Adverse Drug Reactions, Contraindications and Drug interactions of OTC Analgesics

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Adverse Drug Reactions, Contraindications and
Drug Interactions of OTC Analgesics

• P.Naina Mohamed
• Pharmacologist

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Adverse Drug Reactions, Contraindications and
Drug Interactions

• The basic knowledge of mechanisms underlying
  Adverse drug reactions, Contraindications and
  Drug interactions of OTC medicines provides the
  understanding of preventive measures.
• Adverse drug reaction (ADR)
• A response to a drug that is harmful or
  unpleasant and unintended and occurs at doses
  normally used in man for the prophylaxis,
  diagnosis or therapy of disease, or for
  modification of physiological function.
• Contraindication
• A condition which makes a particular treatment
  (medicine) or procedure potentially inadvisable.
• Drug Interaction
• A modification of the effect of a drug when
  administered with another drug, food, or herb.

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OTC Analgesics

• Non opioid or Non steroidal anti inflammatory
  drugs (NSAIDs) are available as OTC analgesics.
• They block the synthesis of inflammatory
  prostaglandins by inhibiting Cycloxygenase (COX)
  enzyme and relieve pain, fever and inflammation.

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OTC Analgesics

• Commonly used OTC Analgesics
• Non Opioid Analgesics
• 1. Paracetamol
• 2. Aspirin
• Non Steroidal Anti inflammatory Drugs
  (NSAIDs)
• 1. Ibuprofen
• 2. Diclofenac
• 3. Meloxicam
• 4. Indomethacin
• 5. Mefenemic Acid
• 6. Ketoprofen
• 7. Celecoxib

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Non Opioid Analgesics

• Paracetamol has only weak anti inflammatory
  property and it is indicated only for Pyrexia and
  Mild to moderate pain.
• Aspirin has very less anti inflammatory activity
  compared to other NSAIDs and it is indicated only
  for the inhibition of Platelet aggregation, mild
  to moderate pain and pyrexia.

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Paracetamol (Acetaminophen)

• ADRs
• Paracetamol produces rare adverse drug
  reactions such as
• 1. Mild gastric discomfort (Nausea,
  Vomiting, Anorexia, Abdominal pain)
• 2. Hypersensitivity reactions (Rash,
  urticaria, Angioedema, Anaphylaxis, etc.)
• 3. Nephrotoxicity in toxic doses

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Paracetamol (Acetaminophen)

• Hepatotoxicity
• Paracetamol causes liver damage
  (Hepatotoxicity) in toxic doses.
• Paracetamol (Acetaminophen) overdose
• Saturation of sulfate and glucuronide conjugation
  metabolic pathways
• More paracetamol undergoes CYP2E1 metabolism
• Excessive production of N-Acetyl P- benzo quinone
  imine (NAPQI)
• Depletion of Glutathione (Natural antioxidant)
• Liver damage (Hepatotoxicity)

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Paracetamol (Acetaminophen)

• Paracetamol induced hepatotoxicity can be treated
  by administering N-Acetyl Cysteine which is a
  precursor of Glutathione.
• N-Acetyl Cysteine
• Precursor of Glutathione
• Increase the level of glutathione
• Glutathione detoxifies NAPQI to form cysteine and
  other metabolites
• Prevention of liver necrosis

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Paracetamol (Acetaminophen)

• Contraindications
• 1. Hypersensitivity to Paracetamol
• 2. Hepatic Impairment (Due to its Hepatoxic
  effects)
• Drug Interactions
• Paracetamol
• Hyoscine butyl bromide (Buscopan)
• M3 receptor blockade by Buscopan
• Reduced gut motility
• Increased gastric emptying time
• Reduced absorption of Paracetamol

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Paracetamol (Acetaminophen)

• Drug Interactions
• Paracetamol
• Metoclopramide
• D2 receptor blockade by Metoclopramide
• Increased gut motility
• Reduced gastric emptying time
• Increased absorption of Paracetamol

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Paracetamol (Acetaminophen)

• Paracetamol
• Alcohol
• Alcohol induce the secretion of pro-inflammatory
  cytokines (TNF-alpha, IL6 and IL8), oxidative
  stress, lipid peroxidation, and acetaldehyde
  toxicity
• Inflammation, apoptosis and fibrosis of liver
  cells
• Increased risk of Hepatotoxicity

