area under the serum concentration–time curve in healthy volunteers. Lower doses (25 mg) should also be used in patients receiving alpha-blockers. If desired, higher doses may be administered in these patients but not within 4 hours of administration of alpha-blockers. Sildenafil has been investigated for use in a variety of other applications, including female sexual arousal disorder. The superiority of sildenafil in these investigations is unclear, as a consistently high placebo response, particularly in patients with hypoactive sexual disorder, complicates study interpretation.(Berman et al. 2003, Basson et al 2002) However, these findings are somewhat consistent with those of an additional trial, in which significant positive effects were noted with sildenafil, but only in patients with sufficient testosterone activity.Cardiovascular applications of sildenafil use may someday include management of pulmonary hypertension of a variety of etiologies, heart failure, and Raynaud’s phenomenon.(Cremerset al. 2003)

1.2.6    Contraindications

When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl nitrate (nitroglycerin), amyl nitrite (poppers)along side with sildenafil might be dangerous and it is unadvisable because it will result in a decrease in blood pressure (Smith et .al ,2005)

In men for whom sexual intercourse is inadvisable due to cardiovascular risk factors taking of Viagra may be very dangerous. (Viagra prescribing information, 2004).

1.3   INCIDENCE OF SILDENAFIL USE

Sildenafil (Compound UK – 92480) was synthesized by a group of pharmaceutical chemists working at Pfizer’s sandwich, Kent research facility in England. It was initially studied for use in hypertension and angina pectoris (a symptom of ischaemic heart disease). The first clinical trials were conducted in Morrison Hospital in Swansea (ABM et.al 2008).  Phase 1 clinical trails under the direction of Ian Osterloh suggested the drug had little effect on angina but could induce marked penile erections (Boolell et.al 1996, Terret et.al 1996). Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patented in 1996, approved for use in erectile dysfunction by the FDA on march 27, 1998, becoming the first oral treatment approved to treat erectile dysfunction in the United States and offered for sale in the United States later that year (King  et.al 1998) Annual sales of Viagra peaked in 2008 at its #1,934 million (US annual sales of Viagra 2008).

1.4  MARKETING AND SALES OF SILDENAFIL

In the United States, even though sildenafil is available only by prescription from a doctor, it was advertised directly to consumers on Television (famously being endorsed by former United States Senator Bob Dole and football star Pelé). Numerous sites on the internet offer Viagra®for sale after an “online consultation”, often a simple web questionnaire.(Cimine,1999, Devine et al 2002)the Viagra® name has become so well known, many fake aphrodisiacs now call themselves “herbal Viagra® or are presented as blue tablets imitating the shape and colour of Pfizer’s product. Viagra® is also informally known as “vitamin v”, “the blue pill”, or “blue diamond”, as well as various other nicknames in 2000, Viagra® sales accounted for 92% of the global market for prescribed erectile dysfunction pills.(keith a 2000) by 2007, Viagra®global share had plunged to about 50%( mcquire 2007)due to several factors, including the entry of cialis and levitra, along with several counterfeits and clones, and reports of vision loss in )people taking pde5 inhibiitors.(Mullin et al. 2008)(Berenson et al. 2008).    In February 2007, it was announced that boots, the uk pharmacy chain, would try over-the-counter sales of Viagra® in stores in ManchesterEngland. Men between the ages of 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist. (over the counter Viagra piloted)on may 6, 2013, Pfizer, which manufacturers Viagra®, told the associated press they will begin selling the drug directly to patients on its website.(Pfizer to sell Viagra online).

1.5   REGIONAL ISSUES ON SILDENAFIL

European Union

Pfizer’s patent on sildenafil citrate expired in some member countries of the EU, Austria, Denmark, France, Germany, Ireland, Italy, The Netherlands, Spain, Sweden, the United Kingdom and Switzerland on 21 June 2013.( Jim Edwards (October 21, 2009)A UK patent held by Pfizer on the use of PDE5 inhibitors (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.(Murray et al 2009)

United States

Sildenafil is available as a generic drug in the United States. As of 2016 branded pills cost about 50 times more than generic ones.(Skinner et al 2016).

