WEEK 7 Flashcards
(66 cards)
1
Q
MEDIATORS OF INFLAMMATION
A
- Inflammatory mediators (initiate and control inflammation) include histamine, kinins (bradykinin), neuropeptides, cytokines, eicosanoids etc
- What are eicosanoids? (prostaglandins)
- Group of polyunsaturated fatty acids
- Formed from arachidonic acid in phospholipid layer of cell membranes
- Important→ involved in majority of inflammatory reactions
- Most anti-inflammatory therapy is based on the manipulation of their biosynthesis
2
Q
PROSTAGLANDINS (PGs) (eicosanoids)
A
- Kidney→ maintaining renal blood flow
- Inflammation → vasodilation and increased capillary permeability
- Stomach→ Lowers acid/ pepsin secretion, increases mucus secretion
- Platelets→ Aggregation
- Pain→ Central and peripheral mediator release
- Fever→ Pyrogen production
- Pregnant uterus→ Smooth muscle contraction
3
Q
ANTI-INFLAMMATORY DRUGS
A
- Main drugs used for their broad spectrum anti-inflammatory effects are: NSAIDS and Steroidal anti-inflammatory drugs (glucocorticoids)
- Both classes exert their effect by inhibiting the formation of eicosanoids
- Anti inflammatory drugs used under more limited circumstances include:
- Disease modifying anti rheumatic drugs (DMARDS)
- Drugs used to treat gout
- Antihistamines
4
Q
NSAIDs (Non steroidal anti-inflammatory drugs) OVERVIEW
A
- Grouped based on common mechanism of action- inhibition of cyclooxygenase (COX)
- Mixture of synthetic and semisynthetic drugs, >50 on the market
- First- generation NSAIDs– aspirin & Second generation NSAIDs- coxibs
5
Q
NSAIDs (Non steroidal anti-inflammatory drugs) Pharmacological actions of NSAIDs
A
- Drugs share common therapeutic properties; analgesia (pain), anti-inflammatory (inflammation) anti-pyretic (fever)
- Antiplatelet effect; aspirin inhibits platelet aggregation; irreversible inhibition of COX1→ reduced thromboxane synthesis→ use after myocardial infarction and stroke to prevent vascular occlusion
6
Q
NSAIDs (Non steroidal anti-inflammatory drugs) ANALGESIC ACTIONS
A
- Peripheral effects→anti-inflammatory action→ inhibits PG production at site of pain and inflammation
- PGs (E&F) sensitise nociceptive fibre nerve endings to other inflammatory mediators (e.g. histamine) amplifying basic pain message
- Small component of analgesic action is due to a central effect (mainly in the spinal cord) reducing PG synthesis
7
Q
NSAIDs (Non steroidal anti-inflammatory drugs) ANTI-INFLAMMATORY ACTIONS
A
- PGs produce vasodilation; facilitates actions of other mediators → Increased vascular permeability leading to oedema
- Inhibition of PG synthesis reduces this part of inflammatory reaction
- NSAIDs do not inhibit other mediators involved in an inflammatory reaction; thus inflammatory cell accumulation for example, is not inhibited
8
Q
NSAIDs (Non steroidal anti-inflammatory drugs) ANTIPYRETIC ACTIONS
A
- During a fever, leukocytes release inflammatory pyrogens (e.g IL-1) as part of the immune response
- IL-1 stimulates generation of PAGEs in hypothalamus which cause the set-point for temp to increase
- The antipyretic effect of NSAIDs is largely through their inhibition of PGE production
- NSAIDs do not affect temperature under normal circumstances or in heat stroke
9
Q
NSAIDs (Non steroidal anti-inflammatory drugs) ANTIPLATELET ACTION
A
- Aspirin inhibits platelet aggregation due to irreversible inhibition of COX-1→ reduced thromboxane (TXA2) synthesis
- Use after myocardial infarction and stroke to prevent vascular occlusion; Increased bleeding time as a side effect
- Antiplatelet action may link to the chemopreventive properties of NSAIDs against colorectal cancer
10
Q
NSAIDs (Non steroidal anti-inflammatory drugs) MECHANISMS OF ACTION
A
- All NSAIDs possess the ability to inhibition the enzyme cyclooxygenase
- COX is involved in the metabolism of arachidonic acid to form the prostanoids i.e. the classical prostaglandins (PGs) prostacyclin (PGI2) and thromboxane A2 (TXA2)
