Question 1 James Miller is a 37-year-old builder who visits your pharmacy following a pain in his lower back. He has previously been taking co-codamol 8/500 Two tabs QDS for the last week and would like to take something stronger as he is still in pain. He is usually fit and healthy as he remains active. He takes no other medication.a) Discuss how the questions that you ask will help you determine which treatments (including formulation) would be appropriate for Mr miller to take. (40% of marks)According to (Addison et al., 2012), it is important to distinguish between acute and chronic pain in patients to give the correct treatment. This is done by asking how long the episodes of back pain last and if the back pain is continuous. According to (Cleveland Clinic, 2017) “Chronic pain is pain that is ongoing and usually lasts longer than six months”. Furthermore, knowing how severe the pain is can help you differentiate between chronic and acute. Moreover, asking if Mr James Miller back pain stops him from carrying his normal day to day activities or oblige him to take time off work suggests how severe the pain is. If Mr Miller is not self-employed, has he thought about raising this issue with his manager? Whom might help address the issue by asking Mr James Miller to avoid the activities that trigger his back pain. Mr Miller could also attend an occupational health assessment where a physician gives him advice on adjustments to his work that ensures a safe and healthy work environment.If the patient is experiencing chronic pain then the RICE (Rest, Ice, Compression and elevation) and analgesia would not work, instead the patient should be referred to a GP to rule out some chronic conditions such as osteoarthritis. NSAIDs such as ibuprofen, give musculoskeletal pain relief caused by inflammation. NSAIDs can be used on their own or with other treatments. They may be combined with opiates to reduce side effects of each drug, this is because “…less of each drug can…be given with the same degree of analgesia produced.” (Dale et al., 2012).I would refer the patient to a GP as he has been experiencing pain in his lower back for a week whilst using oral NSAIDs. In the meantime, I would give Mr James Miller 30 grams of Voltarol 1.16% Emulgel (diclofenac diethylammonium 11.6?mg per 1?gram), this is to be used for short term (Excellence, 2019).Word count: 308He later visits his GP and is diagnosed with Osteoarthritis who prescribes Ibuprofen Tablets 400mg TDS to be taken regularly, Co-codamol 30/500 Two QDS to be taken when required, and Voltarol gel to be applied BD when requiredb) Outline the mechanisms of action for Mr Miller treatments. Discuss how the pharmacology of NSAIDS and opiates influences the therapeutic benefits and potential side effects. (60% of marks)According to (Dale et al., 2012), there was a discovery in 1971 that suggested that NSAIDs work by inhibiting arachidonic acid oxidation as a result of the inhibition of the COX enzymes. This therefore, inhibits the production of prostaglandins and thromboxanes. “There are two types of COX enzymes, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining.” (Annette (Gbemudu) Ogbru, 2019). Ibuprofen and Voltarol gel are examples of NSAIDs that are a weakly COX-2 selective. They inhibit COX-2 enzyme which decreases the production of prostaglandins and hence reduces pain. Like with every medicine, Ibuprofen has side effects, (BNF, 2018), the most common are, fluid retention, gastrointestinal disorders, haemorrhage, intraventricular haemorrhage, neutropenia, periventricular leukomalacia, renal impairment, and thrombocytopenia. This is due to the inhibition of the COX enzyme.Similarly Opiates reduce pain, they do this by mimicking the effect of endogenous opioids that our body naturally produces; which can be classified into endorphins, enkephalins, and dynorphins. As stated in (Dale et al., 2012), they do this by binding to one of the opioid receptors (an example of G- protein coupled receptor) and activate them. The opioid receptors are found on pain signalling neurones. When opiates are taken, molecular and chemical changes occur that prevent these neurones from sending signals to each other, and therefore stopping the sensation of pain. This is done by inhibiting the presynaptic knob from producing neurotransmitters and the postsynaptic knob from depolarising. When an opiate bind to the opioid receptor at the presynaptic knob, a G protein is activated and is separated into two sub units, the alpha subunit and the beta-gamma subunit. The beta- gamma subunit attaches to the neighbouring voltage- gated calcium channels, which providentially prevents them from opening. Consequently, if there is an action potential, calcium channels are uncapable of opening, and therefore calcium ions do not flow into the neurone and hence, neurotransmitters are no released into the synaptic cleft. Similarly, opiate bind to the opioid receptors on postsynaptic knob, and the same mechanism is carried out. This time, the beta- gamma subunit binds to the potassium channel which forces the channels to open. Thus, the potassium ions flow out of the postsynaptic knob. For this reason, depolarisation cannot occur. On the other hand, the alpha subunit inhibits the enzyme adenylyl cyclase which inhibits cAMP which causes a change of signalling.In reference to the (BNF, 2018), some of the most common side effects of co-Codamol is abdominal pain, addiction, agranulocytosis, blood disorder, irritability, pancreatitis, restlessness, severe cutaneous adverse reactions (SCARs), and thrombocytopenia. This is due to the inhibition of voltage gated calcium channels, and the opening of the potassium channels.Word count: 476Question 2 Ibuprofen