In the United States, Pfizer received two patents for sildenafil: one for its indication to treat cardiovascular disease (marketed as Revatio) and another for its indication to treat erectile dysfunction (marketed as Viagra). The substance is the same under both trade names.(Skinner et al 2016).

In 1992, Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases.This would be marketed as Revatio. The patent was published in 1993 and expired in 2012. The patent on Revatio (indicated for pulmonary arterial hypertension rather than erectile dysfunction) expired in late 2012. Generic versions of this low-dose form of sildenafil have been available in the U.S. from a number of manufacturers, including Greenstone, Mylan, and Watson, since early 2013.(U.S. Patent) Health care providers may prescribe generic sildenafil for erectile dysfunction. However, the generic is not available in the same dosages as branded Viagra, so using dosages typically required for treating ED requires patients to take multiple pills.( Skinner et al 2016).

In 1994, Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction. ( This would be marketed as Viagra. This patent was published in 2002 and will expire in 2019. Teva sued to have the latter patent invalidated, but Pfizer prevailed in an August 2011 federal district court case.(“Pfizer Wins Viagra Patent Infringement Case Against Teva Pharmaceuticals) In an agreement with Pfizer, Teva will begin to provide the generic drug in 2017.(  U.S. Patent 5,250,534)

Canada

In Canada, Pfizer’s patent 2,324,324 for Revatio (sildenafil used to treat pulmonary hypertension) was found invalid by the Federal Court in June 2010, on an application by Ratiopharm Inc. ( “Revation patent ruled invalid for lack of sound prediction and obviousness”).

On November 8, 2012, the Supreme Court of Canada ruled that Pfizer’s patent 2,163,446 on Viagra was invalid from the beginning because the company did not provide full disclosure in its application. The decision, Teva Canada Ltd. v. Pfizer Canada Inc., pointed to section 27 (3) (b) of The Patent Act which requires that disclosure must include sufficient information “to enable any person skilled in the art or science to which it pertains” to produce it. It added further: “As a matter of policy and sound statutory interpretation, patentees cannot be allowed to ‘game’ the system in this way. This, in my view, is the key issue in this appeal.(Teva Canada Ltd et al.2002) Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision.( John Spears et al 2008) To remain competitive, Pfizer then reduced the price of Viagra in Canada.( “Pfizer Canada drops Viagra price after generic versions get Supreme Court green light”)However, on November 9, 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada.( “SCC Case Information)on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent.( Kirk Makin 2012) Finally, on April 22, 2013, the Supreme Court of Canada invalidated Pfizer’s patent altogether.( GowlingLafleur Henderson LLP et al 2013)

India

Manufacture and sale of sildenafil citrate drugs known as “generic viagra” is common in India, where Pfizer’s patent claim does not apply. Trade names include Kamagra (Ajanta Pharma), Silagra (Cipla), Edegra (Sun Pharmaceutical), Penegra (ZydusCadila), and Zenegra (Alkem Laboratories).

China

Manufacture and sale of sildenafil citrate drugs is common in China, where Pfizer’s patent claim is not widely enforced.

Other Countries

Egypt approved Viagra for sale in 2002, but soon afterwards allowed local companies to produce generic versions of the drug, citing the interests of poor people who would not be able to afford Pfizer’s price.(Allam et al 2002) Pfizer’s patent on sildenafil citrate expired in Brazil in 2010.

Nigeria

Documentations on the use of sildenafil are scarce. However it is a common observation that many brands of sildenafil have flooded the Nigerian drug market and these are commonly sold by  in pharmacies and  patent medicine stores alike.

