Pharmacology π Flashcards
what is the definition of Rheumatoid arthritis (RA)?
a chronic, progressive inflammatory disease; characterized by symmetric small joint inflammation, swelling, and deformity and systemic manifestations.
Patho-Physiology of Rheumatoid arthritis (RA)
- The exact aetiology is unclear. However, genetic factors play an important role.
- Activated T cells, B cells, polymorphonuclear leukocytes (PMLS), macrophages, and complement system β-> production of soluble mediators (lysosymes, cytokines, e.g. TNF-a, IL-1, etc.) β> cause joint inflammation, cartilage destruction, bone erosion, and deformity.
what are the clinical manifestations of Rheumatoid arthritis (RA)?
Diagnosis of Rheumatoid arthritis (RA)
Serological
- Abnormal blood antibodies (rheumatoid factor) β> in 80% of RA patients.
- Elevated CRP & ESR
- Positive anti-CCP antibodies.
Joint X-ray
- can show joint swelling and bony erosions typical of RA.
what are the aim of drug treatment of Rheumatoid arthritis (RA)?
- To reduce pain, Stiffness & improve joint function (Symptomatic drug treatment)
- To prevent chronic deformity by arresting the inflammation that results in joint destruction (DMARDs)
symptomatic treatment of Rheumatoid arthritis (RA)
what is the importance of symptomatic treatment of Rheumatoid arthritis (RA)?
- NSAIDs and/or corticosteroids are used as a (bridge therapy) ββ> provide symptomatic relief till the therapeutic effect of DMARDs is observed.
what is the action done by DMARDs?
They prevent disease progression and slow down joint destruction by modifying the immune reactions.
when should DMARDs be started? and how many should be used?
- They should be started as early as possible (within 3 months of symptom onset) -> more favorable outcome.
- 1 or more DMARDs are used depending on disease severity.
How long is the lag between starting therapy by DMARDs & observing an effect?
There is a lag between starting therapy and observing an effect (3 weeks to 3 months).
It is usual to continue DMARDs with conventional NSAIDs drugs.
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what is the mechanism of action of Methotrexate?
- It is a folic acid antagonist β-> cytotoxic and immuno suppressant properties β-> inhibits cytokine production & nucleic acid biosynthesis β-> inhibits activation & proliferation of PMLs, T cells, and macrophages.
usage of Methotrexate
- It is used in more than 60% of RA cases.
- It is given once weekly orally.
how are the toxic effects of Methotrexate reversed?
by the subsequent administration of folinic acid (leucovorin)
adverse effects of Methotrexate
1) GIT: nausea and mucosal ulceration.
2) Myelosuppression especially leucopenia (periodic CBC).
3) Hepatotoxicity is common (monitoring liver functions is essential)
4) Acute pneumonia-like syndrome.
what is the mechanism of action of Leflunomide?
It inhibits the mitochondrial enzyme, dihydroorotate dehydrogenase (DHODH) β> inhibits pyrimidine base synthesis β-> suppresses T cell and B cell proliferation & activation.
what are the adverse effects of Leflunomide?
1) GIT: nausea & diarrhea
2) Hepatotoxicity
3) Hypokalemia
4) Alopecia & rash
what is the mechanism of action of Hydroxychloroquine?
unknown, but might be:
- Inhibition of phagocytic functions.
- Stabilization of lysosomal membranes
what are the side effects of Hydroxychloroquine?
- GIT: diarrhea
- Corneal deposits & Retinopathy: the most disturbing toxic effect, rare, is a result of gradual accumulation of the drug in the retina β> irreversible retinal damage with permanent blindness
- Skin discoloration & rash
- Hemolysis in G6PD deficiency.
what is the mechanism of action of Sulphasalazine?
- A prodrug β> cleaved by gut bacteria - 5-aminosalicylic acid & sulfapyridine.
- Sulfapyridine is thought to be the principal anti-rheumatic agent.
adverse effects of Sulphasalazine
- GIT: nausea, vomiting, diahrrea
- Myelosuppression: Occasional leucopenia and thrombocytopenia.
- Hemolysis in G6PD deficiency.
what is the mechanism of action of Cyclosporine?
- Cyclosporine β> bind cyclophilin β-> inhibit calcineurin β-> inhibit dephosphorylation of NFAT β-> decrease gene expression of IL-2 β-> inhibit T cell proliferation.
adverse effects of Cyclosporine
- Nephrotoxicity
- HTN, Hyperkalemia, Hirsutism, gingival Hyperplasia β4Hβ
what plays a central role in RA?
Inflammatory cytokines
what are biological DMARDs? and what is their method of adminstration?
- Biological DMARDs are antibodies and antibody fusion proteins that inhibit the action of cytokines by blocking the cytokine from binding to its specific receptor
- administered S.C or i.v.
what are the groups of antibodies used in treatment of RA?
chimeric antibodies, humanized antibodies, and human antibodies.
what are cytokine inhibitors used in treatment of RA
Cytokine inhibitors used in the treatment of RA are:
1) Inhibitor of IL-1 (anakinra),
2) Inhibitors of INF (infliximab, etanercept, and adalimumab)
3) Inhibitor of IL-6 (tocilizumab).
which has stronger effect, Biologic DMARDs or methotrexate?
biologic DMARDs
- Methotrexate + any biological agent -> more effective than methotrexate
Examples of biologic DMARDs
what are the main side effects of Biologic DMARDs?
