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PPT Phase II > Adverse outcomes of drug therapy > Flashcards

Adverse outcomes of drug therapy Flashcards

1
Q

what is the difference between an adverse drug REACTION and an adverse drug EVENT?

A

an adverse drug reaction is an unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to the drug. it is an effect that occurs when the drug is used at therapeutic dose e.g. pt experiencing anaphylaxis shortly after taking a drug.
An adverse drug event is an untoward occurence after exposure to a drug that is not necessarily caused by the drug. e.g. pt having a road traffic accident while on a specific medication

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2
Q

name two relatively mild GI adverse effects with NSAIDs

A

heartburn

dyspepsia

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3
Q

name 3 severe adverse GI effects from NSAIDs

A

ulceration
bleeding
perforation

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4
Q

what is the name of the compounds that come from arachidonic acid that protect teh mucosal lining of the stomach from injury from luminal acid-pepsin?

A

prostaglandins

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5
Q

what is the rate-limiting enzyme in prostaglandin synthesis in the stomach mucosa?

A

COX-1

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6
Q

name 5 NSAIDs

A 
ibuprofen
naproxen
indometacin
diclofenac
aspirin
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7
Q

name two COX-2 inhibitors

A

celecoxib

etodolac

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8
Q

What can be given with or after NSAIDs to protect the stomach mucosa?

A

PPIs

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9
Q

What are Type A adverse drug reactions otherswise known as and what does this mean?

A

‘augemented’
Exaggerated response to pharmacological action. Effects are usually dose-related and largely predictable due to pharmacological effects of the drug.
high incidence, low mortality

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10
Q

What are type B adverse drug reactions?

A

‘bizarre’

Unpredictable effects, often immunological in nature

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11
Q

what is meant by primary effects of a type A adverse drug reaction?

A

Reaction is related to therapeutic action of drug.

E.g. beta blocker and bradycardia

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12
Q

what are secondary effects of a type A adverse drug reaction?

A

effects that can be rationalised from pharmacology but the reaction is unrelated to the therapeutic action.
e.g. beta blocker and bronchospasm
diarrhoea with abx

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13
Q

what is derived from arachidonic acid by the enzyme cyclooxygenase (COX)?

A

Prostaglandins

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14
Q

Prostaglandins produced in the COX-1 pathway are associated with what functions?

A

GI (stomach and intestine) mucosal protection from gastric acid.
Regulation of platelet function (primarily aggregation).
Renal function

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15
Q

The COX-2 enzyme is said to be ‘inducible’, what is meant by this?

A

It is formed/activated in response to a stimulus of a molecular kind e.g. it produces prostaglandins secondary to pro-inflammatory mediators, such as cytokines, as a response to pain, fever and inflammation

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16
Q

Why are COX-2 inhibitors being questioned for an increased risk of cardiovascular events compared to non-selective NSAIDs?

A

COX-2 inhibitors do not affect platelet function so are not thought to offer anti-thrombotic cardiovascular protection that non-selective NSAIDs do.

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17
Q

why might some COX-2 inhibitors still cause numerous upper GI problems?

A

because they are not entirely specific and still partly inhibit COX-1

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18
Q

What is the commonest adverse drug reaction from opioids?

A

constipation

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19
Q

what two opioid receptors are located on the gut smooth muscle that have a role in GI motility?

A

mu and delta

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20
Q

which opioid receptor in the gut directly affects the myenteric plexus?

A

mu receptor

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21
Q

what occurs if mu-opioid receptors in the gut are activated?

A

gut motility is inhibited

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22
Q

what is a common ADR of antihistamines? What is the mechanism of action of this?

A

sedation due to blockade of central histaminergic receptors.

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23
Q

why are first generation antihistamines more sedating than second generation? Give an example of each

A

First generation e.g. chlorphenamine, is highly lipophilic so readily crosses BBB
second generation e.g. cetirizine are lipophobic so don’t cross BBB and are therefore less sedating

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24
Q

What is thought to be the reason that atypical antipsychotics have less extrapyramidal side effects?

A

They have less of an affinity for D2 receptors and more affinity for D4 receptors. The D2 receptors is thought to affect the motor system as much as the motivational aspect of the dopamine system.

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25
Q

What antiemetic can cause extrapyramidal symptoms?

A

metoclopramide - thus its use is restricted to severe vomiting

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26
Q

What is the effect of dopamine on prolactin?

A

dopamine inhibits prolactin.

Thus dopamine antagonists can cause hyperprolactinaemia.

