Fentanyl – Drug Profile and Specific and Drug Abuse

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Table of Contents

Introductory Concepts
Over-The-Counter & Complementary and Alternative Medicines
Signal Transduction Mechanisms for Receptors
Review of Two Peer-Reviewed Articles
Fentanyl Metabolism
Sources of variability in drug metabolism
Drug-Drug Interactions
Answers
References

Introductory Concepts

Fentan is a pain relief drug for relieving pain for breakthrough patients suffering from cancer. The chemical name for the drug is Fentanyl. The generic name for the drug is Fentanyl Citrate, while its brand name in Australia is Sublimaze. The administration of the drug is through an injection into a muscle. Similarly, its administration can take place as a slow injection into a vein. The dosage is dependent on the patient’s condition or response. Long-term use of fentanyl can result to dependency. The drug has several side effects such as drowsiness, nausea, constipation, vomiting, sweating, as well as difficulties when sleeping. It is advisable to seek medical attention when these symptoms persist. In some instances, patients may have vision problem, difficulty urinating, hallucinations and unusual slow breathing. Patients who show such symptoms should inform their doctors promptly.

In addition, symptoms such as itching, rash, difficulty in breathing, severe dizziness are fatal and patients having such symptoms should get urgent medical attention (Davidson 2009). Patients should inform their doctors regarding their medical history such as; heart problems, head injury, history of alcohol dependency, low-blood pressure, allergies, as well as liver and kidney disorders among others. Patients who take alcohol should consult their doctors about the use of alcohol while taking the drug. Similarly, it is important for mothers to be aware that fentanyl passes into breast milk and thus, nursing mothers should avoid taking fentanyl as the drug can have serious effects on the child. Equally, pregnant women should take fentanyl only in unavoidable situations. Lastly, patients should inform doctors of all prescription and nonprescription medication they are using and mainly other narcotic pain relievers, painkillers, tranquilizers, antidepressants, as well as MAO inhibitors to get appropriate advice on how to use fentanyl (Brodsky 2000).

Fentanyl is for relieving pain for patients who are suffering from acute pain. In addition, it helps in depressing breathing in patients who are being ventilated. Moreover, doctors use fentanyl as an infusion under the skin in palliative care providers who suffer from intolerable side effects from morphine.

Over-The-Counter & Complementary and Alternative Medicines

A list of conventional over-the-counter (OTC) medicines, complementary alternative medicines (CAMs) and prescription medicines, which undergo clinically relevant interactions with fentanyl drug such as; codeine, hydromorphone, hydrocodone, morphine, oxycodone and methadone.

The source of the information about medicines that show relevant clinical interactions with fentanyl is from Everyday Health website that contains education information concerning various medical issues. The source of the information is trustworthy as a source for relevant and accurate information for education purpose.

Signal Transduction Mechanisms for Receptors

Fentanyl is usually an opioid analgesic drug. It intermingles generally with the opioid mu-receptor, and it joins to kappa delta-type opioid receptors. The mu-binding spots are in various locations such as the spinal cord, human brain, as well as other tissues. Fentanyl exerts its pharmacologic impacts on the central nervous system. The main function of fentanyl therapeutic value is sedation and analgesia. The drug acts by increasing the patient’s lenience for pain and lessening the sensation of distress even though pain remains (Baron 2009). Besides the existence of analgesia, patients indicate signs of mood changes, drowsiness, dysphoria, and euphoria. The drug has the effect of depressing the respiratory center, constricting the pupils, as well as depressing the cough reflex. There are opiate receptors, which possess G-protein receptors that play the role of positive and negative controllers of synaptic transmission (Maurer, Sauer & Theobald 2006, p. 449). Consecutively, the joining of the opiate arouses the exchange of GTP for GDP on the G-proteins complex. The Effector mechanism is adenylating cyclase and cAMP placed at the interior facade of the plasma membrane (Maurer, Sauer & Theobald 2006, p. 449). The opioid reduces intracellular cAMP by inhibiting adenylate cyclase. Furthermore, the release of nociceptive neurotransmitters like substance P, Gaba, acetylcholine, as well as noradrenaline is stopped. Similarly, opioids likewise, inhibit the release of vasopressin, insulin, somatostatin, as well as glucagon. The analgesic activity of fentanyl is associated with its dependant inwardly rectifying potassium paths bringing in hyper-polarization, as well as decreased neuronal excitability (Saren and Brownlie 1983).

Review of Two Peer-Reviewed Articles

Many scholars have researched the effectiveness of the fentanyl drug in human beings. Freye (2008) has done a research about the effectiveness of the drug in relieving pain in patients with breakthrough cancer pain. The author found that the drug has a higher success in reliving the pain for patients suffering from cancer than morphine sulfate immediate relief. The drug offers a novel delivery mechanism, which embarks on effervescence reaction to enhance buccal fentayl absorption. The research entailed a study of volunteers who suffered from breakthrough cancer pain and who were using fentanyl and morphine drugs. The article failed to indicate the sampling method as well as the number of participants that were played part in this study. However, the study entailed a randomized control trial. The next study entailed a study to show reaction of fentanyl with other drugs. The study comprised of a randomized control trial, which entailed a small sample of participants of 35 patients that represented 25 study participants and a control group of 10 patients (Davidson 2000).

