Alcoholism Drinking Health

Definition

Alcoholism is an illness marked by drinking alcoholic beverages at a level that interferes with physical health, mental health, and social, family, or occupational responsibilities.

Alcoholism is divided into 2 categories: dependence and abuse.

People with alcohol dependence, the most severe alcohol disorder, usually experience tolerance and withdrawal. Tolerance is a need for markedly increased amounts of alcohol to achieve intoxication or the desired effect. Withdrawal occurs when alcohol is discontinued or intake is decreased. Alcohol dependents spend a great deal of time drinking alcohol, and obtaining it.

Alcohol abusers may have legal problems such as drinking and driving. They may also have problems with binge drinking (drinking 6 or more drinks at one sitting).

People who are dependent on or abuse alcohol continue to drink it despite evidence of physical or psychological problems. Those with dependence have more severe problems and a greater compulsion to drink.

Alternative Names Alcohol dependence; Alcohol abuse

Causes, incidence, and risk factors

Alcoholism is a type of drug addiction. There is both physical and psychological dependence with this addiction. Physical dependence reveals itself by withdrawal symptoms when alcohol intake is interrupted, tolerance to the effects of alcohol, and evidence of alcohol-associated illnesses.

Alcohol affects the central nervous system as a depressant, resulting in a decrease of activity, anxiety, tension, and inhibitions. Even a few drinks can result in behavioral changes, a slowing in motor performance, and a decrease in the ability to think clearly. Concentration and judgment become impaired. In excessive amounts, intoxication may result.

Alcohol also affects other body systems. Irritation of the gastrointestinal tract can occur with erosion of the lining of the esophagus and stomach causing nausea and vomiting, and possibly bleeding. Vitamins are not absorbed properly, which can lead to nutritional deficiencies with the long-term use of alcohol. Liver disease, called alcoholic hepatitis, may also develop and can progress to cirrhosis. The heart muscle may be affected. Sexual dysfunction may also occur, causing problems with erections in men and cessation of menstruation in women.

Alcohol affects the nervous system and can result in nerve damage and severe memory loss. Chronic alcohol use also increases the risk of cancer of the larynx, esophagus, liver, and colon. Alcohol consumption during pregnancy can cause severe birth defects. The most serious is fetal alcohol syndrome, which may result in mental retardation and behavior problems. A milder form of the condition which can still cause lifelong impairment is called fetal alcohol affects.

The social consequences of problem drinking and alcohol dependence can be as serious as the medical problems. People who abuse or are dependent on alcohol have a higher incidence of unemployment, domestic violence, and problems with the law. About half of all traffic deaths are related to alcohol use.

The development of dependence on alcohol may occur over a period of years, following a relatively consistent pattern. At first, a tolerance of alcohol develops. This results in a person being able to consume a greater quantity of alcohol before its adverse effects are noticed. Memory lapses (black-outs) relating to drinking episodes may follow tolerance. Then, people may lose control over drinking and find it difficult or impossible to stop if they try. The most severe drinking behavior includes prolonged binges of drinking with associated mental or physical complications. Some people are able to gain control over their dependence in earlier phases before a total lack of control occurs. The problem is, no one knows which heavy drinkers will be able to regain control and which will not.

Withdrawal develops because the brain has physically adapted to the presence of alcohol and cannot function adequately in the absence of the drug. Symptoms of withdrawal may include elevated temperature, increased blood pressure, rapid heart rate, restlessness, anxiety, psychosis, seizures, and rarely even death.

There is no known common cause of alcoholism. However, several factors may play a role in its development. A person who has an alcoholic parent is more likely to become an alcoholic than a person without alcoholism in the immediate family. Research suggests that certain genes may increase the risk of alcoholism but which genes or how they exert their influence is controversial. Psychological factors may include a need for relief of anxiety, ongoing depression, unresolved conflict within relationships, or low self-esteem. Social factors include availability of alcohol, social acceptance of the use of alcohol, peer pressure, and stressful lifestyles.

The incidence of alcohol intake and related problems is increasing. Data from many sources indicate that about 15% of the population in the United States are problem drinkers, and approximately 5% to 10% of male drinkers and 3% to 5% of female drinkers could be diagnosed as alcohol dependent (12.5 million people).

Symptoms

Men who consume 15 or more drinks a week, women who consume 12 or more drinks a week, or anyone who consumes 5 or more drinks per occasion at least once a week are all at risk for developing alcoholism. (One drink is defined as a 12-ounce bottle of beer, a 5-ounce glass of wine, or a 1 1/2-ounce shot of liquor).

The following questions are used by the National Institute on Alcohol Abuse and Alcoholism to screen for alcohol abuse or dependence:

• Have you felt that you should cut down on your drinking?

• Do you ever drive when you have been drinking?

• Is someone in your family concerned about your drinking?

• Have you ever had any blackouts after drinking?

• Have you ever been absent from work or lost a job because of drinking?

• Do you have to drink more than before to achieve intoxication or the desired effect?

