Lecture 12

Question 1

Adverse Drug Events (ADEs)

Answer 1

Any untoward medical occurrence that may present during treatment with a drug but which does not necessarily have a causal relationship with this treatment

Question 2

Adverse Drug Reactions (ADRs)

Answer 2

Any noxious change which is suspected to be due to the drug, occurs at standard doses, requires treatment or decrease in dose or indicates caution in future use of the same drug

Question 3

Side Effects

Answer 3

Any undesired effect (secondary effect) other than intended therapeutic effect that occurs when the medication is administered regardless of the dose. The effect could be beneficial, neutral or harmful.

Question 4

Contraindications

Answer 4

A specific situation in which a drug, procedure or surgery should not be used because it may be harmful to the person.

Question 5

Side Effect

Answer 5

• Unintended effect of the medication
• Regardless of the dose
• Not dose-dependent
• Related to the way the medicine works
• May be beneficial, neutral or harmful
• Can be expected
• Can be resolved with time
• Example: Aspirin (blood thinning medication) may cause nose bleeds or bruising

Question 6

Adverse Drug Reaction

Answer 6

• Unintended effect of the medication
• Occurring at the standard dose used
• May or may not be dose-dependant
• Not related to the drug action
• May be unexpected and inexplicable
• Requires interventions (dose adjustment or stop therapy)
• Example: Allopurinol (a treatment for gout) can cause serious skin rashes

Question 7

Rawlins and Thompson (1977) divides ADRs into:

Answer 7

a. Type A: dose-related (augmented)
→ e.g., diarrhea with antibiotic, gastritis with long-term use of NSAIDs or aminoglycoside
nephrotoxicity

b. Type B: non-dose-related (‘idiosyncratic’ or bizarre)
→ e.g., hypersensitivity reactions

c. Type C: dose-related and time-related (chronic or continuous reaction)
→ e.g., osteonecrosis of the jaw with bisphosphonates

d. Type D: time-related (delayed reaction)
→ e.g., become apparent some time after the use of a medicine

e. Type E: withdrawal (end of use)
→ e.g., insomnia, anxiety and perceptual disturbances following the withdrawal of
benzodiazepines

F. Type F: failure of therapy (failure)
→ e.g., occur when the expected response to treatment is not achieved

A and B are Major, others (C, D, E, F) are Minor

Question 8

DoTS Classification

Answer 8

Evaluation of the ADRs according to:
→ the dose used of the suspect drug
→ the time between drug administration (consumption) and ADR occurrence
→ the relationship with different susceptibility factors that determine an increased risk of
adverse reactions

• DoTS is precise but complex and useful in research, while ABCDE is more useful for clinicians.

Question 9

Severity Classification of ADRs

Answer 9

Minor
* No treatment or antidote or prolongation of hospitalisation

Moderate
* Requires treatment or change in treatment or prolongation of hospitalisation for at least one day

Severe
* Requires intensive treatment, life threatening and permanent damage

Lethal
* Directly or indirectly contributes to the death of the patient

Question 10

Allergic Adverse Drug Reactions

Answer 10

• subgroup of Type B reactions
• Immune mechanisms are involved in a number of ADRs caused by drugs.
• The development of allergy implies previous exposure to the drug or to some closely related substances.
• Most drugs are of low molecular weight (300-500 Da) and thus are not antigenic.
• However, they can combine with high molecular weight entities, usually proteins, to form an antigenic
  hapten conjugate.
• Drugs cause a variety of allergic responses, and sometimes a single drug can be responsible for more than
  one type of allergic response

Question 11

Types of Allergic reactions:

Answer 11

a. Type I: IgE-mediated drug hypersensitivity
b. Type II: IgG-mediated cytotoxicity
c. Type III: Immune-complex arthus reactions
d. Type IV: T-cell-mediated drug hypersensitivity

Question 12

Relative Contraindications

Answer 12

• Situation in which caution should be used when two drugs or
  procedures are used together.
  → e.g., warfarin (anti-coagulant) and aspirin (anti-plaletet)
  should not be taken together as both are blood thinner.
• Patients at higher risk of having complications from the
  treatment but benefits outweigh the risk.
  → e.g., X-ray in pregnant women to diagnose tuberculosis

Question 13

Absolute Contraindications

Answer 13

• The event or substance that could cause a life-threatening situation.
• A procedure or medicine that falls under this category must be avoided.
• Examples:
  → Aspirin will cause Reye’ssyndrome with swelling in the liver
  (hepatic dysfunction) and brain (encephalopathy)
  → especially for children or teenagers recovering from chickenpox or
  flu-like symptoms
  → Isotretinoin (an acne drug) is absolutely contraindicated in
  pregnancy → risk of birth defects

