NR565 Advanced Pharmacology Fundamentals Week 1 | 65 questions and answers

Drug Development Process

Pre-clincial Stage (Animal testing) of R&D

INDClinical (Safety and effectiveness)

R&DFinal Product Development

Post-marketing

Variations in drug development process

Preclinical stage of R&D

1. Drug discovery

2. Biological characterization (drug action/ fate)

3. Pre-formulation studies

4. Initial formulations

5. Manufacturing and controls

6. Package label and design

Clinical Stage

Phase 1: Biological effects, safe dosage

Phase 2: New drug treats small amount of patients

Phase 3: Larger size, must be as good as or better than others.

Drug Discovery

1. target identification and validation

2. hit identification and screening

3. lead identification and optimization

4. candidate preclinical and clinical drug development

Graded dose response

Drug response is continuous and gradual. The concentration increases, the magnitude of the effect increases

Types of Drug Response

-Graded - responses that can be measured (BP, HR, Diuresis, Bronchodilation, Pain scale, Coma Score)

-Quantal Effects- may or may not occur (convulsions, pregnancy, rash, sleep, death)

Receptors exist in what two states?

1) Inactive (R)2) Active (R*)Equilibrium favors inactive state (R)

Four major receptor families- receptors are proteins that transduce extracellular signals to intracellular responses

1) Ligand-gated ion channel

2) G protein-coupled receptors

3) Enzyme-linked receptors

4) Intracellular receptors regulating gene expression

Ion Channel Receptors / Gated ion channels

- Rapid onset and short duration (muscle contraction)

Transmit signals across the cell membrane by increasing the flow of ions and altering the electrical potential or separation of charged ions across the membrane

Gated Ion Channel Receptors:

Open or close channels to allow certain ions to pass through cell membrane.

A gated channel for a specific ion. The opening or closing of such channels may alter a cell's membrane potential.

G protein-coupled receptors (Guanine nucleotide regulatory proteins)

-Found in cell membrane

-Made up of 3 major subunits (alpha α, beta β, gamma γ) and can have isotopes (variations)

Generate intracellular second messengers that trigger a change in cell function

Transmembrane receptors

-Extracellular hormone-binding domain

-Intracellular enzyme domain

-combinations cause 2 receptors to bind to each other.

(Insulin, and platelet)

Have its ligand-binding domain on the cell's surface.Key feature: down-regulation of receptors (decrease in number of receptors available for response)

Intracellular receptors

lipid soluble drugs attach to intracellular receptors and initiate direct changes in the cell by affecting DNA transcription

Intracellular receptors are different receptors in what way?

Entirely intracellular so ligand must diffuse into cell to interact with receptor. Must be lipid soluble to be transported attached to plasma protein such as albumin. DNA, RNA transcription into proteins. (i.e. Antineoplastic agents)

Eg: Corticosteroids, mineralocorticoids, sex steroids, vitamin D, and thyroid hormones...producing more sustained responses.

Enzymes

Biological molecules that encourage specific chemical reactions.

Six ways gene expression can be regulated between DNA + protein

1. Transcription --> when/how often

2. Controlling mRNA splicing or processing

3. Selecting which mRNA are exported to cytosol

4. Selectively degrading some mRNAs

5. Selecting which mRNAs are translated by the ribosomes

6. Selectively activating or inactivating proteins once made.

Drug action at receptors

-agonists

-antagonists

-partial agonists

agonists

Agonists, or full agonists, are drugs that produce receptor stimulation and a conformational change every time they bind. Full agonists do not need all of the available receptors to produce a maximum response. --

-Less than 10% needed for maximum response.

Antagonists

-Antagonists are drugs that occupy receptors without stimulating them. Antagonists occupy a receptor site and prevent other molecules, such as agonists, from occupying the same site and producing a response. -

-Antagonists produce no direct response. The response we see following administration of antagonists results from their inhibiting receptor stimulation by agonists. For example, beta blockers such as propranolol and atenolol act as antagonists at the beta-adrenoceptor.

partial agonists

Partial agonists are drugs that have properties in between those of full agonists and antagonists. Partial agonists bind to receptors but when they occupy the receptor sites, they stimulate only some of the receptors. This is sometimes called intrinsic activity. So they can act as part agonist and part antagonist. Partial agonists would require all of the available receptors to produce their full response, and the maximum response for a partial agonist is less than that for a full agonist.The beta blockers acebutolol, penbutolol, and pindolol are partial agonists. Administration can block the effects of adrenergic nerves on heart rate, but partial agonist activity keeps heart rate from falling too low, as might occur following administration of a pure beta-adrenoceptor antagonist.

