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PCTH 325

Pharmacodynamics

Dr. Shabbitsjennifer.shabbits@ubc.ca

September 10, 2013

Resources – OPTIONAL textbooks

or any introductory pharmacology textbook

Resources – course website

http://apt.ubc.ca/pharmacology/documents-downloads/

Important points from last class

1. The pharmacological effect of most drugs occurs asa result of drug-receptor binding

2. Drugs can be endogenous or exogenous moleculesthat bind to receptors via chemical interactions

4. The vast number of receptors in the body can begrouped into 4 main classes based on structure andfunction

3. Drugs can produce both desirable and undesirableeffects, both of which must be carefully considered

5. Drugs can be categorized as agonists (affinity &intrinsic activity) or antagonists (affinity only)

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1. Describe and interpret graded and quantal dose-response curves

2. List the common routes of administration, including considerations for use

3. Describe the process of drug absorption and how this is affected by pH

4. Describe how drugs distribute in the body and the effect of protein binding

5. Define Vd and describe what it can and can’t tell you about a drug’s properties & distributional characteristics

6. Describe how drugs are metabolized and the significance of induction and inhibition

7. Name the primary route of drug excretion

Learning objectives Drug-receptor binding is key to the effect

the AMOUNT of drug at the receptors → DOSE

Dose-response relationships can be quantified

HOW BIG is the response?

WHAT is the response? the NATURE of the drug

• agonists & antagonists

Graded dose-response curves

A graded dose-response curve relates the dose of drug(amount or concentration) to the degree of pharmacologicalresponse (effect) in a specific individual

Deg

ree

of E

ffect

Drug Dose

Generating a graded dose-response curve

1. Give increasing doses of drug to patient experiencing pain

2. Measure response (% pain reduction)

3. Plot dose vs response

x-axis y-axis

Dose (mg) % Response0 0

250 25500 60750 901000 100%

Red

uctio

n in

Pai

n

Drug Dose (mg)

100

50

0

75

25

10000

*often see “log” dose

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Drugs are characterized by efficacy & potency

Efficacy:• The maximal response produced by a drug

How measured? → Emax

“maximal effect”

Potency:• The concentration or dose needed to achieve a predetermined effect (usually 50% of max) in an individual

How measured? → EC50 or ED50“effective concentration or dose”

Determining Emax and ED50 from the graph

Drug Dose (mg)

% P

ain

Rel

ief

100

50

0

75

25

2000

What is the ED50 of this drug?

What is the Emax ?Emax

~90%

300100

(you must include units!)ED50

x-axis intercept for 50% maximal response = ~100 mg

Using potency & efficacy to compare drugs

Drugs A, B, C & D are being marketed as pain relievers.What conclusions can you make about them?

Drug Dose

Deg

ree

of P

ain

Rel

ief

AB

C

D

Limitations of graded dose response curves

Problems:

• Data collected for one individual only – does not take into account inter-individuality

Solution:

Quantal dose response curves analyze drug efficacy in a large population

• Can’t be used for “all or none” responses

• record the number of individuals who meet a particular criteria

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Quantal dose response curves

The frequency distribution of most drugs follows anormal (Gaussian) distribution pattern

Seizure-free patients at 5 years

Drug Dose

Num

ber R

espo

ndin

g

Quantal dose response curves

Seizure-free patients at 5 years

The plot of cumulative responses gives us a quantal doseresponse curve ~ analyze like a graded dose-responsecurve

Drug Dose

% In

divi

dual

s R

espo

ndin

g

Cumulative frequency distribution

Drug Dose

% In

divi

dual

s R

espo

ndin

g

Emax : dose at which all patients respond

ED50: dose that produces a response in 50% of the population

‘steep’ slope ‘shallow’ slope (more population

variability)

100

50

0

Analyzing quantal dose response curves

Assessing the SAFETY & EFFICACY of drugs

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The therapeutic index (TI)

• the ratio of toxic to effective drug dose or concentration

• the larger the therapeutic window the safer the drug

“large margin of safety”

Seizure prevention Coma

TD50/ED50 = 400mg/100mg = 4

A quick summary and some questions

What we know:• drugs are agonists or antagonists• they bind receptors to produce (or prevent) a response• we can measure dose-response relationships

What we still need to learn:• how does drug get into the body?• how does it know where to go?• how does it get out?

Pharmacokinetics

Absorption: gets drug into the body

Distribution: where it goes

Metabolism: what happens to it

Excretion: how it gets out

Pharmacokinetics – the ADME processes Routes of administration

Enteral: ‘GI tract’a) oral (po)b) sublingual (sl)

Parenteral: ‘other than GI tract’a) intravenous (iv)b) intramuscular (im)

convenient & inexpensive

rapid onset, good if patient unconscious or drug is poorly absorbed or unstable in gut

TransdermalInhalationalTopical

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Absorption movement of drug from site of administration into the blood

How? Passive diffusion (>95% of drugs)

Depends on: • Size

• Lipid solubility – structure, ionization, pH, pKa

• Blood flow at site of administration

• Total surface area for absorption

Effect of pH on drug absorption

HA H+ + A- B + H+ BH+

Weak acid Weak base

Predicting absorption

~ Thought Question ~

If we know how much drug is given, how can we predict how much of it will be

absorbed?

