Pharcology Of Common Drug Types Flashcards
DESCRIBE THE MECHANISM OF ACTION OF NSAIDS. include knowledge of the arachidonic acid cascade (20)
NSAID drugs such as Ibuprofen and Aspirin block cyclooxygenase (COX) enzymes in the human body. There are thought to be three types of cyclooxygenase enzyme in humans, COX-1, COX-2, and COX-3- but the existence of COX-3 has only been showed in animal studies. COX enzymes play a key role in the arachidonic acid cascade. When tissue is damaged enzymes (phospholipase A2) convert fatty acids into arachidonic acid. COX enzymes can bind to arachidonic acid and convert it to a series of intermediary molecules. The range of intermediaries produced depends on the specific cells and tissues involved. However, eventually these intermediaries are converted into a group of chemicals called prostanoids which include prostaglandins and thromboxanes. Prostaglandins are key inflammatory mediators that can activate and sensitise free nerve endings and trigger the key signs of inflammation. Thromboxanes are involved in regulation of haemostasis (blood clotting). In general, the main mechanism of action of NSADs is to block COX enzymes. By blocking production of prostaglandins NSAIDs can reduce their availability to activate free nerve endings and thus act as analgesics and anti-inflammatories. By blocking production of thromboxanes they can act to reduce haemostasis. Prostaglandin production in the brain is also involved in the development of fever, so blocking prostaglandin production there can result in the antipyretic effect of many NSAID drugs.
Its key to note that aspirin irreversibly binds to COX enzyme with a covalent bond. So, to overcome the effects of aspirin new COX enzymes will need to be produced. Other NSAIDs reversibly bind to a COX enzyme as they hop on and off the COX.
WHAT ARE THE 4 MAIN THERAPEUTIC EFFECTS OF NSAIDS? describe in full. (20)
- anti inflammatory effects – prostaglandins are vasodilators, so by inhibiting the production of prostaglandins there is reduced vasodilation and therefore reduced swelling and redness. Prostaglandins also induce the release of substance P, which sensitised free nerve endings and reinforces the inflammatory response. Substance P will not be released without prostaglandins, so NSAIDs that block the release of prostaglandins reduce inflammation.
- analgesic effects – this means that a drug reduces pain. NSAIDs do this by reducing peripheral and central sensitisation. NSAIDs reduce the production of prostaglandins, which can sensitise free nerve endings at the location of tissue damage, but the reduction of prostaglandins will reduce the sensitisation of peripheral regions and how many nociceptive signals are sent to the CNS. Prostaglandins are also produced by the dorsal horn, so if this is reduced there will be reduced neurotransmitter release by the second order neuron.
- antipyretic effects – this is where a drug prevents or reduces fever. When our body has an infection, the hypothalamus increases body temperature by stimulating a prostaglandin. However, NSAIDs reduce the production of this prostaglandin, which therefore reduces fever.
- platelet aggregation – this is where the platelets clump together to form clots, which is usually caused by thromboxane. However, NSAIDs reduce thromboxane production, and so they reduce the blood clotting response.
How do NSAIDs have anti-inflammatory effects?
prostaglandins are vasodilators, so by inhibiting the production of prostaglandins there is reduced vasodilation and therefore reduced swelling and redness. Prostaglandins also induce the release of substance P, which sensitised free nerve endings and reinforces the inflammatory response. Substance P will not be released without prostaglandins, so NSAIDs that block the release of prostaglandins reduce inflammation.
How do NSAIDs have analgesic effects?
this means that a drug reduces pain. NSAIDs do this by reducing peripheral and central sensitisation. NSAIDs reduce the production of prostaglandins, which can sensitise free nerve endings at the location of tissue damage, but the reduction of prostaglandins will reduce the sensitisation of peripheral regions and how many nociceptive signals are sent to the CNS. Prostaglandins are also produced by the dorsal horn, so if this is reduced there will be reduced neurotransmitter release by the second order neuron.
How do NSAIDs have antipyretic effects?
this is where a drug prevents or reduces fever. When our body has an infection, the hypothalamus increases body temperature by stimulating a prostaglandin. However, NSAIDs reduce the production of this prostaglandin, which therefore reduces fever.
