Toxicity/ Adverse Drug Reactions Two Flashcards
What does ADR stand for?
Adverse drug reactions
Whats the incidence of ADR?
- May account for 20% morbidity and mortality
- ~5% all hospitalizations
- 1-44% chance the patient will experiance ADR while in hospital as they use stronger and larger doses of drugs (Depends on reporting)
- Among top ten leading causes of deaths
Roughly how much world wide is the cost of ADR?
40-50 billion $ per year
In a uk study, they found that ADR was what?
Most reactions were either definitely or possible avoidable
How are toxic mechanisms evaluated?
- Mechanistic studies (huge importance)
What are the benefits of mechanistic studies?
They may provide procedures for the prevention of toxicity and strategies to antagonize the effects.
How are mechanistic studies important in drug development?
- It may identify moities within the structure that are (pro)toxic
- Elucidation of toxic mechanisms can lead to the characterization of physiology of biochemical pathways that may help in the design of new classes of drugs.
what are the ADR mechanistic classifications?
Simplest classification of ADR:
Type One: Predictable, dose-dependent on the known pharmacology of the drug. (lawsuit)
Type Two: Not-predictable, no clear dose-dependency and not due to the known pharmacology of the drug (publication)
What are the mechanistic classification’s of adverse drug reactions
The concept takes into account: A= Dose dependent B= Not predictable C= Chemically predictable D= Delayed E= Withdrawl
safe vs toxic dose, what causes this to change?
Reactions are often due to the known pharmacology of the drug and are therefore dose-dependent and predictable (this includes overdoses)
What percentage of Americans are using opiods?
35%
Whats the examples of dose-dependent and predictable drug toxicity?
NSAIDS Analgesic Paracetamol Perhexiline Penicillins
How many people use NSAIDS?
70 million prescriptions per a year
20-30 billion aspirin tablets purchased in the USA
Whats a ADR with NSAIDS?
NSAID induced:
- gastro-duodenal ulceration and bleeding reported in 15-30% chronic users
may be responsible for 5-10billion USD and 25k deaths per year.
What modern drug development has prevented ulceration complications of NSAIDs?
Enteric coating
What causes the NSAID GI toxicity?
- Oral ingestion results in NSAID induced lesion by interacting with phophotidyl choline and reduce the ability of gastric mucosa to protect itself from HCl
- it also inhibits COX, this is problematic as some prostaglandins are cytoprotective and so initial lesion results in overt damage.
COX produces prostaglandins
What condition can aspirin cause in children?
Reyes syndrome
What is reyes syndrome?
Very rare but serious condition that causes inflammation and swelling of the brain and fatty degeneration of the liver
- Exclusive to children
- 30-40% die
Whats the early symptoms of reyes syndrome?
Start with vomiting, varying neurological disorder, deterioration in consciousness, changes in personality
At a molecular level what occurs in reyes syndrome?
Generalized disturbance in mitochondrial metabolism, eventually resulting in metabolic failure in the liver and other tissues.
What is another major complication of NSAIDS?
Acute renal toxicity
What is acute renal toxicity with regards to NSAIDs?
- Acute ischemia renal insufficiency may occur within hours of initial dose in susceptible patients
- Characterized by marked decrease in urine, weight gain.
Who are prone to developing NSAIDS renal toxicity?
Those with dehydration, haemorrhage, congestive heart failure, excessive diuresis, underlying renal disease.
Or if on ACE, ARB and NSAIDS…
Can NSAIDS renal toxicity be reversed?
Yes, if drugs immediately stopped.
What are factors that NSAIDS affect in the renal system?
- COX is present through the vasculature, allows formation of prostaglandins
- CYP present in the PCT and LOH
NSAIDS affect these two productions.
What happens when COX and CYP are inhibited by NSAIDS?
COX inhibition leads to no formation of PGs which are crucial for maintenance of renal perfusion pressure through renal blood flow.
