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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
Q

CYCLOSPORINE: MECHANISM OF ACTION

A
  • 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
26
Q

CYCLOSPORINE: USES

A
  • 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
27
Q

CYCLOSPORINE: ADVERSE EFFECTS

A
  • 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
Q

CYCLOSPORINE: PHARMACOKINETICS DRUG INTERACTIONS

A
  • 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
Q

CYCLOSPORINE: Tacrolimus (FK506)

A
  • 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
Q

GLUCOCORTICOIDS: OVERVIEW

A
  • 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
Q

GLUCOCORTICOIDS: PHARMACOLOGICAL EFFECTS

A
  • 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
Q

GLUCOCORTICOIDS: MECHANISM OF ACTION

A
  • 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
Q

GLUCOCORTICOIDS: CLINICAL USES

A
  • 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
Q

ADVERSE EFFECTS OF CORTICOSTEROIDS

A
  • 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
Q

ANTIRHEUMATIC DRUGS

A
  • 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
Q

DMARDs (DISEASE MODIFYING ANTIRHEUMATIC DRUGS)

A
  • 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
Q

Nonbiologic DMARDs: DMARDs include

A
  • 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
Q

Nonbiologic DMARDs: Methotrexate

A
  • 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
Q

Biologic DMARDs (bDMARDs)

A

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
Q

Biologic DMARDs (bDMARDs) Etanercept

A
  • 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
Q

DRUG SELECTION

A
  • 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
Q

PEPTIC ULCER: OVERVIEW

A
  • 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
Q

PEPTIC ULCER: RISK FACTORS

A
  • 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
Q

PEPTIC ULCER: H Pylori and peptic ulcer

A
  • 90% of duodenal ulcer patients and 70% of gastric ulcer patients→ infected with H. Pylori
  • 30% of gastric ulcers due to NSAIDs
45
Q

PEPTIC ULCER: Drug treatment approaches

A
  • Eradicating Helicobacter pylori infection
  • Reducing secretion of gastric acid
  • Neutralising the acid after its is released
  • Increasing mucosal resistance
46
Q

GROUPS OF ANTI-ULCER DRUGS: ANTIBIOTIC

A
  • 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
Q

GROUPS OF ANTI-ULCER DRUGS: ANTISECRETORY AGENTS: H2 ANTAGONISTS

A
  • 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
Q

GROUPS OF ANTI-ULCER DRUGS: ANTISECRETORY AGENTS: PROTON PUMP INHIBITORS

A
  • 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
Q

GROUPS OF ANTI-ULCER DRUGS: MUCOSAL PROTECTANTS

Colloidal bismuth sucralfate

A
  • 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
Q

GROUPS OF ANTI-ULCER DRUGS: ANTACIDS

A
  • 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
Q

GROUPS OF ANTI-ULCER DRUGS: ANTIMICROBIAL AGENTS

A
  • 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
Q

VOMITING (EMESIS) OVERVIEW

A
  • 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
Q

VOMITING (EMESIS) CAUSES

A
  • Emesis is causes by the ‘Ems’
  • Medications, motion sickness, metastases, meningeal irritation, mental anxiety, mucosal irritation, mechanical obstruction, motility, metabolic, microbes, myocardial
54
Q

CLASSIFICATION OF ANTIEMETICS: Serotonin (5HT3) receptor antagonists

A
  • 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
Q

CLASSIFICATION OF ANTIEMETICS: Dopamine (D2) receptor antagonists

A
  • 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
Q

CLASSIFICATION OF ANTIEMETICS: Dopamine (D2) receptor antagonists: Metoclopramide (MAXOLON)

A
  • 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
Q

CLASSIFICATION OF ANTIEMETICS: Dopamine (D2) receptor antagonists: Domperidone

A
  • 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
Q

CLASSIFICATION OF ANTIEMETICS: Histamine H1 receptor antagonists

A
  • 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
Q

CLASSIFICATION OF ANTIEMETICS: Muscarinic (ACh) antagonists

A
  • 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
Q

CLASSIFICATION OF ANTIEMETICS: Substance P/Neurokinin NK1 receptor antagonists–> Aprepitant (EMEND)

A
  • 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
Q

CLASSIFICATION OF ANTIEMETICS: Substance P/Neurokinin NK1 receptor antagonists–> Neurokinin Antagonists

A
  • 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
Q

CLASSIFICATION OF ANTIEMETICS: Glucocorticoids

Dexamethasone

A
  • 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
Q

CLASSIFICATION OF ANTIEMETICS: Cannabinoids

A
  • 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
Q

NAUSEA AND VOMITING IN PREGNANCY (NVP)

A
  • 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
Q

TREATMENT OF MOTION SICKNESS

A
  • 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
Q

CINV→ CHEMOTHERAPY INDUCED NAUSEA AND VOMITING

A
  • 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