Adverse Drug Reactions 2

PCOL2605/NURS2005

Brooke Storey-Lewis
Discipline of Pharmacology

COMMONWEALTH OF AUSTRALIA
Copyright Regulation
WARNING
This material has been reproduced and communicated to you by or on behalf of the
University of Sydney pursuant to Part VB of the Copyright Act 1968 (the Act).
The material in this communication may be subject to copyright under the Act. Any
further reproduction or communication of this material by you may be the subject of
copyright protection under the Act.
Do not remove this notice

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Characterisation of Adverse Drug Reactions
Edwards & Aronson (2000) Lancet 356, 1255

A Augmented

B Bizarre

C Chronic

The University of Sydney Page 40

Adverse Drug Reactions 2
Learning Outcomes
Digoxin Toxicity:
1. Define and understand the ‘therapeutic index’ of a drug
2. Describe the mechanism of action and pharmacokinetics of digoxin
3. List symptoms of digoxin toxicity
4. Describe and understand the role p-glycoprotein plays in digoxin toxicity
5. Describe how digoxin toxicity is prevented and treated

Sulfonamide Hypersensitivity:
6. Describe immediate (type I) and delayed (type IV) hypersensitivity reactions
7. List symptoms of sulfonamide hypersensitivity reactions
8. Describe and relate the structure of sulfonamide antibiotics and non-sulfonamide antibiotics to sulfonamide
hypersensitivity reactions
9. Discuss the likelihood of cross-reactivity in sulfonamide hypersensitivity reactions

Chronic Corticosteroid Use:

10. Recall the mechanism of action and clinical uses of corticosteroid drugs
11. List adverse reactions which may occur following chronic corticosteroid administration
12. Describe how chronic inhaled corticosteroid use can lead to oral candidiasis
13. Describe how chronic corticosteroid use can lead to adrenal suppression
The University of Sydney Page 41
Type A: Digoxin Toxicity

– Prof. Carroll introduced you to digoxin in

the Heart Failure lecture

– Cardiac glycoside used in the treatment

of heart failure and cardiac dysrhythmias

– Derived from the foxglove plant Digitalis

https://commons.wikimedia.org/w
iki/File:Digitalis_lanata_1.JPG

The University of Sydney Page 42

Type A: Digoxin Toxicity
AMH, 2018

!!

The University of Sydney Page 43

Digoxin has a low Therapeutic Index (TI)
– Relationship between efficacy and safety

– Gives an indication of the safety margin of a drug

– Determining TI can be complex and depends on the stage of drug development

– A high therapeutic index is desirable, a low therapeutic index means that the dose which causes
therapeutic effect is close to the threshold dose at which adverse effects occur

TD50 = dose which produces adverse reactions in

50% of a population. May be substituted with LD50
where animal studies are the determinant.

ED50 = dose which produces therapeutic response in

50% of a population

The University of Sydney Page 44

Muller PY and Milton MN (2012). Nat. Rev. Drug Disc. 11, 751.
Type A: Digoxin Toxicity

Mechanism of Action
– Slows heart rate and reduces AV nodal conduction by an
increase in vagal tone and a reduction in sympathetic activity.
Increases the force of myocardial contraction (positive ionotropic effect)
by increasing the release and availability of stored
intracellular calcium. (AMH, 2018)

The University of Sydney Page 45

Type A: Digoxin Toxicity

Mechanism of Action
– Inhibits Na+/K+ pump
– Increases intracellular Na+
– An increased intracellular concentration of Na+ reduces the efflux of Ca2+
from the cell, which normally occurs via the Na+/Ca2+ pump
– This results in an increased intracellular concentration of Ca2+
– Intracellular Ca2+  muscle contraction

The University of Sydney Page 46

Type A: Digoxin Toxicity
Pharmacokinetics (MIMS online, 2018)
– Administered orally or IV

– Absorption from stomach and upper small intestine (70-80%)

– 20-30% bound to plasma proteins, extensive distribution to body tissues (heart, liver, skeletal muscle)