Question 14

SE/ADRs and Contraindications of Commonly Used Drugs

Answer 14

• Antihistamine
• Paracetamol
• Opioids
• Selective serotonin reuptake inhibitors (SSRIs)

Question 15

Antihistamine Drugs

Answer 15

• It is a pharmaceutical class drugs that act to treat histamine-mediated
  reactions.
• Two main classes of histamine receptors: H1 and H2 receptors
• Antihistamine drugs bind to H1 receptors → treat allergies and allergic
  rhinitis
• Drugs that bind to H2 receptors → treat upper gastrointestinal
  conditions (excessive stomach acid)
• H1 antihistamine further classified → first and second-generation
  agents
  → first-generation drugs more easily across the blood-brain barrier into the central nervous systems
• First-generation drugs bind to both central and peripheral H1 receptors, while second-generation drugs
  selectively bind to peripheral H1 receptors.
  → different therapeutic and side effect profiles

Question 16

Mechanism of Action of Antihistamine

Answer 16

• Histamine induces an increased level of vascular permeability → fluid moving from capillaries into the
  surrounding tissues
  → increased swelling and dilation of vessels
• Antihistamines stop this effect by acting as antagonists at the H1 receptors
  → clinical benefits: reducing allergy symptoms and any related symptoms
• Parietal cells in the gastrointestinal tract secrete hydrochloric acid (HCI) → undergo regulation by
  acetylcholine, gastrin and histamine
  → Histamine is released from enterochromaffin-like (ECL) cells → binds to H2 receptors on parietal cells →
  ↑cAMP → ↑PKA → phosphorylation of proteins involved in H+
  ions transportation → ↑ HCI
  → The use of antihistamines specific to H2 receptors → block entire process and ↓ stomach acid

Question 17

Side Effects/ADRs Antihistamine Drugs

Answer 17

• H1 receptor antihistamines generally cause noticeable ADRs that are dose-dependent.
  → far more seen in first-generation antihistamines
• Second-generation antihistamines do not easily cross the blood-brain barrier → limited side effect
• H2 receptor antihistamines do not commonly cause ADRs, except for cimetidine
• H1 receptor antihistamines → anticholinergic properties (first-generation drugs)
  → sedation and insomnia (in some users)
  → drug mouth
  → dizziness and tinnitus
  → euphoria, decreased coordination and delirium (high doses)
  → cardiotoxic (QTc-prolonging effects)
• Side effects of H2 receptor antihistamines → diarrhea, constipation, fatigue,
  dizziness and confusion
• Cimetidine
  → its antiandrogenic effect → gynecomastia (men) and galactorrhea (women)
  → inhibition of cytochrome system → drug toxicity and interactions with other medications

Question 18

Contraindications

Answer 18

• They are relatively contraindicated in any patient with QTc prolongation due to their
  cardiotoxicity.
• Other QTc-prolonging drugs require further careful monitoring for further prolongation of the
  QTc interval → risk of potentially fatal cardiac arrhythmias
• Usage in pregnant women is a relative contraindication.
• Women who are lactating should avoid antihistamines.
• Patients with impaired renal or hepatic function should use antihistamines carefully.

Question 19

Piriton

Answer 19

• It is used to treat allergic reactions with itchiness.
• Inverse agonist for histamine H1 receptor

Question 20

Negative and Positive Side Effects of Piriton

Answer 20

Negative: Drowsiness
Positive: May help in sleeping for those who cannot sleep due to itchness

Question 21

Relative Contraindications of Piriton

Answer 21

→ inappropriate for hypertensive patients due to inhibition of
vasodilation and hypotension

→ patients with cardiovascular diseases, urinary retention and
increased ocular pressure

→ pregnant women or patients with impaired renal or hepatic
function

Question 22

Paracetamol (Acetaminophen): Non-Opioid

Answer 22

Analgesic Drug

Question 23

Short term side effects (Paracetamol)

Answer 23

a. Hepatic
→ increased aminotransferase (AST): a biomarker
of liver damage
→ hepatoxicity may occur at therapeutic range
→ effects of glutathione deficiency due to
malnutrition, chronic alcohol use, etc.

b. Cardiovascular diseases
→ peripheral edema, hypertension, hypotension,
tachycardia and chest pain
→ blockage of COX-2-dependent prostaglandins
(e.g., prostacyclin and PGE2
) is most plausible
explanation

c. Dermatologic
→ Allergic skin reaction such as rash
(common 1-10%); possibly due to COX inhibition

d. Gastrointestinal
→ nausea, vomiting: very common, 10% or more
→ abdominal pain, diarrhea, constipation, dyspepsia: 1-10% (common)
→ due to inhibition of gastric prostaglandin synthesis

Question 24

Long term side effects of Para:

