Toxicology - Exam 1 (intro, pharm/tox, PD, PK)

Rationale behind having pharmacology in the chiropractic curriculum

herb/nutrient/drug interactions

majority of pts will be on 3+ meds (5+ = polypharmacy)

sometimes pharmaceutical intervention is necessary for a pt’s tx plan

Toxicology

study of adverse effects of chemical, physical, biological agents on living organisms and the ecosystem

Pharmacology

study of science of drugs including their uses, effects, and modes of action

Drug

substance that a person exposes themselves to in order to result in a specific outcome that brings about a change in biologic function

All drugs need to interact with a

molecule (target is usually a receptor or enzyme)

_____ and _______ can also be classified as drugs using this logic

herbs; high dose nutrients

Prior to FDA approval for use in humans, every drug must fulfill two requirements

efficacy and safety

FDA approval is not required (efficacy and safety) prior to marketing for

supplements

Pharmacokinetics (PK)

what the body does to the drug

ADME

PharmacoDynamics (PD)

what the Drug does to the body

Drug targets

hormone and neurotransmitter receptors and enzymes

Cellular communication via chemical messages (2)

signal transduction

cell signaling pathway

Signal transduction pathway

signaling molecule (ligand) = hormone/neurotransmitter/drug

receptor = accepts the molecule

effector system = leads to physiological effect

Intracellular receptors (in cytosol/nucleus)

bind lipid soluble signaling molecules (steroid + amine hormones)

Cell surface receptors (immbedded in cell membrane)

bind water soluble signaling molecules (peptide + amine hormones)

ion-channel-linked or enzyme linked

What is the MC cell surface receptor

G-protein linked

Effector system moves signal from receptor to direct action by

converting signal to molecular form OR amplifies signal

Effector system permits _____ and _____ of responses

modulation; regulation

Secondary messengers

generated in response to ligand binding

• activate variety of reactions

• provide coordinated response

• part of amplification of signals

Two examples of secondary messengers

cAMP and cGMP

Analog

compounds similar to a ligand (can bind to ligand’s receptor/enzyme) that can activate or block activity

Agonist

binds to receptor/enzyme and activates activity

Antagonist

binds to receptor/enzyme and blocks activity

Types of enzyme inhibitors

irreversible inhibitors (inactivators)

reversible inhibitors - competitive or non-competitive

Irreversible inhibitors (inactivators)

destroys enzymes ability to interact with its normal substrate regardless of substrate concentration

• involves formation/breaking of covalent bonds on enzymes

• aspirin and penicillin

Competitive Reversibile inhibitor

competes with substrate for active site by binding it and blocking access

an increase in substrate concentration can knock off reversible inhibitors

Non-competitive Reversible Inhibitor

bind away from active site and can change shape of enzyme’s active site

MOST of enzyme inhibitors are

competitive + reversible

Free vs bound ligand/substrate/drug - many are

bound to carrier proteins (SHBG, albumin)

Duration of ligand/drug action

depends on length of time that bonding lasts until new receptor/enzyme is formed and concentration of endogenous ligand/drug

Concentration of available receptors/enzymes language

upregulation - more receptors added

downregulation - loss of receptors

Affinities

strength of ligand/receptor

• important consideration for efficacy!

pH can alter

ionization at active site

interfere with receptor binding

alter ionization of drug and/or cofactors

Therapeutic index

ratio of dose that produces toxicity in half the population (TD50) that produces a clinically effective response (ED50 = effective dose at 50%)

Narrow therapeutic margin/window

drugs that has an effective dose that is close to its toxic dose

easy to overdose

Wide therapeutic margin/window

drugs that have a toxic dose far away from its effective dose

hard to overdose

Potency

measure of amount of a drug necessary to produce the median effect (1/2 of maximum response)

Efficacy (Emax)

measure of magnitude of the effect of the drug

Crude preparations

whole herb/plant/glandular preparation

Pure preparations

single constituent/one molecule

Pharmaceuticals

drug product that is given at a specific dose via a particular route of administration

made from pure preparation

Pharmaceutical administration types

(MC) tablets/capsules - oral

solutions/suspensions (liquid) - oral, parenteral, topical

patches (slow release) - low dose, lipid soluble drugs

aerosols - oral, inhaled, intranasal

ointments/creams/gels - topical, rectal, ocular, vaginal

Enteral

drugs absorbed in GI tract

Oral (PO)

absorption can be decreased due to significant first-pass metabolism

require higher dose!!

Sublingual (SL)/Buccal (BUCC)

enable direct absorption of drugs into systemic venous circulation

prevents first-pass metabolism

only used for low doses

Rectal (PR)

systemic/local application

largely avoids first-pass metabolism

used for larger doses or unpleasant tasting meds

Parenteral

drugs given via needle

Intravenous (IV)

instantaneous and complete absorption (100% bioavilability)

bypass first-pass metabolism

easy to overdose

good for drugs w/short half-lives

Intramuscular (IM)

large doses in glutes and hormones

avoids first-pass metabolism

more completely absorbed than oral

Subcutaneous (SubQ)

injected into adipose tissue under dermis

avoids first-pass metabolism

slower absorption than IM (no large doses)

Intrathecal (IT/ITH)

injections into subarachnoid space

drugs that don’t cross the BBB

Intra-articular (IA)

injections directly into joint capsules

What type of parenteral has the greatest reliability and control of systematic dosing

intravenous (IV)