1.6  MIS-USE OF MEDICATION

Medications are said to be mis-used when a person takes a legal prescription medication for a purpose other than the reason it was prescribed or when that person takes a drug not prescribed to him or her, that is mis-use of a medication. Mis-use includes taking a drug in a manner that is not recommended by a health are professional. This happens when a person hopes to get a bigger or faster therapeutic response from medications such as sleeping or weight loss pills. It can also happen when the person wants to get high which is an example of prescription drug abuse (Michael Klein, July 2010).

Prescription mis-use has been defined differently and rather inconsistency based on status of drug prescription, the uses without a prescription, intentional use to achieve intoxicating effects, route of administration, co-ingestion with alcohol and the presence or absence of dependence symptoms (Barrett  et. al, McCabe et al). Chronic use leads to a change in the central nervous system which means the patient has developed tolerance to the medicine that more of the substance is needed in order to produce desired effects. When this happens, any effort to stop or reduce to use of this substance would cause withdrawal symptoms to occur  (Antai-Otory et al).

The rate of prescription drug abuse is fast overtaking illegal drug abuse in the United States. According to the National Institute of Drug abuse, 7 million people were taking prescription drugs for non-medical use in 2010. Among 12th graders prescription drug mis-use is now second only to cannabis (POMP center of Excellence 2010-2011). Nearly 1 in 12 high school seniors reported nonmedical ofvicodin, 1 in 20 reported abuse of oxycontin (PDA. Dec 2011).

Avenues of obtaining prescription drugs for misuse are varied: sharing between family and friends, illegally buying medications at school or work, and often “doctor shopping” to find multiple physicians to prescribe the same medication, without knowledge of other prescribers.

Increasingly, law enforcement is holding physicians responsible for prescribing controlled substances without fully establishing patient controls, such as a patient “drug contract.” Concerned physicians are educating themselves on how to identify medication-seeking behavior in their patients, and are becoming familiar with “red flags” that would alert them to potential prescription drug abuse . “Combating Prescription Drug Abuse in Your Practice”)

1.7   EPIDEMIOLOGY OF DRUG MIS USE

The initiation of drug and alcohol use is most likely to occur during adolescence, and some experimentation with substances by older adolescents is common. For example, results from 2010 Monitoring the Future survey, a nationwide study on rates of substance use in the United States, show that 48.2% of 12th graders report having used an illicit drug at some point in their lives. In the 30 days prior to the survey, 41.2% of 12th graders had consumed alcohol and 19.2% of 12th graders had smoked tobacco cigarettes. In 2009 in the United States about 21% of high school students have taken prescription drugs without a prescription.(“CDC Newsroom Press Release June 3, 2010”). And earlier in 2002, the World Health Organization estimated that around 140 million people were alcohol dependent and another 400 million with alcohol-related problems.(Baker et. Al 2003)

Studies have shown that the large majority of adolescents will phase out of drug use before it becomes problematic. Thus, although rates of overall use are high, the percentage of adolescents who meet criteria for substance abuse is significantly lower (close to 5%)  (Effective Child Therapy: Substance abuse Dependence Copyright 2012)

According to BBC, “Worldwide, the UN estimates there are more than 50 million regular users of morphine diacetate (heroin), cocaine and synthetic drugs.( “Drug Trade,2000)

1.8   SPECIAL POPULATION OF PEOPLE IN DRUG MIS USE

1.8.1   Immigrants and Refugees

Immigrant and refugees have often been under great stress.(Drachman et al 1992) physical trauma and depression and anxiety due to separation from loved ones often characterize the pre-migration and transit phases, followed by “cultural dissonance,” language barriers, racism, discrimination, economic adversity, overcrowding, social isolation, and loss of status and difficulty obtaining work and fears of deportation are common. Refugees frequently experience concerns about the health and safety of loved ones left behind and uncertainty regarding the possibility of returning to their country of origin.(Pumariega A et al.2005) For some, substance abuse functions as a coping mechanism to attempt to deal with these stressors.( National Institute on Alcohol Abuse and Alcoholism.)

