Sesh 8: Adverse Drug Reactions Flashcards
Side effects (
Some side effects are discovered in clinical use many years later . Such as COX2 inhibitors which are NSAIDs .
Can increase risk of havign fatal heart attack or stroke
Why are animal models used ?
Test carcinogenicity
Tetrogenivity ( cause damage to unborn fetus )
Clinical trials phases ;
Phase 1 - healthy volunteers small numbers. The studies focus on safety and tolerability. Identify side effects
Phase 2 - first study in patients and establish efficacy and establish a safe therapeutic dose
Phase 3 - larger study with lots of people . Looks at efficacy in clinical practice in comparison to gold standard treatment
Phase 4- conducted after marketing authorisation and aim to assess long term outcomes of safety and efficacy
Clinical tries. Why are medicines not completely safe ?
Clinical trials don’t fully account for use of drugs in real world settings
They identify the more common and predictable side effects but rare side effects may only be apparent once it’s use for a longer period of time
What is the definition of adverse drug reactions
ADR - unwanted or harmful reaction experienced following administration of a drug.
2 types of classification for ADRs
Augmented- related to the known action of the drug . Dose related so can be reversible .
Individuals can be more susceptible due to genetic factors. So lack of enzymes due to genetic factors can lead to build up of toxic levels
bizarre -
Unrelated to known pharmaceutical action of the drug , so unpredictable .
Types of reactions can be categorised(
Type C - continuing reactions (chronic )
Type D - delayed effects ( not immediately apparent )
Type E- end of treatment effects (withdrawal symptoms )
F- failure of treatment
In DOTs classification ADRs are classified;
ADRs at sub-therapeutic doses are hyper-susceptibility reactions
ADRs at therapeutic doses are collateral effects
ADRs at supra-therapeutic roses are toxic effects
Define sub-therapeutic doses
Therapeutic doses
Supra therapeutic dose
Sub therapeutic - a dose of a drug that does not achieve a particular therapeutic effect.
The therapeutic dose of a drug is the amount needed to treat a disease.
Supra therapeutic - Administered at levels greater than would be used in actual treatment of a medical condition.
Time dependant reactions include 6 sub-categories ;
Rapid First dose Early Intermediate Late Delayed
Patients may have different susceptibility to drugs . Key risk factors include
Age
Gender
Physiological factors
Disease - liver kidney disease can affect
Exogenous factors- poly pharmacy or certain foods such as grape fruit juice
Genetics- g6p dehydrogenase deficiency
Drugs or their metabolites can cause cell damage/death:
Necrosis - loss of integrity of the cell membrane results in release of extracellular products which result in an inflammatory response
Apoptosis : programmed cell death 2pathways
Extrinsic (death receptor pathway)
Mitochondrial (internal pathway)
Apoptotic pathway
2 apoptotic pathways; extrinsic and mitochondrial .
The extrinsic, or death receptor pathway is activated via stimulation of these death receptors by death ligands.
This recruits adaptor proteins, which then activate a protease cascade involving Caspase-8, an initiator caspase, and caspase 3, an effector caspase and results in apoptosis.
The mitochondrial pathway can be activated by DNA damage,
stimulates the transcription of
gene p53,
the p53 protein then activates a pathway via a pro-apoptotic Bcl-2, cytochrome-c is then released from the mitochondria,
activating a protease cascade involving Caspase-9 (another initiator
caspase), and Caspase-3 (the effector caspase). This also results in apoptosis.
(The Bcl-2 family of proteins
are expressed when survival factors activate the survival receptors. Withdrawal of these survival
factors activates the mitochondrial pathway.
The 2 pathways of apoptosis are linked, as Caspase-8 can also activate pro-apoptotic Bcl-2 proteins
triggering the mitochondrial pathway.
Once apoptosis is initiated, the cell begins to die and phagocytosis results. There is blebbing of the
plasma membrane, and proteases break-down the cell. Damaged cells display signals that attract
macrophages, which then phagocytose the remains of the cell, removing them from the body.
Drug metabolism
As drugs are metabolised in the body, metabolites are formed. Stable
metabolites are removed by excretion, but reactive metabolites can be cytotoxic.
The liver plays a key role in drug metabolism, with cytochrome p450 enzymes in the liver starting the breakdown of drugs to metabolites
The liver can be exposed to high levels of reactive metabolites, and many
drugs have hepatotoxic effects
The kidney eliminates drugs and metabolites, but renal tubes are exposed to high levels during excretion which can damage the kidney.
Cell damage ; covalent and non covalent interactions
» Reactive drug metabolites can form covalent bonds with target
molecules e.g. DNA, proteins, lipids and carbohydrates
Covalent interactions can lead to carcinogenesis and teratogenesis
Metabolites can also alter target molecules by non-covalent
interactions:
> Lipid peroxidation, chain reactions result in alteration of membrane permeability
> Reactive oxygen species, can be directly cytotoxic
>Depletion of Glutathione, which usually protects cells from oxidative stress
> Modification of sulfhydryl groups, targets are molecules involved in maintaining
intracellular calcium concentrations
Carcinogenesis mechanism ;
The mutation increases oncogene expression this leads to uncontrolled proliferation of the cells .
Mutations in anti-apoptotic genes such as p53 prevent cell death so tumour can’t be regulated by the body
Teratogenesis mechanisms ;
Drugs and their metabolites can effect fetal development .
Teratogenic drugs can cause miscarriage or structural malformations (ace inhibitors )
3 main phase of fetal development
Blastocyst formation
Organogenesis
Histogenesis
Hypersensitivity reactions into 4 types;
hypersensitivity
reactions into 4 types:
> Type I reactions (immediate or anaphylactic hypersensitivity reactions). Drugs/metabolites
provoke production of Ig-E antibodies, which attach to mast cells or eosinophils, and inflammatory mediators such as histamine and cutokines are released.
> Type 2 reactions (antibody-dependent cytotoxic hypersensitivity reactions) involve Ig-G or Ig-M
antibodies bound to cell surface antigens. This triggers activation of the complement system,
and may also promote attack by NK cells.
> Type III reactions (complex-mediated hypersensitivity reactions). IgG antibodies react with
soluble antigens to form antigen-antibody immune complexes that can activate complement, or
attach to mast cells and stimulate release of mediators.
> Type IV reactions (cell-mediated or delayed hypersensitivity reactions) are mediated by T cells
rather than by antibodies.
The main mechanisms involved in ADRs
Cell damage
Carcinogenesis
Teratogenesis
Allergic
Example ADRs - type A
Many common ADRs fit into type A category and result in predictable pharmacological effects.
Dose related so managed by altering the dose
E.g opioids treatment for chronic pain. Opioid receptors located throughout the entire GI tract. The main physiological effects are decreased peristalsis , and enhanced fluid absorption, can lead to constipation in patients who use morphine so will need laxatives alongside
Anaphylaxis with penicillin
Severe Type I Hypersensitivity reaction, sudden onset that results from the
release of histamines, leukotrienes and other mediators. Life threatening
uticarial rash, swelling of soft tissues, bronchoconstriction and hypotension.
Occurs with the first dose, even at sub-therapeutic doses
Another example of type B ADR;
Thalidomide - teratogenesis
Severe malformations of fetus if taken between 21-36 days
Affect upper limbs
X
A prolonged period of exposure to corticosteroids at normal therapeutic dose can lead to osteoporosis