Fentanyl Metabolism

About 25% of fentanyl administered gets absorbed from the buccal mucosa. The remainder 75% of fentanyl is swallowed and absorbed in G-tract. Following absorption, fentanyl is distributed to the brain, lung, heart, spleen and kidney. A little percentage is redistributed to muscle and fat. Roughly, not more than 7% and 1% of the fentanyl is excreted in its original status in urine and feces respectively. The metabolic of fentanyl are excreted in the urine. Most of the fentanyl taken is metabolized through cytochrome P450 3A4 isoezyme mechanism and excreted in urine. Metabolism of drug is important in enhancing the hydrophilic of xenobiotics in order to make their elimination by the kidney more efficient (Bowen 2005). The metabolism involves a chemical change that changes the shape and charge of the drug so that it is not in a position to attach receptor, as well as exert its effect on function of the receptor (Ghosh and Sidana 2012). Metabolism reaction of fentanyl occurs into two phases.

The phase I entail a series of reactions that makes the drug more hydrophilic, as well as offer functional group essential to initiate phase II reaction. Phase I takes place during fentanyl absorption either in the liver or gut. The metabolism in phase I is mediated by P450 cytocrome enzymes (Davidson 2000). Phase I metabolism is a fictionalization reaction, while phase II metabolism is a conjugation reaction. The end of phase I metabolism is marked by the initialization of phase II metabolism. Compounds that remain at the end of phase I go through phase II metabolism that entail conjugation with endogenous elements that is possible because of the presence of functional substances added in phase I. Phase II is also important in detoxification of reactive drug metabolites that are produced in phase I reaction. Glucuronide formation is essential in the elimination of endogenous substances such as steroid hormones, bilirubin and bile acid (Ronald 2008).

Sources of variability in drug metabolism

Enzyme induction results when hepatic blood flow rises or because of the stimulation of the CYP450 enzymes. Fentanyl drug causes enzyme induction. In addition, enzyme induction depends on the age and liver diseases. Induction of enzyme causes increased synthesis of CYP 450 resulting in decreased duration and intensity the fentanyl drug. The presence of inducers enzyme can augment the creation of toxic metabolite and raise the danger of hepatotoxicity and harm of liver and kidney (Amsel 1992).

Drug-Drug Interactions

According to Hegde (1980), taking some drugs together with fentanyl may bring in detrimental complications. Some of the complications can enhance a patient’s risks for side effects such as memory loss, difficulty breathing, as well as drowsiness (Burton 2008). A patient who is taking fentanyl should avoid using alcohol, beta-blockers, as well as amphetamines, alvimopan (Kubasek 2012). Many drugs that or therapeutic purposes use lipophilic that enhance their movement via the biological membrane. Nonetheless, their secretion from the body is slow and require conversion into water-soluble through phase I and phase II metabolism before secretion (Boeree 1990). This process entails the use of CYP enzymes. The use of fentanyl drug together with other drugs such as amphetamines causes CYP inhibition. It is important for physicians to understand the drugs that result to fentanyl inhibition to facilitate multiple medications.

Primary metabolism of paracetamol takes place in the liver where it is metabolized into non toxic products. There are three pathways that are followed. Metabolic pathways refer to a number of chemical reactions taking place in series within a cell. The series of chemical reactions modify the original product to form another one. The pathways involved in the metabolism of paracetamol are glucuronidation, sulfation and N-hydroxylation and rearrangement. Glucuronidation takes 40% to 67% of the paracetamol metabolism. Sulfation is thought to take between twenty to forty percent of the metabolism. Lastly, the N-hydroxylation takes less than fifteen percent of the whole metabolism. In the metabolism, enzyme referred to as cytochrome P450 is involved. This process gives valuable product referred to as N-acetylimidoquinone. This is an alkylating metabolite which is later permanently conjugated together with groups of glutathione knowns as sulfhydryl. The above described pathways give nonreactive and non-toxic. These products are then removed from the body through the kidney. However, the product that is produced in the third pathway is toxic and account for the toxic impacts of paracetamol.

There are chemicals that might leads to liver injuries. These chemicals are referred to as hepatotoxins and cause a condition known as hepatotoxicity. In the metabolism of paracetamol, there is the production of the toxic metabolite, N- acetylimidoquinone. This product contribute to the hepatoxicity that is caused by paracetamol. The production of this toxic substance is caused by two enzymes of cytochrome P450. They are CYP2E1 and CYP2A2.

