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Pharm term paper

Pharm term paper outline
Medication safety and adverse drug reactions
Evaluation of (Western) drug interactions with nutraceutical
Development of drug tolerance and drug resistance
Requirement: Write an essay on one of the topics above in English
(> 2000 words; submit in MS Words format)
1. Background: statistic: no of people suffering from adverse
reaction & fatal data
(Preventable ADRs) : US statistics
The Institute of Medicine reported in January of 2000 that from 44,000 to 98,000
deaths occur annually from medical errors.1 Of this total, an estimated 7,000 deaths
occur due to ADRs. To put this in perspective, consider that 6,000 Americans die
each year from workplace injuries.
However, other studies conducted on hospitalized patient populations have placed
much higher estimates on the overall incidence of serious ADRs. These studies
estimate that 6.7% of hospitalized patients have a serious adverse drug reaction with
a fatality rate of 0.32%.2 If these estimates are correct, then there are more than
2,216,000 serious ADRs in hospitalized patients, causing over 106,000 deaths
annually. If true, then ADRs are the 4th leading cause of death—ahead of pulmonary
disease, diabetes, AIDS, pneumonia, accidents, and automobile deaths.
These statistics do not include the number of ADRs that occur in ambulatory
settings. Also, it is estimated that over 350,000 ADRs occur in U.S. nursing homes
each year.3 The exact number of ADRs is not certain and is limited by methodological
considerations. However, whatever the true number is, ADRs represent a significant
public health problem that is, for the most part, preventable.
2. Definition: adverse drug reaction & medication safety
Adverse drug reaction
- An adverse drug reaction (ADR) can be defined as ‘an appreciably harmful or unpleasant
reaction resulting from an intervention related to the use of a medicinal product
> include toxic effects & side effects
Medical safety
Medical safety refers to the safety regarding the medical devices,
diseases, and health care of the diseased patients. Medical safety
can also be termed as the safety and efficacy of medications that
are carried out by people.
3. Types of adverse drug reactions
- drug toxicity
> different divisions
1. Dose
Dose-related [quantitative]
 Drug property: therapeutic index (TD50, ED50)
 Disease state
 Multiple drug therapy (can mention western&Chinese med )
 Age
Non-dose related
 Biological variations (genetic)
2. Exposure
Acute: <24hrs
Chronic: >3 months
Local (organ-based)
> extent
Classification (Ralph)
 6 types
1. Type A: dose-related=
2. Type B: non-dose related=biological variations
3. Type C: dose-related and time-related= reaction brought by
prolonged exposure of accumulative dose of drugs
4. Type D: Time-related (delayed)=reactions that occur sometime
after the use of drug
5. Withdrawal=reactions that occur after the withdrawal of
6. Unexpected failure of therapy=reaction causing the failure
of therapy
4. Guidelines managing the adverse reactions for medical
Surveillance: report system
1. Distribution
8, 5
- ADR: most common iatrogenic illness > complicate 5-15%of therapeutic drug courses
- In the US, > 100,000 deaths attributed annually to serious ADR ; 3-6% of hospital
admission are because of ADR ; 6-15% of hospitalized patients (2.2. million people in the US
in 1994) experience a ADR
- A recent review (2015) showed that 3.6% of patients were admitted to hospitals in Europe
due to ADRs and 10% of patients developed side effects during their inpatient stay
- The latest report issued by MiDatabank in cooperation with the Medicines and Healthcare
Products Regulatory Agency, shows an increasing trend in the number of reported ADRs in
the period between 2011 and 2016 across the UK
- The prevalence of ADR-related hospitalisations was relatively more consistent among
studies in developed countries than developing countries
2. Determinants: Common risk factors
9, 7, 2(p. 2), (5?), pharm-L06 (Chinese med), 8(p.3)
Pharmacological: dose, drug formulation, pharmacokinetic or pharmacodynamic
abnormalities, and drug interactions
> Increased levels of reactive drug metabolites, their impaired detoxification, or decreased
cellular defense against reactive drug products
Immunological & Genetic : body reactions
> ethnic variation
- patient-related
 age: both very young and old
- elderly
> take multiple drugs
> liver dysfunction with age > loss of ability of drug metabolism
> change of fat tissue to water proportion
Decrease of water content > increase in concentration of water-soluble drugs
Increase proportion of fat tissue > increased accumulation of lipid-soluble drugs
> kidney dysfunction > failure of drug excretion
> retention time of drug in human body increases with age > prolonged time of drug effects
- smaller capacity of drug elimination
- less likely to be studied in research
- more variable and less predictable drug absorption and metabolism
- infants and very young patients: low/ clearly evaluated capacity of drug metabolism because
they are not full developed
1. Neonates have immature renal tubular function when they
are below the age of 8 weeks, avoiding digoxin, aminogly- cosides, ACE inhibitors, NSAIDs
is a must (De-gregori et al., 2009).