Immigrants and refugees may bring the substance use and abuse patterns and behaviors of their country of origin. or adopt the attitudes, behaviors, and norms regarding substance use and abuse that exist within the dominant culture into which they are entering.( Caetano R et al.1998)

1.8.2      Street Children

Street children in many developing countries are a high risk group for substance misuse, in particular solvent abuse.( UNODC. “Understanding Substance Use Among Street Children”) Drawing on research in Kenya, Cottrell-Boyce argues that “drug use amongst street children is primarily functional – dulling the senses against the hardships of life on the street – but can also provide a link to the support structure of the ‘street family’ peer group as a potent symbol of shared experience.( Cottrell-Boyce et al. 2010 )

1.8.3     Musicians

In order to maintain high-quality performance, some musicians take chemical substances. As a group they have a higher rate of substance abuse The most common chemical substance which is abused by pop musicians is cocaine( Breitenfeld et al 2008) because of its neurological effects. Stimulants like cocaine increase alertness and cause feelings of euphoria, and can therefore make the performer feel as though they in some ways ‘own the stage’.

1.9  FACTORS PROMOTING MIS-USE OF MEDICATION

1.9.1 Peer Pressure /Adolescence

Several reasons exist which explains why people use drugs. Curiosity and peer pressure are among the greatest reasons people choose to try drugs. Because the brains of adolescents are still developing, specifically the pre-frontal cortex (area of the brain that enables decision-making and supports self-control), the risk of children making poor decisions increases. In addition, peer pressure plays a role, further escalating the risks. Children whose grades are poor or have family members who abuse drugs or engage in criminal activities, particularly parents or other elders, are more susceptible to substance abuse. However even those without these risks can be influenced by pears to use drugs, according to the National Institute on Drug Abuse (NIDA).

1.9.2 Stress/Depression

Stress and depression are major contributing factors to drug mis-use. The NIDA reports many people begin using drugs to feel better, particularly those with social anxiety, stress related disorders and depression. In addition, individuals with these disorders are more likely to relapse after a period of sobriety. Leaving stress management techniques and receiving proper support are helpful to those with stress and depression risks. In some cases, medical interventions like prescription anti-depressants are beneficial coping tools.

1.9.3     Home and family

Family members are chief influencers of a person’s behaviour, offering support or negatively affecting the decisions and lifestyle of an individual. The impact of the home environment is generally most important in childhood, according to NIDA. In addition, NIDA reports scientist estimate genetic factors may account for 40 to 60 percent of an individual’s vulnerability to drug abuse, which proves family plays a role in both biological and environmental factors that may determine a person’s risk of drug mis-use, which proves family plays a role in both biological and environmental factors that may determine a person’s risk of medication  mis-use. Parents who monitor their children’s behaviour and support positive friendships can help prevent drug mis-use. Resources are available to help parents establish connections with their children that may hinder drug mis-use. (Lewis, 2015)

1.10     EPIDEMIOLOGY OF RECREATIONAL USE OF SILDENAFIL

Soon after sildenafil was marketed in the United States, inappropriate use in several patients in the Iowa Medicaid system was noted.(Bowersox Nk et al.1999) Use of the drug in conjunction with nitrates, as well as prescriptions for large quantities that might have indicated abuse or diversion, was reported in 1999. In December 2000, ethnographers from a nationwide drug abuse epidemiology network reported the sometimes fatal practice of using sildenafil with ethamphetamine or other drugs.(Child And Adolescent Work Group, 2003)  Use of sildenafil in conjunction with MDMA was popular in Canada just 1 year after sildenafil’s market introduction.(Ward et al 1999) News reports of the combination abuse of sildenafil and MDMA were also noted in the British Journal of Intensive Care in 1999.(Ward,1999 et.al ).

