SBT Flashcards
What are causes of inflammation?
- Invasion – pathogens (disease-causing), allergens (non-disease)
- Injury – heat, UV, chemicals
What are signs of inflammation?
Signs:
- Calor - warmth (increased blood flow)
- Rubor – redness (increased blood flow)
- Dolor – pain (sensitisation/activation of sensory nerves)
- Tumor – swelling (increase post-capillary venule permeability)
- Functio laesa – loss of function (pain/injury)
Inflammation: produced by both innate and adaptive immune systems
Clinically: these processes are very important
Chronic inflammation: severe tissue damage eg atherosclerosis
Acute responses: eg anaphylaxis, sepsis
Anti-inflammatory drugs are regularly prescribed.
What are the cardinal signs of inflammation?
- heat
- redness
- swelling
- pain
- loss of function
What are the beneficial effects of inflammation?
- Entry of antibodies. Increased vascular permeability allows antibodies to enter the extravascular space, where they may lead either to lysis of microorganisms, through the participation of complement, or to phagocytosis by opsonisation. Antibodies are also important in neutralization of toxins.
- Fibrin formation. Fibrin formation from exuded fibrinogen may mechanically impede the movement of micro-organisms, trapping them and so facilitating phagocytosis.
- Stimulation of immune response. The drainage of this fluid exudate into the lymphatics allows particulate and soluble antigens to reach the local lymph nodes where they may stimulate the immune response.
What are the harmful effects of inflammation?
- Destruction of normal tissues. Enzymes such as collagenases, elastases and other proteases may degrade normal tissues, resulting in their destruction. For example in type III hypersensitivity reactions and in some types of glomerulonephritis small vessels are damaged.
- Swelling. The swelling of acutely inflamed tissues may be harmful. At right is a dog with a swollen face due to an anaphylactic reaction. If that swelling occurs in the larynx, VERY BAD. Inflammatory swelling is especially serious when it occurs in an enclosed space such as the cranial cavity. Thus, acute meningitis or an intra-cerebral abscess may raise intracranial pressure to the point where blood cannot move easily in the brain, there is depression of cardiac and respiratory centers and, death.
- Inappropriate inflammatory response. Sometimes, acute inflammatory responses appear inappropriate, such as those which occur in type I hypersensitivity reactions where the provoking environmental antigen (e.g. pollen) otherwise poses no threat to the individual.
What is the involvement of local hormones in inflammation?
Many of the signs of inflammation are produced by chemical mediators that orchestrate the complex responses involved: ‘local hormones’ or ‘autacoids’.
- Produced in response to a wide range of stimuli
- Synthesised or released only as and when required
- Local release for local action
- Inactivated locally to minimise systemic effects
Some of the above properties are similar to other forms of chemical signaling, whereas others differ.
Examples of local hormones: gastrin, CCK, glucagon, VIP, substance P, motilin,
Others that mediate chemical signalling different to above: NA, DA, 5-HT, etc
What is histamine?
• Synthesised from histidine amino acid by histidine decarboxylase
• Metabolised by imidazole-N-methyltransferase (INMT) and diamine oxidase
• Synthesised, stored and released from,
- Mast cells, which express receptors for IgE, C3a and C5a on cell surface (connective tissues)
- Basophils (blood)
- Neurones in brain
- Histaminergic cells in gut
• Pre-made, ‘ready-to-go’ in secretory granules composed of heparin and acidic proteins
• Released by allergic reactions (IgE-mediated), production of complement agents C3a and C5a, insect stings, trauma etc through a rise in [Ca2+]i.
• Release of histamine inhibited by stimulation of β-adrenoceptors
What is the complement system?
c3b, C3bi= opsonins; c5b-9: cell lysis; c3a, c5a: ↑vascular permeability; ↑ chemotaxis
Histamine, a dibasic vasoactive amine, is held by ionic forces within intracellular granules by macroheparin
C3a and C5a, the small (approximately 10KDa) cleavage fragments released by complement activation, are potent mediators of inflammation. They are anaphylatoxins and act as cell activators with nanomolar affinity, exerting their functions through binding to specific receptors (C3aR and C5aR or C5L2 respectively). Recent studies suggest that locally generated complement effector molecules including C3a and C5a contribute to pathological processes in inflammatory and immunological diseases as well as adaptive immune response besides its host defence mechanism. Targeting the receptors and/or their ligands can reduce undesired inflammatory responses and tissue damage in certain pathological conditions. In this article we describe the recent developments in this important area and focus on the role of C3a/C5a in inflammatory and autoimmune diseases and in adaptive immune responses.
