Applied pharmacology Flashcards
Define Analgesic:
It is the objective of all treatment in types of pain, irrespective to it’s origin to achieve symptom control & improve the quality of the patients life
Define NSAIDS
Non-steroidal ant-inflammatory drugs, these are a class of drugs that are used to treat pain & inflammation, they work by inhibiting COX enzymes which produce prostaglandins.
Prostaglandins are chemicals in the body that promotes, pain, fever & inflammation
Examples: Naproxen, Aspirin & Ibuprofen
Describe the arachidonic cascade
Refers to the complex series of biochemical reactions involving arachidonic acid (an omega-6 fatty acid) that ultimately leads to the production of various inflammatory mediators. This cascade plays a central role in inflammation, pain, and fever. phospholipase A2 produces arachidonic acid is released, it can be converted into various metabolites through the action of different enzymes, COX-1 and COX-2 are enzymes that convert arachidonic acid into prostaglandins and thromboxanes
Define COX enzymes
They play a role in the body’s inflammatory response & production of prostaglandins
There are 2 types of COX enzymes, COX-1 & COX-2
Describe the function of COX-1 enzymes
Location: most cells/tissue
Function: produce prostaglandins that protect stomach lining by promoting mucus secretion & HCO3- to buffer the stomach acid.
COX-1 is involved in regulating blood flow to the kidneys & regulate kidney function
Describe the function of COX-2 enzymes
Location: found in macrophages, fibroblasts, mast cells and endothelial cells
Function: active during injury/inflammation, produce prostaglandins, promotes fever, raising body temp above set point.
COX-2 inhibitors can be used to reduce fever and regulate cell growth & tissue repair
Describe the function of COX-3 enzymes
Located: Brain and spinal cord
Function: Similar in to COX-1 (a variant), proposed to produce prostaglandins in the CNS, it may contribute to pain perception & pain response.
More research is needed, not sure the function in humans
Describe the binding ability of NSAIDS
Refers how the drugs interact with COX enzymes to exert therapeutic effects and side effects
Describe a non-selective NSAID
E.g., Aspirin or ibuprofen, inhibit both COX 1 & 2, offer broad pain relief, but increase GI and renal side effects due to COX1 inhbition
Describe a selective COX-2 inhibitor
E.g., celecoxib, Target COX-2 enzymes specifically, which reduces inflammation/fever, whilst lowering risk of GI issues, however may promote cardiovascular risk
Describe a partially selective NSAID
Offers a middle ground, provides some COX-2 selectivity, still poses risk to GI tract
Describe the binding mechanism of NSAIDS
- NSAIDS bind to active site of COX enzymes, this prevents the conversion of arachidonic acid into prostaglandins
- Non-selective NSAID bind to both COX-1 & COX-2 to block enzyme activity
- Selective COX-2 inhibitors (e.g., celecoxib) are designed to bind more specifically to COX-2, based on structural differences in the enzyme’s active site, while avoiding COX-1.
Describe the anti-inflammatory effects of NSAIDS
When NSAIDS inhibit COX enzymes they decrease the synthesis of prostaglandins, reducing effects of fever, pain, swelling & inflammation
A reduction in prostaglandins e.g., histamine/substance P, limits excessive blood flow & fluid leakage from blood vessels, creating decreased vasodilation and permeability
Pain relief: NSAIDS decrease the sensitization of nociceptors as they reduce pain associated with inflammation
Describe the analgesic effects of NSAIDS
When prostaglandins bind to receptors on nociceptors they make free nerve endings more responsive to pain, heat, pressure etc
Prostaglandins also enhance the sensitivity of pain pathways in the spinal cord and brain.
By inhibiting COX-1 and COX-2, NSAIDs decrease the production of prostaglandins, thus lowering nociceptor sensitization. This results in reduced pain perception and a decrease in pain intensity.
