Pharmacology 3620 - Midterm 1

What is the goal of drug therapy?

To prevent, cure or control various diseases

What are the 4 element's of the doctor's prescription?

Drug, Dose, Route of Administration and Dosing Interval

What are the four chemical classifications of drugs?

Small Molecules (natural or synthetic organic chemicals)
Peptides (eg. Insulin)
Proteins (enzymes, hormones, antibodies)
Oligonucleotides (binds to RNA to alter gene expression)

What are the three different types of name for a drug? Which is the official?

Chemical (IUPAC)
"Generic" (The official name - acetominophan)
Brand (Drug company - Tylenol)

Pharmacokinetics vs Pharmacodynamics

Pharmacokinetics is what the body does to the drug (ADME)
Pharmacodynamics is what the drug does to the body (receptors, signalling)

Pharmacokinetics definition

-Quantitative description of drug concentrations over time
-Specific routes and optimum doses

Importance of pharmacokinetics

-Therapeutic/toxic effects are related to: dose, concentration in blood/tissues, length of time in body
-Concentration at site of action relates to drug effects (more so than dose)

What are the Drug Disposition Processes?

Absorption
Distribution
Metabolism
Elimination

What ADME stage(s) is bioavailability relevant to?

Absorption

What ADME stage(s) is Half-life relevant to?

Distribution, metabolism, elimination

What ADME stage(s) is volume of distribution relevant to?

Distribution

What ADME stage(s) is Clearance relevant to?

Metabolism
Elimination

What physiological factors affect the pharmacokinetics of a drug?

-Metabolism
-Membrane Permeability & Transport
-Protein Binding

What are all ADME processes dependent on?

Drug movement across membranes

What are the tissue/membrane barriers to drugs?

GI Mucosa
Skin Epithelia
Blood capillaries
Placenta
Cells of the organs

What are the 4 pathways for Membrane Permeation?

Passive, Facilitated, Active and Endocytosis

What are the main differences between passive and carrier-mediated transport?

Passive travels down a concentration gradient, mediated doesn't matter
Energy is required for mediated (direct or indirect)
Mediated can become saturated, Passive is linear (first order)
Passive is independent of other compounds, whereas mediated there could be competition/antagonists
Passive the drugs must be small and lipophilic

What is Fick's Law?

Passive Diffusion Rate:

P x SA x (C-high - C-low) / X

P is membrane permeability
SA is surface Area
(Chigh - Clow) is concentration gradient
X is membrane thickness

What physiochemical properties favour drug passive diffusion through membranes?

small size
good lipophilicity
lack of charge (unionized)

What chemical structures increase lipophilicity? What structures decrease lipophilicity?

Increase: alkyl groups, carbon rings, aromatic rings, Halogens (Fluorines)
Decrease: N/O/S, -OH, -COOH PO3

How is lipophilicity measured?

Put drug in a tube which contains both a lipophilic drug (octanol) and an aquesous liquid.

Measure the concentration of drug in both.

PC = [DRUG]octanol / [DRUG]buffer

Higher PC means more lipophilic

What is the Henderson-Hasselbach Equation? What is its relevance to drugs?

pH = pKa + log[A-]/[HA]

We want drugs unionized for passive transport. Some drugs could be active in ionized form, or unionized.

What is the general pH for the stomach? Intestines? Blood? Tissues?

Stomach - low
Duodenum - (higher than stomach)
Jejunum/Ileum - (higher than duodenom)
Blood and Tissues - 7.4
Urine 5-8

Gievn pKa, how can you tell when a drug will be absorbed?

Whenever the drug becomes unionised

What are the three types of facilitated drug transport across membranes?

Uniporter - one drug one direction
Antiporter - drug one direction ion other
Symporter - drug and ion same direction

What are the physiochemical properties of drugs that necessitate carrier-mediated transport across membranes?

Good hydrophilicity
Ionized
Metabolized to a conjugate (Phase II metabolism - sulfate, glucuronide or glutathione added)

What affects the rate and extent of drug absorption

Environment, chemical characteristics, route of administration

What are the physiochemical characteristics affecting intestinal drug absorption?