About histamine receptors…
- Four types of histamine receptors- H1, H2, H3, H4
- All G-protein-coupled receptors which produce physiological effects by activating second messenger systems
- Differential expression of receptors:
H1 - Gq/PLC, PIP2 production, generation of DAG/IP3 - smooth muscle, endothelium, CNS H2 - Gs/AC, generation of cAMP, stimulation of PKA - parietal cells to gastric acid secretion, heart H3 - Gi, decrease in cAMP levels - neuonal presynaptic terminals H4 - Gi, decrease in cAMP levels - basophils, bone marrow, gut
- Stimulation of H1 and H2 receptors produce many of the actions of histamine-mediated inflammation
- H1 and H2 antagonists are clinically important
Where do H1 and H2 receptors have effects?
- cardiovascular
- non-vascular smooth muscle
- algesia
- gastric acid
- associated exocrine secretions
What are the cardiovascular effects of H1 and H2 receptor stimulation?
- Dilates arterioles, decreases TPR (H1)
- Increased permeability of post-capillary venules, decreased BV (H1)
- Increase in heart rate (H2) – in vivo reflex to try and retain BP to normal
- Generally involved in decreasing BP (decreases vascular resistance)
What are the non-vascular smooth muscle effects of H1 and H2 stimulation?
contraction (H1) eg bronchoconstriction
What are the algesia effects of H1 and H2 receptor stimulation?
pain, itching and sneezing caused by stimulation of sensory nerves (H1)
What are the effects on gastric acid caused by H1 and H2 receptor stimulation?
increase secretion (H2)
What are the effects on exocrine secretions caused by H1 and H2 receptor stimulation?
increased, due to increased blood flow
What are the pathological roles of histamine?
The most important clinical roles of histamine are:
- Acute inflammation (H1 effects)
- Stimulating gastric acid secretion (H2)
What is the triple response in acute inflammation?
reddening (local vasodilation), wheal and flare
What is antidromic impulse?
Antidromic impulse refers to impulse conduction along the nerve fibre in a direction that is opposite of normal direction (orthodromic) is conduction along the axon away from axon terminal towards the cell body
Antidromic impulses in nerve fibres may be produced by electrical stimulation.
Antidromic impulses release neuropeptides which cause vasodilation distant from the site of irritation → the third phase of inflammation, the flare response
When histamine stimulates afferent fibres, it is known to stimulate an axon reflex:
It orthodromically stimulates nerve impulse travel towards the spinal cord and the dorsal root ganglia, passing antidromically down the other branches of sensory nerves. These antidromic impulses release nerve impulses → vasodilation (flare, reddening) distant from the site of irritation
Degranulation of mast cells, changes in smooth muscle contractility, stimulation of lymphocytes and granulocytes → neurogenic inflammation (Kupfermann, 1991; Dockray, 1992)
About c fibres, substance P and inflammation…
Interestingly, the C fibers interact with the process of inflammation. Observe the figure below. The directions that action potentials conduct should seem quite surprising, because action potentials in certain branches of an afferent neuron aremoving peripherally!! The is called theaxon reflex. In this way, certain painful stimuli not only lead to the sensation of pain in the central nervous system, but also to the release of substance P locally. This increases inflammation by causing histamine release and dilation of blood vessels.
What is dermographia in the triple response?
Reddening: oedema (increase in vascular permeability induced by substance P (SP) and histamine increase in leakage of fluid and plasma proteins from capillaries (ie increase in plasma protein extravasation))
What H1 antagonists are used to treat acute inflammation?
1st Generation
- Mepyramine, diphenhydramine, promethazine
2nd and 3rd generation
- Terfenadine, pro-drug with potential cardiac arrhythmia actions in high concentrations, these are increased with grapefruit juice (which inhibits P450-mediated drug metabolism pathways in liver)
- Fexofenadine, active, non-toxic metabolite of terfenadine
What is the therapeutic and side effects of H1 antagonists?