Mechanisms for Inhibition of COX
- Most NSAIDs enter the long channel in COX enzymes and bind with hydrogen bonds to an arginine halfway down
- Reversibly inhibits the enzymes by preventing access of arachidonic acid
11
Q
ISOFORMS OF CYCLOOXYGENASE: COX 1
A
- Expressed in most tissues and involved in physiological cell signalling
- Most adverse effects are caused by inhibition of COX-1
12
Q
ISOFORMS OF CYCLOOXYGENASE: COX 2
A
- Mainly induced at sites of inflammation and produces the prostanoids involved in inflammatory responses
- Analgesic and anti-inflammatory effects of - NSAIDs are largely due to inhibition of COX-2
13
Q
ASPIRIN
A
- Drug of choice for many sorts of mild pain despite a relatively high incidence of GI effects
- Used for antiplatelet action following MI → Low doses of aspirin used prophylactically to decrease the incidence of transient ischaemic attack
- Used as antipyretics and analgesics in the treatment of rheumatic fever, and rheumatoid arthritis
14
Q
IBUPROFEN AND PIROXICAM
A
- Ibuprofen is effective and well tolerated→ Drug of choice for inflammatory joint disease, owing to its low incidence of side effects
- Used for pain- dysmenorrhea
- Piroxicam - is a potent drug widely used for chronic inflammatory conditions (e.g. arthritis)
- Given only once daily (t1/2 50 hr) but causes a relatively high incidence of gastrointestinal problems (COX-2 Selective)
15
Q
PARACETAMOL
A
- Used as an analgesic and antipyretic only and not as an anti-inflammatory drug (no anti-inflammatory effect)
- Effective for pain, especially headaches and fever
- Used in combination of aspirin (Excedrin)
- Causes a serious, potentially fatal hepatotoxicity in toxic doses (>2-3 times therapeutic)
- Saturates normal liver conjugation systems
Formation of a toxic metabolite, N-acetyl-p-benzoquinone (NPBQI) - Treat with N-acetyl cysteine to increase GSH levels - neutralises
16
Q
ADVERSE EFFECTS OF NSAIDS:
A
- Common, particularly in the elderly and chronic users
- Primarily arise from non-selective inhibition of COX1 and COX2 synthesis
- Most common and serious side effects are:
- Epigastric distress- peptic ulcer, nausea and vomiting
- Microscopic bleeding- almost all patients treated with aspirin
- Renal impairment
- Aspirin should be taken with food and large volumes of fluids to minimise GI disturbances
17
Q
ADVERSE EFFECTS OF NSAIDS: ACTIONS ON GIT
A
- Normally→ PGI2 inhibits gastric acid secretion, whereas PGE2 and PGF2a stimulate synthesis of protective mucus
- Aspirin causes a decrease in PGS and causes: Increase in gastric acid secretion and decrease in mucus protection → May cause pangastritis, ulceration and/or haemorrhage
18
Q
ADVERSE EFFECTS OF NSAIDS: ACTIONS ON KIDNEY
A
- Aspirin can cause acute reversible renal impairment because prostaglandins promote renal blood flow
- Inhibition of PGs may lead to
- Decreased glomerular filtration
- Fluid and NA+ retention- hypertension
- Oedema and hyperkalaemia
- Precipitating renal failure in compromised patients and athletes
19
Q
ADVERSE EFFECTS OF NSAIDS: ADVERSE EFFECTS ON BLOOD
A
- Prolonged bleeding time resulting from inhibition of platelet aggregation → contraindicated for patients with bleeding disorders
- Aspirin (high dose) should not be taken for at least 1 week before surgery
- If taking salicylates, anticoagulants may have to be given at lower dosages
20
Q
ISSUES WITH COX-2 SELECTIVE INHIBITORS
A
- Developed on the theory that selective inhibition of COX-2 only should be able to suppress pain and inflammation posing little or no risk of gastric ulceration
- With coxibs, patients can develop significant gastroduodenal ulcer and bleeding
- Coxibs increase the risk of heart attack since the protective anti-coagulative effect of PGF2 is decreased
- 2 coxibs (rofecoxib and valdecoxib) have been withdrawn as a result. Sales of remaining agents declined since then
