Lecture 3 Pharmacodynamics and Terminology

Clearance

rate of elimination of drug in an hour

1st order elimination kinetics

elimination proportionate to the drug serum concentration

Clearance

rate of elimination of drug in an hour

1st order elimination kinetics

elimination proportionate to the drug serum concentration

1st order elimination kinetics calculated

Cl = elimination/peak plasma concentration

total amount of urine voided in an hour : peak plasma concentration of drug

Zero order elimination kinetics

rate of elimination or clearance is constant - no matter the dosage

e. ethanol and aspirin

alcohol clearance

1-2 drinks = 20-30mg/dL

clearance rate = 20mg/dL/hr

ETOH poisoning Er admmission average =>295 mg/dL

0.08 = 80mg

Half-life (t1/2)

time required for Cmax drug plasma concentration to decrease by one half (50%)

Used to estimate frequency of administration

Cmax

the maximum concentration of drug dose

drug circulation

circulating drug is continuously bio transformed for excretion - if 'unchanged' = biotransformation not required for excretion

half-life calculation

calculated & known per each drug. broad guideline to estimate frequency of adminitration

4x t1/2 = 90% of drug cleared

pharmacodynamics

once a drug is distributes - where does it cause the therapeutic effect

drug-receptor binding is:

saturable, dynamic (increases or suppresses existing processes) and reversible

bind directly to/in bacteria/viruses

some drugs like anti-infective. They present antigen that WBC recognize and try to destroy

they have different mechanisms of action = some interrupt bacteria cell wall, protein synthesis

most drugs bind protein structures to =

receptors

receptor affinity

strength of binding or length of binding. faster acting drugs are very potent but may not have high affinity

characteristics of receptor affinity

is specific, saturable, reversible.

What is drug efficacy?

The degree to which a drug induces maximum therapeutic effect.

What is an example of a drug used for motion sickness nausea?

Gravol

What is an example of a drug used for chemotherapy-induced nausea?

Ondansetron

What does drug efficacy depend on?

The cause of the condition being treated. what works where, best

Potency of a drug

= strength

how much of the drug is required = amount

ex. drug A 20mg & drug B 10 mg = Drug B potency is higher

agonists

drug mimics the endogenous substance (support normal activity). it binds to receptors readily and produces good effects

ex. morphine

primary (full) agonist

extensively and successfully binds to existing receptor

What is a partial agonist?

A drug that produces a smaller maximum response even when all receptors are occupied.

What is low efficacy in pharmacology?

It refers to a drug that has a lower maximum effect compared to full agonists.

Give an example of a partial agonist.

Buprenorphine

What is a common full agonist that is often compared to buprenorphine?

Morphine

what happens when full agonist and partial agonist meet?

in the presence of a full agonist, a partial agonist acts like an antagonist. they compete with each other for binding

when do you need a partial response

when you ween patients off of pain meds

inverse agonist

binds to receptor but induces the opposite effect of the naturally binding substance.

ex. caffeine

how is caffeine an inverse agonist

it binds to receptors for adenosine (naturally calming substance) - caffeine doesn't stimulate SNS it just stops PSNS

antagonists

drug blocks the receptor site to prevent endogenous or endogenous-like substance form binding. no effect other than to block other substances from binding

no efficacy at cellular level

example of antagonist

naloxone (Narcan) - has higher affinity to receptors than opioids, has shorter half-life so you need more dosages of Narcan to meet level of drug you want to displace

6 Major receptor types

1. G-protein (GPCR)

2. Ion channels

3. Nuclear receptors

4 & 5. Enzyme types

6. Non-enzyme 'JAK-STAT'

G-protein

most common

g-protein binding elicits a change.

may be alpha, beta, alpha1 etc. - can selective or nonselective drugs

triggers intracellular messenger - opens or closes channel

g-protein example

epinephrine - stimulates G-protein & second messenger system =sympathomimetic stimulation

ion channels

electrolyte movement. - most bind to voltage-gated channels.

ex. lidocaine (local anesthesia) - closes ion channels = no action potential = no cellular depolarization = no pain transduction

nuclear receptors

ex. hormones

aka. steroid receptors

most bind in cytoplasm = change cell via DNA.

Drug need to be lipophillic to enter plasma membrane

enzyme binding 2 types

intracellular enzymes

transmembrane enzymes

example of transmembrane enzymes

insulin => cell membrane receptors = stimulate transmembrane enzyme: tyrosine kinase => activate cellular glucose uptake

non-enzyme transmembrane

eg. JAK-STAT receptors (used by interferons)

STAT attaches and creates change

What is drug tolerance?

The need for more of a drug to achieve the same effect due to receptor desensitization or decreased number of viable receptors.

What is receptor desensitization?

A process where receptors become less responsive to a substance.

What are some examples of addictive substances that can cause drug tolerance?

Opiates, benzodiazepines, and alcohol.

drug resistance

many variations of kinetic alterations

Ex. increased drug metabolism = drug metabolized at a faster rate, therefore less bioavailable therefore less effective.