m1l1 // intro to clinical toxicology - PART 1

Drug

Substances intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease

Local Effect

Obtained when the drug product is administered at the site where the pharmacological response is desired either by **adsorption or penetration**

Systemic Effect

Obtained when the drug released from the drug product **enters the blood and/or lymphatic streams and is distributed within the body**-or at least several organs-regardless of the site and route of administration

Dosage form (drug product)

Considered to be drug delivery systems that release and deliver drug to the site of action such that they produce the desired effect

Dosage form (drug product)

Designed specifically to meet the patient’s needs including palatability, convenience, and safety

Xenobiotics

Foreign compounds exposed to the biological system

Drug Product Performance

Release of the drug substance from the drug product either for local drug action or for drug absorption into the plasma for systemic therapeutic activity.

* measured based on bioavailability

bioavailability

how well the drug is absorbed

biopharmaceutics 1

bioavailability + pharmaceutics 1

BIOPHARMACEUTICS

Provides the scientific basis for **drug product design and drug product performance**

BIOPHARMACEUTICS

The examination of the interrelationship of the:

* physical/chemical properties the drug;
* the drug product (dosage form) in which the drug is given and the;
* route of administration

BIOPHARMACEUTICS

on the rate and extent of systemic drug absorption

physicochemical property of drug

stability of the drug within the product

* drug must be aqueous or liquid form to be absorbed
* LUNA

stomach

acidic environment

small intestine

basic environment

Dosage Form

manufacture of product

Dosage Form

rate of dissolution/ release of the drug at the absorption site

route of administration

* Design of the drug product
* Release of the drug from the drug product

route of administration 1

• IV - 100% bioavailability

• EV - less than 100% bioavailability

• Per Oral - very minimal bioavailability because of first pass effect 1

Biopharmaceutics Therapeutic objective

* For rapid relief of symptoms, slow extended action, or chronic use

For local or systemic action

* Drug (active pharmaceutical ingredient, API)
* Physicochemical properties (solubility, polymorphism, particle size)

Route of administration

Oral, topical, parenteral, inhalational, etc

Drug dosage and dosage regimen

Large or small dose, frequency of doses, patient acceptance, patient compliance

Type of drug product

* Orally disintegrating, immediate release, extended release tablets
* Transdermal, topical, parenteral, implant, etc

Excipients

Affect drug release

Method of manufacture

Variables in manufacturing process, including weighing, blending, release testing, sterility

Biopharmaceutics and designing drug products: CONSIDERATIONS

* Therapeutic objective
* Drug (active pharmaceutical ingredient, API)
* Route of administration
* Drug dosage and dosage regimen
* Type of drug product
* Excipients
* Method of manufacture

PHARMACOKINETICS

* A.D.M.E.
* The science of the kinetics of drug absorption, distribution, and elimination (ie, metabolism and excretion)

pharmacon

drug

kinesis

movement

L.A.D.M.E

applicable to solid dosage forms

drug input process

increase in the plasma concentration of the drug inside the body

* chronological in nature / sequential / sunod sunod in order

drug output process

decline in the plasma concentration

ex. per oral administration

* simultaneously / sabay sabay nangyayari

Input processes

* Liberation
* Absorption

Liberation

the release of the drug from it's dosage form

• disintegration - conversion to smallest particles

• dissolution - powder/ small particles will be liquid/ aqueous. also known as rate limiting step

rate limiting step

slowest step in every process

Absorption

the movement of drug from the site of administration to the blood circulation

Absorption

Is the process of uptake of the compound from the site of administration into the systemic circulation

Output processes: Disposition of drugs

* Distribution
* Elimination
* Metabolism
* Excretion

Drug Disposition

A term used to describe drug distribution and elimination

Distribution

The process by which drug diffuses or is transferred from intravascular space to extravascular space (body tissues)

Distribution

Is the partitioning of drug molecules among numerous locations in the body

drug distribution 1

transfer of the drug from the systemic circulation to the target organs or site of action 1

Elimination

Refers to the irreversible removal of drug from the body by all routes of elimination (metabolism and excretion)

Elimination

Decline in plasma drug concentration observed after systemic drug absorption

Metabolism (Biotransformation)

Process by which the drug is chemically converted in the body to a metabolite //drug to inactive form // WIPE (water soluble, ionized, polar, excretion)

Metabolism (Biotransformation)

Usually an enzymatic process

Excretion

Removal of intact drug

feces/biliary excretion

high molecular weight drugs (exceeds 150), excreted thru

urine/renal

small particle size or molecular weight (>150) drug is excreted through the

* ex. non volatile drugs

CLINICAL PHARMACOKINETICS

The application of pharmacokinetic methods to drug therapy

significance of clinical pharmacokinetics

Intra- and interindividual variations will frequently result in either a subtherapeutic or toxic response which may then require adjustment to the dosing regimen

Pharmacodynamics

Refers to the relationship between the **drug concentration at the site of action (receptor) and pharmacologic response**, including biochemical and physiologic effects that influence the interaction of drug with the receptor

Drug-receptor interaction

Combining of a drug molecule with the receptor for which it has affinity, and the initiation of a pharmacologic response by its intrinsic activity or efficacy

Pharmacokinetic-pharmacodynamic models

Constructed to relate plasma drug level to drug concentration at the site of action and establish the intensity and time course of the drug

Drug exposure

Refers to the dose (drug input to the body) and various measures of acute or integrated drug concentrations in plasma and other biological fluid

Drug response

Refers to direct measure of the pharmacologic effect of the drug

Drug responses measured:

* Clinically remote biomarkers
* Presumed mechanistic effect
* Potential or accepted surrogate
* Full range of short-term or long-term clinical effects related to either efficacy or safety

Clinically remote biomarkers

Receptor occupancy

Presumed mechanistic effect

ACE inhibition

Potential or accepted surrogate

Effects on blood pressure, lipids, or cardiac output

Toxicokinetics

Application of pharmacokinetic principles to the design, conduct, and interpretation of drug safety evaluation studies and in validating dose-related exposure in animals (eg., preclinical drug development)

toxicokinetics data obtained:

Aids in interpretation of toxicologic findings in animals and extrapolation of the resulting data to humans

Clinical toxicology

The study of adverse effects of drugs and toxic substances (poisons) in the body