Pharmacokinetics

the branch of pharmacology concerned with the movement of drugs within the body

absorption

distribution (through the body)

metabolism

elimination

Pharmacodynamics

the branch of pharmacology concerned with the effects of drugs and the mechanism of their action

drug response

drug selectivity

drug receptors

drug action

Absorption

movement of a drug from its site of administration into the blood

Variables that influence absorption:

-blood flow at site of administration

-dosage form

-route (compliance, bioavailability, onset of action, duration of action)

....Parenteral, oral, topical

Distribution

movement of absorbed drug in bodily fluids throughout body to target tissues

Distribution can occur by:

-transfer through the bloodstream

-passive diffusion (smaller molecules)

Properties that affect distribution:

-Protein binding

-Transport Systems

-Volume of distribution

Metabolism

AKA: biotransformation

-Change of one chemical to another

Definition: chemical change of drug structure to:

1. Enhance excretion

2. Inactivate the drug

3. Increase therapeutic action

4. Activate a prodrug

5. Increase or decrease toxicity

First Pass Effect (Metabolism) Non-synthetic

Happens only with PO and sometimes w/ rectal. Rectum is directly connected to GI tract & there are some veins connected to systemic absorption. Liver 1st B4 it gets to body.

-lose some of drug (reduces the bioavailability)

-happens in liver

Phase I Reactions

Oxidation, reduction, or hydrolysis reactions which prepare the drug for further metabolism

Phase II reactions

Synthetic or conjugation reactions where something is added to the drug to synthesize a new compound

Reactions that increase water solubility and increase easy excretion by the kidneys.

CYP 450 and Drug Metabolism

The majority of drugs are metabolized in the liver by hepatic isoenzymes, the most important of which is the CYP450 isoenzyme.

Variation in the CYP 450 enzyme causes differences in drug metabolism.These variations can be developmental, genetic, or caused by disease states.

These enzymes may be slowed or increased. Concurrent therapy by an inhibitor or inducer may alter metabolism of a medication.

CYP3A4

Major drug metabolizing enzyme.

Found in the lining of the stomach (affected by food)

Grapefruit juice inhibits (nifedipine)

- Increased blood levels in :

azole antifungals, statins, prednisone, prednisolone, dexamethasone, carbamazepine

Drug Metabolizing Enzymes

CYP3A

CYP2C

CYP1A

CYP2E

CYP2D

Elimination

AKA: excretion

Definition: removal of the drug from the body by organs of elimination.

Most drugs are eliminated by the kidneys.

Drugs are also eliminated by:

-Liver

-Lungs

-Gastrointestinal (GI) tract

-Sweat and saliva, and hair

-Mammary glands (breast milk)

Drug interactions

Alterations in biotransformation, metabolized by the same CYP enzyme.

Always consider drug-drug interactions with:

st john's wort

ssri

snri

statin

ACE/ARB

PPI

Warfarin

Bactrim

CYP 2D6

responsible for metabolizing codeine into morphine and hydrocodone into hydromorphone. about 7% of caucasians lack this enzyme and may not get effective pain relief from these medications.

Pts with a highly active CYP 2D6 are at risk for toxicity following admin of either codeine or hydrocodone

A provider may consider testing for CYP2D6 variants prior to starting tamoxifen for breast cancer to:

Reduce the likelihood of therapeutic failure with tamoxifen treatment

Grapefruit juice contains furanocoumarins that have been found to:

Inhibit CYP 3A4, leading to decreased first-pass metabolism of drugs

Polymorphisms:2D6

poor metabolizers

intermediate metabolizers (IMs)

Extensive metabolizers (EMs)

Ultrarapid metabolizers (UEMs)

poor metabolizers

-Metabolize drugs slower

-Leads to high levels of unmetabolized drug resulting in a potential for drug-drug interactions & adverse events

-Slowed drug metabolism

-Greater potential for drug-drug interaction

-Drug conversion to active metabolites is slower;

-potential lower efficacy

intermediate metabolizers

high spectrum of metabolic activity; ranges from better than that of PMs to close to that of EMs

Extensive metabolizers

-normal or reduced CYP 2D6 function

-expressed by the majority of the population

ultrarapid metabolisms (UEMs)