- They also slow healing of peptic ulcers
21
Q
IMMUNOSUPPRESSIVE DRUGS: OVERVIEW
A
- Drugs that inhibit immune responses
- Prevention and treatment of organ rejection and autoimmune disorders
- 2 major toxicities: increased risk of infection and increased risk of cancer
22
Q
IMMUNOSUPPRESSIVE DRUGS: CLASSIFICATIONS
A
- Inhibitors of IL-2 production or action → Cyclosporine and tacrolimus
- Inhibitors of cytokine gene expression → Corticosteroids e.g. prednis(ol)one
- Inhibitors of purine or pyrimidine synthesis (block DNA synthesis) → Azathioprine and leflunomide
- Blockers of T-cell surface molecules involved in signaling → bDMARDS/anti cytokines e.g. infliximab and anakinra
23
Q
IMMUNOSUPPRESSIVE DRUGS: CLINICAL USES
A
- Suppress rejection of transplanted organs and tissues
- Suppress graft-vs-host disease in bone marrow transplantation
- Treat conditions with an autoimmune components including rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus etc
24
Q
CYCLOSPORINE: OVERVIEW
A
- Most important immunosuppressive agent in transplantation
- Cyclic peptide of 11 amino acids derived from the fungus Tolypocladium inflatum Gams
- Crucial for the development of transplant surgery
25
CYCLOSPORINE: MECHANISM OF ACTION
- Selective inhibitory effect on lymphocytes, inhibits IL- 2 gene transcription→ decreased proliferation of B cells and cytotoxic T cells
- Decreased expression of IL-2 receptors
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CYCLOSPORINE: USES
- Key drug used in prevention and treatment of transplant rejection (kidney, heart, liver etc)
- Used routinely with corticosteroids
- Also used in the treatment of autoimmune disorders
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CYCLOSPORINE: ADVERSE EFFECTS
- Nephrotoxicity is the major side effect, up to 75% of treated patients. Renal damage can be intensified by concurrent use of other nephrotic drugs
- Infections: Risk increase for infectious complications in 74% of patients
- Hepatotoxicity occurs in 4-7% of patients
- Hypertension (reduced by fish oil)
- Gum hyperplasia
- Increased risk of lymphomas
28
CYCLOSPORINE: PHARMACOKINETICS DRUG INTERACTIONS
- Most of cyclosporine in the body is bound, - 60-70% to RBC, 10-20% to WBC and plasma protein
- Can be administered orally or IV
- Undergo extensive metabolism by hepatic microsomal enzymes. CYP3A4 inhibitors (diltiazem ketoconazole, erythromycin) increased levels and enzyme inducer (phenytoin, rifampicin, st john's wort) decreased levels
- Grapefruit juice→ increases cyclosporine by 50%-200%
29
CYCLOSPORINE: Tacrolimus (FK506)
- Also known as FK506 is alternative to cyclosporine
- A macrolide antibiotic of fungal origin with similar mechanism of action
- Comparatively new, more potent (ug/kg) and more effective than cyclosporine
- Side effects: More toxic, more patients discontinue the drug due to its toxicity
- Therapeutic use: Prophylaxis of organ rejection in patients receiving liver, kidney or heart transplants
30
GLUCOCORTICOIDS: OVERVIEW
- Early phase of inflammation→ inhibit initial redness, heat, pain, swelling
- Late phase of inflammation inhibit→ wound healing and repair (adverse effects) and proliferative reactions in chronic inflammation (therapeutic)
- Reverse inflammation caused by→ Pathogens, Chemical/physical stimuli, Inappropriate immune responses in hypersensitivity and autoimmunity
31
GLUCOCORTICOIDS: PHARMACOLOGICAL EFFECTS
- Anti-inflammatory→ decreased pain, swelling, redness, warmth
- Immunosuppressant→ decreased lymphocytes
- Effects of metabolism and electrolytes→ decreased protein synthesis→ growth retardation, increased glucose level, fat deposits are mobilise and increased sodium and decreased potassium
32
GLUCOCORTICOIDS: MECHANISM OF ACTION
- Bind intracellular receptors that then dimerise, migrate to the nucleus and modify gene transcription
- Effects are complex- known actions include