– Small amount of metabolism occurs

– Some people (10%) harbour the enteric organism Eubacterium lentum

– T1/2 36-48 hrs

– Majority eliminated unchanged via kidneys

– Substrate of P-glycoprotein

The University of Sydney Page 47

P-glycoprotein is an Efflux Transporter
– In the gut, pumps drugs back into the lumen, preventing absorption
– In the renal tubule, pumps drugs into the urine, increasing elimination
– Many drugs are substrates of P-glycoprotein

– Calcium channel blockers

– Cyclosporin
– Dabigatran
– Digoxin
– Loperamide
https://openi.nlm.nih.gov/detailedresult.php?img=PMC
2147658_1475-2883-2-S1-S8-2&req=4

Drugs which induce P-glycoprotein can reduce the bioavailability and plasma
concentration of other drugs
Drugs which inhibit P-glycoprotein can increase the bioavailability and plasma
concentration of other drugs
The University of Sydney Page 48
https://www.nps.org.au/australian-prescriber/articles/p-glycoprotein-and-its-role-in-drug-drug-interactions
Identifying Potential Drug-Drug Interactions
Drugs which may reduce digoxin elimination via inhibition of p-
glycoprotein, leading to increased concentrations of the drug
– Amiodarone
– Verapamil
– Diltiazem
– Clarithromycin and erythromycin
– Paroxetine and sertraline
– Omeprazole

– https://amhonline.amh.net.au/ EBL
Report
The University of Sydney Page 49
Type A: Digoxin Toxicity
Prevention
– Dose should be tailored according to:
– Renal function
– Clinical response
– Concentration monitoring
– Caution with concomitant drugs causing hypokalaemia

Concentration monitoring (AMH, 2018)

– Generally accepted therapeutic range is 0.5–2 microgram/L (0.6–2.6 nanomol/L) as toxicity is more common at
digoxin concentrations >2 micrograms/L.
– Toxic effects can occur at lower concentrations, particularly in the elderly or in those with electrolyte
disturbance, hypoxia or hypothyroidism
– GI symptoms (e.g. nausea, anorexia) may precede cardiac symptoms (eg arrhythmias).

The University of Sydney Page 50

Type A: Digoxin Toxicity
Treating Severe Digoxin Toxicity
– Antidote available: Digifab (AMH, 2018)
– Antibody fragment which binds to digoxin with high affinity
– Digifab also indicated in the treatment of Oleander or cane toad poisoning
– Oleander contains oleandrin and oleandrigenin
Cardiac glycosides
– Skin of the cane toad contains bufadienolides

https://en.wikipedia.org/wiki/Nerium#/media/File:Nerium_olean https://en.wikipedia.org/wiki/File:Canetoadfemale.jpg
der_flowers_leaves.jpg

The University of Sydney Page 51

Angel of Death
– Charles Cullen is an American serial killer
– Spent 16 years as a nurse in New Jersey
– Confessed to murdering up to 40 patients,
estimated he may have murdered up to 300+
– Victims found with lethal plasma concentrations
of digoxin, insulin or adrenaline
– 18 consecutive life sentences

The University of Sydney Page 52

The University of Sydney Page 53
 Type B: Hypersensitivity Reactions

– Allergic reactions are a common form of ADR

– Commonly manifest as minor skin eruptions

– Serious reactions e.g. anaphylaxis are rare

– Penicillin the most common cause of drug induced anaphylaxis

– 1/50 000 patients

The University of Sydney Page 54

 Type B: Hypersensitivity Reactions

– Allergic or hypersensitivity reactions are immunological

responses to normally innocuous foreign substances

– These responses cause inflammation and subsequent damage

– Hypersensitivity reactions are classified into four types

– I, II, III, IV

The University of Sydney Page 55

Type B: Hypersensitivity Reactions
Type I – Immediate

– Immediate or anaphylactic hypersensitivity, e.g. hayfever, peanut allergy

– Body encounters an ‘antigen’ e.g. pollen and produces IgE antibody against
it
– IgE forms a coat on mast cells
– Upon re-exposure the pollen antigen binds to the IgE, this causes the mast
cell to degranulate/release inflammatory mediators