- Reduce minor inflammatory reactions (eg insect bites, hayfever), BUT NO significant value in asthma
- 1st generation drugs are sedative – drowsiness is a major side effect, but sometimes used as a therapeutic effect
- some (eg promethazine) are anti-emetic – ‘motion sickness’
- anti-muscarinic actions (common in 1st generation drugs) eg atropine-like effects of blurred vision, constipation etc
What are the therapeutic and side effects of using H2 antagonists for gastric problems?
Archetypal
- cimetidine = tagamet
- ranitidine = zantac
Therapeutic and side effects
- reduce gastric acid secretion in treatment of duodenal and gastric ulcers and Zollinger-Ellison syndrome (duodenum and pancreas tumours increasing gastrin secretion)
- increase INMT activity so more rapid breakdown of histamine
- mental confusion, dizziness, tiredness and diarrhoea sometimes as side effects
- cimetidine, decrease in cytochrome P450 activity so adverse drug interaction potential, gynecomastia
What is the generation of bradykinin a result of?
The generation of bradykinin as a result of activation of:
- Hageman factor (HF) and production of plasma kallikrein
- Production of Iysylbradykinin by tissue kallikreins
- Action of cellular proteases in kinin formation
Hageman factor = coagulation factor XII
What is the synthesis of bradykinin via the kinin-kvllikrein system?
Fibrin formation. Fibrin formation from exuded fibrinogen may mechanically impede the movement of micro-organisms, trapping them and so facilitating phagocytosis.
kallidin (bradykinin with a lysyl group attached to the amino terminus)- the lysyl group is removed by aminopeptidase
Bradykinin is metabolised by ACE, aminopeptidase, carboxypeptidase
It is unlikely that binding to negatively charged surfaces alone is sufficient to activate XII, since highly purified preparations of XII and plasma deficient in prekallikrein and high molecular weight kininogen do not undergo this “autocatalysis”
What are the pharmacological effects of bradykinin?
- Potent vasoactive peptide
- Increase vascular permeability
- Vasodilation (decreased BP)
- Pain
- Contraction of smooth muscle (gut and bronchus)
- Stimulation of arachidonic acid metabolism (initiates phospholipase action)
- Chemotactic to leukocytes, which defend the body against infections
- Dry cough
What is the metabolism of bradykinin via?
kininases (ACE, amino peptidase P, carboxypeptidase)
What are the effects of kinins?
- blood coagulation
- regulation of BP & blood flow via RAAS
- cellular proliferation and growth
- angiogenesis
- apoptosis
- inflammation
- vasodilation
- ↑ vascular permeability
- release of tPA
- production of NO
- mobilisation of AA (PGI2, an antiaggregatory vasodilator) by endothelial cells
What is the distribution of 5-HT?
- platelets release 5-HT (and TXA2)
- the EC cells of gastrointestinal tract (mediates gut movement, diarrhoea)
- brain (cognition, aggression, mating, feeding, sleep, pain, vomiting and regulation of behaviour
- some tumours (eg carcinoid) secrete excess 5-HT
Carcinoid - is a slow-growing type of neuroendocrine tumour originating in the cells of the neuroendocrine system
5HT is mainly found in EC cells (distributed in the epithelium small intestine, colon and stomach.
Mediates peristaltic and vagal reflexes. Important in the generation of nausea (via 5-HT3 receptor mediation) – ondansetron (antiemetic) is an antagonist at 5HT3 receptors
What are the inflammatory actions of 5-HT?
• 5-HT stimulates mast cell adhesion and migration
• 5-HT enhances inflammatory reactions of skin, lungs and gut
• 5-HT promotes inflammation by increasing the number of mast cells at the site of tissue injury
• 5-HT may synergise with TXA2 to stimulate platelet activity and vasoconstriction
o Activation of TXA2 receptors increases 5-HT-mediated responses in blood vessels
Why are eicosanoids important?
• Molecules with powerful inflammatory actions
• Targets of major anti-inflammatory drugs:
- NSAIDs
- Glucocorticoids
- Lipoxygenase inhibitors
- Leukotriene antagonists
Important: you need to know how Eicosanoids are made.