- Decreased transcription of genes for COX-2 (decreased PGs), IL-1, IL-2 to IL-6 and IL-8, TNF-a, IFN-y cell adhesion molecules, iNOS
- Decreased histamine release from basophils
- Decreased activation of T helper cells and decreased proliferation of T cells
- Increased synthesis of anti-inflammatory agents
- Block of Vit D3 mediated induction of of osteocalcin gene in osteoblasts and increased activation of osteoclasts (osteoporosis)
- Decreased fibroblast, decreased production of collagen (decreased wound healing)
33
GLUCOCORTICOIDS: CLINICAL USES
- Anti Inflammatory and immunosuppressive uses of glucocorticoids
- Diseases with autoimmune and inflammatory components (e.g. rheumatoid arthritis, inflammatory bowel disease, some haemolytic anaemias)
- Prevention of graft vs host disease following organ or bone marrow transplantation
- Also used in
- Asthma
- Topically in inflammatory conditions of skin, eye, nose or ear (e.g. rhinitis, eczema, allergic conjunctivitis)
- Hypersensitivity states (e.g. severe allergic reaction)
34
ADVERSE EFFECTS OF CORTICOSTEROIDS
- Iatrogenic Cushing's syndrome
- Immunosuppression, risk of infections
- Osteoporosis
- Metabolic effects (e.g. diabetes, hypertriglyceridemia)
- Increased appetite, weight gain, redistribution of fat, buffalo hump, moon face, skin atrophy, growth retardation
- Psychological disturbances
- Poor wound healing, myopathy, easy bruising
- Sodium retaining effects, hypokalaemic alkalosis
- Hypertension
35
ANTIRHEUMATIC DRUGS
- Rheumatoid arthritis is one of the most common chronic inflammatory diseases
- Autoimmune disease with joint changes → Inflammation, Proliferation of the synovium, Erosion of bone and cartilage
- Cytokines, IL-1 and TNF-a play a major role in the pathogenesis
- Most commonly used drugs are NSAIDS, DMARDs and Steroids
36
DMARDs (DISEASE MODIFYING ANTIRHEUMATIC DRUGS)
- Drugs that reduce joint destruction and retard disease progression
- Therapeutic benefits develop slowly, usually more toxic→ close monitoring required
- Nonbiologic DMARDs and biologic DMARDs (bDMARDs)
37
Nonbiologic DMARDs: DMARDs include
- Methotrexate (first drug of choice in RA) - folate antagonist
- Sulfasalazine - NSAID/ antibacterial putative radical scavenger
- Hydroxychloroquine- antimalarial MOA unclear
- Leflunomide- inhibits pyrimidine synthesis
- Cyclosporine- inhibits IL-2 production
Others
- Azathioprine- inhibits purine synthesis
- Gold (sodium aurothiomalate) MOA unclear
- Mycophenolate mofetil→ decreased purine synthesis
38
Nonbiologic DMARDs: Methotrexate
- Drug of choice of RA, faster than all others
- Folic acid antagonist (inhibits dihydrofolate reductase)
- More rapid action than other DMARDs
- More than 50% of patients continue within for >5 years, (ca. 50% stop other DMARDs within 2 years)
- Nausea and mouth ulcers- treat by dose reduction, folic acid co-administration and SC or IM injection
- Can cause blood dyscrasias (some fatal) and liver cirrhosis, is teratogenic and contraindicated in renal impairment
- Drug interactions with trimethoprim and triamterene (folate synthesis inhibitors)
39
Biologic DMARDs (bDMARDs)
Pro inflammatory cytokines TNFa and IL-1 play a major role in RA
Biological disease modoying antirheumatic drugs (bDMARDS)
Also known as anti cytokines
Recombinant engineered antibodies
Anti-TNF agents
Antibodies to TNF-a
Soluble TNF receptor fused to IgG- Etanercept
Anti- IL1 agents
Interleukin- 1 (IL-1) receptor antagonist
40
Biologic DMARDs (bDMARDs) Etanercept
- Action: Highly effective at reducing RA symptoms and disease progression
- Mechanism of action: Suppresses inflammation by neutralising TNF
- Uses: for moderately to severely active RA, superior to methotrexate, affect more rapidly, used in Crohn's disease, psoriatic arthritis and ankylosing spondylitis
- Adverse effects: potential long-term effects unknown. Can cause serious infection.