Some of the symptoms associated with alcoholism include:

• Drinking alone

• Making excuses to drink

• Need for daily or frequent use of alcohol for adequate function

• Lack of control over drinking, with inability to discontinue or reduce alcohol intake

• Episodes of violence associated with drinking

• Secretive behavior to hide alcohol related behavior

• Hostility when confronted about drinking

• Neglect of food intake

• Neglect of physical appearance

• Nausea and vomiting

• Shaking in the morning

• Abdominal pain

• Numbness and tingling

• Confusion

Alcohol withdrawal symptoms vary from mild to severe and may include:

• Rapid heart rate and sweating

• Restlessness or agitation

• Loss of appetite, nausea, or vomiting

• Confusion or hallucinations

• Tremors and seizures

Signs and tests

All physicians should ask their patients about their drinking. A history may be obtained from family if the affected person is unwilling or unable to answer questions. A physical examination is performed to identify physical problems related to alcohol use.

• A toxicology screen or blood alcohol level confirms recent alcohol ingestion, which does not necessarily confirm alcoholism.

• Liver function tests can be elevated. GGPT (glutaryl transaminase) is often elevated more than other liver function tests.

• CBC (complete blood count) – MCV can be elevated (mean corpuscular volume or size of the red blood cells).

• Serum magnesium, uric acid, total protein, and folate tests may be abnormal.

Treatment

Many people with alcohol problems don’t recognize when their drinking gets out of hand. In the past, treatment providers believed that alcoholics should be confronted about denial of their drinking problems, but now research has shown that compassionate and empathetic counseling is more effective.

Three general steps are involved in treating the alcoholic once the disorder has been diagnosed: intervention, detoxification, and rehabilitation. Research finds that the traditional confrontational intervention – where the employer or family members surprise the alcoholic and threaten consequences if treatment is not begun – is NOT effective. Studies find that more people enter treatment if their family members or employers are honest with them about their concerns, and try to help them to see that drinking is preventing them from reaching their goals.

Once the problem has been recognized, total abstinence from alcohol is required for those who are dependent; for those who are problem drinkers, moderation may be successful. Since many alcoholics initially refuse to believe that their drinking is out of control, a trial of moderation can often be an effective way to deal with the problem. If it succeeds, the problem is solved. If not, the person is usually ready to try abstinence. Because alcoholism affects the people closely related to the alcoholic person, treatment for family members through counseling is often necessary.

Detoxification is the first phase of treatment. Withdrawal from alcohol is done in a controlled, supervised setting in which medications relieve symptoms. Detoxification usually takes 4 to 7 days. Examination for other medical problems is necessary. For example, liver and blood clotting problems are common. A balanced diet with vitamin supplements is important. Complications associated with the acute withdrawal of alcohol may occur, such as delirium tremens (DT’s), which could be fatal. Depression or other underlying mood disorders should be evaluated and treated. Often, alcohol abuse develops from efforts to self-treat an illness.

Alcohol recovery or rehabilitation programs support the affected person after detoxification to maintain abstinence from alcohol. Counseling, psychological support, nursing, and medical care are usually available within these programs. Education about the disease of alcoholism and its effects is part of the therapy. Many of the professional staff involved in rehabilitation centers are recovering alcoholics who serve as role models. Programs can be either inpatient, with the patient residing in the facility during the treatment, or outpatient, with the patient attending the program while they live at home.

Medications are sometimes prescribed to prevent relapses.

• Naltrexone (Vivitrol) is an opioid antagonist that decreases alcohol cravings. In April 2006, the U.S. Food and Drug Administration approved an injected form of the drug.

• Disulfiram (Antabuse) works by producing very unpleasant side effects if even a small amount of alcohol is ingested within 2 weeks after taking the drug.

• Acomprosate is a new drug that has been shown to lower relapse rates in those who are alcohol dependent.

These medications are not given during pregnancy or if the person has certain medical conditions. Long-term treatment with counseling or support groups is often necessary. The effectiveness of medication and counseling varies.

Alcoholics Anonymous is a self-help group of recovering alcoholics that offers emotional support and an effective model of abstinence for people recovering from alcohol dependence. There are more than 1 million members worldwide, and local chapters are found throughout the United States.

Al-Anon is a support group for spouses and others who are affected by someone else’s alcoholism. Alateen provides support for teenage children of alcoholics. See alcoholism – support group.

For those who don’t like the 12-step approach, there are several other support groups available. It is important that people dealing with alcohol problems know about these other groups because in the past, those who did not find AA helpful or were troubled by its requirement of submission to a “Higher Power” had no alternatives.

SMART recovery uses research-based cognitive techniques to help alcoholics recover. LifeRing recovery and SOS are two other secular programs. Women For Sobriety is a self-help group just for women – many female alcoholics have different concerns than men. Moderation Management is a program for problem drinkers seeking to moderate their drinking – it recommends abstinence for those who fail at such attempts.

