L8: Safety pharmacology and toxicology Flashcards
(10 cards)
Safety pharmacology?
Detection of potential adverse drug reactions (ADR) at the therapeutic dose and above.
Primary and secondary pharmacodynamic studies?
Primary Pharmacodynamic Studies
Detection of potential ADRs mediated by the intended molecular target (e.g., receptor)
Secondary Pharmacodynamic Studies
Detection of potential ADRs mediated by ‘off target’ actions
Thus safety pharmacology is detection of ADR liability (liability is a fancy term for ‘risk of’)
dosage?
Dosage: “Poison is in everything, and nothing is without poison.
The dosage makes it either a poison or a remedy”
Dosage, benefit and risk; A substance is a drug if benefit exceeds risk
At overdosage risk exceeds benefit by definition
therapeutic dose?
Therapeutic window
All therapeutic drugs can evoke ADRs
There is a therapeutic window if there is a dose or concentration range where:
Taking the drug is judged to be better for the patient than not taking the drug
In other words the effect of the disease would be worse than the ADRs of the drug
The therapeutic window is therefore the target range of dose or concentration when a drug is used therapeutically
Therapeutic window is determined part by pharmacology part by intended use of the drug.
The likely dosage for benefit is determined from animal models of disease
The likely dosage for causing ADRs is determined from safety pharmacology (SP) studies, and together this reveals:
No observable effect level?
No Observable Effect Level (NOEL) – highest dose at which no therapeutic effect is detected (= threshold dose for benefit)
No Observable Adverse Effect Level (NOAEL) – highest dose at which no ADR is detected (= threshold dose for ADRs)
The difference is a guide to the possible therapeutic window.
The therapeutic window is therefore determined from:
The NOEL and NOAEL with allowances for
The severity of the disease and
The severity of the ADRs
If the target disease is lethal, the drug may have value even if it causes serious ADRs at the same dose needed for benefit.
For cancer, for example, the necessary therapeutic window may be much narrower than the difference between the NOEL and NOAEL
Drug discovery for such a disease will be focused now on finding alternative drugs with less severe ADRs and higher NOAELs
If the target disease is innocuous, the drug may be deemed unusable even if it causes only minor ADRs at a dose a little above that needed for benefit
For hayfever, for example, the necessary therapeutic window will be close to the difference between the NOEL and NOAEL
Drug discovery will focus now on finding alternative drugs with higher NOAELs and lower NOELs
Maximum safe concentration (MSC)
MSC: a relative concept and is set by risk: benefit analysis: detriment from ADRs vs benefit obtained by taking the drug
GRAPH
therapeutic window and exposure?
Therapeutic window and ‘exposure’
If a drug is administered to a patient for months or year this means extensive ‘exposure’
If a drug is administered only briefly the exposure is low
If the ADR is lethal any exposure may be unsafe:
Moxifloxacin no longer used for bacterial infection as it has a small risk of causing a lethal cardiac syndrome, torsades de pointes
Flecainide doubled mortality in the CAST study because of 1 year exposure unmasking unanticipated rare but lethal arrhythmia, VF
Therapeutic window and exposure:
If a drug is administered to a patient for months or year this means extensive ‘exposure’
If a drug is administered only briefly the exposure is low
If the ADR is non-lethal the exposure may be important:
Guanethidine causes orthostatic hypotension that, though ‘mild’ is inevitable, meaning it cannot be used to treat hypertension
A drug that causes a high incidence of flu-like symptoms may seem doomed – but COVID vaccines do this – acceptable because of one-off exposure (and the benefit is massive)
A therapeutic window therefore does not mean a therapeutic drug will have no ARDs
The goal is a drug that can be used (to provide a benefit that outweighs any detriment)
In a population, some detriment can be expected
The role of SP is to mitigate against the risks of detriment
GRAPH
At therapeutic use the therapeutic window down here (ed50 red box) have acceptable levels of adverse effects. Pushing dose higher then adverse effects that are dose limiting or use limiting?
ADRs in humans?
fall into 5 types;
type A: Dose-dependent; predictable from known properties of the drug. main cause of ADRs 75% (rarely lethal)
type B: idosyncratic response, not predictable, not always dose related. responsible for 35% but majority of related lethal ones
type c: long-term adaptive changes, commonly occurs with some class of drug
type d: displayed effects e.g: carcinogenicity, low incidence
type e: rebound effects following discontinuation of therapy. commonly occurs with some class of drug.
which types may be predicted by non clinical studies: all but B
Type c, d and e are quite rare.
All except b can be determined by preclinical studies. B is more to do with patient like genetic changes?
types of acute ADRs?
Types of Acute Adverse Drug Reactions (ADRs)
Augmented ADRs (Type A) – Due to exaggerated action on the primary molecular target
This occurs when the drug has a supratherapeutic effect (i.e., the dose is too high or the body is overly sensitive).
Example: Hypotension caused by an antihypertensive drug.
On-target effects in non-target tissues
The drug acts on its intended target, but in tissues outside the intended site.
Example: Headache from glyceryl trinitrate.
Glyceryl trinitrate treats angina by dilating blood vessels (via nitric oxide pathway).
The same mechanism causes vasodilation in brain vessels, leading to headaches.
Off-target effects (Secondary ADRs)
The drug acts on other receptors or molecular targets besides the primary one.
Example: Thyroid dysfunction from amiodarone.
Amiodarone interacts with thyroid-related pathways, not its primary cardiac targets.
Non-specific effects
The drug causes side effects through unknown or multiple mechanisms.
Often seen with “dirty drugs” (drugs with many molecular targets).
Mechanism is unclear or complex.
ADRs from active metabolites
The adverse effect is caused not by the parent drug, but by one of its active breakdown products (metabolites).
Key Concept:
The dose-response relationship is crucial in determining the likelihood and severity of ADRs.
history of safety pharmacology?
ADRs originally examined by toxicologists (LD50 etc)
In 1996 terfenadine was identified as having a liability for causing cardiac arrhythmias
Very rare syndrome called torsades de pointes
Ventricular arrhythmia, no cardiac output, rapidly lethal
Drug used for innocuous condition (hay fever)
Revelation that rare but lethal ADRs, especially (as here) mediated by off target effects (here, on cardiac K channel, not histamine H1 receptor) an unrecognized problem
Not detected by conventional toxicological investigation and thousands of patients has taken drug before risk identified
The ‘discipline’ of safety pharmacology thus invented
