Week 3- pharmacology and therapeutics Flashcards
What are the different types of anti-inflammatory drugs?
-Drugs that inhibit the cyclo-oxygenase (COX) enzyme
-Antirheumatoid drugs=
the so-called disease-modifying antirheumatic drugs (DMARDs),
together with some immunosuppressants
- The glucocorticoids
• Anticytokines and other biopharmaceutical agents
• Antihistamines used for the treatment of allergic inflammation
• Drugs specifically used to control gout
what are NSAIDS sometimes called?
-aspirin-like drugs or antipyretic analgesics
what can NSAIDS help with providing symptomatic relief from?
-fever, pain, swelling in chronic joint
diseases as well as in acute inflammatory conditions
-Also useful to treat postoperative, dental and menstrual pain, as well
as headaches and migraines
where do NSAIDS work on in the body?
fatty acid cyclo-oxygenase (COX)
WHAT ARE THE 2 ISOFORMS OF COX?
COX-1 +2
how does COX work?
by enzymatically combining with arachidonic substrate and other unsaturated fatty acids with 2 oxygen to form unstable intermediates
what is lipoxygenase?
There are several subtypes, which often work sequentially, to synthesise
leukotrienes, lipoxins and other compounds
how is a stimulus causing the production of prostaglandins and leukotrienes?
- there is a stimulus like a injury then phopolipasae A2 is activated and that transforms phospholipids to arachidonic acid.
- COX-1 and 2 chnages arachidonic acid to prostaglandins and lipoxgygenases change arachidonic acid to leukotienes?
what type of cells is COX-1 found in and what does it do?
- COX-1 is present in most cells as a constitutive enzyme.
- It produces prostanoids that act mainly as homeostatic regulators (e.g. modulating vascular responses, regulating gastric acid
secretion) .
what type of cells is COX-2 found in and what does it do?
-not normally found in most cells only renal tissue and CNS
-strongly induced by inflammatory stimuli and
therefore believed to be more relevant as a target for anti-inflammatory drugs
how is PGG2 and PGH2 ftransformed to other PGE2, PGI2(prostacyclin), PGD2, PGF2α and thromboxane (TX)A2?
rapidly transformed in a tissue-specific manner by endoperoxide isomerase or synthase enzymes
what inhibits COX1+2?
aspirin and ibuprofen
what does PGD2 cause?
-cause vasodilation, inhibition of platelet aggregation, relaxation of gastrointestinal and uterine muscle
in many rapidly transformed in a tissue-specific manner by endoperoxide isomerase or synthase enzymes. It has a bronchoconstrictor effect through a secondary action on TP receptors.
- It may also activate chemoattractant receptors on some leukocytes.
what does PGF2α cause?
uterine contraction in humans
what does PGI2 (prostcyclin) cause?
vasodilatation, inhibition of platelet aggregation, renin release and natriuresis through effects on tubular reabsorption of Na+.
what does TXA2 CAUSE?
causes vasoconstriction, platelet aggregation and bronchoconstriction
what does PGE2 CAUSE?
predominant ‘inflammatory’ prostanoid has the following actions:
- EP1 receptors, it causes contraction of bronchial and gastrointestinal smooth muscle;
- at EP2 receptors, it causes bronchodilatation, vasodilatation, stimulation of intestinal fluid secretion
- at EP3 receptors, it causes contraction of intestinal smooth muscle, inhibition of gastric acid
- at EP4 receptors, it causes similar effects to those of EP2 stimulation
during an immune repsonse what prostaglandins dominate?
The inflammatory response is inevitably accompanied by the release of
prostanoids
PGE2 predominates, although PGI2 is also important
acute inflammation: PGE2 and PGI2 are generated by the local tissues and
blood vessels, while mast cells release mainly PGD2
during chronic inflammation what cells are involved and how?
cells of the monocyte/macrophage series also release
PGE2 and TXA2. Together, the prostanoids exert a sort of yin–yang effect in
inflammation, stimulating some responses and decreasing others.
what are the therapeutic affects of COX inhibitors?
These drugs inhibit COX enzymes, and therefore prostanoid synthesis, in inflammatory cells.
Inhibition of the COX-2 isoform is probably crucial for their therapeutic actions which include:
• An anti-inflammatory action: the decrease in prostaglandin E2 and prostacyclin reduces vasodilatation and, indirectly, oedema.
Accumulation of inflammatory cells is not directly reduced.
• An analgesic effect: decreased prostaglandin generation means less sensitisation of nociceptive nerve endings to inflammatory
mediators such as bradykinin and 5-hydroxytryptamine. Relief of headache is probably a result of decreased prostaglandin-mediated
vasodilatation.
• An antipyretic effect: interleukin 1 releases prostaglandins in the central nervous system, where they elevate the hypothalamic set
point for temperature control, thus causing fever. Non-steroidal anti-inflammatory drugs (NSAIDs) prevent this so prevent a fever.
what are some examples of NSAIDS?
include aspirin, ibuprofen, naproxen, indometacin, piroxicam and paracetamol. Newer agents with more selective
inhibition of COX-2 (and thus fewer adverse effects on the gastrointestinal tract) include celecoxib and etoricoxib.
what are some unwanted effects of COX inhibitors?