Penicillins account for

~75% of anaphylactic
deaths
The University of Sydney Page 56
http://www.pathguy.com/sol/14542.jpg
 Type B: Hypersensitivity Reactions
Type IV – Cell Mediated or Delayed Hypersensitivity

– Delayed reaction
– Activation of adaptive immune system and T-cell involvement
– Infiltration of immune cells and release of cytokines
– E.g. Stevens-Johnson syndrome

Rang & Dale’s Pharmacology Chapter 6 provides a good, brief overview of

the immune response
The University of Sydney Page 57
Type B: Sulfonamide Hypersensitivity

– Sulfonamides are antibiotics that interfere with folate synthesis

– Sulfamethoxazole commonly combined with trimethoprim

Resprim/Bactrim/Septrin

– Treatment of pneumocystis pneumonia (PCP), Listeria infection,

shigellosis, cerebral toxoplasmosis, pertussis, MRSA

The University of Sydney Page 58

Type B: Sulfonamide Hypersensitivity
Common cause of hypersensitivity reactions (AMH, 2018)

– Mild: Fever, dyspnoea, cough, rash, eosinophilia

– Serious: Anaphylaxis, Stevens-Johnson syndrome, toxic epidermal

necrolysis, serum sickness-like syndrome, lupus-like syndrome, multi-
organ hypersensitivity syndrome, pneumonitis, hepatitis, interstitial
nephritis, systemic vasculitis and pancytopaenia

The University of Sydney Page 59

Sulfonamide structure: sulfur atom double bonded to two oxygens + nitrogen, and a functional R1 group.

Sulfonamide antibiotics contain two specific structures:

1. An arylamine group at the N4 position

2. Five- or six- membered ring at the N1 position

These two structures are important in hypersensitivity reactions induced by sulfonamide antibiotics.
Non-antibiotic sulfonamides e.g. hydrocholorothiazide lack these structures or occasionally only
contain one.

The University of Sydney Dorn et al, 2018 Current Allergy and Asthma Reports 18, 38 Page 60
Type B: Sulfonamide Hypersensitivity
Sulfonamide antibiotics cause a diverse range of hypersensitivity reactions.

– Type I (Immediate)
– Less common
– Urticaria (hives), anaphylaxis

– Type IV (Delayed)
– More common
https://blogs.nejm.org/now/index.php/e
– Cutaneous rashes can appear days after treatment xanthematous-reactions/2012/06/29/

• HIV infection increases the risk

– Stevens-Johnson Syndrome

The University of Sydney Dorn et al, 2018 Current Allergy and Asthma Reports 18, 38 Page 61
Cross-Reactivity?
With other sulfonamide antibiotics?

Research has shown some cross-reactivity

between different types of sulfonamide
antibiotics

With non-antibiotic sulfonamides?

Strom et al (2003) NEJM 349, 1628-1635

Dorn et al, 2018 Current Allergy and Asthma Reports 18, 38

The University of Sydney Page 62
Cross-Reactivity?

Conclusion: There is an association between hypersensitivity after the receipt of

sulfonamide antibiotics and a subsequent allergic reaction after the receipt of a
sulfonamide non-antibiotic, but this association appears to be due to a predisposition
to allergic reactions rather than to cross-reactivity with sulfonamide-based drugs.
The University of Sydney Page 63
Cross-Reactivity?

Something to think about…

– In the PCOL2605 diuretics practical you were excluded from

taking a diuretic if you had a hypersensitivity to
sulfonamide antibiotics.

Should you have been excluded?

Risk/Benefit?