How do NSAIDs help with platelet aggregation
this is where the platelets clump together to form clots, which is usually caused by thromboxane. However, NSAIDs reduce thromboxane production, and so they reduce the blood clotting response.
WHAT ARE THE MAIN SIDE EFFECTS OF NSAIDS? (20)
The main side effects of NSAID drugs are mostly associated with their primary mechanism of action in blocking cyclooxygenase (COX) enzymes.
- Gastrointestinal – Prostaglandins promote production of alkali mucus in the stomach wall. If the production prostaglandins are inhibited by the action of NSSAID drugs blocking COX enzymes, then there will be a reduction in the production of the protective mucus. Stomach acid and enzymes will be able to attack and destroy the tissues that line the stomach leading to gastritis and ulceration.
- Respiratory – blocking COX enzymes can disrupt the balance of leukotriene production in the lungs. As part of the arachidonic acid cascade, COX enzymes are involved conversion of arachidonic acid into prostaglandins and thromboxanes. However arachidonic acid is also converted into leukotrienes in the lungs. If COX enzymes are blocked by NSAIDs then there is more arachidonic acid available to be converted into leukotrienes. Leukotrienes are powerful bronchoconstrictors so they can induce asthma-like symptoms if they are overproduced in the lungs. This is phenomenon is often termed ‘aspirin (or NSAID) induced asthma. It is particularly problematic in people with genetic predisposition to or in the young.
- Renal – Prostaglandins promote vasodilation in the kidney and therefore promote glomerular filtration. NSAIDS block prostaglandin production and so this action could lead to reduced vasodilation and reduced renal filtration. Sodium retention is also an issue. Together these can lead to possible kidney damage in susceptible individuals or exacerbate renal failure.
- Liver – Reduced prostaglandin production in the liver can lead to an increase in the level of programmed cell death. Prostaglandins usually inhibit this process. Excessive use of NSAIDS can also lead to bile retention which can be cytotoxic and cause these important liver cells to die. This is exacerbated by NSAID effects on the functioning of mitochondria in liver cells. Energy production in mitochondria can be adversely affected again leading g to stresses on the function of key liver cells. Finally, reactive metabolites can be formed in liver tissue because of large quantities of the drugs being broken down. These reactive metabolites can trigger an autoimmune response that can damage liver tissue.
How do NSAIDs negatively affect the gastrointestinal tract
Prostaglandins promote production of alkali mucus in the stomach wall. If the production prostaglandins are inhibited by the action of NSSAID drugs blocking COX enzymes, then there will be a reduction in the production of the protective mucus. Stomach acid and enzymes will be able to attack and destroy the tissues that line the stomach leading to gastritis and ulceration.
How do NSAIDS negatively affect the respiratory system?
blocking COX enzymes can disrupt the balance of leukotriene production in the lungs. As part of the arachidonic acid cascade, COX enzymes are involved conversion of arachidonic acid into prostaglandins and thromboxanes. However arachidonic acid is also converted into leukotrienes in the lungs. If COX enzymes are blocked by NSAIDs then there is more arachidonic acid available to be converted into leukotrienes. Leukotrienes are powerful bronchoconstrictors so they can induce asthma-like symptoms if they are overproduced in the lungs. This is phenomenon is often termed ‘aspirin (or NSAID) induced asthma. It is particularly problematic in people with genetic predisposition to or in the young.
How do NSAIDs negatively affect the renal system
Prostaglandins promote vasodilation in the kidney and therefore promote glomerular filtration. NSAIDS block prostaglandin production and so this action could lead to reduced vasodilation and reduced renal filtration. Sodium retention is also an issue. Together these can lead to possible kidney damage in susceptible individuals or exacerbate renal failure.
How do NSAIDs negatively affect the liver?
Reduced prostaglandin production in the liver can lead to an increase in the level of programmed cell death. Prostaglandins usually inhibit this process. Excessive use of NSAIDS can also lead to bile retention which can be cytotoxic and cause these important liver cells to die. This is exacerbated by NSAID effects on the functioning of mitochondria in liver cells. Energy production in mitochondria can be adversely affected again leading g to stresses on the function of key liver cells. Finally, reactive metabolites can be formed in liver tissue because of large quantities of the drugs being broken down. These reactive metabolites can trigger an autoimmune response that can damage liver tissue.
