Basics of Pharmacology

What is a drug?

any substance that interacts with molecules of an organism to cause biochemical and/or biophysical changes

Natural product to synthetic chemical are examples of what kind of drug?

small molecule

Biologics are an example of what kind of drug?

large molecule drug

How is pharmacokinetics used in drug discovery?

1. how well drug is abs by body

2. how easily drug is distributed by body

3. what drug is metabolized by

4. what transporters the drug uses

What is pharmacokinetics?

What the body does to the drug (ADME)

What is pharmacodynamics?

what the drug does to the body

How is pharmacodynamics used in drug discovery?

1. taking side effect of one drug and isolating the compound that causes that side effect to be the main target of the new drug

2. drug selectivity

What general factors affect drug action?

Diet

Diseases

Genetic Factors

Why can diet affect drug action?

certain foods enhance or decrease a drugs effect

Why can diseases affect drug action?

diseases of liver/kidney can affect drug metabolism and excretion, resulting in more drug in body and therefore enhanced action

How does genetic variability affect drug action?

1. SNPs can affect metabolizing enzymes, either inducing or inhibiting their activity, affecting dose needed for desired effect

2. SNPs can alter target's response to drug, resulting in an increased or decreased effect =

What is local administration of drug?

drug is given directly to site of action

Examples of local administration?

topical: skin, mucous membranes, inhalation

arterial

What is systemic administration of a drug?

drug enters circulation to get to target

Examples of systemic administration of drug?

1. oral/enteral

2. parenteral (via needle): IV, intramuscular

What route of administration gets the most of the drug to the site of action?

IV

What route of administration gets the drug to the site of action the quickest?

IV

Rank the routes of administration from fastest to slowest + how much drug gets to target

1. IV

2. snorting, buccal, inhalation

3. oral

What is passive diffusion?

drug freely moves across membrane

What must a drug be to use passive diffusion?

small, non-polar, lipophilic

Examples of passive diffusion?

simple diffusion, ion channel diffusion

What is facilitated diffusion?

drug used membrane protein that utilizes concentration gradient to cross

What is active transport?

uses energy/ATP

What are types of drug transporters?

1. ATP binding cassette (ABC)

2. Solute Carrier Transporters (SLCs)

What so solute carrier transporters (SLCs) do?

1. help absorb drug

2. serve as drug target

How can a drug get through physiological barriers?

1. go around

2. passive diffusion

3. facilitated diffusion

4. active transport

What determines molecular charge of a drug?

the drugs pKa and the environments pH

If pH < pKa what species is dominant? Are acids and bases charged or uncharged?

protonated species is dominant

acids are uncharged (HA)

bases are charged (HB+)

If pH > pKa, what species is dominant? Are acids and bases charged or uncharged?

unprotonated species dominant

acids are charges (A-)

bases are uncharges (B)

How does charge affect absorption?

charged molecules are not easily absorbed

Where are weak acids better absorbed?

in low pH environments (ex: stomach)

When are weak bases better absorbed?

in high pH environments (ex: small intestine)

Where are acids best dissolved?

in basic environments

Where are bases best dissolved?

in acidic environments

What is ion trapping?

ionizing a drug so that it stays in that tissue/environment and cannot be absorbed

Where do we usually see/want ion trapping? Why?

In tubule of nephron

keeps drugs in urine to be excreted rather than be absorbed back into blood

If you want to trap a basic drug in the tubule, what pH do you want?

low pH in tubule

If you want to trap an acidic drug in the tubule, what pH do you want?

high pH in the tubule

What is bioavailability?

proportion of drug that is absorbed and available in blood

What is bioavailability a proportion of?

ratio of oral to IV dose

What is bioavailability really affected by with oral doses?

first pass effect

What is the first past effect?

oral dose passes through liver + majority is metabolized before entering blood to get to target

What is lipid solubility?

ability of a molecule to cross membranes

What does it mean if a drug is very lipophilic?