- Vasodilation
- Influence RAAS as renin released controlled by PGs
CYP inhibition leads to no HETEs formation which would inhibit NaKATPase
- They may also reduce the effectiveness of diuretics
What is a ADR of analgesics?
Analgesic associated nephreopathy
- May be secondary to acute interstitial nephritis
Caused by years of analgesic abuse
i.e Phenacetin
How does analgesic associated nephropathy present?
Patients often present with hypertension, GI ulceration, UTI, Headaches, depression and CV disease
Whats the survival chances of analgesic associated nephropathy?
5 years around 50%
What is specifically happening in analgesic associated nephropathy at a macro level?
INvovles necrosis within the LOH and medullary capillaries spreading through the papilla.
with regards to metabolism and ADR whats a safety precaution taken in drug design?
Most drugs are designed to be chemically non-reactive
What may metabolism of drugs lead to?
Metabolism may lead to the formation of chemically-reactive species that binds to, and inhibits the biological function of a macromolecule. (toxicity metabolism)
What may the formation of toxic metabolites be influenced by?
1) Dose
2) Inter-individual variability in enzyme expression
3) Pharmacokinetic interactions
Is paracetamol safe?
In normal doses it is metabolized into safe soluble metabolites that are excreted in the urine
But in Overdose normal pathways of metabolism are saturated.
What happens in paracetamol overdose?
Normal pathways of metabolism are saturated
- other routes of metabolism take place
- metabolites can bind to and destroy key proteins
- leads to cell death in the liver
- Enough cell death may lead to liver failure and death
In basic terms why is paracetamol toxic?
Toxicity is due to saturation of detoxification pathways
Is toxicity of paracetamol predictable?
There is some dose-dependency and predictability
At a molecular level how is paracetamol toxic?
The toxic metabolite is a quinoneimine that can react with sulfhydryl groups in critical cellular proteins
Loss of intracellular Ca regulation disrupts mitochondrial function and necrotic cell death
What are two classes of factors that affect toxicity?
intrinsic = Genetic, physiology and pathaological conditions i.e race and age
Extrinsic = Environmental conditons
Whats a major factor in toxicity within individuals?
Inter-individual variability in drug metabolism
What are some Inter-individual variability in drug metabolism?
Lack of metabolism- (enhanced effect)
Lack of metabolic pathway - Compound is bioactivated by another enzyme
Lack of detoxification pathway - Enhanced toxicity
Lack of bioactivation pathway - POOR METABOLIZERS LESS AT RISK
Increase protein expression or catalytic activty - Increased toxic metabolite production
What causes genetic susceptibility to ADR?
Genetic polymorphisms to:
Pharmacokinetics - ADME
Pharmacodynamics - Receptors, ion channels, enzymes, immune systems.
At a DNA level, how can this change toxicity affects?
Even a single base pair change can lead to different protein folding and affect the ability of an enzyme to catalyse a reaction
Whats an example of a DNA change that makes a big difference to toxicity?
CYP2D6 is an enzyme that metabolizes around 25% of all drugs
Around 7% Caucasians have genetic variation that makes this enzyme a poor metabolizer (drug not broken down quickly, builds up and can be toxic)
Whats an example of a drug metabolized by CYP2D6?
Perhexiline (antiangina drug)
lack of metabolism results in its accumulation in cells and results in liver and nerve cell damage
Since perhexiline can be toxic to a lot of people, what happened to it?
Most of the world withdrew it but NZ which instead uses it in conjunction with close monitoring to see how its metabolism is doing and to ensure toxicity does not occur.
What are the most common ADR to penicillin?
Common reactions to oral penicillin include:
- Nausea
- Vomiting
- Diarrhea
- Black hairy tounge
What adverse reactions are associated with high dose penicillin?
Haemolytic anaemia
neuropathy
What do hypersensitivity reactions to penicillin include?
- Skin erruptions
- Urticaria
- Chills, fever
- Anaphylaxis
How many people are allergic to penicillin?
3-10%
1 in 10 of these may be truly allergic though