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Paracetamol (Acetaminophen)

• Paracetamol
• Amyl nitrite, Sodium nitrite or Sodium
  thiosulphate
• Nitrates induce the oxidation of Fe2 (Haeme) to
  form Fe3 (Met-Haeme)
• Increased risk of methemoglobinemia
• Fe3 ions cannot bind with oxygen
• Reduced oxygen carrying capacity
• Discolouration of skin, mouth or nail bed

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Paracetamol (Acetaminophen)

• Paracetamol Leflunomide, Teriflunomide or
  Lomitapide
• Excessive levels of Liver enzymes like ALT AST
• Increased risk of Hepatotoxicity

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Paracetamol (Acetaminophen)

• Paracetamol Prilocaine
• Prilocaine metabolises to form O-Toluidine
• O-Toluidine induce the oxidation of Fe2 to form
  Fe3
• Increased risk of Methemoglobinemia
• Reduced oxygen carrying capacity
• Discolouration of Skin, Mouth or Nail bed

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ASPIRIN

• ADRs
• 1. Risk of bleeding
• 2. Aspirin induced Asthma
• 3. GI bleeding
• 4. Primary Respiratory Alkalosis

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ASPIRIN

• Risk of Bleeding
• Aspirin blocks COX 1 more than COX 2 and has
  the increased risk of bleeding compared to other
  NSAIDs.
• Aspirin
• Blockade of COX 1 of platelets
• Reduced Thromboxane A2 (TXA 2) synthesis
• Decreased Platelet aggregation
• Increased risk of Bleeding

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ASPIRIN

• Aspirin Induced Asthma (AIA)
• Aspirin
• Block Cyclooxygenase 1 (COX 1) enzyme
• Inhibit synthesis of PGE2 in lungs
• Relieving of Inhibitory effects of PGE2 on
  production of
• Cysteinyl-Leukotrienes
• Elevated levels of Cysteinyl-Leukotrienes
• Acute bronchoconstriction , Rhinosinusitis
• Bronchospasm and/or Laryngospasm, Rhinorrhea, and
  
• Nasal congestion

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ASPIRIN

• GI bleeding
• Aspirin
• Block Cyclooxygenase 1 (COX 1) enzyme
• Inhibition of PGE2 synthesis
• Reduced mucous secretion and bicarbonate
  secretion
• Damage of Gastro intestinal mucosa
• Gastro intestinal ulceration
• GI Hemorrhage, perforation
• Life-threatening bleeding (Acute) and Anemia
  (Chronic)

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ASPIRIN

• Primary Respiratory Alkalosis
• Aspirin (Anti infammatory dose)
• Uncoupling oxidative phosphorylation
• Increased CO2 production
• Increased respiratory rate
• Reduction of PCO2
• Primary Respiratory alkalosis

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ASPIRIN

• Contraindications
• 1. First and Third trimester of Pregnancy
• 2. Bronchial asthma
• 3. Patients with severe hepatic damage,
  hypoprothrombinemia, vitamin K deficiency, or
  hemophilia
• 4. Active GI ulcer

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ASPIRIN

• Risk of gastroschisis
• Aspirin
• (First trimester of pregnancy)
• Increased risk of gastroschisis

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ASPIRIN

• Risk of Maternal and Fetal bleeding
• Aspirin
• (Third trimester of Pregnancy)
• Reduced TXA 2 synthesis
• Inhibition of Platelet aggregation
• Increased risk of maternal and fetal bleeding

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ASPIRIN

• Early closure of Ductus Arteriosus (DA)
• Aspirin
• (Third trimester of pregnancy)
• Blockade of COX 1 enzyme
• Reduced PG synthesis
• Early closure of DA

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ASPIRIN

• Drug Interactions
• ASPIRIN
• Acetazolamide, Dorzolamide or Methazolamide
• Aspirin competitively inhibits plasma protein
  binding of zolamides
• Elevated concentrations of unbound (Free)
  zolamides
• Ringing in your ears, headache, nausea, vomiting,
  dizziness, confusion, hallucinations, rapid
  breathing, fever, seizure (convulsions), or coma
• Other Drug interactions
• Similar to NSAIDs