Describe the analgesic effect on central pathway & peripheral nociceptors
Central: NSAIDS may influence central pain processing by COX-2 inhibition at the dorsal horn, reducing prostaglandins, therefore reducing the sensitivity of 2nd order neuron, less likely to propagate pain signal
Peripheral: located at site of injury, NSAIDS inhibit prostaglandin production locally reducing the sensitivity and activation of these receptors
Describe the antipyretic effects of NSAIDS
When pyrogens stimulate the hypothalamus, they increase the production of PGE2, which in turn raises the set point of the hypothalamus, causing the body temperature to increase, resulting in fever.
NSAIDs inhibit PGE2 by reducing it’s synthesis, NSAIDS therefore lower the hypothalamic set point for body temperature.
NSAIDs block the production of PGE2 in the brain, the hypothalamus’s temperature set point returns to normal, and the body initiates cooling mechanisms, such as sweating and vasodilation (dilation of blood vessels), which help to lower body temperature
Describe the platelet aggregation effects of NSAIDS
When BV’s become damaged, platelets are activated and produce thromboxane A2. Thromboxane A2 causes vasoconstriction, it is synthesized from COX-1 enzymes found in platelets.
Thromboxane A” binds to receptors & promotes clumping of platelets, forming a platelet plug
NSAIDs inhibit COX-1, the enzyme responsible for converting arachidonic acid into thromboxane’s. NSAIDs reduce the production of thromboxane A2 in platelets, which results in impaired platelet aggregation, platelets have a reduced ability to clump together.
Therefore, platelets become less effective at forming stable blood clots, this can lead to prolonged bleeding.
Describe the use of aspirin as a NSAID
Aspirin is unique among NSAIDs in that it irreversibly inhibits COX-1. This means that the inhibition of thromboxane A2 production persists for the lifetime of the platelet (around 7-10 days). This is why aspirin is used in the prevention of cardiovascular events (such as heart attacks and strokes) because it prevents clot formation for an extended period. New platelet production is required for blood to clot due to irreversible inhibition.
Name the side effects of NSAIDS
- Reduced GI motility
- Respiratory risk
- Hepatic risk
- Renal risk
Describe the effects on the GI tract from NSAIDS
Stomach produces alkali mucus to protect stomach lining from HCL acid, NSAIDS inhibit the COX enzymes which produce prostaglandins involved in mucus production. Therefore reduction in protective mucus produced. NSAIDS can therefore create a risk if ulceration & gastritis (stomach lining irritation) This can cause abdominal pain, bleeding & vomiting
COX-2 inhibitors are easier on GI than non-selective NSAIDS and pose fewer gastric complications, however long-term use may cause cardiovascular issues (endothelial damage/inflammation)
Describe the respiratory effects of NSAIDS
NSAIDs, particularly aspirin and COX-1 inhibitors, can cause bronchospasm, commonly seen in people with aspirin-sensitive asthma. This creates symptoms of SOB, wheezing & coughing
NSAIDs can also cause hypersensitivity reactions in some individuals, leading to allergic rhinitis or nasal congestion. While rare, NSAIDs can cause severe respiratory issues like pulmonary edema or interstitial lung disease in susceptible individuals.
Describe aspirin induced asthma mechanism
NSAIDs can worsen asthma symptoms by interfering with the balance of prostaglandins in the respiratory tract. COX-1 inhibitors (like aspirin) decrease the production of protective prostaglandins while promoting the production of leukotrienes, which can trigger inflammation and airway constriction.
Describe the renal effects caused by NSAIDS
Prostaglandins have protective effects on the kidneys, by reducing production via NSAIDS protection of the kidneys is reduced.