Support Groups

Members of AA have help available 24 hours a day, associate with a sober peer group, learn that it is possible to participate in social functions without drinking, and are given a model of recovery by observing the accomplishments of sober members of the group. Other support groups are smaller, but growing, and all have an online presence which provides support even at home late at night.

Expectations (prognosis)

Alcoholism is a major social, economic, and public health problem. Alcohol is involved in more than half of all accidental deaths and almost half of all traffic deaths. A high percentage of suicides involve the use of alcohol in combination with other substances. Additional deaths are related to the long-term medical complications associated with the disease. Only 15% of those with alcohol dependence seek treatment for this disease. Relapse after treatment is common, so it is important to maintain support systems in order to cope with any slips and ensure that they don’t turn into complete reversals. Treatment programs have varying success rates, but many people with alcohol dependency have a full recovery.

Complications

• Pancreatitis

• Heart muscle damage

• Nerve damage

• Esophageal bleeding

• Brain degeneration

• Cirrhosis of the liver

• Delirium tremens (DTs)

• Depression

• Erectile dysfunction

• Fetal alcohol syndrome in the offspring of alcoholic women

• High blood pressure

• Increased incidence of cancer

• Insomnia

• Nutritional deficiencies

• Suicide

• Wernicke-Korsakoff syndrome

Calling your health care provider

If severe confusion, seizures, bleeding, or other health problems develop in a person known or who is suspected to have alcohol dependence take the person to the emergency room or call the local emergency number such as 911.

Prevention

Educational programs and medical advice about alcohol abuse have been successful in decreasing alcohol abuse and its associated problems. Alcohol dependency requires more intensive management.

The National Institute on Alcohol Abuse and Alcoholism recommends that women have no more than 1 drink per day and men no more than 2 drinks per day. One drink is defined as a 12-ounce bottle of beer, a 5-ounce glass of wine, or a 1 1/2-ounce shot of liquor.

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Abstract/Executive Summary

Though glycaemic regulation is an important and effective method of preventing and limiting the progression of complications associated with diabetes, type 2 diabetes is a disease that is often difficult to manage. It is estimated that 20.8 million people are diagnosed with diabetes in United States alone and a worldwide prevalence of approximately 180 million that is expected to double by 2030 (Neumiller et al., 2008).

Introduction of dipeptidyl peptidase-4 (DPP-4) inhibitors offered an alternative to the conventional medicines for intensifying glucose-reducing treatment after metformin monotherapy failing to do so and thus flagged a major possible progression in type 2 diabetes management. DPP-4 inhibitors trigger insulin secretion and decrease glucagon release in a glucose-dependent manner by prolonging the activity of incretin hormones. Compared to insulin secretagogues sulphonylureas and glinides, this results in a more glycaemic control. Ultimately, DPP-4 inhibitors have a good safety profile which can be used in elderly people and patients with minor renal impairment without having to need to adjust the dosage; they have a neutral effect on body weight and do not induce hypoglycaemia on their own. Health concerns, reported predominantly in after-market surveillance programmes, including cardiovascular complications and the risk of developing acute pancreatitis, are being studied extensively (Sesti et al., 2019).

Many affected patients would potentially require multi-drug therapy to achieve appropriate glycaemic goals. Dipeptidyl peptidase-4 (DPP-4) inhibitors have constructed a new class of oral drugs for the treatment of type 2 diabetes symptoms, these inhibitors have become extensively integrated into clinical practice.

Introduction

Diabetes is an increasing problem in the world especially Type 2 which accounts for more than 90% of all diabetes cases in the world (Healthline, n.d.). Although it is a preventable disease, most people will not know they are diagnosed until it is too late therefore, they must undergo necessary treatment. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a recently approved new class of drugs that are used for the treatment of type 2 diabetes, they are known as gliptins and are prescribed to people when they do not respond well to drugs like metformin and sulphonylureas. DPP-4 inhibitors work by preventing the action of the DPP-4 enzyme which breaks down incretin hormones that are produced by the endocrine cells in the epithelium of the small intestine (Watson and Dokken, 2015). There are two types of incretin hormones in humans, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). These hormones induce the release of insulin after a meal or when needed therefore people with Type 2 diabetes who cannot produce enough insulin require them the most. The three main DPP-4 inhibitors are Sitagliptin, Saxagliptin and Linagliptin. Their trade names are Januvia, Onglyza and Tradjenta respectively.

GLP-1 and GIP are degraded rapidly after their secretion by DPP-4 enzyme which results in their inactivation, this is done by cleaving a dipeptide from the N-terminus. DPP-4 can often be found attached to cell membranes as well as circulating in the blood stream (Bennett, 2018). After discovering that DPP-4 was associated in the degradation of the incretin hormones, it led to the production and use of DPP-4 inhibitors which aims to increase the half-life of endogenous GLP-1 and GIP.

