Pharm Tox Exam 1

pharmacology

the study of substances that interact with living systems through chemical processes

drug

chemical agent that affects living protoplasm

agonist

activator, drugs bind and activate a receptor, mimic endogenous ligands, green and blue lines

full agonist

activate receptor to the max that is capable, green line

partial agonist

activates but does not reach max activity, can compete with full agonist to reduce activation of a receptor, blue line

inverse agonist

decreases constitutive (intrinsic) activity, not an antagonist but the graph can look similar to a partial antagonist, red line

antagonist

inhibitor of agonist, binds and inhibits receptor from binding with agonist, does not change constitutive activity, black line

allosteric modulators and example

bind secondary site to enhance or inhibit action of an agonist, ex. benzos

biologics

larger molecule with receptor (antibody) that binds to endogenous molecules

chemical antagonists

inhibits drug by directly (chemically) interacting with them

osmotic agents

interacts (almost exclusively) with water

hormones

synthesized within the body, chemical messengers

xenobiotics

chemicals not synthesized in the body

poisons

any substance that has the capacity to cause harm, depends on the dose

what is A, B, C and D?

pharmacokinetics

ADME, the effect the body has on the drug

pharmacodynamics

the effect the drug has on the body, mechanisms of action

drugs usually alter rate or magnitude of intrinsic responses, not creating new

rational drug design

predicting drug structure based on knowledge of the receptor or target, then optimizing

personalized medicine

fit drug to individual patients based on genetic screening and biomarkers

absorption

movement of drug from site of admin to central compartment (blood)

bioavailability

how much of the drug reaches the active site or systemic circulation, after GI absorption and liver metabolism

bioequivalence

drugs that contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration

Which of the following best defines a prodrug in pharmacology?
a. exhibits antagonistic effects on multiple receptors simultaneously
b. is administered through intravenous injection for rapid onset of action
c. biologically inactive drug metabolized into an active drug within the body
d. a drug that directly stimulates neurotransmitter release

c. biologically inactive drug metabolized into an active drug within the body

acidic and basic drugs bind to what proteins?

acidic drugs bind to albumin, basic drugs bind to alpha1-acid glycoprotein

drug accumulation in BBB, bone and fat

more lipophilic drugs are able to cross the BBB

tetracyclines and heavy metals accumulate in bone, osteoporosis releases them later

fat stores lipid soluble drugs

what common pain reliever is ionizable?

aspirin

redistribution

termination of drug effect after withdrawal of a drug, lipid soluble drug are not eliminated as fast

placental transfer of drugs depends on

lipid solubility, extent of PPB, degree of ionization

first order kinetics

the amount of drug metabolized per unit time is proportional to the plasma concentration of the drug (Cp) and the fraction of drug removed by metabolism is constant

zero order kinetics

metabolic capacity is saturated at the concentrations usually employed, so a constant amount of drug is metabolized per unit time, does not depend on concentration, occurs at toxically high drug concentrations

inducible biotransforming enzymes

broad spectrum enzymes with predictable genetic variation, CYPs

phase I reactions

what is the purpose?

oxidation (CYP), reduction, hydrolysis

to deactivate (or active if prodrug) and slightly increase water solubility

phase II reactions

what is the purpose?

conjugations

add polar group that greatly increases water solubility to allow elimination

where does metabolism happen?

primarily in the liver, some in GI, kidneys, lungs

clinical pharmacokinetics

used to find a quantitative relationship between dose and effect, framework to interpret drug concentration and how to adjust dose as needed

where does excretion happen?

kidneys (30% of unchanged drugs), feces (unabsorbed oral drugs or metabolites in bile), lung (volatile)

dose-response curve EC50

effective concentration of agonist for 50% response

dose-response curve LD50

median lethal effective dose, 50% of animal participants die

hormesis

low dose stimulates receptor, high dose inhibits receptor

pharmacophore

simplest form of structure needed to interact with target or receptor, can be identified by computer modeling and optimized

affinity

measured binding of ligand to receptor, determined by chemical structure, represented by dissociation constant

specificity

how promiscuous the drug is, non-specificity can come from racemic mixtures and leads to side effects

potency

drugs have the same response but one is at a lower concentration, when the EC50 is less or the dose-response curve more to the left

a mix of affinity and efficacy

efficacy

the capacity of a drug to activate a receptor and generate a response

radioligand assays

measures functional response to determine affinity of ligand for receptor

positive synergism

super-additive effects of two drugs used together

negative synergism

less then additive effect of two drugs used together

what factors modify drug action?