is administered orally for the relief of pain and inflammation. In recent years, there have been a large number of “fast acting” ibuprofen formulations appear on the market, using several different formulation strategies. For instance, ibuprofen is available as “Anadin” 200 mg tablets and as fast acting “Anadin LiquiFast” (200mg liquid-filled capsules).a) Explain why ibuprofen in liquid-filled capsules is expected to have a more rapid onset of action than conventional tablets. Your answer should give an overview of the oral absorption of ibuprofen, and justify the difference between the two formulations with pharmacokinetic data where appropriate. (70 % marks)Medicines are absorbed when entering the blood stream, the level of absorption can affect the speed and the quantity of the drug at the site of action, this known as bioavailability. If a medicine releases a drug too quickly, blood levels may become too high, whereas slow release results in low levels of absorption. The properties of the drug and the human physiology, pH levels in the stomach and speed of emptying can affect absorption and bioavailability. Therefore, different formulation can be used to release the drug at the desired speeds. Tablets and capsules are two types of formulations.Drugs that are orally administered “…pass through various parts of the enteral canal, including the oral cavity, esophagus, and various parts of the gastrointestinal tract” (Shargel, Wu-Pong and Yu, 2004). The total amount of time for the drug to be absorbed, distributed and metabolised and excreted is from 0.4 to 5 days.A capsule has a gelatine layer that is broken down as soon as it becomes wet which enables the drug to be released faster, whereas a tablet first needs to travel down the oesophagus and into the stomach where it gets broken down by the acid in the stomach into smaller particles. This is the reason for a faster rate of absorption in capsules than tablets.Both capsules and tablets particles will travel into the small intestine which takes between 4 to 5 hours, where most of them would be absorbed into the blood. The lumen of the small intestine has a microvilli structure that increases surface area and allows fast absorption. When the drug such as ibuprofen reaches the blood stream it binds to a protein molecule called Albumin. Different drugs bind to albumin in different amount depending on their affinity to plasma proteins. All the ibuprofen molecules bound to albumin would be filtered out as they pass through the liver, and the remaining molecules would remain in the blood stream and have affect on the body. The ibuprofen rich blood will enter the liver from the hepatic portal vein at the bottom and will exit the hepatic vein at the top. More of the ibuprofen would be removed by a process called first past metabolism. This is done in two phases, during phase 1, ibuprofen is hydrolysed and then an ionised group is added in phase 2. This is water-soluble and therefore easily secreted in urine. A more finite amount of the ibuprofen is left to treat the sites of pain and inflammation. The remaining drug in the blood stream goes through the first pass metabolism several times until it is all excreted via the kidneys and the bladder.Word count:437Ibuprofen is also available as a transdermal gel (e.g. Ibuleve Maximum Strength) for the management of musculoskeletal pain. Each application of gel contains between 50 and 125 mg of ibuprofen.b) Discuss why a smaller dose of ibuprofen may be used in the transdermal gel than in the oral tablets for the management of muscular pain. (30 % marks)Tablets are given at a higher dosage because most of the drug gets filtered during the fast pass metabolism and therefore excreted and not used by the body. Whereas, topical administrations such as gels diffuse passively into the blood stream via the skin. Since it is more concentrated on the affected skin, it is more affective. The transdermal gel also has a bioavailability of 100% as it does not go through first pass metabolism, unlike ibuprofen tablets where it “…is rapidly absorbed from the gastrointestinal tract with a bioavailability of 80-90%.” (Medicines.org.uk, 2019)Word count: 91ReferencesAddison, B., Brown, A., Edwards, R. and Gray, G. (2012). Minor illness or major disease?. 5th ed. London: Pharmaceutical Press, pp.77,78-79,83-86,.Annette (Gbemudu) Ogbru, M. (2019). COX-2 Inhibitors Drug Class Information on RxList.com. [online] RxList. Available at: https://www.rxlist.com/cox-2_inhibitors/drugs-condition.htm [Accessed 29 Jan. 2019].BNF. (2018). 76th ed. London: BMA, pp. 1107, 447.Cleveland Clinic. (2017). Acute Pain vs. Chronic Pain | Cleveland Clinic. [online] Available at: https://my.clevelandclinic.org/health/articles/12051-acute-vs-chronic-pain [Accessed 23 Jan. 2019].Dale, M., Rang, H., Ritter, J., Flower, R. and Henderson, G. (2012). Rang & Dale’s pharmacology. 7th ed. Edinburgh: Elsevier, Churchill Livingstone, p.318-319,512-514, 521.Excellence, N. (2019). DICLOFENAC SODIUM | Medicinal forms | BNF content published by NICE. [online] Bnf.nice.org.uk. Available at: https://bnf.nice.org.uk/medicinal-forms/diclofenac-sodium.html#PHP77530 [Accessed 1 Feb. 2019].Gibson, G. and Skett, P. (2001). Introduction to drug metabolism. Cheltenham, UK: Nelson Thornes Publishers, pp.1-13. (Gibson and Skett, 2001)Medicines.org.uk. (2019). Ibuprofen 200 mg film coated tablets – Summary of Product Characteristics (SmPC) – (eMC). [online] Available at: https://www.medicines.org.uk/emc/product/7351/smpc [Accessed 1 Feb. 2019].Shargel, L., Wu-Pong, S. and Yu, A. (2004). Applied biopharmaceutics & pharmacokinetics. 5th ed. New York: Appleton & Lange Reviews/McGraw-Hill, Medical Pub. Division, p.384.Overall word count: 1312