Lipophilcitiy
Molecular Weight
Drug Ionization
Chemical Stability

What are the pharmaceutical factors affecting intestinal drug absorption?

Timing of drug release
Site of drug release
Tablet Additives

What are the physiological factors affecting intestinal drug absorption?

Surface Area
Blood circulation
pH of lumen
Gastric emptying time
First-pass effect
Intestinal drug transporters (efflux and uptake)

What are the interaction factors that affect intestinal drug absorption?

Co-prescribed drugs
Food
Diseases

What is bioavailability, and how is it measured?

Fraction of drug dose that makes it to systemic circulation unchanged

F= AUCoral/AUCIV

Use blood concentration vs time graph

What is the first pass effect?

Drug gets absorbed from intestine enterocytes, travels into portal vein to be taken to liver hepatocytes, and then into the systemic circulation.

During this time, metabolism can occur in enterocytes or hepatocytes, either eliminating the drug or activating it.

Parameter AUC

-Exposure
-Takes into account magnitude of drug [ ] and duration of drug levels

What are generic drugs to brand drugs? What steps are taken before they can be sold?

Generic drugs are drugs that contain the same ingredients, but are generally cheaper.

To be sold, they must deliver the SAME amount of drug at the SAME rate.

They mus have comparitive bioavialability within 80-125%. You do not need an IV basis for this, just compare the generic and brand AUC

What is Comparitive Bioavialability?

Compairing the AUC of two drugs orally, not the IV.

This is done to compare generic and brand name drugs to make sure the generic drugs can be sold

What is drug distribution dependent on?

-Blood flow rate
-Structure of tissue capillaries
-Capillary and tissue membrane permeability
-Binding of drug to plasma or tissue proteins

What is drug distribution?

The movement of drugs from systemic blood to tissues and vice versa

How can we see where s drug distributes in the body?

-Radioactive tags and scans.
-PET imaging (colour gradients in brain)

What does a drug concentration graph look like over time?

-High in initial time when injected
-Sharp decrease during distribution phase
-Slower decline during elimination phase

What can a volume of distribution value tell you?

If high, means the drug spends more time in tissues, therefore elimination time will take longer as half-life is longer

If a person is obese, what is the effect on volume of distribution?

Because they are fat, they have more fat deposits. High lipophilic drugs will have more volume to occupy, so their volume of distribution will increase. The volume of distribution for hydrophilic drugs will remain unaffected.

What is the lowest volume of distribution a drug can have? Why is it that value?

4L, because body blood plasma volume is 4L so drug did not distribute to tissues

How do you calculate volume of distribution?

Amount (dose)/ Blood concentration

Estimating Vd from concentration vs time curve

Inject IV
Numerator (amount in body)= IV dose
Denominator= Estimated concentration at t=0
-->eyeball where curve would have been at time=0, after taking many samples over time

Why can Vd be greater than total body volume?

-Extensive tissue binding or accumulates in organs/tissues
-Its just a proportionality constant

How does Vd differ between drugs? Between people?

-Drugs have different values.
-People have different values (varies with height, weight, age)

What can you use Vd for?

A persons Vd is the same for the same drug, so once known you can use it to calculate the right dose to administered to get a predetermined concentration

How does Vd affect peak plasma concentration?

Small Vd= high plasma concentration=potential toxicity

What ways can a drug travel through capillaries?

Passive Transport - transcellular
Fenestrations (small holes) - transcellular
Gap Junctions - paracellular

How does the blood-brain barrier prevent drugs from entering?

Tight junctions to prevent paracellular, efflux transporters to prevent transcellular

How does plasma protein binding to drugs affect things?

-Drugs are considered active when they are free in the blood. If they are bound to proteins, they aren't active.
-Lowers the volume of distribution since they remain in plasma

Free fraction theory

Concentration of free drug is clinically relevant

What are Albumin and Alpha-Acid Glycoprotein?