- Other side effects: injection site reaction, heart failure, cancer, can also cause blood dyscrasias and demyelinating CNS disorders (MS like) but minimal
41
DRUG SELECTION
- The 3 major groups differ in time course of effects, toxicity and ability to slow RA progression
- NSAIDS provide rapid relief of symptoms only
- Glucocorticoids→ symptoms relief and disease progression decreases, serious toxicity
- DMARDs→ decreased joint destruction and disease progression. Slow, more toxic
- Current treatment is more aggressive and starting DMARDs early is recommended
42
PEPTIC ULCER: OVERVIEW
- Ulcer in the lower esophagus, stomach or duodenum
- Develop when there is an imbalance between mucosal defensive factors and aggressive factors
- Major defensive factors are mucus, bicarbonate, prostaglandin, NO and growth factors
- Major aggressive: H. pylori, NSAID, gastric acid and pepsin
- Duodenal ulcers 4x more frequent than gastric, esophageal
- Release of hydrochloric acid (HCL) from the parietal cells of the stomach influenced by histamine, gastrin and acetylcholine
43
PEPTIC ULCER: RISK FACTORS
- H. Pylori infection of the gastric and or duodenal mucosa
- Long term use of NSAIDS (aspirin, iruporgen)
- Alcohol and Smoking
- Chronic diseases (emphysema, rheumatoid arthritis, diabetes)
44
PEPTIC ULCER: H Pylori and peptic ulcer
- 90% of duodenal ulcer patients and 70% of gastric ulcer patients→ infected with H. Pylori
- 30% of gastric ulcers due to NSAIDs
45
PEPTIC ULCER: Drug treatment approaches
- Eradicating Helicobacter pylori infection
- Reducing secretion of gastric acid
- Neutralising the acid after its is released
- Increasing mucosal resistance
46
GROUPS OF ANTI-ULCER DRUGS: ANTIBIOTIC
- All patients with proven duodenal ulcer and those with gastric ulcers who are H pylori- positive should be offered eradication as primary therapy
- First- line therapy→ a proton pump inhibitor + clarithromycin 500mg and amoxicillin 1g or metronidazole 400mg for 7-14 days
- Second - line therapy→ a proton pump inhibitor, bismuth 120 mg, metronidazole 400mg, and tetracycline 500mg for 7-14 days
- Common side effects: Diarrhoea (30-50% of patients; usually mild) Flushing and vomiting when taken with alcohol (metronidazole) Nausea, vomiting, abdominal cramp, headache, rash
47
GROUPS OF ANTI-ULCER DRUGS: ANTISECRETORY AGENTS: H2 ANTAGONISTS
- Histamine H2- receptor antagonist
- Block the action of histamine (H2 receptors) on the parietal cells and reduce acid secretion.