2. Physiologic hypoalbuminemia in neonates affects drug dosing. Caution is recommended when dealing with high pro- tein binding drugs such as
NSAIDs (Anderson and Lynn, 2009).
3. Neonates, have low body fat; they might be affected by fat
soluble drugs (Ibanez et al., 2009). 4. Increased anesthetic effects due to immature blood
barrier at <8 weeks of age (Schoderboeck et al., 2009).
5. Predisposition to hypotension due to poor cardiac compliance and immature baroreceptors (Pellicer et al., 2009).
 Gender
- Female: lower bodyweight and organ size, more body fat, different gastric motility
and lower glomerular filtration rate > affect the way the body deals with drugs by
altering the pharmacokinetics and pharmacodynamics of the drugs including drug
absorption, distribution, metabolism and elimination.
- Different frequency and severity of ADR to antiretroviral drugs
- Female: more active hepatic enzyme (CYP3A4) > different effects on drug
metabolism e.g. higher metabolism of midazolam vs men: more other enzymes
- More likely to suffer from torsade de pointes ventricular tachycardia when prescribed
with drugs that prolong cardiac repolarization
- Different pharmacodynamic effects on cardiac and psychotropic drugs e.g. higher
efficacy of Chlorpromazine and fluspirilene on women for same dosage and plasma
- Male: affected fertility when prescribed with colchicine that treats diseases including
Familial Mediterranean fever vs female: no effect on fertility
- Female: more common hepatic drug reactions > hepatotoxicity
- Female: more drug effects due to specific issues like pregnancy, menstruation
e.g. pregnancy > lower efficacy of anti-epileptics due to faster elimination
 Habit of contraception: female
 Race and ethnicity
 Determinants of susceptibility include kinetic factors, such as gene polymorphisms in
cytochrome P450 enzymes, and dynamic factors, such as polymorphisms in drug
- Hypersensitivity reaction to abacavir: Caucasian higher risk
- angiotensin-converting enzyme (ACE) inhibitors: African Americans were found to
be more susceptible to developing ACE-related angioedema
> National Institute for Health and Care Excellence guidance has suggested that
patients of African or Caribbean descent should be prescribed an angiotensin-II
receptor blocker in favour of an angiotensin converting enzyme (ACE) inhibitor for
hypertension [S2]
cardiovascular drugs: black patients- higher risk of angioedema, intracranial
blood pressure lowering drug: black patients - higher risk of angioedema
east-asian patients – higher risk of cough
thrombolytic therapy when using streptokinase and tissue plasminogen activators:
black patients have higher risk of bleeding
Social factors
Alcohol drinking
 Direct
- Cause ADR with consuming alcohol with some drugs e.g. nausea, vomiting,
headaches, drowsiness, fainting, loss of coordination, hypotension
e.g. cause internal bleeding in patients suffering from peptic ulcer or ex-peptic ulcer
or gastritis when they uptake alcohol with NSAIDS due to severe ulceration
- Unexpectedly amplify the drug effect
e.g. alcohol magnify inhibitory effect of sedatives and narcotics at their site of action
in brain
- indirect
- cause damage to the organs responsible for drug metabolism
> chronic consumption > activation of enzymes that converts drug into toxic
substances that damage organs including liver
> alcohol damages liver (liver cirrhosis & hepatitis) > impaired ability of
metabolizing drugs > increase the toxicity of drugs
e.g. increase beta blockers’ toxicity
 smoking
- decreased pharmacological effects by affecting liver enzymes which induce hepatic
cytochrome P-450 isoenzymes like 1A2 to which many drugs bind.
