Caffeine is the most frequently used psychoactive stimulant worldwide. It is a naturally occurring central nervous system (CNS) stimulant of the methylxanthine class. This medication is most often obtained from coffee beans, but it is also found naturally in some types of tea and cacao beans. It is also used as an ingredient in soft drinks and energy beverages. Caffeine's principal purpose is to counteract weariness and sleepiness, although it has several other applications.

According to a research released by the US Food and Drug Administration (FDA), the typical adult drank around 300 mg caffeine per day between 2003 and 2008, with teens ingesting approximately 100 mg/d. Caffeine is unlikely to cause acute medical issues at amounts found in food and beverages; nevertheless, a shifting market in which energy drinks are not subject to FDA regulatory requirements has increased worries about caffeine-related health risks.

Caffeinated energy drinks' increasing popularity over the last decade has generated fresh worries about their influence on public health. Energy drinks, as indicated above, contain significantly more caffeine than traditional cola beverages, with caffeine levels ranging from 75-300 mg per cup. Caffeine-containing substances such as guarana, kola nut, or yerba mate are also common.

Caffeine has different CNS, cardiovascular, and metabolic effects depending on how much is consumed. Caffeine dosages of 85-250 mg (the equivalent of 1-3 cups of coffee) may provide sensations of alertness, reduced tiredness, and easier thinking flow. High dosages (250-500 mg) might cause agitation, anxiety, sleeplessness, and tremors. Caffeine, at large amounts, can produce a hyperadrenergic syndrome, which can lead to seizures and cardiovascular instability. 

What is Caffeine?

Caffeine's primary mechanism of action in the brain is through adenosine receptors. It easily penetrates the blood-brain barrier because it is both fat and water-soluble, resulting in antagonism to all four adenosine receptor subtypes (A1, A2a, A2b, A3).

Adenosine receptors are found throughout the body and are not exclusive to the CNS. Direct blockade of receptor A1 leads in favorable inotropic effects in heart muscle. Similarly, adenosine receptor antagonism promotes catecholamine release, adding to caffeine's systemic stimulatory effects and further increasing cardiac inotropy and chronotropy. 

Caffeine controls vascular tone by a complicated interplay that involves direct inhibition of vascular adenosine receptors to promote vasodilation and stimulation of endothelial cells to produce nitric oxide.

This action relaxes the vascular smooth muscle cells much further. This vasodilation is countered by an increase in sympathetic tone caused by catecholamine release and positive cardiac inotropic and chronotropic effects, resulting in vasoconstriction.

Because numerous constriction and dilation mechanisms are at work, the total effect is personalized and depending on caffeine dosage, frequency of usage, and comorbidities such as diabetes or hypertension. Caffeine appears to raise systolic blood pressure by 5 to 10 mmHg in those who consume it seldom. However, there is little to no immediate impact on consumers.

Furthermore, adenosine receptor blockade increases medullary ventilator responsiveness to carbon dioxide, enhances central respiratory drive, and improves diaphragm contractility. Caffeine causes diuresis by increasing renal blood flow, glomerular filtration, and salt excretion. It also stimulates stomach acid secretion and gastrointestinal (GI) motility.

Caffeine is predominantly metabolized in the liver by the cytochrome P450 oxidase system, specifically the enzyme CYP1A2. Metabolism produces one of three dimethylxanthines, which include paraxanthine, theobromine, and theophylline, each having its own set of effects on the body. These metabolites are subsequently processed further and eliminated in the urine.

Caffeine has a half-life of around 5 hours in the normal adult. However, metabolism can be influenced by a variety of variables. When compared to nonsmokers, smokers' half-life is shortened by up to 50%. Pregnant individuals, particularly those in the third trimester, will have a half-life that can last up to 15 hours.

Due to decreased activity of cytochrome P450 enzymes and immature demethylation mechanisms, newborns will have a considerably extended half-life, up to 8 hours for full-term infants and 100 hours for preterm infants. Children above the age of 9 months will have elimination half-lives equivalent to adults. Patients with liver illness or those using cytochrome inhibitors will also have longer half-lives due to decreased enzyme activity. 

Caffeine causes a range of metabolic alterations, including hyperglycemia (via increasing gluconeogenesis and glycogenolysis), increased renal filtration, ketosis, and hypokalemia, in addition to its cardiovascular effects. Caffeine has a strong stimulatory effect on stomach acid production and GI motility.