How are prostanoids formed?
¥ Prostanoids are not ‘ready-to-go’ (unlike histamine)
¥ Prostanoids are generated from arachidonic acid (AA, poly-unsaturated fatty acid). This is rate-limiting step
¥ AAs are produced from phospholipids (PLs) via 1-step/2-step pathways
¥ These steps are triggered by many agents, e.g. thrombin on platelets and antigen-antibody reactions on mast cells
Thrombin binds to platelet glycoprotein Ib (Gp Ib), and this interaction contributes to platelet activation.
Bradykinin and adrenaline are known initiators of the cascade and can initiate phospholipase action at the cell membrane.
What are cyclooxygenases?
¥ Conversion of AA to prostanoids requires the enzyme cyclooxygenase (COX)
¥ Two main isoforms COX-1 and COX-2
¥ COXs are fatty acids, attached to endoplasmic membrane
¥ COX-1
- constitutively active
- responsible for ‘physiological’ roles of PGs/TXs such as regulation of peripheral vascular resistance, renal blood flow, platelet aggregation, gastric cytoprotection
¥ COX-2
- Needs to be stimulated (e.g. by inflammatory cytokines- IL-1, TNF)
- Responsible for role of PGs/TXs in inflammatory responses (pain and fever)
¥
COX-3
- Variant of COX-1; pain perception of CNS
What is the cyclooxyrgenase pathway?
Membrane prostaglandin E2 synthase-1 (mPGES-1) is a terminal prostaglandin synthase that isomerizes PGH2 into PGE2.
Both lipopolysaccharide (LPS) and cytokines activate intracellular signaling cascades in endothelial cells in small blood vessels and in vascular-associated macrophages, termed perivascular cells, in the brain (Fig. 1) [5–7]. This cascade results in phospholipase A2 degrading phospholipids into arachidonic acid and increased expression of cyclooxygenase type 2 (COX-2) [8, 9]. COX-
2 converts arachidonic acids to PGH2, from which specific PG synthases synthesize various PGs [10, 11]. In addition, macrophages and dendritic cells of the abdominal cavity
including Kupffer cells in the liver can produce PGE2 in response to LPS [12, 13] and sensory neurons of the vagus nerves express receptors for PGE2 that can activate afferent
nerve fibers [14] (for review see [15, 16])
About anti-inflammatory lipid mediators: lipoxins and CyPGs…
There is a switch for PG synthesis from pro-inflammatory (PG & LTs) at onset of inflammation to anti-inflammatory lipoxins and 15dPGJ2 (cyPG) during resolution
¥ Activation of monocytes is important in their action
How?
Ð Lipoxins recruit monocytes to clear inflamed site of necrotic apoptotic neutrophils
¥ Regulate activation levels of neutrophils and dampen their damaging effects (↑phagocytosis of neutrophils)
By acting in concert with cyPGs,
¥ Promote phagocytic clearance of apoptotic cells by macrophages → resolution of inflammation
¥ CypG – inhibits macrophage activation→ ↓ uncontrolled tissue damage; ↓NF-B activation (helps to ↓ activation of inflammatory genes)
What are cyclopentenone prostaglandins (cyPG)?
Activated neutrophils control inflammation including mediator release from distant immune cells but simultaneously mediate pulmonary tissue damage. Thus, keeping in mind potential inflammatory adverse effects, modulation of neutrophil activation or trafficking might be a reasonable therapeutic approach in chest trauma-induced lung injury.
What are the actions of eicosanoids - local hormones?
