Identify how the interaction of the drug with its molecular target(s) accounts for the major therapeutic effect (i.e. the effect you want the drug to cause in clinical practice; e.g. for paracetamol – pain relief).
Morphine is an opioid that binds with the opioid receptors at the spinal cord, medulla oblongata, the spinal trigeminal nucleus, and the grey region. The receptors onto which morphine binds are of mu (µ). Kappa and delta types, of these receptor types, µ are the most important for analgesia effects to be realized. There are two µ subtypes: the µ1 and the µ2 (Stoelting 1999, p. 96). The µ1 subtype is involved in analgesia more than the µ2, the second subtype, which is involved more in respiratory depression. In addition, the µ2 subtype is also involved in mediating bradycardia and physical dependence (Hasslesstrom & Sawe 2001, p. 349).
Include a Description of How the Drug Alters Function At the Cellular Level
The presence of Morphine activates the G-protein and this is important for it to elicit its effect within the cell. Upon being activated, the G protein alters the permeability at the neural receptors (Chay, Duff, & Walker 2002, p. 336). When the permeability is affected, neuronal activity is altered through hyperpolarization of the membrane. When neuronal activities stop, analgesia is initiated (Dolin 2000. p. 25). The opiate receptors at the Central Nervous System are the main areas where morphine acts. At the brainstem centers, hyperpolarization results in analgesia being achieved. Morphine directly affects respiratory activities, causing respiratory depression. (Bhandari, Bergqvist & Kronsberg 2005, p. 355).
The respiratory depression involves the reduction in the reception capacity of the human respiratory centers, which in turn inhibits their effective reaction to an increase in the amount of carbon dioxide as well as electrical stimulation (National Center for Biotechnology Information 2011, p. 2). Apart from the analgesic effect, morphine has also been found to affect the cough center, which then causes depression in the human cough reflex. The cough center is located in the human brain in the medulla. Here morphine causes a depressant effect when it binds to and interacts with the opioid receptors. When morphine is given in smaller doses, antitussive effects may occur in place of analgesia (Meldrum 2003, p. 2472).
Include a Description of How the Altered Cellular Function Manifests As a Change in Body System Function, and the Eventual Major Therapeutic Response
Orthostatic hypotension can be caused by morphine through peripheral vasodilatation. Morphine can also cause hypotension through the release of histamine. Some of the detectable features after morphine intake include histamine release, flushes, red eyes, and sweating. Morphine also affects the endocrine system through hormone secretion (Anand, Hall, & Desai 2004, p. 1680). The drug alters the secretion of Adrenocorticotropic hormone, cortical, and luteinizing hormone and this affects various body functions and activities.
Morphine also alters the immune system by reducing the secretion of various hormones responsible for enhancing immunity (Health Grades 2011). Morphine has elimination halftime of one and a half hours to four and a half. The bolus administration makes the onset time to be slow, taking between 15 to 30 minutes. The reason for this is that morphine has a low lipid solubility of about 2.5 % of Sublimaze. Morphine is a weak base with a pH of 8 and this makes it easy to ionize. The ionized form inhibits the passage of the drug through the lipid membrane (Stoelting & Miller 2000, p. 67). The extrahepatic clearance mechanisms are mostly renal due to the relatively high plasma clearance.
Morphine is demethylated and is converted to 3 and 6 glucuronide metabolites (Armstrong & Cozza 2003, p. 517). It is present in higher concentrations when the plasma concentration is at its highest. Morphine interacts with the receptors at the central nervous system and inhibits some neurotransmitter release. The neurotransmitters that are inhibited contribute to the sensation of numbness and pain reduction, which are required to achieve the therapeutic goal (Meldrum 2003, p. 2473). Since the activities at the neuronal membranes are reduced after intake of morphine, pain and other feelings are experienced to a lesser degree or eliminated.
When taken orally, the drug is absorbed through the stomach walls, after which it is secreted through renal means (Emergency Medical Paramedic 2010). A small amount of morphine components is excreted in the bile.
It is thought that the Delta receptors may be involved in the development of physical dependence on morphine. Care should be taken to avoid abuse since it may permanently impair the renal and hepatic functions if taken in large quantities.
Using 4 journal articles, critically review the evidence for the clinical effectiveness of your drug in humans. Your answer should identify and critique the
According to Trescot et al. (2008, p. 183), morphine, being an opioid, is not very effective in the treatment of non-chronic cancer. The research illustrated that the drug was weaker than previously thought and through gold-standard therapy; most patients were dissatisfied with morphine use as a pain reliever. The research was conducted from a review of past literature and the findings were against the use of morphine in the treatment of non-chronic cancer. Three systematic reviews were conducted.