Caffeine Absorption

Caffeine has approximately 100% oral absorption and is the most often used method of administration. Caffeine can be obtained from coffee beans, cocoa beans, kola nuts, tea leaves, yerba mate, and the guarana berry, or it can be ingested as a powder or tablet.

When taken orally, the onset usually takes 45 to 60 minutes and lasts 3 to 5 hours. When taken with meals, absorption is slightly slowed. It can be administered parenterally, which is a typical technique for treating newborn apnea of prematurity or post-dural puncture headaches.

Caffeine can also be absorbed rectally, insufflated, or breathed. In general, insufflation or inhaling is a kind of abuse with the goal of becoming high. These pathways result in much quicker absorption, generally within minutes, and avoid first-pass metabolism.

Although this method may result in a faster start of effect, many studies have indicated that caffeine inhalation has a lower bioavailability; roughly 60% to 70%. The length of action is reduced when taken this method.

Caffeine Coffee vs Tea

Caffeine levels in tea and coffee can vary substantially depending on the drink's origin, kind, and preparation ( 11 ). Tea leaves have a caffeine content of 3.5 percent, whereas coffee beans have a caffeine content of 1.1–2.2 percent. As a result, 1 cup (237 ml) of brewed coffee has more caffeine than a cup of tea. 

Energy drinks

Caffeine-containing beverages are known as energy drinks. The caffeine content in energy drinks can vary greatly, and the labels on the beverages may not always indicate the real caffeine content. Energy drinks may also contain sweets, vitamins, herbs, and supplements.

Energy drink manufacturers say that their products may boost alertness and improve physical and mental performance. This has contributed to the beverages' popularity among American teenagers and young adults. There is minimal evidence that energy drinks may increase alertness and physical endurance temporarily.

There is insufficient data to suggest that they increase strength or power. But we do know that energy drinks, due to their high caffeine content, can be hazardous. Furthermore, because they contain a lot of sugar, they might lead to weight gain and aggravate diabetes.

Caffeine bad for you

Caffeine, like other medicines or treatments, has a long list of negative side effects connected with its usage. Caffeine's side effects range from moderate to severe, and in some cases fatal, and are typically connected to the dosage ingested and an individual's sensitivity to the substance. 

The following are the most prevalent adverse effects. The most common causes of death include cardiac arrhythmia, hypotension, myocardial infarction, electrolyte abnormalities, and aspiration. 

• Mild

Anxiety, restlessness, fidgeting, sleeplessness, flushing, increased urination, muscular spasms or tremors, irritability, agitation, high or irregular heart rate, GI distress are all symptoms of anxiety. 

• Severe

1. Disorientation
2. Hallucinations
3. Psychosis
4. Seizure
5. Arrhythmias
6. Ischemia, and
7. Rhabdomyolysis

Caffeine withdrawal symptoms might occur if habitual users abruptly discontinue usage. These effects generally appear 12 to 24 hours after the previous intake, peak in 1 to 2 days, and can continue up to a week. 

Caffeine withdrawal can be avoided if it is gradually reduced rather than suddenly stopped. If symptoms do occur, they can be quickly reversed by re-administration of caffeine.

Caffeine Toxicity

When acute caffeine ingestion is suspected, the history should address the following:

• Use of prescription medications or over-the-counter (OTC) drugs
• Use of illicit drugs
• Recent caffeine ingestion 

Caffeine generates a particular toxidrome (caffeinism) when used in excess over a lengthy period of time. This toxidrome consists largely of the following features:

• Central nervous system (CNS): Headache, lightheadedness, anxiety, agitation, tremulousness, perioral and extremity tingling, confusion, psychosis, seizures
• Cardiovascular –Racing heart rate and chest pain
• Gastrointestinal (GI) – Nausea, vomiting, abdominal pain and, diarrhea

CNS findings on physical examination include the following:

• Anxiety, agitation
• Tremors
• Seizures
• Altered mental status
• Dilated Pupils 

Epidemiology of Caffeine poisoning

Caffeine poisoning is a very common toxicologic emergency, with the number of instances gradually increasing over the last decade. The Substance Abuse and Mental Health Services Administration (SAMHSA) reported a 10-fold increase in the frequency of emergency department visits involving energy drinks from 2005 to 2009. 

More over half of the visits by patients aged 18 to 25 involved the use of energy drinks in conjunction with alcohol or other substances.

Caffeine is the most widely used drug in the world, and it is taken by people of all colors and ethnicities. Additional age-related problems occur as a result of the marketing of numerous energy drinks to youth and youth-related activities, such as extreme sports. Students and athletes frequently consume them in order to improve their performance.

