Prescriptions, Drug Approval, Pharm basics, Receptor theory, Pharmacokinetics

Week 1 lectures

Which federal institution determines what is a prescription drug and what isn’t?

The Food and Drug Administration (FDA)

Describe an over the counter drug

• can be safely self-administered by the layman

  • instructions are on the package must be written for lay comprehension

• they have been deemed safe enough to allow consumers to make educated decisions about their own use

• these are still considered drugs

Describe a prescription

• mechanisms to ensure the practitioner and patient get what is desired and agreed to

• it represents the end of a diagnostic process

What are the 3 types of prescriptions?

1. prescriber’s order for the patient’s chart or MR

2. written order pharmacist refers to

3. patient’s medication container

What is the importance of the Federal Comprehensive Drug Abuse Prevention and Control Act of 1970?

• aka the Controlled Drug Act

• regulates the manufacture, distribution and sale of certain chemicals identified as controlled substances and penalties for misuse

• enforcement was entrusted to the Drug Enforcement Administration (DEA)

Describe a Schedule I drug and give examples

• controlled substance with no accepted medical use and has a high potential for abuse

• heroin, lysergic diethylamide (LSD), marijuana, peyote, methaqualone, and certain fentanyl

Describe a Schedule I drug and give examples

• controlled substance with high potential for abuse with severe psychological or physical dependence, but accepted medical use

• morphine, methadone, cocaine, amphetamine (Adderall), methylphenidate (Ritalin)

What are some special prescribing concerns for schedule II drugs?

• valid to provide the pharmacy a script up to 14 days

• provider must see patient to prescribe

• no refills

• street address of patient must match ID

• warning label required due to abuse potential, caution on drug interactions, sedation likelihood

• some states restrict who can prescribe

Describe a Schedule III drug and give examples

• abuse potential is present and dependence liability is less then C1 and C2, accepted medical use

• anabolic steroids, Dronabinol (synthetic THC), codeine with acetaminophen

Describe a Schedule IV (4) drug and give examples

• abuse potential and dependence liability less than C3 and accepted medical use

• diazepam (Valium), lorazepam (Ativan), alprazolam (Xanax), lorcaserin (Belviq)

• Benzos and sleep meds

Describe a Schedule V drug and give examples

• abuse potential and dependence liability less than C4 with accepted medical use

• cough medications with codeine, antidiarrheal with low dose of opiates (Lomotil), pregabalin (Lyrica) and some analgesics

_______ prohibited mislabeling and adulteration of drugs

• occurred because what was in the prescription bottle was different than the label

Federal Pure Food and Drug Act of 1906 (FDA)

_______ required new drugs to be safe as well as pure BUT did not require proof of efficacy

Food, Drug, and Cosmetic Act 1938

_______ required proof of drug efficacy as well as safety for new drugs and for drugs released since 1938

• this established guidelines for reporting information about adverse reactions, clinical testing, and advertising new drugs with warnings at the end of the ad

Kefauver-Harris Amendent 1962

Describe each phase of approval for a new drug:

1. Pre-Clinical

2. Phase 1

3. Phase 2

4. Phase 3

5. Phase 4

1. Researchers look for the best delivery system (topical, inhaled, oral); includes animal testing (in vitro testing)

2. Drug is tested in small number of patients with the targeted disease )20-80 pts); first in human trials to test safety, dosage, and pharmacokinetics

3. Researchers look for the best delivery system (topical, inhaled, oral); testing effectiveness; dose finding (10 mg vs 20 mg); 25% move to phase 3

4. Get FDA approval; multisite trial; thousands of patients to confirm safety and efficacy

5. Companies look for additional applications for the drug beyond what is was originally used for (post marketing surveillance)

Which clinical phase was usually open label (non-blinded - for patients)?

Clinical phase

which clinical phase is usually single-blinded with a control

Phase 2

which phase is double-blind, crossover?

phase 3

T/F: compounded drugs do not go through clinical phases

true

• caution is always recommended because the actual concentrated drug is regulated but not all tests are administered: potency, safety, and efficacy

The study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes

Pharmacology

Explain the difference between Medical pharmacology and toxicology

Medical Pharm - the study of medications and their therapeutic or desired effects; science of substances used to prevent, diagnose, and treat disease

Toxicology - the undesirable effects of chemicals on living systems; toxic at certain levels or concentrations

What are the 4 categories of the nature of drugs?

Physical nature

• solid, liquid, gas (inhaled)

Drug size

• large drugs can’t diffuse between body compartments and may need to be injected to get to the bloodstream (ex: vancomyocin (antibiotic))

Lipophillic vs hydrophillic

• a drug needs to be lipophilic to cross the blood brain barrier

Routes of administration

• oral, IV, sublingual, inhalation, topical

Agonist vs Antagonist

• Agonist - induces response

• Antagonist - inhibits response

Pharmacokinetics vs Pharmacodynamics

Pharmacokinetics is what the body does to the drug (ADME).

Pharmacodynamics is what the drug does to the body (agonist, antagonist(.