TELL ME EVERYTHING YOU KNOW ABOUT PARACETAMOL. Use, mechanism of action, metabolism, overdose
It provides relief from pain and fever. It doesn’t effectively inhibit COX enzymes in peripheral enzymes, so it is not an anti-inflammatory- which is why it is not technically an NSAID. However, it does target COX-2 enzymes in the CNS, and there is some evidence that it increases the activity of descending modulary pathways. Paracetamol breaks down in 2 phases. The product of the first phase is very toxic, so the second phase needs to happen fast before it can damage the liver. However, the metabolite in the second phase is available with a limited daily supply, so an overdose of paracetamol will occur if a person ingests too much compared to the amount of the second metabolite available.
TELL ME EVERYTHING YOU KNOW ABOUT OPIATE DRUGS - what it is, how it works, side effects (20)
An opioid is a compound that has similar physiological effects to opium, this means that is downregulates the excitability of nociceptive pathways. For a drug to be an opioid it has to bind to specific opioid receptors and mimic the action of the neurotransmitters involved. For example, endorphins and enkephalins. Mild opioids are less efficient at activating receptors, whereas strong opioids activate the receptors well. Strong opioids tend to have a higher potency, binding more strongly or interacting with higher efficacy. They activate the receptors more strongly.
There are a range of receptors that opioids can bind to, including Mu and delta receptors on free nerve endings, and kappa receptors in the spine. When one of these receptors are activated, it triggers a cascade in which nerve cell excitability is reduced, so their ability to send nociceptive signals is reduced. This caused analgesia (pain relief). When this happens at the receptors of free nerve endings in peripheral reigons, it reduces the likelihood of peripheral sensitisation and inflammation.
Opiate receptors are found on the first order neuron in the spine, and when activated reduce the release of the neurotransmitter glutamate across the synapse. This reduces the sensitivity of the first order neuron. The opioid drug also binds to opiate receptors on the second order neuron, which also reduced its sensitivity. Therefore, the reduction of sensitivity causes a reduction in the nociceptive signals sent to the brain, and so reduces the feeling of pain.
Opiate drugs can also act in the brain. One key area is that they can act to increase the activation of descending pain modulatory pathways. This would lead to a reduction in nociceptive signalling to the brain and a possible reduction the intensity of the pain experience. Also, opioids can reduce the perception of pain by stimulating reward pathways in the brain.
Side effects: Euphoria (dysphoria in some people), physical dependence, constipation, vomiting and nausea, depression of cough reflex, respiratory depression, tolerance effects. Longer term issues include immune suppression, decreased sex hormone production, opiate induced hyperalgesia.
What is an opioid
An opioid is a compound that has similar physiological effects to opium, this means that is downregulates the excitability of nociceptive pathways. For a drug to be an opioid it has to bind to specific opioid receptors and mimic the action of the neurotransmitters involved. For example, endorphins and enkephalins.
What receptors do opioids bind to
There are a range of receptors that opioids can bind to, including Mu and delta receptors on free nerve endings, and kappa receptors in the spine.
How do opioids reduce central and peripheral sensitisation
Opiate receptors are found on the first order neuron in the spine, and when activated reduce the release of the neurotransmitter glutamate across the synapse. This reduces the sensitivity of the first order neuron. The opioid drug also binds to opiate receptors on the second order neuron, which also reduced its sensitivity. Therefore, the reduction of sensitivity causes a reduction in the nociceptive signals sent to the brain, and so reduces the feeling of pain.
How do opioids act on the brain
One key area is that they can act to increase the activation of descending pain modulatory pathways. This would lead to a reduction in nociceptive signalling to the brain and a possible reduction the intensity of the pain experience. Also, opioids can reduce the perception of pain by stimulating reward pathways in the brain.
Side effects of opioids
Side effects: Euphoria (dysphoria in some people), physical dependence, constipation, vomiting and nausea, depression of cough reflex, respiratory depression, tolerance effects. Longer term issues include immune suppression, decreased sex hormone production, opiate induced hyperalgesia.
What is an analgesic?
a drug that relieves or reduced pain. These drugs work by limiting the amount of nociceptive signals that reach the brain in the spinothalamic tract.