The University of Sydney Page 64

Type C: Chronic Administration of Corticosteroids
– Adrenals located superior to the kidney
– Adrenal medulla
– Produces catecholamines e.g. adrenaline, noradrenaline

– Adrenal cortex
– Produces mineralcorticoids e.g. aldosterone
– Produces glucocorticoids
• Endogenous cortisol/hydrocortisone
– Contributes to homeostasis
The University of Sydney Page 65
Type C: Chronic Administration of Corticosteroids
Mechanism of action:
• Cortisol and synthetic glucocorticoids diffuse into the cell
• Bind to glucocorticoid nuclear receptors located in the cytosol
• Receptor-glucocorticoid complex enters the nucleus and binds DNA
• Leads to:
• Synthesis of specific mRNA
• Repression of genes via inhibition of transcription factors

The University of Sydney Rang & Dale’s Pharmacology Ch. 33 p.408 Page 66
Type C: Chronic Administration of Corticosteroids
Glucocorticoids:
– Metabolic effects
– Decrease uptake and utilisation of glucose, increase gluconeogenesis
– Increased protein breakdown, decreased protein synthesis

– Anti-inflammatory and immunosuppressive effects

– Downregulation

– Musculoskeletal effects
– Increased bone catabolism
The University of Sydney Page 67
Type C: Chronic Administration of Corticosteroids
Clinical uses of glucocorticoids:
– Replacement therapy for patients with adrenal failure
– Anti-inflammatory/immunosuppressive therapy
– Asthma/COPD (e.g. fluticasone inhaler)
– Rhinitis (e.g. mometasone)
– Eczema (e.g. topical hydrocortisone cream)
– Autoimmune diseases (e.g. oral prednisolone/prednisone)
– Organ transplantation anti-rejection
The University of Sydney Page 68
Type C: Chronic Administration of Corticosteroids

– Immune suppression  infection or injury

– Osteoporosis
– Hyperglycaemia and diabetes
– Muscle wasting
– Inhibition of growth in children
– Cushing’s syndrome
– Adrenal suppression

The University of Sydney Page 69

Type C: Chronic Administration of Corticosteroids
Immunosuppression
E.g. Oral candidiasis (thrush) with fluticasone use
– Oral thrush is caused by the fungus Candida albicans
– Inhaled corticosteroids lead to local anti-inflammatory and
immunosuppressive effects
– Managed using a “spacer”
– Increase drug delivery to the airways
– Reduce deposition in the mouth
https://www.nhs.uk/conditions/oral-thrush-mouth-thrush/

The University of Sydney Page 70

Type C: Chronic Administration of Corticosteroids
Adrenal Suppression
– Glucocorticoid release is controlled by a negative feedback mechanism
involving the hypothalamus & anterior pituitary
– Administration of glucocorticoids reduces the patient’s ability to
synthesise corticosteroids due to suppression of feedback mechanism
– May lead to atrophy of the adrenal glands
– Glucocorticoid drugs must not be suddenly withdrawn
– Abrupt withdrawal may lead to adrenal insufficiency (Type E ADR…?)

The University of Sydney Page 71

Adverse Drug Reactions 3
PCOL2605/NURS2005

Brooke Storey-Lewis
Discipline of Pharmacology
COMMONWEALTH OF AUSTRALIA
Copyright Regulation
WARNING
This material has been reproduced and communicated to you by or on behalf of the
University of Sydney pursuant to Part VB of the Copyright Act 1968 (the Act).
The material in this communication may be subject to copyright under the Act. Any
further reproduction or communication of this material by you may be the subject of
copyright protection under the Act.
Do not remove this notice

The University of Sydney Page 73

Adverse Drug Reactions 1, 2, 3
Learning Outcomes
Thalidomide and teratogenesis
1. Define “teratogen” and list some examples of drugs which can have teratogenic effects
2. Describe the thalidomide tragedy
3. Describe the categorisation of drugs for use in pregnancy
4. Recognise examples of drugs belonging to category A, B, C, D, X
5. Understand limitations of and common misconceptions relating to the categorisation of drugs for
pregnancy
Withdrawal Syndromes
6. Define “physical dependence”
7. List examples of drugs which, upon cessation, may produce withdrawal symptoms
8. List symptoms which may occur following cessation of opioids and benzodiazepines
9. Describe how withdrawal is managed
Oral Contraceptive Failure
10. Understand the role of Cytochrome P450 enzymes in drug metabolism
11. Identify drugs which are CYP3A4 substrates/inhibitors/inducers
12. Understand how CYP3A4 induction may cause oral contraceptive failure
13. Understand how the induction or inhibition of metabolic enzymes may affect the plasma concentration
of drugs
The University of Sydney Page 74
Characterisation of Adverse Drug Reactions
Edwards & Aronson (2000) Lancet 356, 1255