Discussion

Development of Sitagliptin:

The idea of glucagon-like peptide 1 (GLP-1) as a well-validated solution to type 2 diabetes treatment and the preclinical evidence of inhibition of DPP-4 as an alternative oral route to GLP-1 therapy led Merck to launch a DPP-4 inhibitor programme in 1999. The DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide were licensed to start the programme but the development was discontinued due to extreme toxicity that was observed in rats and dogs during trials. The discovery of both compounds inhibiting the associated proline peptidases DPP-8 and DPP-9 directed to the hypothesis that the inhibition of either or both enzymes could induce a series of harsh toxicities in the preclinical species that were used (Thornberry and Weber, 2007). In reality, the toxicities reported was recapitulated using a selective dual DPP8/9 inhibitor but not a selective DPP-4 inhibitor. As a result, studies in medicinal chemistry shifted its focus to discovering a selective DPP-4 inhibitor. Due to lack of selectivity, initial work on the sequence of amino acids linked to isoleucyl thiazolidide was discontinued. Nonetheless, two-screening SAR experiments have resulted in the discovery of a highly selective sequence of B-amino acid piperazine. A number of bicyclic variants were prepared in an attempt to stabilise the piperazine moiety, which was thoroughly metabolised in vivo, resulting in the discovery of a potent and selective sequence of triazolopiperazine. Such formulations usually exhibited great pharmacokinetic properties in preclinical species unlike their monocyclic counterparts. Optimisation of this sequence led to the development of JANUVIATM (sitagliptin), a selective DPP-4 inhibitor for treatment of type 2 diabetes (Kumar, Tripathi and Garg, 2013). Sitagliptin was first approved by the FDA for the treatment of type 2 diabetes in 2006 (Drugs.com, 2019). It is available in doses of 25, 50 and 100 mg tablets. It is used as a monotherapy or in conjunction with other diabetic drugs, including metformin, sulfonylureas and pioglitazone A (Sekar et al., 2016).

The usage of sitagliptin and metformin combination was approved by the FDA in April 2007 and is distributed in doses of 50/500 mg or 50/1000 mg under the trade name Janumet. In a monotherapy trial, 743 patients with diabetes were randomised to receive 5, 12, 25 or 50 mg twice daily of sitagliptin. All doses of sitagliptin resulted in a heavy reduction in HbA1c after 12 weeks of treatment (Sekar et al., 2016).

Mechanism of action of Sitagliptin:

sitagliptin prolongs the life span and activity of the incretins; GLP-1 and GIP via inhibition of the DPP-4 enzyme. After a meal, the secretion of GLP-1 and GIP are triggered by the L-cells and K-cells respectively. Inhibition of DPP-4 allows for levels of active incretin hormones to be increased; essentially, sitagliptin augments the ability of glucose synthesis by pancreatic beta cells which in turn releases insulin as a response to glucose concentration increasing. The release of insulin contributes to the glucose reduction process in the liver (Pathak and Bridgeman, 2010). JANUVIATM (sitagliptin) enhances insulin release and reduces glucagon levels in the bloodstream in a glucose-dependent manner by increasing and prolonging active incretins concentration. Sitagliptin displays DPP-4 selectivity and does not inhibit in vitro DPP-8 or DPP-9 activity at concentrations resembling those from therapeutic doses (RxList, n.d.).

Adverse effects of Sitagliptin:

the most frequent adverse reactions were upper respiratory tract infection, nasopharyngitis, and headaches in more than 5% of patients receiving the DPP-4 inhibitor sitagliptin. Seeing as renal and hepatic pathways are associated in eliminating oral doses of sitagliptin, patients with renal and hepatic insufficiency were also tested. Following the intake of carbon-14 labelled sitagliptin, roughly 13% was detected in stool and 87% in urine. Of the 87% that was found in urine, 24% was structurally unchanged, while 36% were active parental metabolites (Mrknewsroom.com, 2013).

Development of Saxaglipton:

A longer duration of action was desirable during the development of DPP-4 inhibitors. Compounds that had a vinyl substitution at the β-position of α-cycloalkyl-substituted glycines and their oxygenated metabolites did not result in deterioration of potency but resulted in a desired increase in duration of action is what caused Bristol-Myers Squibb pharmaceutical company to develop saxagliptin. Consecutive exploration of molecules with a hydroxylated adamantyl group led to saxagliptin, this is distinguished by the potency in vitro and in vivo, good oral bioavailability (F = 75%), good period of activity (t 1/2 = 2.1 hours) as well as no inhibition of CYP3A4 (Gallwitz, 2010). A 24-week clinical study showed that saxagliptin as a monotherapy was effectively successful in lowering HbA1C by 0.4 to 0.9%. It showed to be well tolerated in the dose ranges of 2.5 to 40 mg (Dave, 2011). Saxagliptin was effective and well tolerated in type 2 diabetes patients with moderate to severe renal impairment with contraindicated metformin. In patients with end-stage renal disease or haemodialysis, saxagliptin was not effective (Nowicki et al., 2011). Saxagliptin was FDA approved in 2009

Mechanism of action of Saxagliptin:

saxagliptin and its active metabolite M2 which are two times less effective than the parent drug and are also competitive DPP-4 inhibitors that enhance glycaemic control by preventing the inactivation of GLP-1 and GIP incretin hormones. It raises levels of GLP-1, promoting the release of insulin, and reduces levels of postprandial glucagon and glucose. Saxagliptin and M2 are much more selective for inhibiting DPP-4 than DPP-8 or DPP-9 enzymes or a large group of several other proteases (Dave, 2011).

