PHARMACOLOGY

Chemical Forms of Drugs that Produces Toxicity

1. Parent Drug – chemical form that produced desired therapeutic effect

2. Toxic metabolites

Types of toxic reaction

1. Pharmacological2. Pathological (on brain, stomach,

heart, lungs, duodenum & colon, kidney, pancreas, eyes, liver & gall bladder, bladder & prostate)

3. Genetoxic

Prevention of accidental exposures in children

Smaller packing Packs a blisters pack Child-resistant closures Adequate labeling Systematic information

Intentional poisoning

1. Suicidal/parasuicidal intent – most common cause of significant overdose of drugsA. Taking substance of abuseB. Criminal poisoning

Absorption of poisons

Ingestion Injection (intramuscular &

intravenous) Inhalation (nostrils) Suppository (anal & vaginal) Topical application (skin & mucous

membrane)

Management of drug overdose

1. Proper diagnosis (confirming the type and degree of poisoning)a. Case history – most essential

items, every effort should be made to clarify the toxic agents involved, dose & time of exposure.

b. Clinical features - may be characteristics & helpful in making the diagnosis

c. Confirmation in the laboratory

Treatment (4 principles)

1. Decontamination2. Symptomatic & supportive care3. Enhanced poison elimination 4. Antidote therapy

Medicines that changed the world

Opium Small pox vaccine Salvarsan Insulin Penicillin Enovid Thalidomide

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Drug Screening

Involves a sequence of experimentation & characterization

Anti-infective drugs will generally be tested against a variety of infectious organisms

Hypoglycemic tested for its ability to lower glucose levels

Preclinical safety and toxicity testing

Candidate drugs that survive the initial screening & profiling procedures must be carefully evaluated for potential risk before & during clinical testing.

All follow pre-clinical safety test:

Acute toxicity Sub-acute toxicity Chronic toxicity Effect on reproductive performance Carcinogenic potential Mutagenic potential Investigate toxicity

Goals for preclinical toxicity

Identifying all potential human toxicities

Designing test to further define the toxic mechanism

Predicting the specific & most relevant toxicities to be monitored in clinical trials

Limitations of preclinical testing

Toxicity testing is time consuming & expensive

Large numbers of animals are needed to obtain valid clinical data

Extrapolation of toxicity data from animals to humans is not completely reliable

For statistical reasons, rare adverse effects are unlikely to be detected

Evaluation in humans (confounding factors in clinical trials)

The variable natural history of most diseases

Presence of other diseases & risk factors

Subject & observer bias

Phases of clinical trials

Approval of the drugs involves a systematic series of vents

It’s often requires 4-6 years of clinical testing to accumulate required data

Testing in humans is begun after sufficient acute & subacute toxicity animal toxicity studies have been completed

Chronic safety testing in animals is usually done concurrently with clinical trials

Volunteers/patients must be informed of the investigational status of drug as well as possible risk & must be allowed to decline/to consent to participate & receive the drug

To make sure you use drug safely Make sure that you understand &

follow the instructions on taking drugs

Don’t share medicines Let your health care provider know

about all other drugs, supplements & herbs you are taking

Clinical trials

CT follows strict scientific guidelines These guidelines deal w/ many

areas, including the study’s design, who can be in the study, & kind of information people must be given when they are deciding whether to participate

Every trial has a chief investigator, who is usually a doctor.

Investigator prepares a study action plan, called a protocol

This plan explains what the trial will do, how & why.

How many people will be in the study

Who is eligible to participate in the study

What study drugs participant will take

What medical test they will have & how often

What information will be gathered

Phase 1

The effects of the drugs as a function of dosage are established in a small # of healthy volunteers.

These are done to determine whether humans & animals shows significantly different responses to the drug & to establish the probable limits of the safe clinical dosage range

# of patients: 20-100

Length: several months

Purpose: mainly safety

% of drugs successfully tested: 70%

Phase 2

Drugs is studied for the 1st time in patients w/ the target dse to determine its efficacy

100-200 re involved in the study Done in clinical centers Broader toxicities can be detected

Phase 3

Results meet expectations, applicant will be made for permission to market the new agent# of patients: several hundreds to several thousandsLength: 1-4yrsPurpose: safety, dosage, effectiveness% of drugs successfully tested: 25-30%

Phase 4

Constitutes monitoring of drugs Safe reporting drug – induced

toxicities This occurs post market introduction

to determine & monitor life-cycle management, safety surveillance, adverse effect, & PK: delivery & operational improvements.