• medication errors

• patient compliance

• rate and extent of absorption

• body size and composition

• distribution in body fluids

• binding in plasma and tissues

• rate of metabolism and excretion

• physiological variables

• pathological factors

• genetic factors

• interaction with other drugs

• development of tolerance and desensitization

• drug-receptor interaction

• functional state of targeted system

• selectivity of drug, propensity to produce unwanted effects

• placebo effects

• resistance to antimicrobial or antineoplastic agents

pharmacogenetics

study of genetic bases for variation in drug response, large effects from small number of DNA variants

pharmacogenomics

study of larger number of variants, genetic component of variable drug responses, can be across populations

how genes affect PK, PD, efficacy and ADE of drugs

difference between gene and allele

a gene is a DNA sequence that codes for a protein, alleles are different versions of one gene

different between mutation and polymorphism

a mutation is a change in the gene’s DNA sequence, a polymorphism is a mutation that is present in 1% or more of a population

relationship between genotype and phenotype

genotype is the DNA sequence itself, phenotype is how the genes physically present (different based on regulation and expression of genes)

haplotype

group of alleles that are inherited together from one parent, the closer genes are on a chromosome the more likely they are to be inherited, set of single nucleotide polymorphisms (SNPs) found to be statistically associated on one chromatid

frequency of polymorphisms

important when deciding what is generally best for the population you are treating

non synonymous coding SNPs

codes for a different amino acid

synonymous coding SNPs

changes gene sequence but codes for the same amino acid

noncoding SNPs

can be in the promoter region and affect the transcription of the gene

can be intronic and affect splicing

gene duplications

increases number of enzymes and can increase how quickly a drug is metabolized

large deletion

if a gene has redundancy this shows how important it is and will not be as affected by deletions

consequence of SNPs

• nonsynonymous substitutions

• splice site mutations

• early stop codon, degradation of mRNA, reduced amount of protein

• increased proteolysis

• changed promoter function

• intronic SNPs can lead to truncated protein, from early stop codon

codeine and mutations

prodrug that is metabolized by CYP2D6, individuals missing a copy of the gene don't get full effects of drug

warfarin and mutations

warfarin inhibits VKORC1 to stop clotting and is metabolized by CYP2C9, mutations can affect how effective warfarin is or how quickly it is metabolized

important drug characteristics for drug development

1. drugs ability to interact with receptor: size, charge, shape, atomic composition of drug, drug shape or chirality

2. transportation to site of action

3. appropriate duration through ability of the body to inactivate or excrete drugs

signal transduction pathways

• activated by receptors on the surface of cells

• two major functions: ligand binding domain (LBD), message propagation (effector domain)

• regulatory action may be exerted on effector proteins or on transducers (intermediary signaling molecules)

• one receptor can create a large effect because of the ability to amplify the signal, often through enzyme cascades

• excellent drug targets

what are the four types of receptor structures?

1. nuclear or intracellular receptors

2. ligand-gated ion channels

3. G coupled protein receptors

4. enzyme-linked receptors

G protein coupled receptors (GPCR)

• span plasma membrane as bundle of 7 alpha helices

• target for many drugs due to large quantity and physiological importance

• mediated by secondary messengers

• signal transducer with one or more effector proteins (AC, PLC, cGMP, PDE6, Ca and K)

GPCR alpha subunit types

• alpha subunit types: Gs, Gi, Gq and G12/13

  • Gi decreases cAMP

  • Gs increases cAMP

  • Gq increases IP3 and Ca

• can be homo or heterodimers of subtype

Gq-PLC-DAG/IP3 Ca Pathway

Gq or Gi recruits PLC which generates DAG and IP3, releases Ca

Ca regulates metabolic processes, secretion, contraction, gene expression and electrical activity

types of ion channels

• voltage gated: Na+, K+, Ca2+

• ligand gated: glutamate (excitatory), GABA (inhibitory), ACh

• transient receptor potential channels: nociception, hot and cold sensation, mechanosensation, sensation of chemicals

enzyme linked receptors

• receptor tyrosine kinases: receptors for hormones like insulin, GF, ephrins

• Jak-STAT receptors: regulates transcription, no intrinsic enzymatic activity

• receptors that stimulate cGMP synthesis

nuclear (intracellular) hormone receptors

• transcription factors that regulate gene expression

• receptors for steroid hormones like androgens, estrogens, glucocorticoids, thyroid, vitamin D