Adverse effects of Saxagliptin:

In a clinical trial that lasted for 52 weeks, the test subjects were split into two groups; one group being given Onglyza (saxagliptin) and the other group taking a placebo. Urinary tract infection, fever, headache, nasopharyngitis and diarrhoea were the most frequent adverse effects at 52 weeks. In the 52 weeks of treatment, few patients experienced hypoglycaemia events; 1.3% of patients with saxagliptin and 2.5% of patients with the placebo. Also, rates were no different from those recorded at 24 weeks. During the study, no patient had a significant episode of hypoglycaemia. Small increases were detected at 52 weeks in systolic (0.8 mmHg) and diastolic (0.3 mmHg) blood pressure equivalent within both groups. Increases in serum lipids, total cholesterol, low- and high-density lipoprotein cholesterol, and triglycerides in each category of therapy were minimal (Matthaei et al., 2016).

Saxagliptin is readily absorbed orally with a bioavailability of approximately 67%. It is widely dispersed in extravascular tissues with the highest concentrations being located in the intestinal tissue and kidney. It is primarily hydrolysed by CYP3A4/5 to the main metabolite M2 and some other minor metabolites and therefore dosage should be lowered in patients with concurrently strong CYP3A4 inhibitors. Both renal and hepatic pathways excrete saxagliptin. 75% of saxagliptin is removed through urine and 22% through faeces (Dave, 2011).

Development of Linagliptin:

the research for the discovery of an optimal and more potent oral DPP-4 inhibitor began with the screening of over 500,000 different molecules by using high-performance screening (HTS), which detected many compounds that were members of different structural classes with a low micro molar inhibition of DPP-4. One of these candidates was a compound based on the xanthine scaffold, which is made up of four residues of varying structural features which showed characteristics that were deemed a very promising starting point for the search for an effective DPP-4 inhibitor (Eckhardt et al., 2015).

Tradjenta

(

linagliptin) is a small xanthin based molecule. The substantial structural heterogeneity that underlies the DDP-4 inhibitor class members demonstrates distinct pharmacological properties. Linagliptin is a novel chemical class for the therapy of type 2 diabetes in this regard, as no other xanthine-based DPP-4 inhibitor is currently licenced for this indication. Linagliptin is a competitive, reversible DPP-4 inhibitor with a slow dissociation rate from the enzyme. Linagliptin is extremely selective for DPP-4, being at least 10,000 times higher than DPP-8 and DPP-9 selectivity. The corresponding selectivity for sitagliptin and saxagliptin, on the other hand, is approximately 4-fold and 100-fold lower (Thomas et al., 2008). Linagliptin seems to be the DPP-4’s most effective inhibitor in its class. Linagliptin inhibited in vitro DPP-4 activity with an IC50 of 1 nM compared to 19, 62, 50 and 24 nM respectively for sitagliptin, vildagliptin, saxagliptin, and alogliptin. After 24 hours of administration, DPP-4 inhibition in vivo was significantly higher than any other DPP-4 inhibitor and decreased in the order of linagliptin, sitagliptin, saxagliptin, and vildagliptin for the duration of action (Forst and Pfützner, 2013). Linagliptin was discovered and produced by Boehringer Ingelheim, a pharmaceutical company based in Ingelheim, Germany. It was approved by the FDA in May of 2011 (Eli Lilly and Company, 2011).

Mechanism of action of Linagliptin:

just like the other two previous drugs; linagliptin is also a DPP-4 inhibitor which prevents the degradation of the GLP-1 and GIP by the enzyme therefore in turn increases the concentration of active incretin hormones circulating around the body which induces the release of insulin in a glucose-dependant manner while at the same time decreasing the levels of glucagon in the body also. GLP-1 and GIP have the sole purpose is to maintain a natural regulation of glucose homeostasis within the body (Freeman, 2011).

Adverse effects of Linagliptin:

nasopharyngitis, hypertension, back pain and headache were the most commonly reported adverse effects during the clinical trials. There were rare side effects involving gastrointestinal system. It has been established that linagliptin is well tolerated either when administered alone or in combination in all the studies. In a dose ranging research, the frequency of adverse effects and the tolerability profile throughout all active dose groups have been similar and comparable to that of the placebo. Although linagliptin’s activity is driven by ingestion of oral glucose, it has a low tendency to induce hypoglycaemia, which is expressed in clinical trials. In all the studies, it was frequently reported that hypoglycaemic occurrences with linagliptin treatment were mild and rare. Furthermore, linagliptin had no effects on body weight and adjustment to dosage is not required for people with renal or hepatic impairment (Htike and Lawrence, 2012).