It is absorbed easily/can easily cross membranes, but it has low solubility

Why do you want a drug to be a mix of lipophilic and hydrophilic?

want it to be lipophilic so it can be absorbed/cross membranes

want it to be hydrophilic so it can be dissolved (increase solubility)

What is the partition coefficient?

The ratio of a drug's concentrations in oil and water

What does the partition coefficient tell us?

how lipophilic something is

What does a log partition coefficient > 1 (logP >1) mean?

drug is lipophilic

What does a log partition coefficient <1 (logP < 1) mean?

drug is hydrophilic

What does it mean if logP > 3?

drug is extremely lipophilic and can cross BBB

What is a prodrug?

Drug thats polar/ionizable groups are masked with lipophilic residues to allow drug to cross membranes and be absorbed, and then is cleaved in the plasma to reveal true drug

What does it mean if someone's Vd is low (15-18)?

Drug has low distribution and is mostly in the ECF (plasma and ISF)

What is the Volume of Distribution formula?

Vd= amount of drug given/resulting concentration

What does it mean if someones Vd is around 40?

drug is evenly distributed between ECF + tissues

What does it mean if someones Vd is > 40?

high distribution of drug, lots of drug is tissues

An increased plasma concentration of drug has what affect on Vd?

decreased Vd

A decreased plasma concentration of drug has what affect on Vd?

increased Vd

What factors affect the ability of a drug to distribute throughout the body?

Volume

Blood Flow

Protein binding

How does blood flow affect drug distribution?

Organs with high blood flow will have higher concentrations of drug that organs with low blood flow

How does protein binding affect drug distribution?

protein bound drugs will not freely diffused out of plasma and therefore have decreased distribution

What do you have to do if a drug binds proteins in the plasma?

increase the dose so desired concentration reaches target tissue

How does lipid solubility affect Vd?

more lipophilic=increased Vd

How do you adjust dose if drug has large Vd?

must increased dose to reach desired blood concentration

What is metabolism of a drug?

conversion of a drug into a new substance (metabolite)

Where does drug metabolism occur?

1. liver

2. kidney

How does the liver metabolize drugs?

1. oxidation

2. conjugation

What is oxidation?

CYP450 + other enzymes convert drug into metabolite

What is conjugation?

addition of chemical group to make drug more soluble for excretion

What is the goal of metabolism?

de-toxify drug and make it more soluble for excretion

What is not required for a drug to be excreted?

metabolism

What is the function of CYP450 enzymes?

main enzymes involved in oxidative metabolism

What happens if you induce CYP450 enzymes?

increasing metabolism and therefore decreasing drug concentration and effect

What happens if you inhibit CYP450 enzymes?

decrease metabolism and therefore increased drug concentration and effect

How can plasma protein binding cause drug interaction?

if drug is bound to ptn in plasma and patient takes another drug with a higher affinity for protein binding, the first bound drug will be displaced and be distributed thus increasing its effect

What is first order elimination kinetics?

constant fraction of a drug is eliminated per unit time

Example of first order elimination kinetics?

1/4 drug removed every hour

In first order elimination, what is elimination proportional to? Example?

drug concentration

Ex: 1/2 drug removed every hour. start with 100g of drug, removes 50 for first hour, but then only 25 second hour

Which order of elimination kinetics has all elimination processes saturated?

zero order elimination

In first order elimination, if you increase the drug concentration what happens?

the amount eliminated increases

What is zero order elimination kinetics?

constant quantity of drug is eliminated per unit time

Example of zero order kinetics?

10g of drug removed every hour

What order elimination kinetics is drug elimination independent on concentration?

zero order

What is half life?

time required for drug concentration in plasma to decrease by 1/2 its initial value

What is half life used for?

determining drug dose intervals

How does a low half life affect dosing?

drugs with a low half life must be dosed more often

What is half life dependent on?

Volume of distribution

What happens to half life if you increase a drugs Vd?

half life increases

drugs with a low Vd have what half life?

short half life