Following the initial reports of sildenafil misuse, ethnographers and health care professionals noted the use of sildenafil in social settings in which the concurrent abuse of other agents, including club drugs, is prominent.(Aldridge et.al 1999,  Mcleodet.al 2002) Club drugs—substances used in a recreational fashion to enhance social experiences—most notablyinclude MDMA, gamma hydroxybutyric acid (GHB), ketamine,and amyl nitrite (“poppers”) (Romanelli F et al 2003).These compounds can result in hallucinations, social dis-inhibition, and increased libido. However, temporary ED may also be associated with their use. Because of this adverse effect, the user may seek agents to assist in the achievement of an erection, with the foremost of those agents being sildenafil. Reports in fall 2001 noted combination use of sildenafil and MDMA across the United States, including notable usage trends in Los Angeles and Miami.(Office of National drug control policy)(Smith KM et al 2005) Sildenafil tablets weresold with ecstasy or GHB at raves in Honolulu. The practice of ingesting MDMA in conjunction with sildenafil was referred to as“hammer heading,” “sextasy,” or “X’s and O’s” in Miami in late2002.(Office of National drug control policy) Hammer heading refers to the throbbing headache and prolonged, painful erection that may result from the drug  cocktail. Combination use with methamphetamine (“tina”) was noted, in addition to the “trail mix” combination of sildenafil and MDMA reported in the consumer health media in 2001.(Levine J et al 2003).

A significant portion of the literature describing the use of sildenafil in recreational settings comes from Great Britain. The authors of one British review in 2000 reported that the PDE5 inhibitor was supplied via the Internet, as well as from street sources. (Downieet al.2000)  Opioid abusers were seeking the drug to improve sexual performance thatmight be adversely affected by long-term opiate use. Healthy men were also seeking the drug in the belief that it would improve their sexual performance A number of epidemiologic studies have been conducted to determine the extent of sildenafil use and characteristics of recreational users .Shortly after sildenafil’s availability in England, recreational use was noted in 10% of nightclub attendees (10 men, 5 women; 14 white, 1 African-Caribbean).(Aldridge J et.al 1999) On average, the users were 26 years old (range, 19–34). Amyl nitrite was most commonly used in conjunction with sildenafil; other agents included MDMA, GHB, and ethanol. All users reported sildenafil in gestation either at home or in club settings. Responses indicated that sildenafil enhanced sexual desires and feelings of “warmth”; all participants remarked that they would use the drug again. The drug was acquired from a variety of sources, including friends, dealers, the Internet, and sex shops. This assessment must be interpreted with caution, as the potential for recall bias may have influenced the results, and the data may not be representative of recreational use patterns in other countries. Assessing changing patterns of drug consumption among regular users may provide valuable trending information and potentially serves as an early warning system. Drug use in dance venue attendees is therefore often measured, as these individuals are generally considered members of a high-risk population. Concomitant use of MDMA and sildenafil was reported by 2% of1,151 respondents to a survey administered in a British dance music publication.37 The mean (± SD) age of respondents was 24± 5.49 years; 60.5% were male. Poly-substance use was commonly reported: 60% indicated use of at least three compounds in the previous month. MDMA was the substance most frequently used (96%), both within the previous month or over the course of a lifetime. Yet again, this investigation relied upon participant recall, and results may not be easily extrapolated to other potential users, venues, countries, and time periods. Notably, sildenafil had been available in the United Kingdom for less than 1 year at the time of this study. The concomitant use of sildenafil and club drugs poses risks of drug interactions and adverse effects not only to the individual user but also from a public health perspective. Such concerns include the practice of high-risk sexual behaviors, which may increase the transmission of sexual diseases, most prominently human immunodeficiency virus (HIV). Potentially fatal drug–drug interactions between sildenafil and protease inhibitors have also been reported, with the latter agents inhibiting the metabolism of sildenafil and thereby increasing serum sildenafil concentrations and therefore the drug’s potential for adverse effects.(James et al. 1998 ; Nandwani et al 1999; Solomon et al.