¥ Cells specialise in making particular eicosanoids
- mast cells: PGD2
- platelets: TXA2
- endothelial cells: PGI2, PGE2
¥ Act at specific G-protein-coupled receptors
- PGs subtypes act at DP, FP, IP and EP (EP1, EP2, EP3) receptors
- TXs at TP receptors
¥ - LTs : LTB4 at BLT receptors; LTC4, LTD4 & LTE4 at Cys-LT receptors (-chemotactic; bronchoconstrictor & ↑ vascular permeability; oedema, ↑secretion of thick, viscous mucus)
¥ Exert diverse and often contradictory actions in inflammation
¥ Subjected to local inactivation
About EP receptors…
EP receptors are G-protein-coupled receptors and classified into four subtypes: EP1, EP2, EP3, and EP4. These receptors can be grouped into three categories on the basis of their signal transduction: the EP1 receptor increases intracellular Ca2+. The receptors, which mediate increases in intracellular cyclic adenosine monophosphate (cAMP), consist of the EP2 and EP4 receptors. The EP3 receptor expressed in the brain is an inhibitory receptor that mediates decreases in intracellular cAMP, although other splicing variants of the EP3R have different signaling pathways
About leukotriene receptor antagonists…
Examples: Zafirlukast, montelukast, pranlukast, zileuton
¥ Block receptor for cysteinyl LTs (LTC4, LTD4, LTE4, etc)
These LTs cause airway oedema, secretion of thick mucus and smooth muscle contraction
Receptor blockade is useful in following:
Ð Prevention of mild to moderate asthma
Ð Early to late bronchoconstrictor effects of allergens
Ð Exercise-induced asthma and asthma provoked by NSAIDs
What are side effects of leukotriene receptor antagonists?
Ð GI upset
Ð Irritability
Ð Dry mouth, thirst
Ð Rashes, oedema
What is more potent out of leukotrienes and histamine?
leukotrienes
About poly-unsaturated fat intake in disease…
- The poly-unsaturated fatty acids (PUFAs; omega-3 essential fatty acids) are of considerable interest because of their (perceived) beneficial effects for our health
- Substances such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oils play a significant part in inflammation
- Derivatives of EPA and DHA (resolvins and neuroprotectins, respectively) have anti-inflammatory actions
About poly-unsaturated fatty acids in inflammation…
¥ Fish oils provide substrates for the generation of alternative eicosanoids
¥ Fish oils cause increased proportion of ecosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in inflammatory cells at the expense of AA
¥ Less natural substrate (i.e., AA) is available, therefore there is ↓ production of PGE2, TXB2, LTB4, 5-HETE, LTE4
¥ Thus EPA and DHA act as substrates for the generation of alternative eicosanoids
Consequence of interaction of EPA with COX/LOX:
¥ ↑ LTB5, LTE4, 5-HPETE - eicosanoids of different structure to those generated from AA
¥ LTB5 is 10-100 less chemotactic to neutrophils
TXB2 (Thromboxane B2) is a stable metabolite of thromboxane A2 in platelets which may be released during anaphylaxis. Reportedly possesses chemotactic properties. Often used to measure arachidonic acid metabolism. It is a prostaglandin derivative that is released during anaphylaxis, which induces arterial contraction and platelet aggregation by stimulating TP-α receptors.
TXB2 is a stable, biologically inert metabolite formed from the non-enzymatic hydrolysis of TXA2, which has a half-life of about 30 seconds.1 Urinary analysis of TXB2 accurately reflects intrarenal TXA2 synthesis,2 while measurement of 11-dehydro and 2,3-dinor thromboxane metabolites gives the best estimate of systemic TXA2 secretion
What are the anti-inflammatory metabolites of EPA and DHA?
- A novel group of mediators have also been identified from COX-mediated action on EPA and DHA.
- E-series resolvins (resolvin D1-D4; EPA-derived mediators) have anti-inflammatory actions.
- Docosatrienes and neuroprotectins (D-series resolvins; DHA-derived mediators) also have anti-inflammatory effects.
What are the basics of NSAIDs?
• Archetypal NSAID is aspirin (ASA)
• NSAIDs are:
- Analgesic (prevention of pain)
- Anti-pyretic (lowering of raised temperature, fever)
- Anti-inflammatory (decrease an immune response)
• NSAIDS are used to treat:
- Low grade pain (chronic inflammation eg arthritis)
- Bone pain (cancer metastases)
- Fever (associated with infections)
- Inflammation (decrease symptoms – oedema, redness, itch)
Responses are depended on inhibitory profiles on different COXs.
What are the pharmacological mechanisms of NSAIDs?