COX-1 helps maintain normal kidney function/blood flow, Na+ balance & GFRF
EFFECTS OF NSAIDS:
1. It can affect the Na+/K+ balance, causing low Na+ or hyperkalemia, this can cause muscle weakness, arrythmias and dizziness
2. Decreased blood flow: reduced prostaglandins productions results in vasoconstriction of renal arteries, so less blood reaches the kidneys, this creates risk of dehydration, chronic kidney failure & heart failure. It can cause oedemas & fluid retention
3. Fluid retention/oedema: NSAIDS interfere with kidneys ability to excrete Na+, therefore causing swelling which creates risk of kidney disease/cirrhosis
Describe the effects of NSAIDS on liver function
NSAIDs are primarily metabolized by the liver, and their potential to cause liver damage is linked to their interaction with cytochrome P450 enzymes. These enzymes help metabolize the active ingredients of NSAIDs, and variations in the metabolism process can lead to liver injury. Some NSAIDs also increase the production of reactive metabolites, which can be toxic to liver cells.
EFFECTS:
1. Increased ROS production: reactive O2 species levels increase causing oxidative stress & mitochondrial damage
2. Mitochondrial damage: NSAIDS can interfere with ATP synthesis, leading to liver cell dysfunction
3. Toxic metabolites: these may accumulate & can damage to mitochondria & liver cells.
4. Cholestasis: NSAIDS may impair bile flow, leading to bile accumulation in blood and liver, creating symptoms of jaundice
How can we minimise side effects associated with NSAIDS
Take with Food: Taking NSAIDs with food or milk can help reduce the risk of gastric irritation.
Avoiding Prolonged Use: Using NSAIDs for short periods, or under medical supervision, can help mitigate the long-term risks.
Monitoring for Side Effects: Regular monitoring for GI bleeding, kidney function, and liver function is recommended during prolonged NSAID use.
For sensitive patients use PPI’s (proton pump inhibitors) to reduce stomach acid quantity to protect stomach lining
Describe the function & use of paracetamol
Paracetamol is used as an analgesic (pain reliever) and antipyretic (fever reducer).
Outline the mechanism of action of paracetamol
Paracetamol is thought to inhibit the enzyme COX, specifically the COX-2 isoform in the brain, although it has a much weaker effect on COX-1 compared to nonsteroidal anti-inflammatory drugs (NSAIDs).
By inhibiting COX, paracetamol reduces the synthesis of prostaglandins in the central nervous system, which helps alleviate pain and fever.
Describe the dangers associated with a paracetamol overdose
Overdose on paracetamol can lead to hepatic toxicity (liver damage) and even death.
Liver toxicity: Paracetamol is metabolized via liver enzymes, however in large doses the liver cells become overwhelmed, and a toxic metabolite called NAPQI (N-acetyl-p-benzoquinone imine) is produced in excess.
NAPQI depletes liver stores of glutathione which is a vital antioxidant, this creates damage to liver cells, which can lead to acute liver failure, need for transplant or death
Describe the phases during a paracetamol overdose
Initial Phase (0-24 hours): Symptoms may be mild, including nausea, vomiting, and abdominal pain. This phase can often be mistaken for a common stomach upset.
Second Phase (24-72 hours): Liver damage becomes more apparent, with symptoms like jaundice (yellowing of the skin and eyes), dark urine, and elevated liver enzymes in blood tests.
Third Phase (72-96 hours): This is the most critical phase, where liver failure occurs. Symptoms can include confusion, bleeding, and multi-organ failure.
