Pharmocology, Veterinary Antimicrobials: Drug Classes, Uses, and Safety, Veterinary Pharmacology: ADME, Drug Trials & Antimicrobial Therapy

Define Pharmacology

Study of how drugs affect a biological syster

Define Drug

any chemical agent which affects any biological process

List the 4 mechanisms of actions

1. Replace (act as substitute) for other chemicals (ex: K bromide, Hetastarch)

2. Increase or stimulate certain cellular activities

3. Depress or slow certain cellular activities

4. Interfere with function of foreign cells (ex: antimicrobial)

Drug classifications

- Chemical structures ( ex: macrocylic lactones)

- Main affect (ex: analgesics)

- Therapeutic use (ex: NSAID)

- Mechanism of action (ex: beta blocker)

3 parts of drug nomenclature

- Chemical name

- Generic name

- Trade name

Define dosage

Amount of drug to be administered, usually based on weight (ie: mg/kg)

Concentration

How the drug is formulated into a solution (ie: mg/ml, strength of pills or capsules)

Injection volume

A liquid measurement based on weight (ie: ml/kg)

Drug formulation

- Solids: grams, milligrams, micrograms

- Liquids: liter, milliliter, microliter

Stages of drug development

- Drug discovery and screening

- Pre-clinical safety and toxicity testing

- Evaluating drugs in humans

Stage 1: discovery and screening

Chemical development; in-vitro studies of function in cells, tissues, and at receptors.

Stage 2: pre-clinical safety and toxicity

In-vivo animal studies when no alternatives or non-animal replacements are available; pharmacology and behavioral pharmacology; potency/efficacy (ED50); tolerance; acute and chronic toxicity (LD50); teratogenicity; carcinogenicity

Stage 3: evaluating drugs in humans

FDA drug review process and clinical trials if approved to proceed.

ED50

Effective dose for 50% of population

LD50

Lethal dose for 50% population

Do you want a larger or smaller gap between ED50 and LD50

Larger gap = safer drug

Clinical Trials Phase 1

Healthy adult volunteers (20-80); safety, pharmacokinetics (PK), side effects.

Clinical Trials Phase 2

Patients (fewer than 300); efficacy, safety, PK, side effects; single-blind, placebo-controlled.

Clinical Trials Phase 3

Specific patient subpopulations (fewer than 3,000); efficacy for specific indications; randomized, double-blind, placebo-controlled.

Clinical Trials Phase 4

After FDA approval; efficacy for specific indication, drug utilization patterns, additional efficacy; monitor rare/severe side effects or toxicity.

Pharmacokinetics

what the body does to the drug; movement of the drug withing the body

Pharmacodynamics

What the drug does to the body

Pharmacotherapeutics

clinical purpose or indication

Pharmacognosy

Identifying crude materials as drugs

Drug sources

plants, animals, minerals, microbes, and synthetics

What factors influence drug effects

weight

age

gender

physiological and pathological factors

genetic factors

immunological factors

psychological factors

environmental factors

tolerance and cumulation

drug interactions

Pharmacodynamics relies on...

drug receptors

chemical interactions

effect and efficacy

toxicity/adverse effects

Types of Drug interactions

- drug-drug

- drug-alternative therapy

- drug food

drug-laboratory test

Where can drug interactions occur?

Interactions may occur at absorption, during distribution, during biotransformation, during excretion, or at the site of action

Dose

Amount administered

Frequency

How often the drug is administered

Efficacy

Greatest effect a drug can produce

Potency

Amount of drug needed to produce an effect; a more potent drug produces an effect at a lower dose.

Ceiling effect

A point beyond which increasing dose does not increase the effect

Safety

Considered in relation to therapeutic and toxic concentrations

Therapeutic index

Ratio of minimum toxic concentration to median effective concentration

What happens if you increase the dose of a drug with a low therapeutic index?

increases the likelihood of toxicity

What does a dose response curve tell us?

dose, frequency, efficacy and safety for a drug in population

Which drug is the most potent?

Drug X

Which drug has the greatest efficacy?

Drug X and Z have equal efficacy

Is Y or Z more potent?

Y is more potent but less efficacious than Z

How to read a Dose-Response Cuve

Further left = more potent

Taller = more effective

Which is more potent?

Drug A. It takes a lower dose to reach the same efficacy

Factors that affect the response to drugs

Dosage, route of administration rate of absorption, rate of elimination, physiochemical properties of the drugs and the patients signalment

Enteral route options

PO, rectal, sublingual, buccal

Parenteral route options

Not within the alimentary canal. ie: inhalation, IM, SC, IP, topical

Central route options

Intrathecal and intracerebroventricular

Routes of administration from most rapid to slowest

IV > IN > intrarectal > sublingual > IM, SQ > IP > PO > topical

Which route of administration is the safest?

PO

Which route has the most likelihood of of toxic effects

IV

Which routes needs time to absorb?