D Delayed

E End of Use

F Failure

The University of Sydney Page 75

 Type D: Drug-Induced Teratogenesis
– Teratogenesis the process by which congenital malformations are
produced in an embryo or foetus. Teratogenesis is caused by an
agent or factor – termed a teratogen

– A famous teratogen is Agent Orange

– Agent Orange is a herbicide and defoliant that was used by the US military
during the Vietnam War
– Contained contaminant traces of dioxin TCDD

The University of Sydney Page 76

Drug-Induced Teratogenesis
– Rang & Dale’s Pharmacology Ch. 57 p 697-699
– Many drugs have been found to be teratogenic in animals, however few are
known to be teratogenic to humans
– Examples:
– Warfarin: Foetal warfarin syndrome, foetal bleeding, spontaneous abortion
– Sodium Valproate: Neural tube defects incl. spina bifida
– Isotretinoin: Ear malformations, cleft palate, micrognathia, heart defects, brain
malformations

The University of Sydney Page 77

Drug-Induced Teratogenesis: The thalidomide tragedy
– Thalidomide marketed in 1957 - safe hypnotic and sedative

– Recommended specifically in pregnancy for morning sickness

– No teratogenic effects in murine studies

– In 1961 sudden increase in phocomelia (‘seal limbs’) in newborns

At this stage 1 million tablets were being sold

daily in West Germany alone and estimated
10000 malformed babies already born

The University of Sydney Page 78

The University of Sydney Distaval thalidomide advertisement, 1960. Page 79
British Medical Journal, Vol. 1, No. 5168, pp. 4-5.
Drug-Induced Teratogenesis: The Thalidomide Tragedy

– Dr William McBride,
gynaecologist and obstetrician
working in Sydney first alerted
the world to the dangers of
thalidomide
– Published a Letter to the Editor
in the Lancet December 1961
describing the foetal
abnormalities

The University of Sydney Page 80

Drug-Induced Teratogenesis: The Thalidomide Tragedy
– At therapeutic doses, thalidomide produces virtually 100%
malformed infants if taken in the first 3-6 weeks of gestation
Day of Gestation Type of Deformity
21–22 Malformation of ears
Cranial nerve defects
24–27 Phocomelia of arms
28–29 Phocomelia of arms and legs
30–36 Malformation of hands
Anorectal stenosis
The University of Sydney Page 81
Drug-Induced Teratogenesis: The Thalidomide Tragedy

J Korean Orthop Assoc. 2008 Dec;43(6):685-693.

The University of Sydney Page 82

Drug-Induced Teratogenesis: The thalidomide tragedy
Mechanism?
– Still not fully resolved
– Hypothesised: Folic acid antagonism, inhibition of DNA synthesis, inhibition of angiogenesis,
damage to forming sensory nerves
– Turns out that mice are resistant to the teratogenic effects ..
Outcome?
– Withdrawn from the market in 1961
– Changed the way medicines are prescribed in pregnancy
– Now restricted to treatment of multiple myeloma (AMH, 2018)

The University of Sydney Page 83

Using Medicines in Pregnancy
– Women use at least one drug during pregnancy
– Most drugs can cross the placenta
– Drugs have the potential to cause harm to the foetus
– Birth defects
– Unwanted pharmacological effects e.g. dependence

– Following the thalidomide tragedy, the government established the

Australian Drug Evaluation Committee in 1963
– Drugs were categorised based on their risk when used during pregnancy
– Categories only valid at recommended therapeutic doses

The University of Sydney https://www.nps.org.au/australian-prescriber/articles/classifying-drugs-in-pregnancy#article Page 84

Category Definition Examples

Paracetamol
Drugs which have been taken by a large number of pregnant women and women of childbearing age without
Salbutamol
A any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus
Amoxicillin
having been observed.
Codeine
Drugs which have been taken by only a limited number of pregnant women and women of childbearing age,
Montelukast
without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus
B1 having been observed.
Evolocumab
Clopridogel
Studies in animals have not shown evidence of an increased occurrence of fetal damage.
Drugs which have been taken by only a limited number of pregnant women and women of childbearing age,
without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus Phenylephrine
having been observed. Rivastigmine
B2 Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased Tropicamide
occurrence of fetal damage.

