Pharmacodynamics Dr. Shabbits jennifer.shabbits@ubc.ca September - - PowerPoint PPT Presentation

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PCTH 325

Pharmacodynamics

• Dr. Shabbits

jennifer.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 as

a result of drug-receptor binding

• 2. Drugs can be endogenous or exogenous molecules

that bind to receptors via chemical interactions

• 4. The vast number of receptors in the body can be

grouped into 4 main classes based on structure and function

• 3. Drugs can produce both desirable and undesirable

effects, both of which must be carefully considered

• 5. Drugs can be categorized as agonists (affinity &

intrinsic activity) or antagonists (affinity only)

2

• 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
• f 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 pharmacological response (effect) in a specific individual

Degree of Effect 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) % Response 250 25 500 60 750 90 1000 100

% Reduction in Pain Drug Dose (mg) 100 50 75 25  1000    

*often see “log” dose

3 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) % Pain Relief 100 50 75 25 200      What is the ED50 of this drug? What is the Emax ? Emax

 ~90%

300 100 (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 Degree of Pain Relief

A B 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

4 Quantal dose response curves

The frequency distribution of most drugs follows a normal (Gaussian) distribution pattern

Seizure-free patients at 5 years

Drug Dose Number Responding

Quantal dose response curves

Seizure-free patients at 5 years

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

Drug Dose

% Individuals Responding

Cumulative frequency distribution

Drug Dose % Individuals Responding

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

Analyzing quantal dose response curves

Assessing the SAFETY & EFFICACY of drugs

5 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

Transdermal Inhalational Topical

6 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?

7 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 Excretion FREE 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

8 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 = dose Vd

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)

9 Vd ~ a clinical example

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

• f blood is drawn for analysis a plasma

concentration of 25g/L is obtained. What is the volume of distribution of this drug?

A clinical example ~ solution

** ALWAYS check your units! 30mg = 30,000g = 30x103g

Conc = dose  Vd = dose = 30x103g = 1200L Vd conc 25g/L

What does this mean?

What is volume of distribution?

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

• f 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

• f 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

10 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)

11 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 I P450 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 before reaching 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)

12 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