Henderson–Hasselbalch equation:

pH = pKa + log [unprotonated form][protonated form]

U

P

Practice calculation 1

A pain relief drug (pKa=1.8) is taken in the hopes of relieving a headache. How much of it will diffuse across the gastric mucosal barrier and into the blood when taken orally?

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Practice calculation 2

Suppose the person taking this drug finds that it upsets her stomach. She decides to fix this by taking an antacid at the same time. Her stomach is no longer upset but her headache won’t go away. Why?

(assume the antacid raises the stomach pH by 2 pH units)

How does the drug know where to go?

It doesn’t.

drug circulates throughout body in the blood

encounters receptors for which

it has affinity

binds

pharmacological response

Distribution

Absorption

Metabolism

ExcretionFREE DRUG

Distribution

the process by which drug reversibly leaves the bloodstream

• drug moves between body compartments• drug reaches the site of action

Distribution depends on:

1. Blood Flow: highly perfused tissues get drug 1st

& in largest amount (brain, heart, liver, kidney)

2. Lipid Solubility: only unionized drug can diffuse across membranes

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Distribution depends on:

3. Protein Binding• drugs reversibly bind proteins in the blood

(collectively called plasma proteins ex: albumin)

• proteins are too large to leave bloodstream

protein-bound drug can’t reach target receptors

Only free drug is pharmacologically active

Effect of protein binding

Non-protein bound drug Protein bound drug

Volume of distribution (Vd)

Drug administration: amount (dose) of drug (mg, g)

Drug analysis: concentration of drug (mg/L, g/mL)

we need to know the volume Vd

Concentration = doseVd

Which volume do we use?

Volume of distribution (Vd)

There are several physiological fluid compartments into which drugs can distribute

• assume a 70 kg ‘man’• body is 60% water• density of water = 1 kg/L 70kg x 1L/kg x 0.6 = 42 L

Total Body Water (TBW)

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Vd ~ a clinical example

A 30mg dose of the antidepressant Nortriptyline is administered to a patient iv. When a sample

of blood is drawn for analysis a plasma concentration of 25g/L is obtained.

What is the volume of distribution of this drug?

A clinical example ~ solution

** ALWAYS check your units!

30mg = 30,000g = 30x103g

Conc = dose Vd = dose = 30x103g = 1200LVd conc 25g/L

What does this mean?

What is volume of distribution?

What does a large Vd like 1200L tell you about the physicochemical properties

of Nortriptyline?

distributes outside actual fluids distributes to tissues/membranes must be a lipophilic drug

NOT a real, physiological volume

IS a proportionality constant that relates the amount of drug in the body to its concentration in the blood

What Vd tells you (& what it doesn’t)

The magnitude of Vd indicates the extent of drug distribution in the body, but not the location

Large Vd: drug distributes outside blood and body fluids into tissues

Small Vd: drug has limited distribution, typically restricted to blood or physiological fluids

Blood/plasma Organs/tissues

Small Vd Large Vd

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A visual representation of Vd Metabolism

the irreversible biotransformation of drug in the body typically involves making it more polar to enhance renal excretion

Occurs primarily in the liver in 2 steps: • Phase I oxidation and Phase II conjugation

Phase I: Cytochrome P450 enzymes

A superfamily of enzymes grouped by amino acid sequence – add or uncover polar chemical groups to water solubility (–OH, –NH2, –COOH)

Proportion of Drugs Metabolized by P450 Enzymes Parent Drug

Drug Metabolite

P450 induction and inhibition

P450 enzymes can be induced or inhibited by certain substances or drugs

Induction:

Inhibition: metabolic activity of enzyme = [drug] ( (ex grapefruit juice)

Has important implications for people on multiple medications → frequent cause of adverse drug reactions

↓

↓

metabolic activity = [drug] (ex alcohol)

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Phase II Reactions

Mediated by multiple enzymes located in ER or cytosol of hepatocytes

Conjugation reactions covalently add large, polar endogenous molecules to parent drug or Phase I metabolite inactive and excretable

(glucuronide, glutathione, sulfate, acetate, amino acids etc)

phenytoin

p-OH-phenytoin

phenytoin-ether-glucuronide

Phase IP450

Phase II glucuronyl transferase

Metabolism pathways

DRUG PHASE I PHASE II URINE

skip phase I

drug excreted unchanged

First Pass Metabolism

Because of hepatic metabolism, a portion of an orally administered drug dose is inactivated by the liver beforereaching the systemic circulation (and the target organ)

need to adjust dosage

(ex: 40 mg po = 2 mg iv)

Excretion

irreversible loss of drug or metabolite from the body primarily via kidney(also bile, feces, sweat, saliva, tears, expired air & breast milk)

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Things to do

1. Review learning objectives

2. Check email for welcome messages – update with SIS if necessary

3. Make sure you completed Lecture 1 readings, concept map overview and course policies

4. Bring a calculator to next class