Plasma proteins that bind to drugs to prevent them form being free and distributing

What are the three methods of drug elimination?

Biliary (Liver)
Urinary (Kidney)
Metabolism

Less common ways drugs can be eliminated

Saliva, breast milk, sweat, semen

What is the difference between Phase I and Phase II metabolism? What is the purpose?

Phase I oxidizes (CYP)
Phase II adds a metabolite (sulfation, acetylation, glucuronidation, glutathione conjugation)

Purpose: lipophillic drugs remain in cells, hydrophillic drugs can be eliminated, pro-drugs need to be activated

What is the process of elimination by the kidneys?

-Through the nephron
-10% of renal blood flow goes through, free drugs diffuse through Bowman's capsule.
-The blood actively secretes drugs into the nephron through the proximal tubule.
-Water reabsorption at Loop of Henle= concentrated filtrate
-Distal tubule: hydrophobic, uncharged drugs diffuse back into the blood. **This is why drugs need to be metabolized to be more hydrophilic so they don't diffuse out during elimination
-Ionized, hydrophilic drugs pass into urine
-

What is the drug elimination process by biliary excretion?

-De-oxygenated blood from portal vein brings drug into liver hepatocytes by diffusing via transporters, fenestrations and sinusoids (capillary spaces).
-For elimination, drugs diffuse into bile ducts and bile collects into gall-bladder until it's time for excretion into duodenum.

How does the rate of elimination change over time?

Rate of elimination decreases as amount of drug decreases (first order kinetics)

How do you calculate rate of elimination?

=Vmax x C / Km + C

When drug concentration is less than Km = Vmax x C / Km: first order

When drug concentration is more than Km (very rarely) = Vmax and is therefore independent of concentration: zero order

What is clearance? How do you calculate it?

Clearance is a measurement of the body's EFFICIENCY at eliminating a drug from the body.

CL = (rate of elimination)/(concentration of drug)
Units= volume/time

But hard to do, so CL = DoseIV / AUC

Estimating a drug's clearance

CL= Dose (IV)/AUC

Clearance for different drugs and people

Different for diff drugs
Different between diff people
Affected by drug-drug interactions and disease

What is half-life? How do you calculate it?

The time for the blood concentration to divide in half.

T 1/2 = 0.693xVd / CL

***Independent of dose***

How many Half-life's before the drug is considered eliminated?

3-5 times. At 5 times, there is 3% left.

How does Vd and CL affect Half-Life?

Higher volume of distribution, means drug is in more tissue so half life is longer.

Higher CL means that the body is more efficiently eliminating the drug so he half life is decreased.

When certain drug dosing regimens are useful

-Regular basis: chronic disease (diabetes), short term durations (infections)
-Continuous IV infusion: when rapid and sustained attainment of drugs levels are needed

What is the impact of taking drugs repeatedly over a period of time?

Drug isn't completely removed before the next dose is taken, so the amount of drug in blood increases, overtimes reaches steady state when the rate of dosage is the same as the rate of elimination.

What is steady state?

The situation where the rate of drug dosage equals the rate of drug elimination

Concentration vs time for constant rate IV infusion

-Rise steadily then reach plateau "steady state"
-Time to reach steady state= Time it takes for drug to be eliminated

If you change the dosage rate, what is the impact on steady state?

Increased dosage rate increases the steady state MAX CONCENTRATION, doesn't affect TIME to reach steady state

For most drugs, its a first order linear relationship, so steady state concentration slowly increases, so you can monitor before toxic effects.

For some drugs, its is non-linear and therefore there is a sharp increase in steady state concentration that can result in overdoses

What effect does different dosing intervals have on steady state? On a person?

No difference in steady state. In terms of the person and drug, it depends on the drug, as for some drugs an extended difference in high and low concentration is toxic, but for others it is helpful for its effect.

What is the main method of drug elimination?

Metabolism (70%), then Renal (25%)

What does Phase I metabolism add to drugs? What does Phase II metabolism add to the drug?