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27
Q

what are the 3 symptoms of hyperprolactinaemia?

A

galactorrhoea
amenorrhoea
breast tenderness

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28
Q

Name 5 long-term effects of increased prolactin

A 
weight gain
osteoporosis
risk of breast, prostate and pituitary cancer
cardiovascular effects
depression
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29
Q

Describe the metabolism of paracetamol when overdosed

A

Paracetamol is primarily metabolised by conjugation with glucuronide and sulphate.
A small amount is oxidised to quinone imine (N-acetyl-p-benzo-quinone imine, NAPQI) which is toxic. NAPQI is inactivated by a conjugation reaction with glutathione and excreted in urine.
In an overdose, the sulphate and glucuronide pathways are saturated with more of the drug so more toxic metabolite gets produced. If insufficient glutathione is available, the toxic NAPQI is not eliminated and reacts with cellular proteins and nucleic acids in the liver, eventually causing irreparable damage

30
Q

what is used to treat a paracetamol overdose and describe the mechanisms of this

A

Use agents that initiate glutathione synthesis, such as methionine or N-acetylcysteine, to eliminate the toxic NAPQI and prevent liver damage

31
Q

If a patient is given an antibiotic such as amoxicillin and came up in a rash, implying it was an allergic reaction, and it turned out the patient had glandular fever (also known as infectious mononucleosis), would this be a true drug reaction?

A

No - patients subsequently tolerate other pencillins without an adverse reaction.

32
Q

What are the symptoms of allergy anaphylaxis?

A 
sudden onset urticaria
generalised pruritis
angiodema
SOB
Wheeze
increased HR
low BP
33
Q

What is the percentage risk of having an allergic reaction and an anaphylaxis reaction?

A

allergic reactions: 1-10%

Anaphylaxis in 0.01-0.05% cases of “penicillin” administration

34
Q

People with a hx of what conditions are at a higher risk of having allergic reactions to drugs?

A

hx of atopy (asthma, hay fever, eczema)

35
Q

If a patient has a hx of anaphylaxis, urticaria or rash immediately after penicillin, which 3 classes of drugs should you not prescribe again in future?

A

penicillins
cephalosporins
beta-lactam abx

36
Q

Name 4 abx to remember not to give to someone who has had an allergic reaction to penicillin in the past that do not have ‘cillin’ in their name

A

Tazocin (contains piperacillin)
Co-amoxiclav (contains amoxicillin)
Imipenam (beta-lactam antibiotic)
Meropenem (carbapenem)

37
Q

Name 3 classes of drugs that can cause drug-related AKI

A

antiretroviral drugs
aminoglycoside abx
NSAIDs

38
Q

Why should ACEi be used with caution in someone who has renal impairment?

A

Because they cause vasodilation of the efferent artery which reduces GFR and this can be dangerious in a pt who already has a reduced GFR

39
Q

What is the effect of NSAIDs on renal function?

A

They inhibit prostacyclin synthetsis leading to renal afferent arteriolar vasoconstriction which reduces GFR which could be dangerious in someone with an already low GFR

40
Q

what are the risks of taking an NSAID (e.g. naproxen) with ramipril (ACEi)?

A

Risk of AKI because both reduce GFR.
ACEi vasodilates efferent arteriole
NSAIDs vasoconstrict afferent arteriole.

41
Q

Name some drugs that have beneficial interactions

A
  1. combination of antihypertensive drugs to enhance hypotensive effects
  2. paracetamol + codeine gives increased analgesia
  3. amoxicillin + clavulanic acid - reduces bacterial resistance
42
Q

What is the most common type of Cytochrome P450?

A

cytochrome P4503A

43
Q

Name 4 classes of drugs that cytochrome P450 (CYP) is responsible for the metabolism of

A 
Ca channel blockers
benzodiazepines
HIV protease inhibitors
HMG-CoA-reductase inhibitors
ciclosporin
non-sedating antihistamines
warfarin
44
Q

Where are cytochrome P450 enzymes present?

A

GI tract and liver

45
Q

Name 5 Cytochrome P450 inhibitors

A 
fluconazole
clarithromycin
erythromycin
grapefruit juice
ritonavir
46
Q

name 4 cytochrome P450 inducers

A

carbamazepine
rifampicin
rifabutin
st. John’s wort

47
Q

what does CYP induction lead to?