- Relieve the pain of peptic ulcer and increase healing
- Rapid absorbed orally, full course is 6 weeks, used in peptic ulcers, zollinger- Ellison syndrome etc
- Side effects: Usually minor, headaches, dizziness, confusion, diarrhea muscle pain, antiandrogenic effect→ gynecomastia, reduced libido, pneumonia
48
GROUPS OF ANTI-ULCER DRUGS: ANTISECRETORY AGENTS: PROTON PUMP INHIBITORS
- Proton pump inhibitor (omeprazole)
- Bind to the H+/ K+-ATPase enzyme system (proton pump) or parietal cell, suppressing secretion of H+ into the gastric lumen→ >90% inhibition
- Used for short term treatment of erosive esophagitis and active duodenal ulcer. Treatment of pathologic hypersecretory conditions
- Adverse effect→ minor effects: pneumonia, fractures, rebound acid hypersecretion, hypomagnesemia
49
GROUPS OF ANTI-ULCER DRUGS: MUCOSAL PROTECTANTS
| Colloidal bismuth sucralfate
- Coat ulcer crater and protect it from the corrosive actions of acid and pepsin, inactivate pepsin
- Alternative for patients who cannot tolerate H2 antagonists, or for long term maintenance
- Well tolerated, constipation is common
50
GROUPS OF ANTI-ULCER DRUGS: ANTACIDS
- Raise the luminal PH of the stomach, frequent disease increase ulcer healing
- Sodium bicarbonate→ water soluble, rapid action→ systemic alkalosis
- Magnesium hydroxide→ fairly rapid→ diarrhoea
- Aluminum hydroxide→ slower action→ constipation
51
GROUPS OF ANTI-ULCER DRUGS: ANTIMICROBIAL AGENTS
- Eradication of H pylori→ rapid healing and low recurrence rate
- Standard triple therapy: bismuth, metronidazole and tetracycline for 2 weeks→ - 90% eradication rate
- Treatment with a single antimicrobial drug is less effective (20-40%)
52
VOMITING (EMESIS) OVERVIEW
- Complex reflex brought about by activation of the vomiting center (VC) which requires its principal stimulatory inputs from the chemoreceptor trigger zone (CTZ) cerebral cortex, and inner ear. It is a forceful expulsion of gastric contents through the mouth
- Maybe accompanied by retching→ repetititve contraction of abdominal muscles with or without actual vomiting
- Can be life saving - ingestion of toxic substance (e.g. alcohol, tainted food)
53
VOMITING (EMESIS) CAUSES
- Emesis is causes by the ‘Ems’
- Medications, motion sickness, metastases, meningeal irritation, mental anxiety, mucosal irritation, mechanical obstruction, motility, metabolic, microbes, myocardial
54
CLASSIFICATION OF ANTIEMETICS: Serotonin (5HT3) receptor antagonists
- The most effective drugs available for CINV (chemotherapy induced nausea and vomiting)
- Blocks the depolarising action of serotonin (5- hydroxytryptamine) through 5HT3 receptors on vagal visceral afferents in GIT as well as CTZ (chemoreceptor trigger zone)
- Useful for treating
- Cytotoxic drug induced vomiting , Radiation induced vomiting, Post op nausea and vomiting
- Ondansetron, dolasetron, granisetron, tropisetron
- Well tolerated with minor side effects → Headache, flushing, constipation or diarrhoea, abdominal discomfort, and rash on IV injection
- Only given during first 24 hours of cytotoxic drug treatment
55
CLASSIFICATION OF ANTIEMETICS: Dopamine (D2) receptor antagonists
- Broad spectrum antiemetics
- Act by blocking dopamine D2 receptors in CTZ
- Useful for more severe NV:
- Drug induced, Disease induced, Malignancy associated
- Side effects: Significant degree of sedation , Acute muscle dystonia, Extrapyramidal effects (parkinsonism)
56
CLASSIFICATION OF ANTIEMETICS: Dopamine (D2) receptor antagonists: Metoclopramide (MAXOLON)
- Acts through D2, 5HT4 and 5HT3 receptors (has prokinetic actions)
- Peripheral D2 antagonism→ Increases gastric emptying and enhances lower esophageal sphincter tone
- However Central D2 antagonist leads to → Extrapyramidal effects, hyperprolactinemia
5HT3 antagonist leads to → Minor increase in ACh release and central action appears only in large doses
- 5HT4 antagonist causes increased release of ACh leading to→ Decreased gastric emptying time and lower esophageal sphincter tone effects
57
CLASSIFICATION OF ANTIEMETICS: Dopamine (D2) receptor antagonists: Domperidone
- An antidopaminergic drug