This is due to linagliptin being mostly excreted non-renally. Less than 10% of the linagliptin dose in people with normal hepatic function undergoes renal clearance. In comparison, 80–90% of sitagliptin and vildagliptin are excreted through the renal route, meanwhile saxagliptin is excreted via both renal and hepatic pathways. Since linagliptin is excreted only to a small extent by the renal system, the main route of removal is through the entero-hepatic system. Linagliptin’s hepatic metabolism is low and its metabolites are pharmacologically dormant, including its main metabolite CD1790 (Graefe-Mody et al., 2012).

Conclusion

Type 2 diabetes treatment is intricate; many patients are required to take multiple drugs to achieve the optimal glycaemic targets. Even though the DPP-4 class of inhibitors is not yet fully studied, clinical studies and trials suggest that the mechanisms of action of these drugs complement those of commonly used diabetic drugs. This attribute make these class of drugs suitable for the use of the elderly, for those with numerous co-morbidities that restrict the use of other medications, and for those with complicated insulin therapy (Green, 2010).

NICE recommends the usage DPP-4 inhibitors in the UK as a second- or third-line choice in type 2 diabetes management (Htike and Lawrence, 2012). DPP-4 inhibitors are an important alternative to the anti-hyperglycaemic drugs available today for type 2 diabetes. DPP-4 inhibitors provide the benefits of an enhanced tolerability profile, defined by a minimal risk of hypoglycaemia and no weight gain, with comparable efficacy to existing agents. Moreover, there is growing evidence that DPP-4 inhibitors have additional effects that are beneficial on β-cell function and improve cardiovascular risk through mechanisms that have not yet been fully developed. A number of DPP-4 inhibitors for the treatment of type 2 diabetes have been approved. In the coming years, clinical use and understanding of DPP-4 inhibitors, will increase substantially. This is due to a significantly improved safety profile compared to sulfonylureas, DPP-4 inhibitors could become the ideal oral drugs for combination therapy in type 2 diabetes, especially in patients who are not appropriately controlled on metformin monotherapy alone. (Forst and Pfützner, 2013).

To summarise the drugs, sitagliptin was developed after the discontinuation of the original DPP-4 inhibitors threo- and allo-isoleucyl thiazolidide due to the fact that they caused severe toxicity in the animals during the clinical trials. After a successful attempt of developing sitagliptin to treat type 2 diabetes, it paved the way for other pharmaceutical companies to develop better and more potent DPP-4 inhibitors. The development of saxagliptin was primarily to produce a drug that shares the same molecular target as sitagliptin while having better pharmacokinetic properties such as higher bioavailability and a longer mode of action which saxagliptin does exactly that.

Linagliptin displayed the best pharmacological properties in its class out performing both sitagliptin and saxagliptin inside the body. It showed the highest selectivity for the DDP-4 enzyme without interfering with other molecular sites as much as the previous two in addition, linagliptin had a much lower IC50 than any other gliptins in the same class making it the most potent DPP-4 inhibitor.

Galvus (vildagliptin) is also another DPP-4 inhibitor developed in Switzerland with a recommendation of oral ingestion once a day has been approved by many European regulators. Novartis Pharmaceuticals Corporation revealed in February 2007 that they had received an approval letter from the United States. Food and Drug Administration (FDA) seeking additional data, such as a clinical trial to demonstrating the safety and efficacy of vildagliptin in specific groups of patients with renal impairment. Although vildagliptin is available in many countries, in the United States it is still commercially undeveloped and not FDA approved (Drugs.com, n.d.).

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A medication error can be defined as ‘a failure in the treatment process (prescribing, dispensing or administration) that leads to, or has the potential to lead to, harm to the patient.1 A psychological approach of classifying errors has been created and is represented in the flow chart below. So each type of error irrespective of whether it is during prescribing, dispensing or administration should fall into one of the sub categories below.

Figure 1: The classification of medication errors based on a psychological approach.1

In the UK, 216 claims against GPs handled by the medical defence union between 1995 and 2001 were directly related to errors in prescribing, monitoring or administering medicines. When the department of health implemented the plan for improving patient safety one of its main goals where to reduce the number of serious errors in the use of prescribed drugs by 40%.8

The National Patient Safety Agency (NPSA) is a special health authority that has been established to collect, analyse, and integrate information from NHS organisations, which will aid to produce alerts, guidance or signals to prevent adverse events from occurring. Medication errors can cost human life, livelihood or even careers of medical givers and also pose a huge financial burden on the NHS. It is important that these errors are reported and used as a lesson to prevent reoccurrence.8

There are different types of medication errors and are as follows

Wrong/unclear dose or strength, or wrong frequency

Omitted medicines

Wrong Medicine

Mismatch between patient and medicine

Wrong Formulation

Wrong Route

SCENARIO

A 60 year old man with known multiple myeloma presents to the hospital to receive his sixth cycle of VAD; The physician wrote:

Vincristine 1.6mg continuous infusion over Days 1-4

Doxorubicin 9.0 mg/m2/day continuous infusion Days 1-4

Dexamethasone oral 40mg/day Days 1-4, 9-12 and 17-20

Medication errors

The pharmacist dispensed

Vincristine 1.6 mg/day on days 1, 2, 3 and 4

Doxorubicin 90 mg/m2/day on days 1, 2, 3 and 4

Dexamethasone 40mg/day on days 1-4

Three weeks later

The patient comes back to the hospital complaining of

Shortness of breath and

Severe pain in his extremities. (He described it as shooting, burning pain associated with tingling and numbness).