Main therapeutic action is by inhibition of COX:
- COX converts AA to PGs and TXs
- COX-1 (constitutively active, platelets)
- COX-2 (inducible enzyme eg by IL-1beta and TNFalpha)
- Inhibition of COX-2 reduced PGs/TXs inflammatory agents
- Aspirin acts irreversibly on COX; others act reversibly and tis is significant in its use as a prophylactic in cardiovascular disease
- Older generation NSAIDs inhibit both COX-1 and COX-2
- Newer COX-2 selective agents are ‘super aspirins’?
- Paracetamol is a special case
About paracetamol…
• Analgesic without anti-inflammatory effects
• Little inhibiton of COX-1 or COX-2 in peripheral tissue
• Weakly inhibits COX-3 in CNS – this doesn’t explain all of its effects
• Modulates serotonergic neurotransmission??
• Inhibits COX-mediated generation of hydroxypeptides from AA metabolism?
- Hydroxypeptides stimulare COX activity
Other NSAIDs include etodolac, meloxicam, ibuprofen, naproxen, indomethacin, etc
What is the antipyretic action of NSAIDs?
• Bacterial endotoxins produced during infections stimulate macrophages to release interleukin-1 (IL-1)
• IL-1beta acts on the hypothalamus to cause PGE2 release (via COX-2)…
- Increased PGE2 depresses temperature sensitive neurons
• PGE2 elevates set point temperate – onset of fever
• NSAIDs block PGE2 production, so set point is lowered back to normal value and fever dissipates
• NSAIDs have no effect on normal body temperature
What is the analgesic action of NSAIDs?
- PGs sensitise and stimulate nociceptors
- Oedema produced by inflammation also directly activated nociceptive nerve fibres
- PGs interact synergistically with other pain producing substances (eg kinins, 5-HT, histamine) to produce hyperalgesia (increased sensitivity to pain)
- Blockade of PG production breaks this cycle and leads to pain relief
- Useful for pain associated with production of inflammatory agents (PGs/TXs) eg arthritis, toothache headache (as NSAIDs inhibit PGs-mediated vasodilatation)
COX-1, COX-2 and COX-2 inhibition in CNS.
What is the anti-inflammatory action of NSAIDs?
PGE2 and PGI2 have powerful acute inflammatory effects
- Arteriolar dilatation (increased blood flow)
- Increase permeability in post-capillary venules
- Both processes increase influx of inflammatory mediators into interstitial space
Inhibition of their formation reduced redness and swelling.
NSAIDs provide only ‘symptomatic relief’
- They do not cure the underlying cause of inflammation
- Eg help, but do not cure arthritis
Decreased COX-2-generated PGs; effects develop gradually.
What are the systems involved in the pharmacology of NSAIDs?
- Cardiovascular system
- Skeletal
- Gastrointestinal tract
- CNS
- Genital tract
- Kidney and body fluids
- Lung and respiratory
- Skin
How do NSAIDs act on the cardiovascular system?
TXA2 – major role in vascular haemostasis
- Platelet aggregation
- Vasoconstriction
NSAIDs decrease TXA2 (COX-1 product) levels and so increase bleeding time
- Possibly problematic in surgery or childbirth
Where platelet aggregation is increased in disease, aspirin has a role in prophylactic treatment.
Why is aspirin beneficial in cardiovascular disorders?
over time less irritant effects, benefit of PGI2 and PGE2 not lost
What effects do NSAIDs have on the skeletal system?
PGs with acute inflammatory effects contribute to swelling and pain in arthritis (joint pains)
- Arteriolar dilatation
- Increased microvascular permeability
- Hyperalgesia – increased sensitivity to pain
NSAIDs thus diminish these effects but do not treat the cause.
What effects do NSAIDs have on the GI tract?
PGs (PGE2/PGI2) important in protecting the gastric mucosa
- Stimulate mucus secretion
- Inhibit gastric acid secretion
NSAIDs decrease these cytoprotective mechanisms
- Bleeding and ulceration can result
Gastric side effects are the most common adverse reactions to older NSAIDs.
COX-2 selective inhibitors may be gastric-friendly’, as it is suggested that COX-1 is expressed in gut.
NSAIDs = acidic
They causes:
- Decreased mucus secretion
- Decreased HCO3-
- Increased acid secretion
- Increased LT production
- Increased blood loss
Interfere with tissue healing (COX-2 inhibition)
Nausea, dyspepsia, GI contraction (COX-1 inhibition)
What are COX-2 selective agents?