- Tobacco stimulates sympathetic nervous system
- Smoking affects therapeutic responses of certain drugs such as theophylline, oral
contraceptives, insulin
e.g. insulin-dependent diabetic smokers needed 15–20% more insulin than non-smokers,
and up to 30% more if they smoked heavily
> increase the rate of hepatic clearance by increased binding of heparin to antithrombin
III due to activated thrombosis
> decrease the rate of insulin absorption thanks to the cutaneous vasoconstriction after
subcutaneous administration
e.g. smoking > reduced effect of beta blockers on blood pressure and heart rate
Drug-related factors
Polypharmacy: number and severity of ADR increases with increasing number of
drugs taken
ADRs may occur due to drug interaction, synergism, duplication, additive effect,
discontinuation of therapy (inability of some patients especially the elderly to keep
track of using their medications), changing the dose to save money, skipping some
medications and physiological antagonism
Skipping some of the drugs in treatment > shortage of treatment & development of
adverse events
Prescribing cascade caused by polypharmacy which includes drugs used to treat other
drugs’ ADR give raise to other ADR > endless line of medication
e.g. prochlorperazine to prevent drug- induced dizziness > Prochlorperazine for
instance may cause postural hypotension which may exacerbate any hypotensive
effect of antihypertensive drugs > cause accidents e.g. hip fracture due to serious
>maybe caused by misdiagnosis by physicians: see ADR as the symptom of diseases
> prescribe more drugs > worsening of the ADR or putting patients at risk of new
e.g. 1. Thiazide diuretics may cause hyperuricemia which leads to prescribing
colchicines which in turn may cause diarrhea
Drug-drug interaction: effects of a drugs changed by another drug
Frequency & prevalence of interactions depend on the number of concomitant drugs
and complexity of regimen
>two classification
1. pharmacodynamic: lead to additive or antagonistic pharmacological effects
2. pharmacokinetic: involve induction or inhibition of metabolizing enzymes in the
liver or elsewhere, displacement of drug from plasma protein binding sites, alterations
in gastrointestinal absorption, or competition for active renal secretion
Addition of non-prescription medication: drug combination may sometimes cause
synergistic toxicity (greater than the sum of the risks of toxicity of either agent used
e.g. Patients concurrently receiving corticosteroids and NSAIDs had a risk of peptic
ulcer disease that was 15 times greater than that of nonusers of either drug
e.g. Both vancomycin and narcotics induce dose-dependent skin reactions and
synergize to cause adverse reaction
Adverse effects occur when take certain herbal medicine with some orthodox drugs
e.g. uptake of Dan Shen (Radix Salvia Miltiorrhiza)
>With chronic warfarin, cause exaggerated prolongation of prothrombin time,
leading to internal bleeding
>Reduce the efficacy of anti-ulcer drugs by forming non-absorbable precipitates
Chemical properties and molecular weight of the drugs (hypersensitivity reaction)
Larger drugs with greater structural complexity: more likely to induce immune
response (immunogenic) [S8]
e.g. drugs heterologous antisera, insulin
Route of drug administration [S8]
Topical, intramuscular, intravenous administration: more likely to cause
hypersensitivity reactions when compared with oral administration
R: efficiency of antigen presentation in skin, adjuvant effect of repository drug
preparation, high conc of circulating drug antigen rapidly achieved by I.V.
Types of ADR
2, 6, 8
 Many ADR: preventable [S7: abstract, S2 p.2
- many are preventable with adequate foresight and monitoring: Epidemiological
studies tend to find that between a third and a half of ADRs are (at least potentially)
 prevention
1. identification of susceptibility: physicians should have adequate knowledge of risk
factors of ADRs > stay vigilant when encountering patients with higher susceptibility
& make cautious choice on the use of drugs in the treatment
e.g. co-prescription of folic acid with methotrexate: reduce ADRS associated with
folate deficiency
2. Monitoring
- monitoring: keep track of body condition of patients
e.g. monitoring electrolytes and renal function when treating with renally active
drugs or diuretics
e.g. monitor the change in liver function tests in a patient treated with antituberculous
chemotherapy can prevent the development of acute liver failure
3. Diagnosis
- Identify the types of ADRs and the drugs causing ADRs by investigation through
observations on the sign and symptoms resulting from ADRs [esp. those of immediate
generalized reactions which are the most life-threatening form of ADRs
>signs such as wheezing, urticaria: manifest thew imminent cardiovascular collapse >
death > stop the prescription of the drugs immediately], enquiry about the medication
history of the patients, and features of ADRs like such as asking if ADRs stop when
patients stop taking the drugs
- Evaluation on the appearance signs and symptoms of immediate generalized reactions
which are the most life-threatening form of ADRs
>signs such as wheezing, urticaria: manifest thew imminent cardiovascular collapse >
death > stop the prescription of the drugs
Investigation to confirm the diagnosis
e.g. testing the intracellular tissue deposition of the drug or a metabolite (eg indinavir
crystalluria and nephropathy).
e.g. Skin testing for type I hypersensitivity reactions (8)
> detect the presence of antigen-specific IgE
4. Reporting system for surveillance
- Todays’ problem
1. Many cases of ADRs: underreported > system developed x give analysis of data with
high accuracy [2]
- Nowadays reporting system
1. Yellow Card Scheme in the UK, operated by the Medicines and Healthcare
Products Regulatory Agency (MHRA) and the Commission on Human Medicines
(CHM) [2]
 Collect data of information from a report which can be submitted through the
internet: an identifiable patient, a reaction, a suspected medicinal product and an
identifiable reporter [2]
2. Reporting of ADRs detection to a national centre responsible for providing
general information about drugs which is then sent to the WHO worldwide
database for data analysis by WHO Collaborating Centre for International Drug
Monitoring [6]