Drugs which have been taken by only a limited number of pregnant women and women of childbearing age,
without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus
Fluticasone
having been observed.
B3 Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is
Omeprazole
Salmeterol
considered uncertain in humans.

The University of Sydney Page 85

Category Definition Examples

Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, Frusemide
C harmful effects on the human fetus or neonate without causing malformations. These effects may be Morphine
reversible. Accompanying texts should be consulted for further details. Ibuprofen

Drugs which have caused, are suspected to have caused or may be expected to cause, an increased Doxycycline
D incidence of human fetal malformations or irreversible damage. These drugs may also have adverse Valproate
pharmacological effects. Accompanying texts should be consulted for further details. Atorvastatin

Drugs which have such a high risk of causing permanent damage to the fetus that they should not be used Isotretinoin
X in pregnancy or when there is a possibility of pregnancy. Thalidomide

The University of Sydney Page 86

Using Medicines in Pregnancy
Accessing pregnancy category information:
https://www.tga.gov.au/prescribing-medicines-pregnancy-
database

The University of Sydney Page 87

Problems with pregnancy categorisations
Misconceptions
– A, B, C, D implies a hierarchy of risk - category C is worse than category B NO
– Drugs within the same category carry a similar risk NO
– Sodium valproate vs. paroxetine

– Category D drugs are unsafe to use throughout the whole pregnancy NO

– Some drugs may only cause defects in the early stages of pregnancy

– Category D drugs are unsafe no matter the dose or route of administration NO

– Fluconazole single oral dose for thrush vs. IV for systemic fungal infection

– Animal data is directly translatable to humans NO

The University of Sydney https://www.nps.org.au/australian-prescriber/articles/classifying-drugs-in-pregnancy#article Page 88

Type E: End of use/Withdrawal
Abrupt cessation of a drug where there is physical dependence may
lead to a withdrawal syndrome
Examples include:

– Opioid withdrawal e.g. morphine

– Benzodiazepine withdrawal e.g. temazepam
– Alcohol withdrawal

Can also be referred to as abstinence syndrome.

The University of Sydney Page 89

Type E: End of use/Withdrawal
Physical Dependence:

– Dependence occurs as a result of repeated administration of a drug

– Dependence can be psychological or physical

– Physical dependence refers to a state in which withdrawal of the drug causes

adverse physiological effects
– Withdrawal effects can also be experienced when administering an antagonist
(e.g. heroin & naloxone)

Rang & Dale’s Pharmacology Ch. 49 p.601

The University of Sydney Page 90
Type E: End of use/Withdrawal
– Effects can persist for days or weeks

– Drugs which display withdrawal effects should be withdrawn

gradually and symptoms monitored – dose is tapered

– In the case of withdrawal associated with recreational/illicit drug use

pharmacological intervention can be used to reduce the intensity
– E.g. methadone and opioid withdrawal, benzodiazepines and alcohol
withdrawal

The University of Sydney Page 91

Type E: End of use/Withdrawal
Opioid withdrawal can lead to:

– Restlessness/anxiety
– Runny nose
– Diarrhoea/vomiting
– Shivering
– Piloerection
– Hostility

The University of Sydney Page 92

Type E: End of use/Withdrawal
Benzodiazepine withdrawal can lead to:

– Anxiety
– Dysphoria
– Irritability
– Insomnia or nightmares
– Sweating
– Memory impairment
– Hallucinations or psychosis
– Tremors and seizures/convulsions