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NSAIDs

• ADRs
• 1. Gastro intestinal ulceration (Anorexia,
  nausea, dyspepsia, abdominal pain, and diarrhea)
• 2. Hypersensitivity reactions (Pseudoallergic
  and allergic reactions)
• 3. Risk of Hemorrhage
• 4. Risk of Thrombosis
• 5. Early closure of Ductus Arteriosus
• 6. Renal Ischemia
• 7. Risk of Edema

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NSAIDs

• Gastro intestinal Ulceration (Mechanism1)
• NSAIDs (Oral)
• Local irritation to gastric mucosa
• Back diffusion of acid into gastric mucosa
• Tissue damage
• Gastro intestinal ulceration
• Anorexia, nausea, dyspepsia, abdominal pain, and
  diarrhea

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NSAIDs

• Gastro intestinal Ulceration (Mechanism 2)
• NSAIDs (Non selective)
• Block Cyclooxygenase 1 (COX 1) enzyme
• Inhibition of PGE2 synthesis
• Reduced mucous secretion and bicarbonate
  secretion
• Damage of Gastro intestinal mucosa
• Gastro intestinal ulceration
• GI Hemorrhage, perforation
• Life-threatening bleeding (Acute) and Anemia
  (Chronic)

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NSAIDs

• Gastro intestinal Ulceration (Mechanism3)
• NSAIDs
• Block Cyclooxygenase 1 (COX 1) enzyme
• Inhibit the synthesis of Potent vasodilators like
  PGE2 and PGI2 from vascular endothelium
• Reduced gastric mucosal blood flow
• Gastro intestinal ulceration

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NSAIDs

• Hypersensitivity reactions (Pseudoallergic
  reactions)
• NSAIDs
• Block Cyclooxygenase 1 (COX 1) enzyme
• Inhibit synthesis of PGE2 in lungs
• Relieving of Inhibitory effects of PGE2 on
  production of
• Cysteinyl-Leukotrienes
• Elevated levels of Cysteinyl-Leukotrienes
• Bronchoconstriction , Rhinosinusitis
• Bronchospasm and/or Laryngospasm, Rhinorrhea, and
  
• Nasal congestion

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NSAIDs

• Hypersensitivity reactions (Pseudoallergic
  reactions)
• NSAIDs
• Block Cyclooxygenase 1 (COX 1) enzyme
• Inhibit synthesis of Constitutive PGs
• Acute urticaria and/or angioedema (skin, lips,
  and mouth)

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NSAIDs

• Hypersensitivity reactions (Allergic reactions)
• NSAIDs
• IgE mediated reaction
• Allergic reactions (Urticaria, Angioedema or
  Anaphylaxis)

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NSAIDs

• Risk of Hemorrhage
• NSAIDs
• Blockade of COX 1 of platelets
• Reduced Thromboxane A2 (TXA 2) synthesis
• Decreased Platelet aggregation
• Increased risk of Bleeding

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NSAIDs

• Risk of Thrombosis
• NSAIDs
• Blockade of COX 2 enzyme of blood vessels
• Inhibition of Prostacyclin (PGI 2) synthesis
• Reduced restriction on prothrombotic and
  atherogenic stimuli by PGI 2
• Increased risk of thrombosis
• Elevated risk of Myocardial infarction, Stroke

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NSAIDs

• Early Closure of Ductus Arteriosus
• NSAIDs
• (During last trimester of pregnancy)
• Blockade of COX enzyme
• Inhibition of Synthesis of Prostaglandins
• Early closure of Ductus arteriosus (DA)
• Fetal blood flows in to lungs
• Respiratory failure, impaired right ventricular
  function, tricuspid regurgitation and right heart
  dilatation

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NSAIDs

• Renal Ischemia
• NSAIDs
• (In patients with CHF, CKD, etc)
• Blockade of COX 2 enzyme of renal cells
• Inhibition of synthesis of Vasodilator
  Prostaglandins (PGE 2 and PGI 2)
• Reduction of renal blood vessel dilation and
  blood flow
• Renal ischemia

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NSAIDs

• Risk of Edema
• NSAIDs
• (In patients with CHF, CKD, etc)
• Blockade of COX 2 enzyme of renal cells
• Inhibition of synthesis of Prostaglandins
• Reduction of inhibitory effect of PGs on Cl
  reabsorption and ADH activity
• Fluid retention
• Edema and Hypertensive complications