- Blocks the action of dopamine, it has strong affinities for dopamine D2 and D3 receptors in the CTZ
- With low antiemetic actions, is used together with metoclopramide, cyclizine (antihistamine) and 5HT3 receptor antagonists (such as granisetron)
- Poorly crosses BBB
- Rare extrapyramidal effects
- Hyperprolactinemia can occur
58
CLASSIFICATION OF ANTIEMETICS: Histamine H1 receptor antagonists
- Antihistamines
- Block acetylcholine in the vestibular apparatus and histamine H1 receptors in the nucleus of the solitary tract
- Used for motion and morning sickness
- Afford protection for 4-6 hours, Given ½ to 1 hour before journey
- Dimenhydrinate or promethazine
- Cause sedation and impair vigilant performance
59
CLASSIFICATION OF ANTIEMETICS: Muscarinic (ACh) antagonists
- Anticholinergics
- Used in motion sickness
- Act by blocking cholinergic link from vestibular apparatus to vomiting centre
- Hyoscine (scopolamine) mainly used
- Dry mouth, blurred vision, sedation (although less than antihistamines)
60
CLASSIFICATION OF ANTIEMETICS: Substance P/Neurokinin NK1 receptor antagonists--> Aprepitant (EMEND)
- Selective, high affinity antagonist of human substance P at neurokinin 1 (NK1) receptors
- Interferes with the substance P pathway that produces N/V
- No affinity for 5HT3, DA or corticosteroid receptors
- Only used in combination with other antiemetics
- Indicated for the prevention of acute and delayed NV with highly emetogenic cancer chemotherapy
61
CLASSIFICATION OF ANTIEMETICS: Substance P/Neurokinin NK1 receptor antagonists--> Neurokinin Antagonists
- Substance P is the prototypic neuropeptide of the 50 known neuroactive molecules
- Now recognised as a member of the tachykinin family of neurotransmitters
- Neurokinins are tachykinins found in mammals (substance P, NKA, NKB)
- 3 categories of NK receptors (NK1, NK2, NK3)
- Currently considered a modulator of nociception, stress, anxiety, nausea, vomiting
62
CLASSIFICATION OF ANTIEMETICS: Glucocorticoids
| Dexamethasone
- Synthetic anti-inflammatory glucocorticoid
- Dexamethasone and methylprednisolone inhibit 5HT3 receptors at clinical concentrations
- Used to suppress CINV, short term and intermittent use only
- Only acute side effects: flushing and perineal itching- minor since only single dose given
63
CLASSIFICATION OF ANTIEMETICS: Cannabinoids
- Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy.
- Cannabis-based medications are based on its active element, delta-9-tetrahydrocannabinol (THC)
64
NAUSEA AND VOMITING IN PREGNANCY (NVP)
- MVP also called morning sickness occurring particularly in the first 3 months, can be very severe
- Nausea reported in 70-80% of pregnant women & vomiting occurs in approx 50% of pregnancies
- Drug use in NVP is problematic → as higher teratogenic effect during the 1st trimester
- Health conscious pregnant women usually do not take well proven safe drugs
- Can be treated with ginger and/or pyridoxine (B6)
- Only drug recommended is the H1 antihistamine doxylamine . either alone or with pyridoxine
65
TREATMENT OF MOTION SICKNESS
- Caused by→ Sea, air, automobile and space travel.
- Drug therapy is most effective when given prophylactically (preventative)
- Muscarinic antagonists is the most effective drug for prevention and treatment of motion sickness,
- Antihistamines→ Drugs block ACh receptors in addition to histamine receptors→ blocking pathway connecting inner ear to VC
- DA antagonists e.g. metoclopramide are ineffective
66
CINV→ CHEMOTHERAPY INDUCED NAUSEA AND VOMITING
- Many anticancer drugs cause severe NV→ dehydration, electrolyte imbalances, nutrient depletion and esophageal tears
- 3 types of emesis following cytotoxic chemotherapy
- Acute (post treatment) occurs within first 24 hours after administration of cancer chemotherapy, due to stimulation of CTZ
- Delayed→ CINV that begins after first 24 hours, may last for 120 hours. Unclear mechanism
- Anticipatory: learned or conditioned response from poorly controlled nausea and vomiting associated with previous chemotherapy
- Antiemetics are more effective when given before chemotherapy than when given after chemotherapy
- To suppress CINV, a combination of drugs is more effective than monotherapy