A

increased metabolism and excretion of drug.
tolerance or decreased effectvieness.
increased doses needed.
slow development - days to weeks.
these effects are seen in combinations such as the combined oral contraceptive and rifampicin, and when carbamazepine is given to someone on warfarin

48
Q

What does CYP enzyme inhibition lead to?

A

Sensitivity
decreased doses needed
drug accumulation
rapid development - occurs within days.
Se this in pts taking statins and then given clarithromycin.
seen in pts taking warfarin and given amiodarone.

49
Q

If a patient on warfarin was given carbamazepine, what would the effect on INR be?

A

INR would decrease.
carbamazepine is a CYP inducer so warfarin will be metabolised quicker thus INR will become low (blood will clot too quickly)

50
Q

what are the phases of the drug development process?

A
  1. drug discovery and phase 0 trials
  2. phase 1
  3. phase 2
  4. phase 3
  5. regulatory approval
  6. phase 4
51
Q

How long does the research and development of a new drug take on average?

A

12 yrs

52
Q

what is the average cost of the production (research and development journey) of a new drug?

A

£500 million

53
Q

What goes on in drug discovery and phase 0 trials?

A

Research begins in laboratory with research aiming at understanding disease processes at a cellular or molecular level.
potential targets for treatments are then identified.
Researchers may look for natural compounds such as plants, fungi or animals for the basis of drugs. Knowledge gained from genetics and proteins also used to create new molecules using computer technology.

54
Q

What is involved in phase 1 of drug trials?

A

Pre-clinical testing to check for safety and efficacy. Need to then get clinical trial approval.

55
Q

in phase 1 of a drug trial, what is the novel drug tested on?

A

computerised models
cells
animals

56
Q

approval by who is needed before any testing in humans can occur?

A

The Medicines and Healthcare products Regulatory Agency (MHRA)

57
Q

Are humans used in phase 1 trials?

A

yes, if the clinical trial application is approved by the MHRA then the drug will be tested on a small group of healthy individuals.

58
Q

Who is the drug tested on in phase 2 drug trials and what are the aims?

A

efficacy of compound tested in volunteers with the disease.

aim is to determine most effective dose and method of delivery, and to reconfirm product safety

59
Q

Most drugs that fail during clinical trials do so at what phase and why?

A 
Phase 2
Because they turn out to:
Be ineffective
Have safety problems
Have intolerable side effects
60
Q

how many patients are used in phase 2 trials generally?

A

100-500 pts.
Uses lowest number of pts possible to provide sufficient statistical power to determine efficacy (this is to avoid unnecessarily exposing volunteers to potentially harmful substances).

61
Q

What are the aims of phase 3 trials?

A

Reconfirm the phase 2 findings in a larger population.
Identify the best dosage regimen.
Sufficient safety and efficacy data needed to demonstrate an overall risk-benefit of drug needed in order for medicine to be submitted to the regulartory authority.

62
Q

the licencing application for drugs is based on what data?

A

safety and efficacy data

63
Q

what percentage of medicines fail at phase 3 drug trials?

A

10%

64
Q

What year was the Committee on Safety of Drugs set up in and what was it set up in response to?

A

1963

Set up due to thalidomide problems

65
Q

What did the committe on safety of medicines then get renamed as under the terms of the Medicines Act of 1968? What was it then renamed in 2005?

A

Committee on Safety of Medicines (CSM).

In 2005 became Commission on Human Medicines (CHM)

66
Q

What did the Medicines Act of 1968 require?

A

Medicines to be licensed before being allowed onto UK market.

67
Q

Drugs that have passed phase 3 trials must get permission to market the drug from who?

A

the MHRA

68
Q

What must the submission for marketing authorisation to the MHRA include?

A 
Manufacturing process
Pharmacology and toxicity of the compound
Human pharmacokinetics
Results of the clinical trials
Proposed labelling
69
Q

What occurs in phase 4 of a drug trial?

A

Post marketing studies/surveillance - monitoring of long term effectiveness and safety.
Cost effectiveness
Yellow card scheme

70
Q

At what dose of paracetamol should you monitor patient if they have overdosed?

A

> 200mg/Kg (e.g. 12g for a 60Kg person) or if dose is unknown

71
Q

If a person presents to you within 4 hours of taking a paracetamol overdose that exceeds 200mg/kg, what should you do?

A

Record paracetamol at 4hrs and treat if indicated.

72
Q

If a patient presents more than 8 hrs after taking a paracetamol overdose of >200mg/kg, what should you do?

A

commence NAC
Record immediate paracetamol level.
Measure ALT.

PPT Phase II (37 decks)

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