Describe the side effects of paracetamol
- liver damage: can cause liver toxicity leading to acute liver failure from overdose or prolonged use
- Kidney damage: severe overdoses may cause acute kidney failure
- GI issues: can cause nausea & vomiting in event of an overdose
- Allergic reactions: itching, swelling, redness etc
Describe the function of Mu receptors, agonists & antagonists associated with it
Mu activation: These receptors are found in the brain, gut & spinal cord, when receptors become activated, they block pain signals from reaching the brain. Mu activation is associated with symptoms of euphoria, sedation & respiratory depression
Agonist: Strong opioids: e.g., morphine, Partial agonists: buprenorphine
Natural opioid: endorphins
Antagonist: Naloxone, naltrexone, used to reverse opioid overdose
Describe the function of Kappa receptors, agonists & antagonists associated with it
Causes Analgesia, Dysphoria, sedation,
Agonist: Weak/mild opioids: Butorphanol
Endogenous ligand: Dynorphins
Side effects: Increased urination due to inhibition of ADH hormone
Hallucinations, dysphoria
Less chance of addiction as less desirable for recreational use
Describe the function of Delta receptors, agonists & antagonists associated with it
Use: Mild analgesia, modulates mood e.g., antidepressant neuroprotective against damage after stroke or neurodegenerative disease
Experimental drugs for chronic pain & depression
Agonist: Endogenous ligand: Enkephalins
side effects: Risk of seizure
Less is known about delta receptors as they are less studied. In research for depression but are not commonly used in clinical therapy
Define a mild opioid ad give 3 examples
Mild opioids:
An opioid is a compound that resembles opium in its physiological effects. As it binds to opioid receptors & mimics the action of endogenous peptide neurotransmitters
e.g., codeine & tramadol
Describe the function of mild opioids
opioids interfere with pain processing at the spinal cord by sensory neurons by binding to opioid receptors on neurons as well as in the brain. Substance P is inhibited by opioids, so pain cannot be transmitted. Opioids also increase activity of inhibitory neurons, by reducing their excitability, further reducing pain perception & promoting a sensation of euphoria
GI motility: opioids can act on the GI tract & cause slower movement of food through the digestive tract, leading to side effects e.g., constipation.
Describe the molecular mechanism of mild opioids
Pain signals are caused by release of substance P & glutamate from nociceptive neurons at dorsal horn
1.. mild opioid crosses blood-brain barrier & binds to Mu receptors which are coupled with G proteins in dorsal horn of SC.
2. when bound, G proteins become active & reduces production of CAMP
3. This reduction of CAMP leads to a decreased influx of Ca2+, inhibiting release of substance P & glutamate, resulting in a decreased transmission of pain to the next neuron
4. On the postsynaptic neuron, opioid receptor activation causes opening of K⁺ channels and closing of Ca²⁺ channels. Potassium efflux leads to hyperpolarization of the postsynaptic neuron, making it less likely to fire AP.
5. Inhibition of Ca2+ influx reduces the ability of the postsynaptic neuron to depolarize and transmit the pain signal to the brain. Both effects lead to a reduced excitability of the postsynaptic neuron, effectively dampening the pain transmission process.
Describe the mild and severe side effects of mild opioids
Mild: Sedation: Like stronger opioids, mild opioids can cause drowsiness or sedation, but this is usually less intense.
- Constipation: Opioids reduce gastrointestinal motility, leading to constipation, which is a common side effect.
- Nausea and Vomiting
SEVERE:
- Addiction & dependance caused by chronic overuse
- Tolerance, builds up over time leading to higher doses being taken increasing risk of overdose
- Hypotension
- Severe respiratory depression: severe overdose can cause respiratory arrest
Define a strong opioid and give 3 examples
A strong opioid is a type of opioid analgesic that is used to manage severe pain. These medications are more potent and effective than weaker opioids, and they typically work by binding to opioid receptors in the brain and spinal cord, blocking pain signals and altering the perception of pain.
e.g., Morphine, fentanyl & oxycodone
Outline the mechanism of action of a strong opioid such as morphine
- strong opioids bind to Mu receptors in the brain & SC
- Opioids block pain signal by binding to Mu receptors in the dorsal horn of SC
- Glutamate & P substance are inhibited and Ca2+ influx is reduced in presynaptic neuron
- Opioids activate K+ Channels, creates K+ efflux, reducing Ca2+ effects leading to decreased excitability of the neuron, less likely for AP to fire
- Pain perception is blunted as opioids bind to thalamus/cortex, reducing excitability of neurons in the brain
- Dopamine is released in response to opioids, creating euphoria which can cause potential for abuse & addiction
Describe the long-term effects of strong opioids
- GI dysfunctions: can cause severe constipation due to reduced GI motility
- Immune suppression: long-term use may impair immune function which makes people more susceptible to infections
- Decreased sex hormones: e.g., testosterone, can lead to hormonal imbalances
Describe the mild & severe side effects of strong opioids
Mild: Constipation, nausea, vomiting & sedation, euphoria (reinforces addiction)
Severe: RS depression, leads to shallow breathing & hypoxia/ RS arrest
Overdose: loss of consciousness, RS arrest or death
Hypotension: can cause low BP due to dizziness or fainting
Tolerance build-up: more opioid needed to produce effect, increasing overdose risk
Define an anaesthetics
A substance e.g., lidocaine that induces a loss of sensation/consciousness to prevent pain/discomfort during a medical procedure, 2 types: local & general
Describe the use of local and general anaesthetics
Local: is sensation specific, blocks sensations in a specific area of the body, where the drug is applied or injected. (lidocaine)
General: induce a state of controlled consciousness, the patient is unaware of pain or procedure, affects the whole body, used for major surgeries, (e.g., propofol, sevoflurane).
