Pharmacology Flashcards
What are the main actions of NSAIDs
- Anti-inflammatory
- Analgesic
- Anti-pyretic
What is the primary action of NSAIDs?
-Inhibit prostaglandin biosynthesis by direct action on cyclo-oxygenase enzymes
What are the two main mechanisms by which NSAIDs inhibit cyclo-oxygenase (COX)?
- An irreversible, time dependent inhibition of the enzyme
- A rapid, reversible competitive inhibition of the enzyme
Describe aspirin’s mechanism of action
- inactivates the enzyme
- aspirin acetylates the alpha-amino group of the terminal serine of the enzyme forming a covalent bond
- further synthesis of prostaglandins requires synthesis of new enzyme
Describe ibuprofen’s mechanism of action
- Binds reversibly to the enzyme
- Competes with natural substrate, arachidonic acid
What are prostaglandins?
- Called prostaglandins because it was believed that they originated from the prostate gland
- Family of compounds - PGE2 and PGF2a were the first ones isolated and structures determined
- Generated in tissues from a precursor (arachidonic acid) by cyclo-oxygenase enzymes - thromboxanes, prostaglandins and leukotrienes are all products of arachidonic acid metabolism
What are the two main types of cyclo-oxygenase?
COX-1:
- Constitutive -expressed normally and regularly in a wide range of tissues
- Important in maintaining GIT integrity
COX-2:
- Inducible
- Involved in inflammatory response
- Implicated in cancer development
What is the role of prostaglandins in inflammation?
Inflammation always accompanied by release of prostaglandins
- Predominantly PGE2 but also PGI2
- PGD2 from mast cells
PGE2, PGI2 and PGD2
- Act as potent vasodilators
- Also synergise with other inflammatory mediators (e.g histamine and bradykinin)
- Potentiate histamine and bradykinin actions on postcapillary venule permeability and pain sensory nerves
How does anti-inflammatory action work on prostaglandins?
Prostaglandins are important mediators of inflammation
- Particularly vasodilation and resultant oedema
- Less effect on cellular accumulation or migration
Therefore NSAIDs only affect aspects of inflammation in which prostaglandins play a significant part. NSAIDs can reduce many of the local signs and symptoms of inflammation i.e redness, heat, swelling, pain
What anti-pyretic effects do NSAIDs have?
Body temperature is regulated by the hypothalamus
- fever occurs when the hypothalamic thermostat ‘set point is raised
- bacterial endotoxins cause release of factors (e.g interleukin 1) from macrophages
- interleukin 1 causes generation of prostaglandins in the hypothalamus (PGEs)
- prostaglandins increase the thermostat set point
Therefore NSAIDs act by preventing the formation of prostaglandins and prevent the rise in temperature - no effect on normal body temperature
Describe the analgesic effect of NSAIDs
Inflamed regions painful due to histamine and bradykinin release
- activate nocioceptive afferent nerve terminals
- register a painful stimulus
Prostaglandins sensitise nocioceptive nerves to these compounds
Therefore by preventing prostaglandin production NSAIDs prevent sensitisation to pain-producing compounds
What family does aspirin belong to?
Salicylates
Give some details about aspirin
- pro drug (acetylsalicylic acid) - can directly acetylate COX enzyme
- Also metabolised to active compound (salicylic acid) by plasma and tissue esterases
- Salicylate found in plasma within 30 mins
- Peak plasma concentration within 1-2 hours
Give some details about aspirin
- pro drug (acetylsalicylic acid) - can directly acetylate COX enzyme
- Also metabolised to active compound (salicylic acid) by plasma and tissue esterases
- Salicylate found in plasma within 30 mins
- Peak plasma concentration within 1-2 hours
What are some unwanted effects of salicylates?
- Stomach: bleeding, ulcers
- Systematic: tinnitus, dizziness, impaired hearing, nausea, vomiting, hypersensitivity
- Metabolic changes: acid/base balance affected
- Haemostasis: blood coagulation affected through and action on platelets
- CNS effect: stimulation initially, ultimately coma and respiratory depression
- Renal: insufficiency in susceptible patients and with chronic use and overdose
Describe propionic acids and give some examples
- Not prodrugs
- Well absorbed
- Last for 4-6 hours
- e.g ibuprofen, naproxen
Describe propionic acids and give some examples
- Not prodrugs
- Well absorbed
- Last for 4-6 hours
- e.g ibuprofen, naproxen
What is an example of a fenamate?
Mefenamic acid
What are some features of paracetamol (acetaminophen)?