• Dyspepsia, nausea, vomiting and other GI effects. Gastric and intestinal damage may occur with chronic use, with risk of haemorrhage, ulceration and
perforation which can be life-threatening. The cause is suppression of gastroprotective prostaglandins in the gastric mucosa.
• Adverse cardiovascular effects. These can occur with many non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs and may be related to inhibition
of COX-2 in the kidney or elsewhere leading to hypertension.
• Skin reactions. Mechanism unknown.
• Reversible renal insufficiency. Seen mainly in individuals with compromised renal function when the compensatory prostaglandin I2/E2-mediated
vasodilatation is inhibited.
• Bronchospasm. Seen in ‘aspirin-sensitive’ asthmatics. Uncommon with coxibs.
• ‘Analgesic-associated nephropathy’. This can occur following long-term high-dose regimes of NSAIDs and
is often irreversible.
• Liver disorders, bone marrow depression. Relatively uncommon
what are the main clinical uses of NSAIDS?
• Antithrombotic: e.g. aspirin for patients at high risk of arterial thrombosis (e.g. following myocardial infarction). Other NSAIDs that cause less
profound inhibition of platelet thromboxane synthesis than does aspirin, increase the risk of thrombosis and should be avoided in high-risk individuals if
possible.
• Analgesia (e.g. for headache, dysmenorrhoea, backache, bony metastases, postoperative pain): – short-term use: e.g. aspirin, paracetamol, ibuprofen
– chronic pain: more potent, longer-lasting drugs (e.g. naproxen, piroxicam) often combined with a low-potency opioid
– to reduce the requirement for narcotic analgesics (the NSAID ketorolac is sometimes given postoperatively for this purpose)
• Anti-inflammatory: e.g. ibuprofen, naproxen for symptomatic relief in rheumatoid arthritis, gout, soft tissue disorders
• Antipyretic: paracetamol
how does aspirin work and what does it do?
• In addition to its anti-inflammatory actions, aspirin strongly inhibits platelet aggregation, and its main clinical use now is in the
therapy of cardiovascular disease
• It is given orally and is rapidly absorbed; 75% is metabolised in the liver
what are some unwanted side effects of aspirin?
• With therapeutic doses: GI symptoms, often including some gastric bleeding (usually slight and asymptomatic)
• With larger doses: dizziness, deafness and tinnitus (‘salicylism’); compensatory respiratory alkalosis may occur
• With toxic doses (e.g. from self-poisoning): uncompensated metabolic acidosis may occur, particularly in children
• Aspirin has been linked with a rare but serious post-viral encephalitis (Reye’s syndrome) in children and is not used for paediatric
purposes
• If given concomitantly with warfarin, aspirin can cause a potentially hazardous increase in the risk of bleeding
what is paracetamol, how does it work?
Paracetamol is a commonly used drug that is widely available over the counter.
It has potent analgesic and antipyretic actions but much weaker anti-inflammatory effects than other NSAIDs
Its cyclo-oxygenase inhibitory action seems to be mainly restricted to the central nervous system (CNS) enzyme.
• It is given orally and metabolised in the liver (half-life 2–4 h)
what does toxic doses of paracetamol lead to?
• Toxic doses cause nausea and vomiting, then, after 24–48 h, potentially fatal liver damage by saturating normal conjugating
enzymes, causing the drug to be converted by mixed function oxidases to N-acetyl-pbenzoquinone imine. If not inactivated by
conjugation with glutathione, this compound reacts with cellular proteins causing tissue damage
• Agents that increase glutathione (intravenous acetylcysteine or oral methionine) can prevent liver damage if given early
what is paracetamol normally used as?
• Mainly used for pain and as an antipyretic
• Paracetamol does NOT have significant anti-inflammatory effect (although
central action on COX enzymes is postulated)
due to over dose how is paracetamal prevent by this?
-no more than 32 tablets sold over the counter
who are in the special patient groups for paracetamol?
- Children
- Low body weight (<50 kg)
- Liver impairment (or those with risk factors for hepatotoxicity)
what paitents is paracetamol preferred for comparsed to NSAIDS?
- Elderly (need to consider weight)
- Patients with: hypertension, CVD, renal impairment, GI issues
- Patients on medicines interacting with NSAIDs, i.e. warfarin
what class of drug is aspirin?
antiplatelet and analgesic
what is the role of apsirin as an anti-platelet
-to inhibit thrombus formation in the arteries
what is the standard dose for aspirin as an anti-platelet?
75 mg can be upped to max – 300 mg daily (loading dose dep
what is the standard dose for aspirin as an analgesic therapy?
Standard oral dose: 300-900 mg every 4 – 6 hours when required
(max. 4 g per day)
who are in the special patient groups for paracetamol?
• Contraindicated in children under 16 (except when specifically indicated - Kawasaki
syndrome)
• Contraindicated in patients with: previous or active peptic ulcerations, bleeding
disorders, severe cardiac failure, previous hypersensitivity to aspirin or NSAID
• Elderly
• Caution in patients with: asthma
what are some of aspirins interactions occurring with?