Describe what ADME stands for and is related to

Absorption (medication is broken down and absorbed into the bloodstream

Distribution

Metabolism (half-life)

Elimination or Excretion

• all define Pharmacokinetics- the body does to the drug

Describe ligand-gated ion channels and when they are used

• lipid soluble chemical (drug) crosses the plasma membrane and acts on the intercellular receptor (inside cell) (1)

  • for lipid soluble drugs (ex: steroid molecules)

• some ligand gated channels will have the drug bind extracellular but elicit activity intracellularly (2 and 3)

  Hydrophilic - process occurs within the plasma membrane

Describe Voltage gated channels

• bind to allosteric site to open the VG channel. Molecules flow in and out based on the charge (4)

Describe G-coupled receptors

The G coupled receptor binds extracellularly to activate the G-protein. The receptor changes shape activating the G protein. The G protein will dissociate from the subunit and which stimulates creation of the secondary messenger that relays signals within the cell, influencing various physiological processes. (5)

Subunit is within the plasma membrane

Describe enzyme linked receptors

• On the cell surface (plasma membrane) and ligand are usually large and hydrophilic molecules (insulin, growth factors).

• The ligand binds to the receptor’s extracellular domain and activates an intrinsic enzyme activity leading to phosphorylation cascades and signal transduction

This type of receptor, once bound by the ligand is able to reach the nucleus and alter gene expression (transcription)

Intracellular receptors (steroid receptors)

Receptor is below the plasma membrane in the cytoplasm or nucleus

What do ligand gated channels, G protein coupled receptors, Enzyme linked receptors and intracellular receptors have in common?

all have intracellular effects

A nicotinic acetylcholine receptor is an example of _______

a. voltage gated channel

b. ligand gated channel

c. G protein-coupled receptors

d. enzyme-linked receptor

b. ligand gated channel

embeded in the plasma membrane

Explain the dose-response curve

A graphical representation showing the relationship between the dose of a drug and its pharmacological effect, indicating how varying doses can produce different levels of response.

Efficacy vs potency

Efficacy - the maximum effect a drug can produce regardless of dose; activity

Potency - amount of drug needed to produce a given effect; affinity

Potency:

What is the Effective Concentration 50 (EC50), Effective Dose 50 (ED50)?

concentration or dose needed to elicit 50% the maximal response

it is a measure of potency

Potency:

What is Lethal concentration 50 (LC50), Lethal Dose 50 (LD50)?

Lethal in 50% of the test population; it is dose specific

Death

Potency:

What is toxic concentration 50 (TC50), Toxic Dose 50 (TD50)?

Toxic in 50% of the test population; not causing death

What is the therapeutic index?

The ratio of the toxic or lethal dose to the effective dose: LD50/ED50

A drug with a higher index is safer than one with a lower therapeutic index

• It determines if a drug is worth it to administer by comparing safety to efficacy.

How does therapeutic index relate to therapeutic window?

Therapeutic index: A ratio that compares the toxic dose of a drug to its effective dose; numerical estimate of safety

Therapeutic window: the actual range of drug concentrations in the blood that gives efficacy without unacceptable toxicity; practical range used in patients

what relationship is seen between the ligand (drug molecule) and drug response in an agonist?

Increasing the concentration of the drug will increase the biologic response UNTIL no more receptors are available for the agonist to bind and or the max response is reached

what relationship is seen between the ligand (drug molecule) and drug response in a partial agonist?

Similar response as the agonist (ncreasing the concentration of the drug will increase the biologic response) BUT it will never produce 100% of the response even at very high doses

• it is less efficacious than the full agonist

Explain when an agonist works alone versus an agonist and a competitive antagonist are working (ex: treating overdose)

An agonist works alone to activate receptors and produce a desired therapeutic effect, while the presence of a competitive antagonist blocks the agonist's action by occupying the same receptors (two keys fighting for a spot on the lock), reducing the overall response.

When the agonist and competitive antagonist are present the same maximal effect can be achieved by the agonist but it takes a higher dose

Explain a noncompetitive antagonist

• allosteric means binding to a different site

• it has the same noncompetitive antagonist effect (lowers efficiacy)

• often reversible

• multiple binding sites for different molecules and each have different effect and can dampen effect of others that are binded

Explain non-competitive antagonism

• agonist and antagonist can be bound simultaneously, but antagonist binding reduces or prevents the action of the agonist

  • same binding site can “bump” in and out

What are spare receptors?

Spare receptors are those that exist in excess over what is necessary to elicit a maximal biological response. They are not all needed for full activation, allowing for greater sensitivity to agonists.

2 of 20 receptors can be activated and have same effect as 20 of 20 activated

• the excess that are activated enhance the ability of tissue to detect and respond to low concentrations of agonists

Compare Tachyphylaxis to tolerance

Tachyphylaxis - a rapid decrease in the response to a drug after repeated administration in a short period of time due to receptor desensitization, depletion or neurotransmitters or mediators, or physiological adaptation (body opposes drug effects)

• develops slowly

Tolerance is when a drug had theraputic effects but over time the body needs more of the drug or greater potency to get the same desired effect

• develops quickly

Name two classes of antagonists

• beta blockers

• narcan

Image to compare full agonist, partial agonist, antagonist, and inverse agonist

Image to compare full agonist, partial agonist, antagonist, and inverse agonist