Toxic Effects of Drug for Dieteteics

1. Principles of toxicologyPrinciples of toxicology
-It is the science of the adverse effects of chemicals
on living organisms.
-A descriptive toxicologist performs toxicity tests to
obtain information that can be used to evaluate the
risk of exposure to a chemical pose to human beings
and the enviroment.
-Amechanistic toxicologist attempts to determine
how chemicals exert deleterious effects on living
organisms .
-A regulatory toxicologist judges whether or not a
drug or other chemicals has a low enough risk to
justify making it available for its intended purpose .
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2. Con.Con.
An acceptable daily intake (ADI) is the
input of a chemical that can be consumed
over an entire life-time without any
apprciable risk.
A threshold limit value (TLV) is the
maximum concentration of each chemical
that does not harm the enviroment .
Forensic toxicology that combines
analytical chemistry and the fundimental
toxicology in a medicolegal concept that
assisst in postmorteum investigations to
establish the cause of a stage of a crime up
to the level of death crimes.
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3. Con.Con.
Clinical toxicology focuses on disease
that are caused or are uniquely
associated with toxic substances to
help in diagnosis through new
techniques and treatment of such
intoxications.
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4. Dose-response curveDose-response curve
It is crucially important as it is graded in
individuals quantal in population .
Gradedd doses given to an individual
may result in a greater reponse as it
increases.
Quantal doses given to a population
affect a larger percentage as they are
raised . This is used to determine the
median lethal dose(LD50) of drugs and
other chemicals.
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5. 05/31/15 Dr. Medani A.B. ,2006

6. Risk and its assessmentRisk and its assessment
There is marked differences in LD50 of
drugs , some may be harmful in a
fraction of micrograms and others may
be relatively less harmful in doses of
several grams or even more.
Inspite of the advanced technology , it is
not easy to distinguish between toxic and
non-toxic drugs.
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7. Con.Con.
Pracelsus statement” All substances are
poisons , but the right dose differentiate
the remedy from the poison” .
In risk assessment one should consider the
direct and indirect harmful effects of a
chemical on the enviroment when used in
the quantity and manner proposed.
In a chemical delivered to humans and
enviroment in association with food ,one
should be very careful.
In those given as drugs , one should weigh
the benefit vs harm.
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8. Acute versus chronicAcute versus chronic
exposureexposure
Acute Chronic
*Dose delivered *small doses over a
as a single event long period of time
allow slow
accumulation.
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9. Chemical forms of drugsChemical forms of drugs
that produce toxicitythat produce toxicity
Deleterious effects of any drug are due to
the chemical structure of the parent drug
and its metabolites that are produced by
enzymes , light and reactive oxygen
species.
05/31/15 Dr. Medani A.B. ,2006

10. Toxic metabolitesToxic metabolites
Chemical metabolites of drugs are
mainly the cause of their toxicities.
Unstable metabolites are called reactive
metabolites.
Both stable and unsatble metabolites
are more toxic in cases where CYP450 is
increased.
05/31/15 Dr. Medani A.B. ,2006

11. Phototoxic andPhototoxic and
photoallergic reactionsphotoallergic reactions
Many chemicals are biotransformed into
their toxic metabolite by hepatic enzymes.
Some chemicals are activated in the skin
by ultraviolet &/or visible radiation.
In photoallergy, drugs may absorb the
light ,then converted to a product that is
more potent as an allergen than the
parent drug.
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12. Con.Con.
Drugs on reaching the skin , either
locally or systemically, may undergo
photochemical reactions within the skin
to induce directly photosensitivity or
enhance the usual sunlight effects.
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13. Reactive oxygen speciesReactive oxygen species
Paraquat and its metabolites lose one
electron paired in electron donation with
oxygen forming a reactive oxygen
species leading to severe lung injury.
05/31/15 Dr. Medani A.B. ,2006