Phase I adds a functional group
Phase II adds a conjugate.

What is a pro-drug?

A drug that requires metabolism to become activated.

What is Cytochrome P450?

-Membrane bound protein in the ER of hepatocytes and enterocytes
-Active site faces cytoplsm
-Associate with NADPH-P450
-Phase I metabolism enzyme. Has a heme group attached which carries the oxygen for oxidation
-Promiscuous

What are the reactions mediated by Cytochrome P450?

Alipathic Hydroxylation (add oxygen in middle)
Aromatic Hydroxylation (-OH to aromatic ring)
Dealkylation )both N and O split bond to leave those on ends
N/S Oxidation

What is the most common CYP enzyme?

CYP3A4

How does grapefruit interact with drugs?

Graefruit juice kills the CYP enzymes in the small intestine, meaning that drugs can't be metabolised so they can't be eliminated, resulting in a higher drug blood concentration, which could become toxic.

Fixes itself in a few days when the intestines shed their lining

What are the products of phase II metabolism meant for typically?

Meant for urinary or biliary excretion

How do drugs go from Phase I to Phase II metabolism

The phase I metabolite has an oxidized "handle" that the phase II enzymes recognize

What do phase II conjugation reactions involve?

Drug, cofactor and enzyme

Glucuronidation: enzyme, intra-ceullular location, co-factor, tissues

Enzyme: UGT
Intracellular location: ER
Co-factor: UDP-GA
Tissues: Intestine and liver

Sulfation: enzyme, intra-ceullular location, co-factor, tissues

Enzyme: SULT
Intracellular location: cytosol
Co-factor: PAPS
Tissues: Intestine and liver

Glutathione conjugation: enzyme, intra-ceullular location, co-factor, tissues

Enzyme: GST
Intracellular location: Cytosol, mitochondria
Co-factor: GSH
Tissues: Liver, all tissues

Acetylation: enzyme, intra-ceullular location, co-factor, tissues

Enzyme: NAT
Intracellular location: Cytosol
Co-factor: acetyl co-A
Tissues: Liver, kideny

Role of glutathione conjugation in tylenol

-3 metabolic pathways: sulfation, glucuronidation, and toxic intermediate (detoxified by glutathione conjugation)
-Overdose will saturate the first 2 pathways, leading to build up of toxic metabolite
-If glutathione (GSH) is depleted = hepatotoxicity

N-acetylcystein

Antidote that replenishes liver GSH stores

Intestinal membrane transporters

Apical uptake: drug absorption into body
Apical efflux: prevent drug entry into circulation

Liver membrane transporters

Apical efflux: excretion into bile
Basal uptake: into blood

Kidney membrane transporters

Apical efflux: excretion into urine
Basal uptake: into blood

Brain membrane transporters

Either high uptake activity: promote tissue entry of drugs
High efflux activity: prevent tissue entry of drugs

Major uptake transporters

-Solute carriers, SLC transporters
-OATP
-OAT
-OCT

OATP

-organic anion transporting polypeptide
-Expressed in: liver*, kidney, intestine, BBB
-Role: Liver uptake for metabolism/biliary excretion, intestinal absorption, brain distribution

OAT

-organic anion transporters
-Expressed in liver, kidney*
-Urinary and biliary excretion, metabolism

OCT

-organic cation transporters
-Expressed in liver*, kidney
-Metabolism, urinary and biliary excretion
-Get cationic drugs into liver

Efflux transporters

-ATP binding cassette, ABC transporters
-P-gp, MDR1
-Multidrug resistance associated proteins (MRP)
-Breast cancer resistance protein (BCRP)

Blocking renal drug transport

-Drug drug interactions
Quinidine blocks digoxin urinary excretion (blocks Pgp, MDR1)
Probenecid blocks penicillin urinary excretion (blocks OATs)

P-glycoprotein

Tissues: intestine, liver, kidney, BBB, *placenta*
Role: limiting intestinal absorption, biliary and urinary excretion, limiting brain and **fetal distribution**