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NSAIDs

• Contraindications
• NSAIDs are contraindicated in the following
  conditions due to their adverse effects on the
  systems
• Active gastric or duodenal ulcer
• Bronchial Asthma
• Third trimester of pregnancy

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NSAIDs

• Drug Interactions
• NSAIDs
• Warfarin, Apixaban, Rivaroxaban, Enoxaparin,
  Dalteparin, Aredeparin, Tinazaparin, Ibritumomab,
  Tositumomab, Cabozantinib, Ponatinib,
  Regoratinib, Prasugrel, Anisindione, Fondaparinux
  or Desirudin
• Increased risk of Bleeding
• (Due to the inhibition of platelet aggregation by
  NSAIDs)
• Unusual bleeding or bruising, swelling, vomiting,
  blood in your urine or stools, headache,
  dizziness, or weakness

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NSAIDs

• Drug Interactions

NSAIDs Leflunomide, Teriflunomide or
Lomitapide Excessive levels of Liver enzymes
like ALT AST Increased risk of (Liver Damage)
Hepatotoxicity Fever, chills, joint pain or
swelling, unusual bleeding or bruising, skin
rash, itching, loss of appetite, fatigue, nausea,
vomiting, dark colored urine, light colored
stools, and/or yellowing of the skin or eyes
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NSAIDs

• Drug Interactions
• NSAIDs
• Adefovir, Cidofovir, Tenofovir, Tacrolimus,
  Sirolimus, Sodium Biphosphate or IV
  Immunoglobulins
• Increased risk of kidney damage
• Increased or decreased urination, sudden weight
  gain or weight loss, fluid retention, swelling,
  shortness of breath, muscle cramps, tiredness,
  weakness, dizziness, confusion, and irregular
  heart rhythm.

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NSAIDs

• Drug Interactions
• NSAIDs
• ACE inhibitors
• Increased risk of Hyperkalemia
• Bradycardia
• Syncope in Elderly and cardiac patients

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NSAIDs

• Drug Interactions
• NSAIDs
• Corticosteroids or SSRIs
• Increased GI complications

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NSAIDs

• Non Steroidal Anti inflammatory Drugs (NSAIDs)
• 1. Ibuprofen
• 2. Diclofenac
• 3. Meloxicam
• 4. Indomethacin
• 5. Mefenemic Acid
• 6. Ketoprofen
• 7. Celecoxib
• All the NSAIDs have more or
  less same adverse drug reactions (ADRs),
  Contraindications and Drug interactions.

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REFERENCES

• Goodman Gilman's The Pharmacological Basis of
  Therapeutics, 12e Laurence L. Brunton, Bruce A.
  Chabner, Björn C. Knollmann
• Basic Clinical Pharmacology, 12e Bertram G.
  Katzung, Susan B. Masters, Anthony J. Trevor
• Harrison's Online Featuring the complete
  contents of Harrison's Principles ofInternal
  Medicine, 18e
• Principles and Practice of Hospital Medicine
  Sylvia C. McKean, John J. Ross, Daniel D.
  Dressler, Daniel J. Brotman, Jeffrey S. Ginsberg
• BNF March 2013

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REFERENCES

• Tintinalli's Emergency MedicineA Comprehensive
  Study Guide, 7e Judith E. Tintinalli, J. Stephan
  Stapczynski, David M. Cline, O. John Ma, Rita K.
  Cydulka, and Garth D. MecklerThe American
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• Poisoning Drug Overdose, 6e Kent R. Olson
• CURRENT Diagnosis Treatment Gastroenterology,
  Hepatology, Endoscopy, 2e Norton J.
  Greenberger, Richard S. Blumberg, Robert Burakoff
• CURRENT Medical Diagnosis Treatment 2013
  Maxine A. Papadakis, Stephen J. McPhee, Eds.
  Michael W. Rabow, Associate Ed.
• CURRENT Rheumatology Diagnosis Treatment,
  2eJohn B. Imboden, David B. Hellmann, John H.
  Stone

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REFERENCES

• http//xa.yimg.com/kq/groups/22038980/2115709304/n
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• http//farncombe.mcmaster.ca/documents/WallaceBest
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• http//onlinelibrary.wiley.com/doi/10.1111/j.1398-
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• http//www.uptodate.com/contents/nsaids-including-
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• http//www.drugs.com/drug_interactions.html

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