principles of drug toxicity and adverse effects

what is toxicology?

the study of adverse effects of chemicals on living systems

what is the WHO definition of adverse drug reactions?

any noxious, unintended, and undesired effect of a drug, which occurs at doses used in humans for prophylaxis, diagnosis or therapy

what are the 5 basic type of adverse drug reaction?

A - augmented

B - bizarre

C - continuing

D - delayed

E - end of treatment

what are type A adverse effects usually induced by?

the same pharmacological mechanisms as the therapeutic effects

by am increase of the therapeutic or other pharmacological effect of the drug

describe type A adverse effects

directly dose-dependent (or plasma concentration dependent)

mostly associated with inappropriate dosage schedule

can arise from changes in drug pharmacokinetics

• as a result of the pathology (kidney/liver failure)

• as a result of aging (lower renal elimination in elderly)

can arise from changes in drug pharmacodynamics

• predisposition due to the concomitant pathology

• consequence of contraindications or patient non-compliance

predictable with respect to both clinical manifestation and probability of onset

what is the most frequent type of adverse effect?

type A (76%)

have relatively less dangerous outcomes with lower rate of mortality

give some examples of type A adverse effects

anticoagulants - bleeding

antihypertensives - hypotension

antidiabetics - hypoglycemia

B1 blockers - symptomatic heart failure, bronchoconstriction

antiepileptics - neurological symptoms (vertigo/confusion)

how are type A adverse effects intervened with and prevented?

intervention - dose reduction in most cases, use of antagonist in serious circumstances

prevention - dose titration, adverse effects monitoring, pharmacotherapy monitoring

what do type B adverse effects develop on the basis of?

immunological reaction on a drug (allergy)

genetic predisposition (idiosyncractic reactions)

have NO direct relationship to dose of drug or pharmacological mechanism of drug action

describe the predictability and frequency of type B adverse effects

generally unexpected and therefore unpredictable

appear with very low frequency (0.1-0.01%)

have more serious clinical outcomes with higher overall mortality

describe how type B adverse effects are intervened with and prevented

intervention - instant drug withdrawal, symptomatic treatment

• pharmacological approach in allergy (antihistamines, adrenaline)

prevention - troublesome. avoiding certain drugs with known risk of reactions

describe type B allergic adverse effects

based on immunological mechanism

require previous exposition before actual manifestation

molecular weight of most drugs not enough for direct immunogenicity (except peptides and proteins of non-human origin)

immunogenicity can be acquired by binding of drug on the macromolecular carrier

what is immunogenicity?

the ability of a foreign substance to provoke an immune response in the body

describe type B idiosyncratic adverse effects

do not require any prior sensitisation

are primarily genetically determined deviations in the human metabolism or biotransformation of the drugs

rare and unpredictable reactions (25% of all ADRs) - specific to individual patient

do not occur in most patients at any dose - no simple dose-response relationship

effects not related to pharmacological properties of the drug but can be very severe (most serious of ADRs)

what brings about type C adverse effects?

mostly associated with cumulative long-term exposure inducing toxic response

mostly the accumulation is not immune but is functional and/or ultrastructural changes induced by a drug

describe type C adverse effects

have a direct relationship to the cumulative dose

treatment is troublesome, as it is largely irreversible in higher cumulative doses

general prevention involves cumulative dose reduction, limitation of time of exposure, monitoring, prevention of non-compliance and drug abuse

what characterises type D adverse effects?

they manifest themselves with significant delay

what can type D adverse effects manifest as?

teratogenesis

mutagenesis/carcinogenesis

tardive dyskinesis - during L-DOPA Parkinson disease treatment

leucopoenia - several weeks after a dose of lomustine

what is teratogenesis?

the process by with congenital malformations or birth defects are induced in an embryo or fetus

prerequisite: penetration of placental barrier

what are mutagenicity and carcinogenicity?

mutagenesis - induction of permanent, heritable changes in the DNA sequence of an organism

carcinogenesis - the process by which normal cells are transformed into cancer cells

60-70% of carcinogenic events are induced by chemical compounds

what is a mutation?

a suddenly occurring and persisting change in the genome

list some certain teratogens

thalidomide

antifolates

isoretinoin and vitamin A (high doses)

warfarin

valproate

list some suspected teratogens

tetracyclines

lithium

ACEi

phenytoin

carbamazepine

what are type E adverse effects?