14. Spectrum of undesiredSpectrum of undesired
effectseffects
A drug may produce many types of
effects, but only one remains the goal of
treatment.
Side effects of a drug are usually non-
deleterious.
Undesirable toxic effects include most of
the other effects.
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15. Types of toxic reactionsTypes of toxic reactions
Toxic effects are either pharmacological,
pathological or genotoxic.
Depending on the concentration of the
chemical ,toxic effects are usually
reversible.
Pharmacological effects discontinue due to
biotransformation,while pathological and
genotoxic effects need repair
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16. An adverse drug reaction (ADR) is an injury
caused by taking a medication.ADRs may occur
following a single dose or prolonged administration
of a drug or result from the combination of two or
more drugs. The meaning of this expression differs
from the meaning of "side effect", as this last
expression might also imply that the effects can be
beneficial.[2]
The study of ADRs is the concern of
the field known as pharmacovigilance. An adverse
drug event (ADE) refers to any injury occurring at
the time a drug is used, whether or not it is
identified as a cause of the injury.
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17. Causes
Type A: Augmented pharmacologic effects - dose dependent and
predictable
Type A reactions, which constitute approximately 80% of adverse drug
reactions, are usually a consequence of the drug’s primary
pharmacological effect (e.g. bleeding from warfarin)or a low therapeutic
index (e.g. nausea from digoxin), and they are therefore predictable.
They are dose-related and usually mild, although they may be serious or
even fatal (e.g. intracranial bleeding from warfarin). Such reactions are
usually due to inappropriate dosage, especially when drug elimination is
impaired. The term ‘side effects’ is often applied to minor type A
reactions.
Type B: Idiosyncratic
Types A and B were proposed in the 1970s, and the other types were
proposed subsequently when the first two proved insufficient to classify
ADRs.
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18. Seriousness and severity
The American Food and Drug Administration defines a serious
adverse event as one when the patient outcome is one of the
following:
Death
Life-threatening
Hospitalization (initial or prolonged)
Disability - significant, persistent, or permanent change,
impairment, damage or disruption in the patient's body
function/structure, physical activities or quality of life.
Congenital anomaly
Requires intervention to prevent permanent impairment or
damage
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19. Location
Adverse effects may be local, i.e. limited to a certain location, or
systemic, where a medication has caused adverse effects
throughout the systemic circulation.
For instance, some ocular antihypertensives cause systemic
effects,[7]
although they are administered locally as eye drops,
since a fraction escapes to the systemic circulation.
Mechanisms
As research better explains the biochemistry of drug use, fewer ADRs are
Type B and more are Type A. Common mechanisms are:
Abnormal pharmacokinetics due to
genetic factors
comorbid disease states
Synergistic effects between either
a drug and a disease
two drugs
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20. Abnormal pharmacokinetics
Comorbid disease states
Various diseases, especially those that cause renal or hepatic
insufficiency, may alter drug metabolism. Resources are
available that report changes in a drug's metabolism due to
disease states.
Genetic factors
Abnormal drug metabolism may be due to inherited factors of
either Phase I oxidation or Phase II conjugation.
Pharmacogenomics is the study of the inherited basis for
abnormal drug reactions.
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21. Phase I reactions
Inheriting abnormal alleles of cytochrome P450 can alter drug
metabolism. Tables are available to check for drug interactions
due to P450 interactions.
Inheriting abnormal butyrylcholinesterase (
pseudocholinesterase) may affect metabolism of drugs such as
succinylcholine[13]
Phase II reactions
Inheriting abnormal N-acetyltransferase which conjugated some
drugs to facilitate excretion may affect the metabolism of drugs
such as isoniazid, hydralazine, andprocainamide.
Inheriting abnormal thiopurine S-methyltransferase may affect
the metabolism of
the thiopurine drugs mercaptopurine and azathioprine.
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22. Interactions with other drugs
The risk of drug interactions is increased with polypharmacy.
Protein binding
These interactions are usually transient and mild until a new
steady state is achieved.These are mainly for drugs without
much first-pass liver metabolism. The principal plasma proteins
for drug binding are:
albumin
α1-acid glycoprotein
lipoproteins
Some drug interactions with warfarin are due to changes in
protein binding.
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23. Cytochrome P450
Patients have abnormal metabolism
by cytochrome P450 due to either inheriting
abnormal alleles or due to drug interactions. Tables are
available to check for drug interactions due to P450
interactions.
Synergistic effects
An example of synergism is two drugs that both
prolong the QT interval.
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24. Treatment
-Modification of dosage
-Discontinuation of drug if necessary
-Switching to a different drug
-For dose-related ADRs, modifying the dose or eliminating or
reducing precipitating factors may suffice.
-Increasing the rate of drug elimination is rarely necessary. For
allergic and idiosyncratic ADRs, the drug usually should be
discontinued and not tried again.
--Switching to a different drug class is often required for allergic
ADRs and sometimes required for dose-related ADRs.
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25. Prevention
Prevention of ADRs requires familiarity with the drug
and potential reactions to it. Computer-based analysis
should be used to check for potential drug interactions;
analysis should be repeated whenever drugs are
changed or added. Drugs and initial dosage must be
carefully selected for the elderly.
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26. Local versus systemicLocal versus systemic
toxicitytoxicity
Local toxicity occurs at the site of first
contact between the toxicant and the
biological system.
Systemic toxicity requires absorption and
distribution of the toxicant.
A toxicant may produce both effects .
Severity of local toxicity depends on the
portal of entry.
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27. Reverible and irreversibleReverible and irreversible
toxic effectstoxic effects
Prohibitively toxic drugs cause
irreversible toxicity.
Ability of the tissue to reverse the drug
toxicity depends on the tissue capacity
to regenerate.
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28. Delayed toxicityDelayed toxicity
Most toxic drug effects occur at
predictable time.
Aplastic anemia occur after weeks of
chloramphenicol treatment stops.
Carcinogenic effects of chemicals are
also delayed type of toxicity.
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29. Chemical carcinogensChemical carcinogens
Either genotoxic or non-genotoxic.
Most gentoxic carcinogen are inactive
which turn in the body into the primary or
ultimate ones by drug metabolizing to
reactive electron defficient intermediates
( electrophiles) .
These electrophiles interact with electron-
rich centers in DNA to produce mutation.
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30. Con.Con.
DNA can reverse this effects if DNA
repair mechanism are normal .
Nongenotoxic carcinogen are promoters
that do not produce a tumor alone, but
can potentiate the effects of genotoxic
carcinogens by facilitation of the
growth and development of dormant or
latent tumor cells.
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31. Laboratory testsLaboratory tests
i/ Mutagenicity testing of the carcinogens
using Ames test of Salmonella typhimurium
for genotoxic carcinogens.
ii/ Using laboratory animals feeding with the
carcinogen for the entire life-span , then do
autopsies and histopathological testing
comparing with control animals. This test is
for genotoxic and promotor carcinogens.
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32. Allergic reactionsAllergic reactions
An adverse reaction that result from
previous exposure to a particular chemical
or to one that is structurally similar.
Hapten + endogenous protien antigen
complex + antibody complex
subsequent eposure {allergy}
05/31/15 Dr. Medani A.B. ,2006