The physician ordered a 2D echocardiogram for the patient which revealed an ejection fraction (EF) of 25% (last month, patient’s EF was 50%)

REPORT

Based on the scenario above, there were three medication errors made

The patient has been given tenfold more doxorubicin than prescribed.

The patient has been given four times more vincristine than prescribed daily

The patient has not been given a dose of dexamethasone for days 9-12 and 17-20

One of the main causes of the patients’ symptoms is due to the increased dose of doxorubicin. Doxorubicin or Adriamycin (which stands for A in the VAD cycle) belongs to a group of drugs called the anthracyclines. They are known to inhibit DNA replication by intercalating into the β-form of the DNA double stranded helix with guanine-cytosine site specific interactions. This causes a buckle in the conformation and results in a distorted DNA helix hence cell death.2

Anthracyclines are known notoriously for causing dose related cardiomyopathy. The summary of product characteristics of doxorubicin states that dosage is usually calculated on the basis of body surface area. The maximum life time cumulative dose is 550 mg/m2. The risk of developing Congestive Heart Failure increases especially once the patient has exceeded 300mg/m2. 3

The patient has just received 360mg/m2 (90mg/m2 x 4days) for the 6th cycle and has previously received 180mg/m2 (9mg/m2 x 4days x 5cycles) assuming all was correct. Making that a cumulative dose of 540mg/m2 which has almost the lifetime dose of 550mg/m2 and putting the patient at a higher risk for already developed or developing cardiomyopathy. The patient came back reporting of dyspnoea and had an ejection fraction that had dropped by 25%. An ejection fraction less than 40% is indicative of cardiomyopathy or heart failure.

The severe pain, numbness and tingling in the extremities can also be related to another dose limiting side effect called hand – foot syndrome. Mostly experienced with the pegylated liposomal type. The mechanism is unknown but one of the theories is that the high turnover rate of keratinocytes (epidermal cells) makes hands and feet more susceptible to damage and also ability of the drug to accumulate in the skin.4 This symptoms are more related to vincristine

Vincristine belongs to a group of drugs called the vinca alkaloids. They are found in the Madagascar periwinkle. They are inhibitors of mitosis in metaphase hence are M-phase specific. They bind to tubulin and inhibit the mitotic spindles forming. Vinca alkaloids can cause dose related neurotoxicity. It normally presents as peripheral paraesthesia (numbness, tingling, and pain).14, 15

The summary of product characteristics recommends that the maximum weekly dose for vincristine is 2mg. Any more than 2mg could be potentially very serious or even fatal. It could cause extreme bone marrow suppression and peripheral neuropathy. This patient is taking 6.4mg weekly which is the main reason why she is experiencing severe burning in her extremities.15

Dexamethasone is synthetic glucocorticoids which acts by inhibiting the action of inflammatory mediators and suppresses the humoral immune responses. In multiple myeloma dexamethasone inhibits the mRNA expression of interleukin-6 (IL-6) in myeloma cells. Myeloma cells produce IL-6 and express its receptor. Hence IL-6 is considered to be a mediator of plasma cell proliferation. It was found that dexamethasone may induce a plasma cell apoptosis by blocking the IL-6 connections.16 There have been very progressive studies that show that dexamethasone can reduce the cancer’s proliferating ability by up to 25-40%. It has also been show to increase the sensitivity of the cancer to other chemotherapeutic agents. So it is very important to keep taking it during the chemotherapy.16, 17

The errors will be based and classified according to the flow chart in figure 1 above

PRESCRIBING PROCESS

Errors that contributed are

Rule based error: The physician wrote the dose as ‘9.0mg/m2/day’. Prescribing guidance in the BNF states that ‘the unnecessary use of decimal points should be avoided, e.g. 3 mg, not 3.0 mg The dose is not wrong but it has been documented and advised against using decimal points when writing doses because the decimal point could be overlooked or not imprinted properly which could cause a patient to be given 10 fold increments.

An appropriate way would be ‘Doxorubicin 9mg/m2/day continuous infusion on Days 1-4’

Illegible handwriting and Clear instructions: looking at the prescription it seems quite obvious that the Vincristine should be divided into four doses for each day, but if the word ‘over’ was not written clearly or smudged, it could indicate 1.6mg every day. The ISMP guidelines also state that when prescribing for chemotherapy ‘Individual single daily doses in mg/m2 and the final calculated dose in mg should be stated.5

An appropriate way would be to add additional instructions to clarify the request.