Draisci et al. (2009, pp. 197-202) researched the effectiveness of morphine and intrathecal sufentanil in hyperbaric bupivacaine-based spinal anesthesia when performing a cesarean section. Using a sample size of sixty-four pregnant mothers, the drug combination was tested and through gold standard therapy, the combination was found to be very effective. The research was a double-blinded trial. Although there were many side effects, the treatment option seemed to work effectively.
Bijur et al. (2008, p. 195) also conducted a study on morphine to test its effectiveness and adverse events in males and females. According to the study, the response rate to the drug was tested on 211 women and 144 men. Through a comparison with a placebo agent, the blinded trial found that women with no baseline pain were more affected than men and that means a change in pain was nearly the same for both sexes. The drug can therefore say to be effective analgesia in all sexes.
Mika (2008, pp. 297-307) conducted a study to establish the best way to prevent morphine resistance. Some patients are resistant to morphine, but if microglia were used, there would be minimal resistance to morphine during treatment. The study concentrated on literature materials to develop a treatment model that would enhance the effectiveness of morphine in anesthesia. These studies show that morphine is an effective pain management drug. The study was purely based on literature review as its methodology with 136 sources being reviewed.
Workbook Learning
Five Clinical Signs in Someone with Highly Activated Sympathoadrenal Axis
- Increased arterial blood pressure
- Reduced vascular conductance in facial artery
- Increased heartbeat
- Hypertension
- Increased respiratory rate
Identify FIVE drugs whose primary pharmacological effect relates to action at the sympathetic nervous system and discuss briefly why each drug is clinically useful e.g. adrenaline increases heart rate and force of contraction and therefore can be used to treat cardiac arrest and as inotropic support in acute heart failure.
Adrenaline increases heart rate and force of contraction and therefore can be used to treat cardiac arrest and as inotropic support in acute heart failure.
Noradrenalin increases blood pressure and vasoconstrictors vessels very effectively. The drug can therefore be used in the treatment of hypotension.
Pseudoephedrine is a drug that causes vasoconstriction and it can therefore be effective in decongesting the nasal cavity.
Tetrahydrozoline is a drug that causes ophthalmic decongestion and can therefore be used to cure diseases like contact dermatitis and blepharitis.
Albuterol is a drug that causes bronchodilation and relaxing the muscles in the airways to increase airflow. It can be used in the treatment of asthmatic conditions
Complete the following table (in your template). For each drug, identify its primary molecular target and explain briefly the normal physiological function(s) of that molecular target. What is the pharmacological effect of each drug?
Write down the names of FIVE receptors from different classes and list their endogenous agonists in the second column.(2.5 marks)
In the third column to your table and give an example of ONE drug that is a clinically relevant selective agonist OR antagonist at each of the receptors. (5 mark)
Discuss The Clinical Significance Of Using A Selective Drug Compared To One Which Acts On Multiple Receptors
One of the benefits of selective drugs is that they do not affect systems of the body that do not have that receptor type (Armstrong & Cozza 2003, p. 518). This means that they target only the intended regions and protect the rest of the cells. Non-selective drugs act upon both the intended and unintended cells and this may cause increased complications.Describe Briefly The Molecular And Physiological Changes That Occur In Patients Taking isosorbide mononitrate
When isosorbide mononitrate is taken twice per day, it causes coronary artery dilation and venous dilation. In addition, it can cause hypotension and headaches. This is because the drug interacts with peripheral arteries and veins. It decreases venous return to the heart and causes a reduction in left ventricular pressures. Since it is a nitrate-class drug, the nitrates are released to enhance coronary artery dilation.
Oxymetazoline took for > 1 week as a topical sympathomimetic nasal decongestant. (5 marks)
The use of oxymetazoline causes vasoconstriction and reduces fluid exudation from postcapillary venules (Drugs Information Online 2011). In addition, the drug causes the heart rate to be altered by vasoconstriction. When the blood vessels are constricted in the nose and sinuses, the areas are drained and congestion decreases. This brings about increased blood pressure and increased heart rate. The drugs are therefore very important in reducing nasal congestion. The affected patients change their respiratory patterns and this enhances breathing and opens up the nasal cavity. The blood vessels in the nasal tissues are forced to shrink by the drug.
Explain Briefly Why Suddenly Stopping These Drugs May Be A Clinical Concern
When these drugs are stopped abruptly, there are chances of developing increased complications, with isosorbide mononitrate increasing the angina complications. For the oxymetazoline, nasal congestion may persist and this may lead to extended complications. The released hormones altered by the drugs may cause increased complications and alter normal body functions. Stopping the drugs abruptly may also cause the body to lose important hormones that may have been regulated by the drugs. Nasal congestion for example may increase if the Oxymetazoline drugs were stopped abruptly.