In cases where paracetamol is used excessively, it causes injuries to the liver resulting to failure of the liver. In severe cases, this may call for a liver transplant since the damage is beyond the control. Use of N-acetylcysteine is vital in the elimination of the paracetamol and supplanting glutathione. The acetylcysteine is a precursor of glutathione. This condition assists the body to produce enough glutathiones to prevent the destruction of the liver. It also neutralises N- acetylimidoquinone to make it non-toxic.

Opioid antagonist includes morphine, cordine, pethidine, codeine and fentanyl. They have the capability to induce analgesia, physical dependence, mood changes and tolerance. These among others prevent compulsive use of drugs. In their mechanism of action, they affect the peripheral nervous system and the central nervous system. In the case of the central nervous system, the opioids act on different areas including the spinal cord. Within the peripheral nervous system, they act on submucous and myenteric plexus. These are found in the gut’s wall, and they cause constipation. They also reduce inflammation in the peripheral tissues such as joints. In a bid to achieve this, the opioids act on the receptors found on the neuronal plasma membrane hence producing impacts on the neurons. There are 3 main kinds of opioids receptors which are mu, kappa and delta.

The physiological effects of opioids include;

Analgesia
Nausea
Sedation
Low concentration
Euphoria
Dry mouth
Pruritis
Fluctuations of body temperature
Experiencing the extremities of heaviness.

Naxolone is of the opioid antagonist used in the treatment of their overdose. In the pharmacological basis, the main action of naxolone is to attach itself to the opioid receptors especially with mu receptors. This is because naxolone harbors a greater affinity to bind with the opioid receptor than the opiates. When it binds with the opioid, it displaces the opiate molecule that was originally attached to the receptor. However, naxolone has a lesser affinity to the other two receptors. When it binds with the receptor it reverses the opiate action. According to pharmacokinetics, naxolone has a less effect when administered orally and acts fast if administered through the intravenous or intranasal route. The naxolone reverses the impact of opiate in duration of one to three minutes. However, the patient might re-encounter the impacts of the opioid once the naxolone is metabolized. This is because it has a smaller half-life than some other types of the opiates. However, it is still recommended in reversing the actions of the opiates (Drugs.com, 2011).

Answers

It has been found that an amiodarone reduces the clearance of warfarin in the human body. However, it does not change the amounts of distribution (Helmark et al, 1992). In addition, it inhibits the cytochrome P450 which catalyze the oxidation of anantiomers of the warfarin (Yun Lu et al, 2008). If the two drugs are used simultaneously, the inhibition of P4502C9 causes an anticoagulant effect.

A decrease in the amount of blood concentration is observed as an impact of the interaction of the St. John’s Wort and midazolam. The CYP 3A4 contains a herbal product that causes this effect. It also increases oral clearance. This interaction also leads to an increment in the rate of midazolam’s metabolism and hence the reduction of its effectiveness (Zhou et al, 2004).

In conclusion, drug abuse is one of the biggest draw back in the society. it prevents human and economic development all over the world. It should, therefore, be addressed with a lot concern.

References

Amsel, M 1992, ‘Drug Variability’. Journal of Medicine, vol.23, no. 2, pp. 67- 70.

Baron, S 2009 About Fentanyl, Palgrave, Macmillan New York,

Boeree, G 1990, ‘Drug-Interactions’, International Journal of Health, vol.43, no. 6, pp. 123-145.

Bowen, D 2005, ‘Drug Secretion and Metabolism’, International Journal of Medicine. Vol.5, no.3, pp.31-39

Burton, S 2008, Complications of Drug-Drug Interactions, Prentice Hall, New York.

Brodsky, N 2000, Fentanyl, Prentice Hall, New York.

Davidson, I 2009, Over-The-Counter & Complementary and Alternative Medicines for Fentanyl, Prentice Hall, New York.

Davidson, P 2000, Sources of variability in Fentanyl drug metabolism, Prentice Hall, New York.

Freye, E 2008, A new Transmucosal Drug Delivery System for Patients with Breakthrough Cancer Pin: The Fentanyl Effervescent Buccal Tablet, Journal of Pain Research, vol.2, no.5, pp. 13-20.

Ghosh, R & Sidana, D 2012, Transduction Mechanisms for Receptors for Fentanyl, Prentice Hall, New York.

Hegde, M 1980, Alcohol and Fentanyl, Journal of Medicine, vol. 23, no. 3, pp.5.

Kubasek, N 2012, Drugs Interactions, Prentice Hall, New York.

Maurer, HH, Sauer, & Theobald, DS 2006, ‘Toxicokinetics of drugs of abuse: Current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine’. Therapeutic Drug Monitoring, vol. 28, no. 3, pp. 447-453.

Ronald, H 2008, Drug-Drug Interactions, McGraw-Hill, Irwin.

Saren, M & Brownlie, D 1983, Renal Excretion of Fentanyl Drug and its Metabolites. Cambridge University Press, Cambridge.

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