33. Idiosyncratic reactionsIdiosyncratic reactions
Are the genetically determined abnormal
reactivity to a test.
This response could be in a form of
extreme sensitivity to low doses or
increased insensitivity to high doses of a
chemical.
These genetic polymorphisms can be due
to inter-individual differences in drug
pharmacokinetics or pharmacodynamics .
This knowledge is used toindividulize
dosages in a science known as
pharmacogenomics.
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34. Interactions betweenInteractions between
chemicalschemicals
Concurrent exposure to more than one
chemical may alter the pharmaacokinetics
of one or both interacting drugs.
The pharmacodynamics of drugs may be
altered due to the competition on receptors.
Functional non-receptor drug interaction
occur when two drugs have different
mechanisms of action.
The combined toxicant therapy may be
equql to,less than or greater than the sum
of effects of the individual agents.
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35. Classification ofClassification of chemicalchemical
interations between drugsinterations between drugs
Additive effect= combined effects of two
chemicals is equal to the effect of each
toxican if given alone.
Potentiation= increased effect of a
toxicant acting simultaneously with a non-
toxic one.
Antagonism=interferance of one chemical
with the action of another (antagonistic
agent = antidote).
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36. Descriptive toxicity testsDescriptive toxicity tests
in animalsin animals
Principles:
-When followed properly the application to
human beings.
-Exposure of lab. Animals to toxic agents
in much lower dose than expected in
humans.
05/31/15 Dr. Medani A.B. ,2006