The receptors of each drug are stimulated at the start of each dose and for this reason, stopping should be gradual but not fast. Reduced ventricular pressures may be altered if the drugs are stopped abruptly. Due to the tolerance that has already been established, future medications may not work. The receptors can also be affected due to altered activities. For this reason, the drugs should be slowly reduced as per the doctor’s directions.
Consider Drugs That Are Antagonists Of Î’ Adrenergic Receptors And Explain How They Produce Clinically Useful Effects
Some of the β adrenergic receptors drugs that can be used are Isoproterenol – Isuprel, Epinephrine – Adrenalin, and Norepinephrine- Levophed. These drugs affect the sympathetic nervous system and they include both alpha and beta receptor drugs. The receptor reacts with ligands to alter the functions of the central nervous system. The beta and the alpha-receptors help in the regulation of neural activities and this alters normal body functions. Morphine also alters the normal operation of the cellular receptors making the body to be resistant to pain and other stimuli. This means that the drugs alter the normal functions of the central nervous system and cause numbness as well as reduce the effects of pain. Given The Β-Adrenoreceptor Antagonists Listed In Table 12-2, Which Drug Would You Choose To Treat Uncomplicated Hypertension In An Elderly Patient With Asthma? Briefly Explain Your Decision
For treatment of uncomplicated hypertension, I would use Calcium channel blockers. This is because they do not force potassium out of the blood and the drugs also have a longer track record. In addition, they are cost-friendly and can therefore be afforded by many patients. The drugs do not affect patients with asthma and should therefore be used especially if the patient is elderly. The reason why other drugs would be dangerous is because of their impact on the potassium levels in patients with high blood pressure. The calcium blocker can however cause airway reactivity, an aspect that may affect normal asthmatic treatments.
References
Anand, KJS, Hall, R & Desai, N 2004, ‘Effects of morphine analgesia in ventilated preterm infants: primary outcomes from the NEOPAIN randomized trial’, Lancet, vol. 363, pp. 1673–1682.
Armstrong, SC & Cozza, KL 2003, ‘Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: Theory and clinical reality’, Psychosomatics, vol. 44, pp. 515-520.
Bhandari, V, Bergqvist, LL & Kronsberg, SS 2005, ‘Morphine administration and short-term pulmonary outcomes among ventilated preterm infants’, Pediatrics, vol. 116, pp. 352–359.
Bijur, PE, Esses, D, Birnbaum, A, Chang, AK, Schechter, C & Gallagher, EJ 2008, ‘Response to Morphine in Male and Female Patients: Analgesia and Adverse Events’, Clinical Journal of Pain, vol. 24, no. 3, pp. 192-198.
Chay, PCW, Duffy, BJ & Walker, JS 2002, ‘Pharmacokinetic-pharmacodynamic relationships of morphine in neonates’, Clinical Pharmacology Journal, vol. 51, pp. 334–342.
Dolin, SJ 2000, Drugs and pharmacology: Total intravenous anesthesia, Butterworth Heinemann, Oxford.
Draisci, G, Frassanito, L, Pinto, R, Zanfini, B, Ferrandina, G & Valente, A 2009, ‘Safety and effectiveness of coadministration of intrathecal sufentanil and morphine in hyperbaric bupivacaine-based spinal anesthesia for cesarean section’, Journal of Opioid Management, vol. 5, no. 4, pp. 197-202.
Drugs Information Online 2011, ‘oxymetazoline nasal’, Drugs. Com, Web.
Emergency Medical Paramedic 2010, Paramedic Analgesia, Web.
Hasslesstrom, J & Sawe, J 2001, ‘Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations’, Clinical Pharmacokinetics, vol. 40, pp. 344-354.
Health Grades 2011, Morphine, Web.
Meldrum, ML 2003, ‘A capsule history of pain management’, JAMA, vol. 290, pp. 2470-2475.
Mika, J 2008, ‘Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness’, Pharmacological Reports, vol. 60, pp. 297-307.
National Center for Biotechnology Information 2011, Morphine dependence, National Center for Biotechnology Information, Bethesda, MD.
Stoelting, RK & Miller, RD 2000, Intravenous anesthetics, in basics of anesthesia, Churchill-Livingstone, Oxford, UK.
Stoelting, RK 1999, ‘Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs’, Pharmacology and Physiology in Anesthetic Practice, vol. 3, pp. 1-17.
Trescot, AM, Glaser, SE, Hansen, H, Benyamin, R, Patel, S & Manchikanti, L 2008, ‘Effectiveness of opioids in the treatment of chronic non-cancer pain’, Pain Physician, vol. 11, no. 2, pp. 181-200.