Jak-STAT receptors

binds cytokines

dimerization induced by ligand (cytokine) binding, JAK proteins bind, JAK phosphorylates other STAT proteins, phosphorylated STAT proteins translocate to the nucleus and regulate transcription

apoptosis signaling pathway

• highly regulated set of reactions

• lead to cell rounding and shrinking of cytoplasm, nucleus condenses

• cell membrane presents phosphatidylserine on outer surface

• recognized by macrophages so they phagocytize the dying cell

two inducing pathways for apoptosis

1. external signals

2. internal signals, triggered by DNA damage or improperly folded proteins

autophagy

catabolic pathway that sequesters damaged cellular contents in vesicles then delivers to lysosomes and contents are degraded

can also provide cells with substrates for energy and biosynthesis

testicular feminization syndrome

deficiency of androgen receptor

myasthenia gravis

autoimmune disruption of nicotinic cholinergic receptor function

insulin-resistant diabetes (type I)

autoimmune disruption of insulin receptor function

cancer

many forms come from mutations in growth factor receptors

xenobiotics

foreign chemicals in the body

plants are dietary xenobiotics

can be beneficial or toxic

enzymes metabolize these and eliminate them from the body

most are lipophilic to cross lipid membranes

downsides of drug metabolism

• different between species, animal models are limited in predicts effects in humans

• inter-individual variations in capacity to metabolize drugs

• drug interactions with metabolizing enzymes

• metabolic activation of chemicals to toxic and carcinogenic derivatives

what is metabolism for?

converts hydrophobic xenobiotics to be hydrophilic so it can easily be eliminated from the body

prevents accumulation and toxicity

rates of metabolism of drugs

if metabolized too quickly, reduced therapeutic effect

if metabolized too slowly, accumulates and causes toxicity

first round of metabolism

bacteria in the gut, varies in each person, changes drug disposition by different gene expression of the microbiome

phase I enzymes

• Cytochrome P450 (CYP): oxidation, has a heme to use oxygen during reactions

• Flavin-containing monooxygenase (FMO): adding an oxygen atom to substrates, high levels in the liver and bound to ER

• Epoxide hydrolase (EH): hydrolysis of epoxide rings

phase II enzymes

• glutathione s transferase (GST)

• glucuronosyltransferase (UGT)

• sulfotransferase (SULT)

• N-acetyltransferase (NAT)

• methyltransferase (MT)

role of CYPs

phase I oxidation

one compound can be metabolized by different CYPs, one CYP can metabolize many drugs or the same drug at different sites, this is the cause of many drug-drug interactions

CYP inducers

increase their own rate of metabolism or metabolism of other drugs

sites of drug metabolism

GI tract, liver, nasal and lung mucosa, ER

toxicity

physiological response to a drug that is an adverse effect, can depend on dose

ED50

concentration of drug where 50% of population will have desired response

LD50

dose that is lethal in 50% of the population (in animal models)

therapeutic index

LD50/ED50, the higher the ratio (larger difference) the safer the drug

graded dose-response curve

normal curve, response increases as dose increases

quantal dose relationship

percentage of the population that responds increases as the dose increases

U-shaped dose-response curve

usually for endocrine disruptors, hormones, essential metals and vitamins

initial high adverse response due to deficiency, then dips when homeostasis is achieved, then beyond required amount toxicity occurs

hockey stick dose-response curve

for toxicants with saturable removal process, no response until reaching a threshold where the removal process is saturated then zero-order increase in adverse response

inverted U-shaped dose-response curve

for ligands that down-regulate receptors, or there is an additional negative effect beyond the concentration that produces the primary positive effect

five rights of safe medication dispensing

drug, patient, dose, route, time