Answer 24

a. higher blood pressure
b. increased prevalence of heart infarction
c. hepatotoxicity
d. enhanced liver damage
e. increased aminotransferase activity

Question 25

Relative Contraindications:

Answer 25

a. Combination with drug-inducing cytochrome P450 (e.g., rifampicin, barbiturates and carbamazepine) b. Can lead to hepatic impairment and digestive ulceration when combined with some NSAIDs (e.g., ibuprofen) c. Alcoholic d. Malnourished patients e. Patients with viral infections (e.g., hepatitis C virus and HIV) that weaken the hepatic function

Question 26

Absolute Contraindications of Para:

Answer 26

patients with severe liver failure (cannot eliminate properly)

Question 27

Opioid Analgesia

Answer 27

* Opioids act both presynaptically (block Ca2+ channels) and postsynaptically (open K + channels) → generate nociceptive transmission * The mu, kappa and delta-opioid receptors mediate analgesia spinally and supraspinally. * Some opioids agents can affect serotonin kinetics → e.g., tramadol, oxycodone, fentanyl, methadone, dextromethorphan, meperidine, codeine and buprenorphine * Methadone also can bind to N-methyl-D-aspartate (NDMA) receptor and antagonises the effect of glutamate → treating neuropathic pain

Question 28

Short-term side effects/ADRs of Opioid:

Answer 28

→ dysphoria, euphoria, sedation, respiratory depression, constipation, suppression of endocrine systems, cardiovascular disorders (e.g., bradycardia), convulsion, nausea, vomiting, pruritus and mitosis

Question 29

Long-term side effects/ADRs of Opioid:

Answer 29

→ tolerance, hyperalgesia and allodynia → serotonin syndrome (opioids with serotonergic activity + other agents with serotonergic activity)

Question 30

Selective Serotonin Reuptake Inhibitors (SSRIs)

Answer 30

→ a class of medications most prescribed to treat depression * They are often used as first-line pharmacotherapy for depression and numerous other psychiatric disorders → safety, efficacy and tolerability * They are approved for both adult and paediatric patients.

Question 31

Current SSRI approved clinically:

Answer 31

a. Duloxetine (cymbalta) b. Fluoxetine c. Sertraline d. Paroxetine e. Fluvoxamine f. Citalopram g. Escitalopram h. Vilazodone

Question 32

FDA labeled indications:

Answer 32

a. Major depressive disorder b. Generalised anxiety disorder c. Bulima nervosa d. Bipolar depression e. Obsessive-compulsive disorder f. Panic disorder g. Premenstrual dysphoric disorder h. Treatment-resistant depression i. Post-traumatic stress disorder j. Social anxiety disorder

Question 33

Mechanism of Action SSRIs:

Answer 33

* Increasing deficient serotonin that researchers postulate as the cause of depression in the monoamine hypothesis. * SSRIs exert action by inhibiting the reuptake of serotonin → increasing serotonin activity * SSRIs have little effect on other neurotransmitters → e.g., dopamine or norepinephrine * SSRIs inhibit the serotonin transporter (SERT) at the presynaptic axon terminal. → increasing serotonin (e.g., 5-hydroxytryptamine or 5-HT) in the synaptic cleft → thus, stimulating postsynaptic receptors for a longer period

Question 34

Side Effects/ADRs:

Answer 34

* SSRIs are widely used due to their fewer side effects than prior commonly used antidepressants → tricyclic antidepressant (TCAs) and monoamine oxidase inhibitors (MAOIs) * They have little or no effect on dopamine, norepinephrine, histamine or acetylcholine (except for paroxetine) → no complaints on xerostomia, sedation, constipation, urinary retention and cognitive impairments * However, in 2004, FDA issued a black box warning for SSRIs → increased risk of suicidality among paediatrics and young adults (up to 25 years old) * Common side effects → e.g., sexual dysfunction, sleep disturbances, weight changes, anxiety, dizziness, xerostomia, headache and gastrointestinal distress * SSRIs have potential to prolong QT interval (esp. citalopram) → fatal arrthymia, torsade de pointed * Coagulopathy also correlates with SSRI use. * SSRIs are metabolised by and have effects on the cytochrome P450 system. → Fluoxetine, paroxetine, sertraline, citalopram and escitalopram → inhibiting CYP2D6 → Fluoxetine and fluvoxamine → inhibiting CYP2C19 → Fluvoxamine → inhibiting CYP1A2

Question 35

Contraindications:

Answer 35

* Concurrent use of MAOIs, linezolid and other medications → increase serotonin levels → could put patients at risk for lifethreatening serotonin syndrome * Paroxetine is contraindicated in pregnancy → category D/X due to its tetratogenic effects in causing cardiovascular defects, esp. cardiac malformations if prescribed in the first trimester