Diagnosis of Caffeine Toxicity  

Laboratory tests are not recommended in hemodynamically stable individuals with minor symptoms and a documented history of caffeine intake. Patients with moderate-to-severe caffeine poisoning symptoms should undergo laboratory testing. The following studies may be useful:

• Complete blood count (CBC)
• Serum electrolyte, glucose, blood urea nitrogen (BUN), and creatinine 
• Total creatine kinase (CK) concentrations
• urinalysis
• urine drug screen
• Serum ethanol concentrations and osmolality 
• Serum pregnancy test
• Thyroid studies
• Arterial blood gas analysis

There is no need for diagnostic imaging in hemodynamically stable individuals with relatively minor symptoms. In specific cases, the following research may be considered:

• Chest radiograph for patients with chest pain, fever, altered mental status, or respiratory complaints
• Computed tomography (CT) of the head for patients with seizures or altered mental status 

Electrocardiography (ECG) and telemetry monitoring should be performed on patients who have chest discomfort, palpitations, tachycardia, or an abnormal heart rhythm.

Management of Caffeine Toxicity 

In situations of minor ingestions, therapy is largely supportive. Prehospital treatment is largely supportive, and the majority of cases are resolved. The following are examples of emergency management procedures for more serious cases:

• ABCs (Airway, Breathing, Circulation)
• Management of hypotension
• Correction of arrhythmias
• Management of seizures 
• Correction of metabolic disturbances
• Treatment of prolonged vomiting
• In rare severe cases, hemoperfusion or hemodialysis

Consultations may involve a visit to a regional poison control center, a medical toxicologist, or a psychiatrist (once the patient is medically stable). Medically unstable individuals are hospitalized for the appropriate degree of treatment based on their clinical presentation.

Additional treatments may be required for more serious ingestions. Patients may require intubation to protect their airways from vomiting or changed mental state. Seizures can be prevented by using benzodiazepines. If intravenous (IV) fluid resuscitation alone fails, patients may require vasopressors to battle persistent hypotension.

Either phenylephrine or norepinephrine should be used as the first-line vasopressor. However, because of its pure alpha agonism as well as reflex bradycardia, phenylephrine is the best choice. Magnesium with beta-blockers can be utilized to treat hyperadrenergic-induced cardiac arrhythmias.

In numerous case reports, the beta-1 selective blocker esmolol has been utilized effectively for this reason. In the case of a fatal arrhythmia, patients will require defibrillation and resuscitation in accordance with ACLS protocol. Activated charcoal, intralipid infusion, and hemodialysis can all aid in preventing additional metabolism and the consequences of caffeine overdose.

Prognosis of caffeine toxicity

Caffeine toxicity is uncommon, although it has resulted in death owing to dysrhythmias, seizures, and aspiration of emesis. Caffeine dosages more than 10 g orally can be deadly in humans. A daily consumption of 400 mg roughly four or five cups of coffee is considered acceptable for adults.

Caffeine-induced ventricular dysrhythmias that are resistant to advanced cardiac life support (ACLS) procedures been described in rare situations. In general, individuals with caffeine toxicity who reach a medical institution and can be maintained through the acute phase have a favorable prognosis.

Contraindications Caffeine

Although caffeine has no absolute contraindications, there are several medical situations in which caution is advised, including:

• Severe anxiety
• Cardiovascular disease 
• Peptic ulcer disease or gastroesophageal reflux disease
• Hepatic impairment
• Renal impairment
• Seizures 
• Pregnancy

Caffeine effect on blood pressure

Caffeine is a vasoconstrictor, which means it shrinks blood vessels and raises blood pressure. Caffeine works by interacting with several receptors in the brain. Other chemicals in coffee, such as antioxidants, are thought to protect blood arteries, according to experts. 

Monitoring

Caffeine's typical daily dosage for humans is 2.4 mg/kg; however, daily doses of up to 400 mg are regarded safe. Caffeine consumption of 100 mg raises blood levels by 5 to 6 mg/L on average. At doses of 80 mg/L, there have been instances of acute intoxication resulting in abnormal mentation, vomiting, and hypotension.

Caffeine is delivered at a loading dosage of 20 mg/kg, followed by 5 to 10 mg/kg per day of caffeine citrate through enteral or parenteral routes, with therapeutic index targets ranging from 5 to 25 mg/L.