‘Vincristine 1.6mg continuous infusion over Days 1-4 (0.4mg/day)’

Same could be said for the Dexamethasone; this would help to clarify instructions

‘Dexamethasone oral 40mg/day on Days 1-4, 9-12 and 17-20 (total of 12 days treatment)’

A patient with heart failure has an ejection fraction of 40% or less. One point for the physician to consider was the patient previous ejection fraction which was 50%. Although the patient’s starting ejection fraction before the chemotherapy was not given, it would be fair to say that it probably was a lot higher than 50%. Coupled with the fact that the patient is 60 years old. It might have been worth considering other treatment options due to cardiotoxicity.

DISPENSING PROCESS

Knowledge based and memory based errors

The pharmacist should have previous knowledge of

Potential cardiac toxicity of doxorubicin, hence should have calculated the dose that the patient had received up till day to ensure that the patient is not in the risk zone.

Dose recommendations of VAD cycle 1.6mg of Vincristine is normally given over 4 days rather than per day and

The Dexamethasone is give every 4days throughout the cycle

Rule-based errors

Good rules not applied or misapplied

It is good practice to check patient previous drug history to be able to highlight drug or dose changes. If the pharmacist had checked that the patient had received it 5 times before, the 90mg overdose would have been spotted.

The prescription was not crosschecked appropriately because it would have also been spotted that 8 days worth of Dexamethasone was not dispensed

Bad rules

The pharmacist did not query the prescription to confirm the dose of doxorubicin or vincristine. It was just ignored and all the precautions to check for safety of a drug were ignored.

Most nurses or another pharmacist know the drugs very well and another way of checking could have been to ask.

Action based errors

Technical errors

The inability of the pharmacist to spot that the doctor has written the Dexamethasone for 8 more days.

The pharmacist missed that the vincristine dose was over 4 days

The decimal point was not spotted in the doxorubicin dose.

Prevention of dispensing error6

Error reporting is important in both detection and prevention: This will help pharmacists, dispensers and technicians to be very careful when dealing with such prescriptions.

Pharmacovigilance is the process of monitoring, evaluating and improving the safety of medicines. It can be carried out from the stage of manufacturing till the administration of the medicine. It also involves detecting, assessing, understanding and preventing the adverse drug

Education: In pharmacy constant education and refresher courses are required to keep up to date with various changes and also to listen to case reports, events or reminders of drugs and their effects.

Computerized systems can contribute to prevention as well as detection: Computer programmes with alerts related to the drug and patient will definitely help with identification and clarification of suspect doses.

Most importantly Standard Operating Procedures should be outlined for every one working in the pharmacy to follow in order to dispense

Examples of medication errors that have been documented and implemented on are

Wrong formulation

A 41-year-old woman with a medical history of proliferative glomerulonephritis from systemic lupus erythematosus was admitted with a diagnosis of cryptococcal meningitis. Her physician prescribed liposomal amphotericin B 5mg/kg/day. She was given amphotericin B deoxycholate 5mg/kg.

The error was notice after she had already had two doses before it was stopped. She developed acute renal failure, anaemia and cardiac arrthymias. The patient was transferred to intensive care despite trying to reverse the toxicity she died six day after admission. 9

Another incident about confusion with amphotericin formulations occurred at Birmingham Heartlands Hospital in July 2007. Two oncology patients died after being treated with the wrong formulation of IV amphotericin. This confusion between the formulations can lead to an overdose resulting in fatality. It said that there had been 53 incidents involving the drug between January 2004 and July 2007.10

Amphotericin B deoxycholate has been reported to produce significant cardiac toxicity (arrhythmias and bradycardia) in adults and children with a history of heart disease and also renal toxicity in overdose.

The NPSA was alerted about these two recent fatal incidents that were reported to the National Reporting & Learning System. Prior to this there have been reports of confusion between the different formulations. In response to this The NPSA issued a Rapid Response Alert to make health care professionals aware of this confusion and to be very careful when prescribing, dispensing or administering this medication.11

Wrong/unclear dose or strength, or wrong frequency

An overdose of Diamorphine was administered by a by an out of hours GP from Germany to Mr David Gray who unfortunately passed away. The NPSA previously published guidelines on the ‘safer use of injectables’ and ‘Ensuring safer practice with high dose ampoules’ but these was not implemented in a large amount of the NHS trusts. When this case was investigated it was noted that previous incidents that have been reported showed that some healthcare professional did not access the suitability and safety of the opioid doses prescribed.12

The NPSA issued another rapid response report ‘reducing dosing errors with opioid medicines’ which include guidelines to aid prescribers in assessing the needs of their patient and prescribe opioids appropriately.13

Conclusion

Medication errors are very common at every stage from prescribing to administration. It is important to be away of the error prone lists, recorded near misses an adverse evnts in order to prevent recurrence but most importantly to keep the patient safe.