Angles in which parenteral drugs are given

IV = 25 deg angle

IM = 90 deg angle

SubQ = 45 deg angle

Transdermal

drugs applied directly to skin

absorption occurs slowly

bypasses first-pass metabolism

Inhalation

delivery to target tissue of lungs

bypasses first-pass metabolism

rapid absorption due to large alveolar surface

Topical

produces localized effects on skin or mucous membranes

bypasses first-pass metabolism

Drug dosages are based on

pharmacokinetic data

Pharmacokinetic principles

the response to a drug is a function of its concentration at its site of action

bioavailability vs elimination

Absorption

passage from site of administration into circulation

Absorption is affected by

partition coefficient - how well substance travels across membranes

pKa and pH

Most drugs are either weak ___ or ___ to prevent ionization at physiological pH

acids; bases

Rates of absorption for enteral medications from Fastest → Slowest

lipid soluble/lipophilic (fastest)

non-ionized liquids

water soluble ionized liquids

suspension solutions

powders

capsules/tablets

coated tablets

enteric coated tablets/hydrophilic (slowest)

• require carriers (facilitated diffusion)

What two things determine the bioavailability of a substance

absorption and first-pass metabolism

Bioavilability

fraction of active substance that gets into the general circulation

20-40% of oral medications reach blood

Most drugs are absorbed via

passive diffusion

Rate of absorption is proportional to

concentration gradient and chemistry of drug

Distribution

transport of drug from point of administration (parental routes) or absorption → site of action

relies on blood and/or lymph

Distribution is affected by

membrane permeability

sanctuary sites

BBB

plasma protein binding

depot storage

blood flow, size of molecule, surface area, contact time

Sanctuary sites

capillary of brain, testes, other tissues = absence of pores that permit aqueous diffusion

What can and cannot cross the BBB

can = benzodiazepines

can’t = some antibiotics

Depot storage

lipophilic drugs can accumulate in adipose tissues + released slowly

drugs can bind to calcium and accumulate in bones/teeth (tetracycline)

Metabolism

biotransformation of substance into other compounds (metabolites)

takes place primarily in liver (+kidneys, blood, brain, lungs, gut)

Liver metabolism passes

First-pass (oral drugs)

• digestive system → liver → first-pass → distribution to site

Second-pass (all administration)

• site of activity → blood stream → liver → metabolized + dumped into bile or back to kidneys

Detoxification in liver - objective is to make compounds more _________ so they can be excreted into bile or urine

water soluble

Phase 1 reactions

makes compounds more polar and/or reactive (capable of undergoing conjugation reactions)

translation = more water soluble

Methods of Phase 1 reactions

(MC) oxidation-reduction rxns

(MC) hydrolysis/hydration rxns

dehalogenation rxns (take off fluoride or chloride)

Cytochrome P450 (Drug microsomal metabolizing system (DMMS))

drug interactions occurs b/c both drugs are using the same isoform for metabolism

• cause increase in serum levels of one or both drugs

OR

drug interactions result of one drug speeding up (inducers) or slowing down (inhibitors) activity of enzymes

CYP Inducers (speed up phase 1)

EtOH, caffeine, tobacco, char-broiled meats

foods high in pesticide residues

prescription drugs (anti-seizure drugs)

Hypericum perforatum (St. John’s wort)

CYP Inhibitors (slow down phase 1)

grapefruit!!

prescription drugs (antifungals, GI drugs)

Silybum marianum seeds

hydratsis canadensis

echinacea purpurea

berberine

Phase 2 reactions (conjugation rxns)

form highly polar, water soluble inactive derivatives/conjugates

final step prior to excretion into urine or bile

Ex: methylation, sulfate conjugation, N-acetylation

Phase 2 rxns in diseases

Glucuronic acid conjugation - Gilbert’s syndrome (polymorphism)

Glutathione conjugation - G6PDH deficiency

Factors that affect metabolism

<5 and >60 slower

women slower

lifestyle

existing liver/thyroid disease

Elimination

irreversible removal of active substance an/or metabolites from the body

main routes = kidneys and bowel

other = sweat, exhalation, breast milk

Biliary excretion favors

larger, fat-soluble compounds

two fates = enterohepative cycling or out w/stool

Volume of distribution

measure of the apparent space in the body to contain the drug

VOD = amount in body(organ) / amount of blood

Clearance

ability of the body to eliminate a drug

C = rate of elimination (each organ or total) / amount in blood

With a larger volume of distribution, you get a _____ drug concentration in blood

lower

First order kinetics

rate of drug metabolism/elimination is directly proportional to concentration

increased drug concentration → increased clearance

half-life is constant (100mg → 50mg → 25mg)

It takes about __ half-lives to clear a drug from circulation

5

Zero order kinetics

rate of drug elimination is constant and is independent of drug concentrations

increased drug concentration → elimination stays the same

can result in accumulation of the drug (100mg → 90mg → 80mg)

Steady State

when the drug accumulated in the serum reaches a plateau

in dynamic equilibrium w/elimination

Maintenance dose

dosage given to maintain steady state

Loading dose

sometimes larger than normal dose is given in order to rapidly establish a therapeutic plasma concentration

**common in drugs that are slowly excreted (long half-lives)

after given then a small maintenance dose will be given to maintain steady state