Caffeine dependency and withdrawal

Caffeine, like many other medications, may be developed into a tolerance. This implies you grow accustomed to its effects on your body and require higher doses to attain the same outcomes. Caffeine may become physically and mentally dependent on you over time in order for you to operate successfully.

If you are caffeine addicted and quit using it, you may have withdrawal symptoms. These might include:

• Fatigue
• Persistent headache
• Sweating
• Muscle pain
• Anxiety.

Caffeine withdrawal symptoms might appear within 12 to 24 hours and continue for up to seven days. The simplest approach to overcome your caffeine addiction is to gradually lower the quantity you consume. This allows your nervous system to adjust to life without the medication.

Caffeine for children, pregnant women and athletes 

Children

Caffeine use should be explored if children exhibit symptoms such as irritability, difficulty to sleep, disturbed sleep, or stomach problems. Caffeine may be found in a variety of soft drinks and chocolate, in addition to coffee and tea. Energy drink usage should also be properly monitored.

Caffeine pregnancy

If you are pregnant, limit your caffeine intake to 200mg or less per day, or avoid it entirely. Caffeine use of more than 400 mg per day during pregnancy is associated to lower birth weights owing to intrauterine development restriction, an increased risk of miscarriage, but not preterm delivery. However, the evidence linking low birth weight with miscarriage is still murky and has to be looked into further. Caffeine is classed as a pregnancy class C medicine.

Athletes

Caffeine is not a prohibited drug and is classified as a Group A drug by the Australian Institute of Sport, which means it is "supported for use in particular conditions in sport" and "given or authorized for use by selected athletes according to best practice guidelines."

Medical indications of caffeine 

Caffeine has been approved by the FDA for the treatment of prematurity apnea as well as the prevention and treatment of bronchopulmonary dysplasia in preterm babies. Caffeine's non-FDA authorized applications include relieving migraine headaches and post-dural puncture migraines, as well as improving athletic performance, particularly in endurance sports.

Caffeine has been linked to lower all-cause mortality. It is also being studied for its effectiveness in treating depression and neurocognitive impairments such as those observed in Alzheimer's and Parkinson's disease.

How much caffeine is okay each day?

In the United States, the Food and Drug Administration (FDA) presently permits only drinks having less than 0.02 percent caffeine, while caffeine powder, which is sold as a nutritional supplement, remains unregulated.

Caffeine affects you differently depending on your body mass, health, and metabolism. It also depends on whether your body is accustomed to receiving regular amounts of caffeine and how much caffeine is in one dosage. According to research, 400mg of caffeine per day or less is an appropriate dosage for the general population.

Approximate caffeine levels per serve include:

• Chocolate drinks: 5–10mg per 250ml
• Instant coffee: 80–120mg per 250ml
• Espresso coffees: 105–110mg per 250ml
• Percolated coffee: 150–240mg per 250ml
• Decaffeinated coffee: 2–6mg per 250ml
• Black tea: 65–105mg per 250ml
• Milk chocolate: – 10mg per 50g serve
• Dark chocolate: 40-50mg per 55g serve
• Cola drinks: 40–49mg per 375ml
• Energy drink: 160mg per 250ml
• Red Bull energy drink: 80mg per 250 ml

Conclusion 

Caffeine intake in moderation is reasonably safe. The issue is that many individuals nowadays use high-energy beverages containing huge amounts of caffeine, which might cause difficulties. Caffeine poisoning has been exacerbated in recent years by the popularity of high-energy beverages.

These highly caffeinated beverages are not only hazardous in and of themselves, but the problem is compounded when combined with other illegal substances such as cigarettes and alcohol. Many people have died as a result of consuming such mixtures in recent years, according to reports.

To get the best outcomes while dealing with caffeine toxicity or side effects, or when utilizing caffeine therapeutically, an interdisciplinary healthcare team is required. In order to avoid toxicity during therapy, inquire with the patient about alternative potential caffeine sources. 

Patients may be ignorant of the caffeine content of different goods (energy drinks, herbal medicines, alertness-promoting drugs), as well as the negative side effects associated with these treatments. Patients in the emergency department or other health care settings who appear to be experiencing caffeine-related symptoms should be advised to restrict their caffeine intake and avoid intense caffeine sources.

Clinicians, nursing personnel, and pharmacists must be prepared to counsel patients who may have overindulged in caffeine. While there are no definite contraindications to caffeine, the general population should avoid it if they have heart problems, panic disorder, anxiety, or increased stress levels. This message is best communicated through an interprofessional team.