drug withdrawal symptoms and rebound phenomenons

are prevented by avoiding abrupt withdrawals, slow decrease in dose, and avoiding long treatment with such drugs

what are the goals of preclinical safety assessments?

to be sure (within reasonable limits) that the products we develop are not harmful to humans

to establish dose-response and exposure-response relationships

allow informed assessment of risks

develop safer drugs and medicines

differentiate between a hazard and a risk

hazard - potential for harm

risk - the probability of harm under specific conditions

what is the importance of regulatory studies?

early identification of unexpected problems

estimation of an initial safe starting dose for human trials

prior to entry into phase 1 trial on humans, what information is required about a drug?

toxicokinetics, pharmacokinetics and metabolism

acute (single-dose) toxicity

repeated dose toxicity

genetic toxicity

effects on embryofoetal development

local tolerability

safety pharmacology

what is the purpose of general toxicology studies?

to determine target organs

to assess reversibility and sex differences

safety for clinical trials

go/no-go decision

what is a dose-response?

the response of an individual organism to varying doses of a chemical (eg, enzyme, blood pressure)

what are the axes for a dose response curve?

y = % of max. response

x = dose (eg, mg/kg or M, plotted as log¹⁰)

what can be determined from dose-response data?

lethal dose, toxic dose, effective dose (ED₅₀)

what are effective dose, toxic dose and lethal dose?

ED = therapeutic dose

TD = dose at which toxicity occurs

LD = dose at which death occurs

what are ED₅₀, TD₅₀ and LD₅₀?

dose at which 50% of the population therapeutically responds/experiences toxicity/dies

what is therapeutic index and give equation

indicates relatively safety of drug

TI = LD₅₀/ED₅₀

what is standard safety margin and give equation

more conservative estimate of safety margins than TI

SSM = LD₁/ED₉₉

LD₁ = dose required to kill 1%

ED₉₉ = dose therapeutically effective in 99%

what is safety pharmacology?

studies that investigate the potential undesirable effects of a drug on physiological functions in relationship to exposure in the therapeutic range

aims to reveal any functional effects on the major physiological systems and vital functions (should be evaluated prior to human exposure)

what are primary pharmacodynamic effects?

studies on the mode of action and/or effects of a substance in relation to its desired therapeutic target

what are secondary pharmacodynamic effects?

studies on the mode of action and/or effects of a substance not related to its desired therapeutic target

what are the 3 main objects of safety pharmacology studies?

1. to provide a new perspective of the potential risk posed to humans by exposure to a new therapeutic agent

2. investigate the mechanism of the adverse pharmacodynamic effects

3. evaluate adverse pharmacodynamic and/or patho-physiological effects observed in preclinical toxicology and/or clinical trials

give the hierachy of organ systems when investigating safety pharmacology

life-supporting function

• cardiovascular

• respiratory

• CNS

secondary systems

• renal

• gastrointestinal

• immune

• other

also considering factors such as patient population eg, immune system in immune compromised patients

what is the hERG channel?

encodes for K_v11.1 Potassium channel which allows K+ ions to flow out of cardiac cells, allowing the muscle to relax between heartbeats

activation causes prolongation of electrical impulses regulating heart beat (delayed T wave)

can lead to fatal arrhythmias

why is hERG important?

its unique structure makes it highly susceptible to unintentional binding by various compounds

as a result, inhibiting hERG is a leading cause of drug-induced cardiotoxicity and common reason for drug withdrawal from the market

what is polymorphism?

the presence of two or more variant forms of a specific DNA sequence

ie, we express different gene versions as a human populations

what are single nucleotide polymorphisms and what is their significance?

result in alteration of amino acid sequence of protein

distinct protein structures could result in phenotypic differences between the subjects, such as variation in response to medication

affect toxicity of drugs in a population

how is absorption and distribution different in elderly people?

absorption: decreased inhalation capacity, increased dermal absorption due to thinner skin, decreased gut absorption due to malabsorption or impaired gut wall function

distribution: altered blood flow and decreased clearance, change in volume of distribution as body fat increases and muscle mass decreases

decreased expression of metabolic enzymes and plasma protein transporting drugs

why do neonates have an increased susceptibility to toxicity?

have increased dermal absorption due to underdeveloped skin

they are underdeveloped for some metabolic enzymes (eg, P450s)

reduced excretion due to immature renal function

different fat/water ratio so different distribution of chemicals