-greater than normal CYP 2D6 function: multiple copies of the CYP 2d6 gene expressed

-may lead to loss of therapeutic efficacy at normal doses

-Accelerated drug metabolism

-Drug is eliminated faster

-Potential for lower efficacy

Up to 21% of Asians are ultra-rapid 2D6 metabolizers, leading to:

Increased dosages needed of drugs metabolized by 2D6, such as the selective serotonin reuptake inhibitors

Cytochrome P450 Enzymes

-major drug metabolizing enzyme system

-race, gender, age, nutrition, stress, and environment are factors that may alter gene expression of families and subfamilies of CYP 450

-Ethnic differences in CYP 450 metabolism have been identified for the CYP 450 enzymes responsible for metabolizing most therapeutic agents

Top 10 CYP450 Drugs

Cipro

Cimetidine

Warfarin

Erythromycin/clarithromycin

ketoconazole

bactrim

paroxetine and fluoxetine

phenytoin

levothyroxine

atorvastatin/simvastatin

health disparities in the US: Barriers to adequate health care

For the culturally diverse in the U.S. patient population, can occur because of:

-language

-poverty

-access

-pride

-beliefs regarding medical practices

-medications may have a different meaning to different cultures

Cultural considerations in pharmacology

-USA culturally diverse

-cultural assessment part of cultural competency for professional nurses-ethnicity

-ethno-pharmacology

-race?; race is socially and politically defined

-health beliefs and practices

-barriers to adequate healthcare

Cultural considerations in the nursing process

-influence of ethnicity on genetics and drug response

-drug polymorphism

-adherence with therapy

-environmental and economic considerations

-pharmacokinetics

-pharmacodynamics

-varying drug response in different racial or ethnic groups

Cultural assessment

-languages spoken; need for interpreter?

-health beliefs and practice

-past uses of medicine-herbal treatments, folk remedies, and home remedies

-over the counter (OTC) drugs and treatment

Ethno-pharmacology

Study of effect of ethnicity on drug uses and responses

African Americans

Studied more than any other ethnic group in relation to differences in drug metabolism & response

-underlying hypertension prevalence is among the highest in the world-HTN occurs at an earlier age than in other races

-require a high dosage of ACE inhibitors or combined therapy with low dose diuretics to effectively reduce blood pressure

-show less effective monotherapy with beta blocker and ACE inhibitors than Caucasians

-US FDA approves the first drug, isosorbide dinitrate/hydralazine (BiDil), especially labeled for use by African Americans

-African American Heart Failure Trial (A-HeFT) demonstrates that by adding isosorbide dinitrate/hydralazine (BiDil) to standard therapy for heart failure increases survival in black patients with advanced failure

-require a higher dose of glucocorticoids than Caucasians to control their asthma symptoms, regardless of asthma status or severity

Puerto Ricans

poorer responses to the COPD/asthma control drug, ipratropium bromide (Atrovent)

Mexicans

better metabolizers of medications that utilize the CYP 450 2C19 subgroup of liver enzymes when compared to Caucasian and Asian counterparts may require lower dosages of medications metabolized by certain CYP 450 subgroup of enzymes

Hispanics/Latinos

may require lower doses of antidepressants than Caucasians and Asian counterparts

Asians and Hispanics

-ethnic variation in drug response

-need lower doses of sedatives and anti-psychotics

Genetic polymorphisms (drug polymorphisms)

Effect the pharmacokinetics of specific drugs or drug classes due to:

-varying expression of the particular CYP 450 enzyme family that metabolizes the drug

-may affect a drug target (receptor)

-we can now test for some of these variants seen among cultures

Genetic polymorphisms interact with:

-a person's inherited genetic variation

AND/OR

-environmental factors that cause changes to DNA outside the nucleus (epigenetics) to determine the treatment outcome (effect) of a pharmacologic agent

Warfarin resistance may be seen in patients with VCORC1 mutation, leading to:

Decreased response to warfarin

Genetic testing for VCORC1 mutation to assess potential warfarin resistance is required prior to prescribing warfarin.

False

Inhibition of P-glycoprotein by a drug such as quinidine may lead to:

Increased levels of a coadministered drug, such as digoxin, that requires P-glycoprotein for absorption and elimination

Pharmacogenetic testing is required by the U.S. Food and Drug Administration prior to prescribing:

Cetuximab