37. Con.Con.
Experimental animals are tested for:
i/Acute toxicity by estimating the LD50 in
two different animal species by two
different routes of adminstration, death
number in two weeks are recorded, signs
of intoxications,lethergy, behavioural
modifications and morbidity.
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38. Con.Con.
ii/Subacute is then tested for 90 days by
using laboratory species in the same
route intende to be used by humans (3
doses) ,detect the needed parameters
and test organs by a pathologist.
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39. Con.Con.
iii/ Chronicity is tested for short term
drugs for 6 month and for long term
drugs for two years.
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40. Incidence of acuteIncidence of acute
poisoningpoisoning
Incidence of acute poisoningecreased
highly due to good packing of drugs,drain
cleaners,turpentine and other house hold
chemicals,improved medical training and
care and increased public awareness of
potential poisons.
Although the most common causes are
house hold cleaners and cosmetics ,drugs
are the most common causes of death.
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41. Con.Con.
Most of death cases occurs intentionally in
adults and accidentally in kids.
Accidental poisoning in kids accounts to
53% of the incidence of poisoning.
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42. Sources of information onSources of information on
poisoningpoisoning
i/ Books..
ii/ Computerized sources.
iii/ Poison centers.
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43. Prevention & treatment ofPrevention & treatment of
poisoningpoisoning
Many acute poisoning incidences by
common sense advice from a physician.
Toxic agents are either having specific
antidote or not .The majority of toxicants
do not have antidote ,so :
-Maintain respiration and circulation.
-Do serial measurements of vitalsigns
and reflexes.
-Observe response to therapy and need
for additional treatment.
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44. Con.Con.
In acute poisoning treatment you
maintain vital functions, keep the
concentration of toxicants in tissue as low
as possible by decreasing its absorption
and enhancing its elimination, then
combat toxicological signs at effecter
sites.
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45. Prevention of furtherPrevention of further
absorptionabsorption
i/Emesis : this used for oral poisoning .It is
contraindicated in case of case of corrosives
for the fear of gastric perforation and
further necrosis of the oesophagus,
aspiration in cases of coma, delirium or
stupor ,in case of ingestion of CNS
stimulants for the fear of convulsion and in
case of ingestion of petrolium distellates for
the fear of peritonitis.It is indicated in case
of dangerous chemicals like pesticides.
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46. Con.Con.
ii/ Gastric lavage is the administration
of a tube into the stomach to wash it
with water ,normal saline or half normal
saline before the absorption of
poisons.This need experts for the fear
of gastric injury, but its
contraindications are similar to those of
emesis.
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47. Con.Con.
iii/Chemical adsorption of many
chemicals to the surface of activated
charcoal avidyl to reduce the
enterohepatic circulation of the drug
and enhance its excretion.
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48. Con.Con.
Chemical inactivation is the changeof
the chemical nature of a poison
rendering it less toxic or decrease its
absorption.This needs time and the
use of neutralizing agents is
contraversal.
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49. Con.Con.
Purgation : The rashionale for using
osmotic harmless cathratic is to
minimize absorption by hastening the
passage of toxicants through the GIT,
usually after the ingestion of enteric
coated tablets by more than one hour.
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