Describe the mechanism of anesthetics
- Local anesthetics work by blocking Na+ channels on nerve membranes, preventing influx of Na+ during an AP
- This prevents the depolarization of nerve fibers therefore AP cannot propagate. This therefore stops the transmission of a pain signal to the brain
- unmyelinated /myelinated fibers are the most affected, as well as pain & temp fibers (A & C fibers)
- Action of local anesthetics are reversible once drug diffuses away from the nerve. Na+ is able to cause depolarization
This explains why localized pain relief can be achieved without affecting consciousness.
Describe the WHO analgesic ladder
It is a step by step guide for HP’s to choose appropriate levels of pain management, from mild to severe pain, it focuses on the use of analgesics, it offers a systematic approach
Define Adjuvant
An adjuvant is a substance that is used alongside a primary treatment to enhance its effect or help in managing side effects. Adjuvants are medications that are not primarily used to treat pain directly but can complement or enhance the effects of the main analgesics.
e.g., antidepressants, benzodiazepines
How is mild pain treated according to the WHO analgesic ladder
For mild pain non-opioid medications are used e.g., NSAIDS or paracetamol with an aim to relieve pain & inflammation.
Adjuvants (antidepressants)may also be used for specific types of pain e.g., neuropathic
How is moderate pain treated according to the WHO analgesic ladder
If pain continues after mild treatment is given then the next step is to use mild opioids e.g., codeine combined with a non-opioid drug e.g., NSAID
For moderate pain less potent opioids are used, preventing risk of addiction & abuse, whilst also using non-opioid medication
How is severe pain treated according to the WHO analgesic ladder
For severe pain strong opioids such as morphine or fentanyl are used
Adjuvants may also be used to address underlying pain issue
Describe the key principles in the analgesic ladder
- stepwise approach: start with least invasive treatment, progress through stages based on pain severity
- Opioid use: should be used appropriately to avoid dependance/abuse and side effects. opioid rotation should be used for chronic pain to prevent dependance
- Adjuvants (non-opioid drus): enhance pain relief & address associated symptoms e.g., depression
- individualized care: pain care should be unique to patient based on patients history, pain severity & treatment response, patient should be closely monitored to allow adjustments
- Balance between benefits & side effects: The goal is to provide the most effective pain relief with minimal side effects. This may involve adjusting doses, combining therapies, or switching medications as needed.
Describe the limitation of the WHO analgesic ladder
- Over-Reliance on Opioids: The ladder advocates for escalating to strong opioids (e.g., morphine, fentanyl) in cases of severe pain, but this can lead to over-reliance on opioids for pain management.
- Risks of Addiction and Dependence: Opioid abuse and dependence are major concerns, especially in populations where the risk of addiction is higher, such as those with a history of substance abuse.
- Lack of Multimodal Approaches: The ladder focuses primarily on pharmacological treatment and does not emphasize multimodal pain management strategies, which combine pharmacological and non-pharmacological interventions like physical therapy
- The ladder is a one-size-fits-all approach and does not fully account for the need for personalized multimodal treatment based on individual pain characteristics and comorbidities.