• Drugs that increase the risk of GI irritation and bleeding – steroids, NSAIDs, SSRI’s,
anticoagulants
• Drugs that increase the risk of renal side effect – Bisphosphonates
• Drugs where aspirin can increase the toxicity of other drugs – Methotrexate
when does the analgesic effect of NSAIDS START TO OCCUR?
• Analgesic effect starts soon after first administration and full effect obtained within a WEEK
when does the anti-inflammatory effect of NSAIDS START TO OCCUR?
may not achieved for up to 3wks
how should selection of NSAID be based on?
based on the characteristics of the drug and
individual patient risk factors for adverse effects
what are the key side effects of NSAID?
- GI mucosa
- Kidney
- Cardiovascular system
IF AN nsaid IS INDICATED what one should be PICKED?
the LOWEST
effective dose should be used for the
SHORTEST duration
why do we get GI side effects with NSAIDS?
-inhibition of COX-1 enzyme and production of its prostaglandins
WHAT ARE THE Standard NSAID
– non-selective?
ibuprofen
indometacin,
mefenamic acid,
naproxen
what are the Standards -
non-selective but
COX-2 preference ?
diclofenac,
etodolac,
meloxicam
what are the Coxibs – COX-2 selective?
celecoxib,
etoricoxib
what kind of GI side effects can NSAIDS cause?
-epitheial damage, ulceration and beleeding
how is the GI side effects of caused?
-Suppression of physiological homeostatic prostanoid (COX-1) inhibition
• Reduced mucus production
• Reduced bicarbonate production
• Reduced mucosal blood flow
-Topical irritation and direct epithelial damage
what are the benefits of the coxibs?
- cox-2 selective
- lower risk of upper GI side effects by no effect to prostaglandins which have homeostatic roles
what are some key points for NSAIDS for GI effects?
- Lowest risk agent preferred
- Start at lowest dose
- Use for the shortest duration (review need)
- Do not use more than one NSAID at a time
- Advise medication to be taken with food to reduce contact
irritation - Co-prescribe with gastroprotection in those patients at risk of GI
ulceration, i.e. PPI - Monitor for adverse events
- Review patient for risk factors
What can NSAIDS interact with tha can increase GI effects?
• Aspirin
• NSAIDs
• Other drugs increasing the risk of GI ulceration and bleeding – steroids,
bisphosphonates
• Other drugs increasing the risk of bleeding: serotonin reuptake inhibitors
(SSRI’s), anticoagulants
what are some monitoring parameters for NSAIDS?
- Reported symptoms of dyspepsia/GI irritation
- Hb
- Signs of GI bleeding – haemoptysis, dark stools
what can NSAID also cause?
increased risk of thrombotic events
what drugs are hgih risk for causing thromatic events using NSAIDS?
COX-2 inhibitors, diclofenac (150mg daily),
ibuprofen (2.4 g or more daily)
what are some key points for NSAIDS for CV EVENTS?
- NSAID selection
- Use lowest effective dose
- Use for the shortest duration (review need of long term therapy)
- Monitor for adverse events
- Review patient for risk factors
what is diclofenac (COX-2 inhibior )contraindicated for?
ischaemic heart disease,
cerebrovascular disease and some
stages of heart failure
what does NSAIDS do to blood pressure?
increase
what drugs have interactions with NSAIDS?
- Antihypertensives (opposite effect)
* Antiplatelet dose aspirin (75 mg) maybe be lowered by using NSAIDS
WHAT ARE SOME MONITORING PARAMETERS FOR nsaids?
• Increase occurrence or first occurrence of CV event
• Risk factors for increased CV risk – BP, medical history of
diabetes/hypercholesterolaemia
what are some renal side effects of NSAIDS?
-in where compensatory prostaglandins are playing a
role to maintain renal function, i.e. advanced age, renal impairment, heart
failure, volume depletion, liver cirrhosis so NSAIDS will reduce renal function
- Decrease renal blood flow and increase the risk of acute kidney injury
• Sodium and water retention – oedema and hypertension
what are some interactions with NSAID that can worsen renal side effects?
- Co-prescribed nephrotoxic medicines – diuretics, ACE-inhibitors
- Anti-hypertensive – (opposite effect)
- Lithium and methotrexate – decreased renal elimination causing toxicity
what are some monitoring parameters for NSAIDS for renal side effects?
- Renal function – GFR, urine output, urea
- BP
- Electrolytes – sodium and potassium
- Oedema (weight, visual signs)
can NSAIDS cause bronochospasm?
yes so cautioned in asthma patients
how does topical therapies of NSAIDS work?
- Available OTC
- Systemic absorption can occur
- Consider potential issues as previously discussed
patients using what drug type shouldn’t use NSAIDS?
ANTI-COAGULANTS
can increase bleeding
what are some counselling points for NSAIDS?
- Take the lowest effect dose for the shortest period
- Take with or after food
- Self monitor for signs of GI disturbance – report
- Do not self medicate with other NSAIDs or aspirin