IM, SQ, topical

3 immune privileged sites

brain, eye, testes

What is the blood brain barrier?

tight junctions of endothelial cells; not fully formed at birth

Function of the blood brain barrier

Protects the brain from foreign substances that may cause injury; protects it from hormones, neurotransmitters, and immune cells

Maintains a constant environment

ADME

Absorption

Distribution

Metabolism

Elimination

Bioavailability

The fraction o the active form of a drug that reaches systemic circulation unaltered

What influences absorption

route, time, dose, metabolism, age, sex, physical activity,, stress, concurrent diseases, previous surgery

What does distribution depend on?

lipid solubility, ionization, tissue perfusion, and protein binding

Half-life

Time required for plasma concentration of a drug to be reduced by 50%.

Helps determine dosing intervals, expected time to steady time, and expected wash-out

Critical concentration

Concentration needed to cause a therapeutic effect.

Loading dose

Higher dose than the dose needed for ongoing treatment

Dynamic equilibrium/steady state

Actual concentration a drug reaches in the body; at steady state, amount received equals amount eliminated in a given time.

Steady state and wash-out are each approximately five half-lives

Pharmacokinetic considerations in clinical practice

- onset of drug action

- drug half-life

- timing of peak effect

- duration of drug effects

- metabolism or biotransformation of drug

- site of excretion

Types of adverse drug reactions

- dose-related

- allergic

- idiosyncratic

Severity

> mild: no change to treatment

> moderate: alter medication

> severe: discontinue medication

> lethal

4 methods of drug molecule movement

- passive diffusion

- facilitated diffusion

- active transport

- Pinocytosis and Phagocytosis

Passive diffusion

moves high to low concentration; no ATP, fastest

facilitated diffusion

Requires a carrier molecule; high to low concentration; no ATP

Factors that affect the rate of movement

concentration gradient

drug molecule size

lipophilic vs hydrophilic

temperature (high temp = faster)

thickness of membrane

Ionized

hydrophilic

good perfusion to systemic tissue via fluid, cannot penetrate cell membranes as well

non-ionized

lipophilic

readily penetrates cell membranes

good GI absorption and blood brain barrier penetration

Lipophilic vs Hydrophilic IM or SQ

Hydrophilic move quickly to capillaries

lipophilic slowly (hors to days)

Lipophilic vs hydrophilic oral medications

lipophilic molecules absorbed well

hydrophilic not readily absorbed

pKa

acid dissociation constant; the pH at which concentrations of ionized and non-ionized forms are equal.

What happens when an acidic drug is placed in higher pH?

becomes ionized

What happens when an acidic drug is placed in a lower pH?

becomes nonionized

What happens when an alkaline drug is placed in a higher pH?

becomes nonionized

What happens when an alkaline drug is placed in a lower pH?

becomes ionized

How do you use the pKa and pH relationship information?

Used to determine the best method of administration (for bioavailability)

Aspirin in a pH of 3 is half ionized and half nonionized. What does this mean for absorption in the stomach and the duodenum?

Stomach pH = 1-3 so in stomach aspirin is 1:1

Duodenum pH = 6-7 so aspirin does not absorb well in the duodenum due to ionized drugs being hydrophilic

Difference between protein bound drug and unboudn drug

- protein bound molecules are not available to exert pharmacologic effects

- unbound drug allow for pharmacologic effect

How does low plasma protein levels affect drug absortion?

Lower protein levels make protein bound drugs more potent

Examples of when to reduce protein bound drugs

liver disease

protein losing enteropathy

protein losing nephropathy

sepsis

malnutrition

Ledgend drug

Drug that is made for veterinary medicine, and not necessarily controlled

- not OTC

What statement needs to be on drug labels for veterinary medicine?

"Caution: federal law restricts this drug to use by or on the order of a licensed veterinarian"

This is the legend

DEA

Drug Enforcement Administration

How many classes/schedules of controlled substances are there?

5

Example of Schedule I

marijuana, heroin, LSD

No currently acceptable medical use and high potential for abuse

Examples of Schedule II

Methadone, hydrocodone, fentanyl

High potential for abuse but has accepted medical use

Examples of Schedule III

Ketamine, buprenorphine, simbadol

potential for abuse but less than schedule I and II

Example of Schedule IV

Tramadol, midazolam, butorphanol

Low potential for abuse

Example of Schedule V

Lomotil

lowest potential for abuse

4 R's of drug therapy

Right drug

Right concentration

Right dosing

Right duration

Bacteriostatic

inhibit growth of bacterial and allows immune system to fight it off

Bactericidal

Kills bacteria

Zone of inhibition

where there is no bacterial growth on growth plate

What does zone of inhibition tell us?

resistance, intermediate susceptibility, and suseptible

How long do cultures incubate for?

24-72 hours

What types of cultures can be performed?

aerobic and anaerobic

MIC

Minimum inhibitory concentration

- the lowest concentration of an antibiotic which still inhibits bacterial growth

What is MIC used for?

used to determine whether the tested strain is susceptible or resistant to the antibicrobial