- injection/infusion-related reactions
- infections (TB, fungal, sepsis, and reactivation of hepatitis B) β> never use 2 biologic DEMARDs together.
- Increased risk of lymphoma and other cancers.
when is the use of TNF-alpha inhibitors contraindicated?
1) Acute and chronic infections
2) Recent malignancies
3) Live virus vaccination
4) Demyelinating disorders
5) Class III or IV heart failure
what are prostaglandins considered as members of?
PGs are members of fatty acid derivatives
what are prostaglandins derived from?
Prostaglandins are derived from arachidonic acid (derived from membrane phospholipid) by the action of cyclooxygenase (COX) enzyme
what are the forms of COX?
classification of NSAIDs
absorption of Acetylsalicylic acid (Aspirin)
absorbed Orally completely from the stomach and GIT
distribution of Acetylsalicylic acid (Aspirin)
- widely distributed to all tissues, including CNS
- Plasma protein binding is high
metabolism of Acetylsalicylic acid (Aspirin)
metabolism of salicylates Occurs by hepatic microsomal enzymes
excretion of Acetylsalicylic acid (Aspirin)
Increased by alkalinization of urine (pH 8).
what is the mechanism of action of Acetylsalicylic acid (Aspirin)?
- Non-selective irreversible inhibition of COX leading to inhibition of both PGs and TXs synthesis.
- Other NSAIDs produce reversible inhibition.
what are the pharmacological effects of Aspirin?
- Analgesic affects
- Antipyretic affects
- GIT effects
- Hepatic effects
- Hematologic effects
- Respiratory effects
- Renal Effects
- Other effects
Analgesic effects of Aspirin
For mild to moderate intensity pain (not severe pain)
antipyretic affects of Aspirin
Aspirin is antipyretic but not hypothermic agent
GIT effects of aspirin
Salicylates can produce 2 types of gastric ulcer:
Acute gastric ulcer
- Occurs as a result of acute ingestion of large doses of salicylates.
Chronic gastric ulcer
- Occurs as a result of chronic ingestion of therapeutic doses of salicylates.
hepatic affects of aspirin
Salicylates can produce 2 types of hepatic injury:
Mild hepatic injury
- It is dose-dependent, reversible & asymptomatic.
- There may be mild increase in serum transaminases (SGOT & SGPT).
Severe hepatic injury
(Reyeβs syndrome)
- A rare & fatal condition occurs if aspirin is used to control fever of some viral infections (e.g. chicken pox, influenza, etc.) in children below 12 years.
- There is severe hepatic injury associated with encephalopathy.
- The etiology is unknown.
hematologic affects of aspirin
Antiplatelet action
- Aspirin in low dose (75-150mg) inhibit platelet aggregation by Irreversible inhibition of COX enzyme β ββ TXA2 β ββ platelet aggregation.
Anticoagulant action
- Aspirin in high doses (> 6 gm /day) inhibits hepatic synthesis of vit K dependent coagulation factors (treated by vit K).
respiratory effects of aspirin
Aspirin induced asthma.
renal effects of aspirin
Analgesic nephropathy:
- It is chronic renal failure due to chronic abuse of analgesics, which produce chronic renal ischemia due to decrease synthesis of renal PGE2 and PGI2.
Salt & water retention:
- Due to decrease RBF and increase aldosterone
Antagonize diuretic effect of diuretics:
- Due to decrease synthesis of vasodilator PGs
other effects for aspirin
- Anti-inflammatory.
- Anti-immunological.
- Anti-rheumatic effects.
what are the therapeutic uses of salicylates?
what are the side effects of salicylates?
precautions and contraindications of using aspirin
- GIT disorders: peptic ulcer and gastritis.
- Hemorrhagic disorders: hemophilia, thrombocytopenia..
- Chronic renal diseases.
- Severe hypertension.
- Pregnancy.
- Chronic liver diseases.
- Before surgery.
- Children <12 years old.
drug interactions of aspirin
- It antagonizes the diuretic effect of diuretics, and the anti-hypertensive effect of anti-hypertensives (e.g. Ξ²-blockers, ACEIs).
- It increases the plasma concentrations of anticoagulants (heparin and warfarin), phenytoin, thyroxin, and other drugs (by displacement) leading to increase their effect and toxicity.
- Antacids decrease aspirin absorption.
compare between nonselective COX inhibitors and selective COX-2 inhibitors in terms of:
- Mechanism
- Pharmacological effects
- Gastric side effects
- Renal side effect
- Thrombotic side effect
- Hypersensitivity reactions
what is the mechanism of action of Acetaminophen (Paracetamol)?
It is a selective Cox III inhibitor so it inhibits PGs synthesis in the brain only.
what are the pharmacological effects of Acetaminophen (Paracetamol)?
- It has analgesic & antipyretic actions without anti-inflammatory action.
- It has little or No effects on the CVS, GIT, respiratory or platelet functions.
what is the therapeutic uses of Acetaminophen (Paracetamol)?
- As analgesic & antipyretic when aspirin is contraindicated (e.g. patients with peptic ulcer, hemophilia, etc).
- Used in pregnancy with greater safety than aspirin.
what are the adverse effects of Acetaminophen (Paracetamol)?
At therapeutic doses:
Acetaminophen is well-tolerated but may cause:
- Skin rash& drug fever (as allergic reactions).
- Hemolytic anemia in patients with G-6-PD deficiency.
- Long term use may lead to renal failure.
At toxic doses:
- Dose dependent hepatotoxicity (hepatic necrosis).