- Good analgesic and antipyretic activity
- Poor anti-inflammatory
- Well tolerated in GIT
- Weak COX inhibitor - may be selective inhibitor of CNS-specific COX, COX-3
- Given orally, well absorbed - peak plasma conc in 30-60 mins - half life in plasma is 2-4 hours for therapeutic doses
Explain side effects of paracetamol
Fewer side effects than other NSAIDs (perhaps due to its selectivity for COX enzymes)
Major issue is hepatotoxicity due to overdose
- Normally inactivated in the liver by glucoronate and sulphate conjugation
- When these enzymes are saturated, toxic metabolites are formed
- Result can be hepatic necrosis
Describe coxibs and give an example
- Selective COX-2 inhibitor
- Used for osteoarthritis and rheumatoid arthritis
- Restricted for when traditional NSAIDs produce too severe GIT side effects
- Cardiovascular risk needs to be assessed
- e.g celecoxib
What clinical analgesic uses of NSAIDs are there?
- Headache
- Dysmennorhea
- Backache
- Bony metastases of cancers
- Postoperative pain
Which NSAIDs are used for short term analgesia?
Aspirin, paracetamol, ibuprofen
What longer lasting NSAIDs are used for chronic pain?
Naproxen, diclofenac
Define pharmacology
Origin, nature, chemistry, effects and uses of drugs
Define toxicology
Study of the adverse effects of chemical, physical or biological agents
Define pharmacodynamics
What the drug does to the body
Define pharmacokinetics
What the body does to the drug
Why is pharmacokinetics important?
- Explain how dose recommendations in inserts are arrived at
- Identify possible drug interactions
- To adjust strategies such as therapeutic dose monitoring
- To safely administer drugs when urgency is required
- Predict the influence of disease on drugs
What are the four main stages of pharmacokinetics?
- Absorption
- Distribution
- Metabolism
- Excretion
What are some routes of drug administration?
- Oral
- Sublingual
- Inhalation
- Topical
- Transdermal
- Intramuscular
- Intravenous
What are some advantages and disadvantages of oral administration?
- Advantage: convenient
- Disadvantage: first pass effect, many variables and barriers
What are some advantages and disadvantages of sublingual administration?
- Advantage: no first-pass effect
- Disadvantage: inconvenient, small dose limit, taste
What are some advantages and disadvantages of inhalation administration?
- Advantage: fast, rapid delivery to blood
- Disadvantage: requires special properties of drug
What are some advantages and disadvantages of topical administration?
- Advantage: convenient, localised
- Disadvantage: only local
What are some advantages and disadvantages of transdermal administration?
- Advantage: prolonged release
- Disadvantage: skin very effective barrier
What are some advantages and disadvantages of intramuscular administration?
- Advantage: rapid for aqueous, slow for oil
- Disadvantage: painful, requires trained personnel
What are some advantages and disadvantages of intravenous administration?
- Advantage: direct, total dose, rapid
- Disadvantage: requires professional, infection risk, rapid response
What is bioavailability?
Fraction of unchanged drug that reaches systemic circulation
What bioavailability does IV injection give?
100%
What four ways can small molecules cross cell membranes?
- Diffusing directly through the lipid
- Diffusing through aqueous pores
- Transmembrane carrier protein
- Pinocytosis
What are the main drug properties that affect absorption?
Lipophilicity and ionisation
What are the factors that affect distribution of a drug?
- Degree of drug ionisation
- Lipid solubility
- pH of compartments
- Cardiac output and blood flow
- Capillary permeability
- Plasma protein binding
Give a brief description of phase I metabolism in the liver
- Generally oxidation, reduction or hydrolysis - introduce/reveal a reactive chemical group
- Products often more reactive
Give a brief description of phase II metabolism in the liver
- Synthetic, conjugative reactions
- Hydrophilic, inactive compounds generated
Describe cytochrome P450 enzymes
- Mixed function monooxygenases
- Throughout the body, extensively in the liver
- 57 human genes coding for CYP P450 enzymes
What are the functions of cytochrome P450 enzymes?
- Biosynthesis of steroids, fatty acids and bile acids
- Metabolism of endogenous and exogenous substrates
Give a summary of drug metabolism
- Aim is to produce metabolites that can be excreted
- Mainly occurs in the liver, metabolites can be active or toxic
- Genetic variability in metabolic enzymes occurs, and expression of metabolic enzymes can be induced and/or inhibited
- Competition for metabolic enzymes occurs and metabolic pathways can be saturated
- Metabolism can affect the bioavailability of drugs
Which type of drugs are eliminated more readily?
Hydrophilic over lipophilic
What are some possible sources of excretion?
- Breath
- Urine
- Saliva
- Perspiration
- Feces
- Milk
- Bile
- Hair
Which organs are the most important in the elimination of drugs and their metabolites?
Kidneys
What is the Cmax of a drug?
Maximum concentration of a drug in plasma following a single dose
What is the Tmax of a drug?
The time taken to reach the peak plasma concentration
What is the absorption half life of a drug?
The amount of time taken to get to half the peak plasma concentration
What is plasma clearance half life/elimination half life?
The amount of time taken to half a drug’s plasma concentration