The University of Sydney Page 93

Type E: End of use/Withdrawal
Onset of withdrawal symptoms is dependent on the half-life of the drug

I.e. shorter t1/2 = faster onset

Withdrawal can be managed using a benzodiazepine with a longer t1/2

e.g. diazepam

The University of Sydney Page 94

Type F: Oral Contraceptive Failure
– 50-80% of women use the pill at some stage during their reproductive lives
– The pill prevents pregnancy
– >30 brands of pill available

– “Combined” pill contains an oestrogen component and a progestogen

component
– E.g. Levlen contains ethynyloestradiol (oestrogen) and levonorgestrel (progestogen)

– Also “progestogen-only” pill

The University of Sydney https://www.nps.org.au/australian-prescriber/articles/choosing-a-combined-oral-contraceptive-pill Page 95

Image: https://www.getthefacts.health.wa.gov.au/condoms-contraception/types-of-contraception/the-pill
Type F: Oral Contraceptive Failure

Mechanism of action not the focus here, however:

1. Prevents ovulation

2. Reduce likelihood of implantation in endometrium

3. Thickens secretions to form physical barrier

The University of Sydney Page 96

Type F: Oral Contraceptive Failure
Adverse effects of oral contraceptives:

– Weight gain
– Nausea or dizziness
– Flushing
– Depression or irritability
– Skin changes
– Amenorrhoea upon withdrawal of the pill (.. Type E?)
– Thromboembolism (Type A – dose dependent/extension of effect)
– Oestrogens increase the plasma concentration of clotting factors

The University of Sydney Rang & Dales Pharmacology Ch. 35 p. 433-434 Page 97
Type F: Oral Contraceptive Failure
Thromboembolism:

– 3-fold increased risk of venous thromboembolism vs. baseline

– Age, smoking, BMI, Hx of thromboembolism etc increase this risk

– Oestrogen implicated  progestogen-only pill is safer

Risk is dose-related

– Historically, amount of oestrogen in pill has varied

– Aim to achieve therapeutic benefit while preventing thromboembolism

The University of Sydney https://www.nps.org.au/australian-prescriber/articles/choosing-a-combined-oral-contraceptive-pill#r13 Page 98

Type F: Oral Contraceptive Failure
Therefore:
The dose of oestrogen in the pill is the minimum required to achieve
therapeutic benefit (prevent pregnancy).

Any mechanism which interferes with this dose, i.e. the plasma
concentrations of the active components of the pill, will increase the
chances of therapeutic failure.

In the case of the pill.. Therapeutic failure would be classified as

pregnancy. Breakthrough bleeding may also occur.
The University of Sydney Page 99
Type F: Oral Contraceptive Failure

What can affect plasma concentrations?

– Digoxin toxicity (Type A) was linked to drug-interactions which
had an effect on elimination

– Oral contraceptive failure is related to drug-interactions which

affect metabolism

The University of Sydney Page 100

Type F: Oral Contraceptive Failure

Combined and progestogen-only pills are metabolised by CYP3A4

Metabolism of the pill by CYP3A4 reduces

the plasma concentration of active drug

The University of Sydney Page 101

Type F: Oral Contraceptive Failure
Some drugs inhibit or induce CYP enzymes.

Inhibition
– Competition for the substrate binding site
– Non-competitive inhibition
– e.g. ketoconazole forms a complex with haem iron of CYP3A4

Induction
– Increased synthesis and expression of CYP enzymes
– Decreased breakdown of CYP enzymes
– Unknown mechanisms

The University of Sydney Page 102

Type F: Oral Contraceptive Failure

Induction of CYP3A4

Increase rate of pill metabolism

Reduce plasma concentration of pill

Reduction in efficacy

Pregnancy!
The University of Sydney Page 103
Type F: Oral Contraceptive Failure

Some examples:
CYP3A4 INHIBITORS CYP3A4 INDUCERS
Clarithomycin Phenytoin
Fluconazole Phenobarbital
Amiodarone Rifampicin
Verapamil St John’s Wort
Diltiazem Glucocorticoids

The University of Sydney Page 104