Examples: celecoxib, valdecoxib, etoricoxib, rofecoxib
¥ Etoricoxib is most selective COX-2 inhibitor
¥ They have no effect on TXA2 in platelets, but decrease PGI2 in blood vessels
¥ Rofecoxib – withdrawn due to CV effects
¥ Not suitable for RA/osteoarthritis; use meloxicam, etodolac, etc. instead
¥ COX-2 + NSAID → ULCER
¥ Diclofenac (an NSAID) - selective for COX-2, but inhibits COX-1 in GIT → ulcers
¥ Less effective analgesic - less inhibition of COX-3 in brain and spinal cord
What are the effects of NSAIDs on the CNS?
- NSAIDs inhibit pyrexia – therapeutic use
- In overdose NSAIDs produce paradoxical hyperpyrexia, stupor and coma
increased metabolism and increased metabolic acid production - Reye’s syndrome risk (brain and liver damage) when used in children with influenza or chicken pox
What are the effects of NSAIDs on the genital tract?
¥ PGs cause pain and smooth muscle spasm during menstruation - NSAIDs used as treatment
Ð Note mefanamic acid reduces blood loss
Ð NSAIDs may be useful in primary dysmenorrhoea
¥ PGs (PGE2 and PGF2α) - important in uterine contractions in childbirth, thus NSAIDs delay contractions
¥ Many NSAIDs increase post partum blood loss because TXA2 production prevented
¥ NSAIDs delay and retard labour
What are the effects of NSAIDs on the kidney?
¥ Vasodilator PGs (E2/I2) regulate renal blood flow
¥ NSAIDs thus reduce renal blood flow
Ð Chronic renal injury may result
Ð Effectiveness of some antihypertensive drugs is reduced by concurrent treatment with NSAIDs
Ð Inhibition of COX-2 ↓ sodium excretion and ↑intravascular volume
Ð Average BP rise = 3/2 mmHg, but varies
Ð Low dose aspirin doesn’t seem to interfere with antihypertensive therapy, but regular use should be avoided
What are the effects of NSAIDs on the respiratory system?
¥ PGs (PGD2, PGF2α) have both constrictor and dilatator effects on airway smooth muscle - but NSAIDS have no effect on normal airway tone
¥ BUT NSAIDs must be avoided or used with caution in asthma
Ð ca. 20% asthma patients wheeze when given aspirin or other NSAIDs because they are hypersensitive to these drugs
¥ At toxic doses aspirin initially stimulates respiration
Ð Actions on respiratory centre and uncoupling of oxidative phosphorylation - medulla stimulated
Ð Respiratory alkalosis caused by hyperventilation (→CO2 washout from lungs)
What are the other indications of NSAIDs?
¥ Helps to achieve closure of patent ductus arteriosus in neonate, if patency is inappropriately maintained by PGE2, PGI2 production (indomethacin, ibuprofen)
¥ Surgical closure
¥ Do not give NSAIDs in 3rd trimester to avoid premature closure of ductus
Low birth weight infants
Treatment is individualised
May close by age 1
Fast breathing/shortness of breath;
Sweating while feeding;
Tiring very easily
- Decrease colonic polyps and prevent colon cancer
- May decrease Alzheimer’s disease risk
- Post-operative pain relief
- Renal colic – upper part of abdominal pain/groin usually caused by kidney stones
What are the aims of treatment of ulcerative colitis?
¥ Reduce symptoms, known as inducing remission (a period without symptoms)
¥ Maintain remission
¥ First-line treatment options: aminosalicylates (sulfasalazine and mesalazine)
¥ ↓ inflammation for mildor moderate ulcerative colitis.
¥ Short-term treatment of flare-ups.
¥ Useful in the long term to maintain remission.
What is the mechanism of action of sulfasalazine?
¥ Metabolised to 5-aminosalicylic acid (5-ASA), and sulfapyridine
¥ Reduces the synthesis of eicosanoids by blocking the activity of cyclooxygenase and lipoxygenase
¥ Cyclooxygenase and lipoxygenase activities are high in ulcerative colitis?
