Pharmacodynamics And Pharmacokinetics

Front 1

What is Pharmacology

Back 1

The study of drugs:
• What they are!
• How they work!
• What they do!

Pharmacology is not to be confused with Pharmacy which concerns
the scientific, legal and managerial aspects of dispensing drugs

It's d

Front 2

Pharmacodynamics

Back 2

what drugs do to the body

D + R ⇒ DR
D: Drug or endogenous ligand
R: Receptor!
DR: Drug-Receptor Complex

Biological Effect is proportionate to the amount of DR

Front 3

Pharmacokinetics

Back 3

what the body does to drugs

Front 4

What is a Receptor?

Back 4

The beneficial therapeutic effects and many of the unwanted
adverse effects of drugs are elicited through interactions with
receptors!
- proteins on the surface or within a cell that recognize and bind
with specific molecules that act as chemical signals!

Front 5

How do drugs work?

Back 5

Drugs elicit their desirable and many of their undesirable effects by mimicking or blocking the actions of hormones and neurotransmitters!

Front 6

What are ligands?

Back 6

Ligands include drugs as well as endogenous signaling molecules such as hormones and neurotransmitters!

Front 7

How do ligands work?

Back 7

Upon recognition and binding an appropriate molecule (ligand), receptor proteins transmit this chemical signal into a biological change in the target cell!

Front 8

Major Classes of Receptors

Back 8

• Ligand-Gated Ion Channels
• Enzyme-Linked Receptors
• G-Protein Coupled Receptors

• Ligand-Activated Transcription Factors

Front 9

What do the different pathways for receptors look like?

Back 9

Front 10

The Lock and Key Model of Ligand-Receptor Interaction

Back 10

Normal hormone = key in lock

Agonists are like bobby pins that pick locks

Antagonists bind to receptors but do not produce a response

Front 11

Chemistry of Drug-Receptor Interactions

Back 11

Most drug-receptor interactions
- reversible
- weak chemical bonds
Irreversible drug-receptor interactions
- not common

- strong chemical bonds (covalent)
- usually undesirable

- difficult reversal of effects/toxicity
- may be mutagenic/carcinogenic

Front 12

Relationship of Drug Concentration and Receptor Binding

Back 12

Front 13

Relationship of Drug Concentration and Receptor Binding

Back 13

B = Bmax × [D]/
[D] + Kd
B - Fraction of total receptors bound
Bmax - Maximal fraction of total receptors
bound
[D] - Concentration of drug
Kd - Equilibrium Dissociation Constant
- Drug concentration at which 1/2 of Bmax is achieved
- A measure of the inherent affinity
of the drug-receptor interaction
- constant; not altered by
concentration of drug or receptor
number

Front 14

Sigmoidal Receptor Binding Curves

Back 14

- Semi-logarithmic transformation

- Common representation of pharmacological data
- Does not change value of Bmax and Kd

Front 15

Graded-dose dependent curves

Back 15

Emax -the maximum response achieved by an agonist
-also referred to as drug efficacy
ED50 -the drug dose at which 50% of Emax is achieved
- also referred to as drug potency

Front 16

Affinity

Back 16

ability of the ligand to bind to the receptor

Front 17

Efficacy

Back 17

maximum response achieved by an agonist

Front 18

Potency

Back 18

where 50% of the maximum response is achieved

Front 19

Quantal Dose-Response Curves

Back 19

Graded Phenomena: - infinite number of intermediate states

- vessel dilation, blood pressure change, heart rate change!

Quantal Phenomena: - “all-or-none”

- death, pregnancy, cure, pain relief, effect of given magnitude

-ex. you can't be "sort of" pregnant

Front 20

Quantal Dose-Response Curves

Back 20

Quantal Dose-Response Curves
• useful to describe population
rather than single individual
responses to drugs
• based on plotting cumulative
frequency distribution of
responders against the log drug
dose

Front 21

Potency

Back 21

• related to the amount of drug needed
to produce an effect of a given
magnitude!
• usually expressed as ED50 (dose to
achieve 50% of the maximum effect
achievable with that drug

-if something is more potent,

Front 22

Efficacy

Back 22

Efficacy
• related to the maximum effect that can
be achieved with a particular drug
• usually expressed as Emax

• the maximum effect that can be
achieved with that drug

Front 23

Potency v.s. Efficacy

Back 23

On the graph, more potency = not a delayed curve and more efficacy = a taller response

Front 24

Agonist Types: Its All Relative

Back 24

A: full agonist (“gold standard”)
maximum potency, maximum efficacy

B: partial agonist
maximum potency, reduced efficacy

C: full agonist
reduced potency, maximum efficacy

D: partial agonist

reduced potency, reduced efficacy

Front 25

A Model for Constitutive Receptor Activation!

Back 25

Front 26

A Model for Constitutive Receptor Activation

Back 26

• agonist (e.g. drug, hormone, neurotransmitter) binding induces a conformational change in the receptor from the inactive (R) to active (R*) state
• agonists may also act to stabilize the active state
• spontaneous dissociation of agonist returns receptor to inactive state
• conformational change to active state can also occur spontaneously in the absence
of agonist (random kinetic fluctuations)

Front 27

Inverse Agonists

Back 27

get rid of the normal affect instead of bringing in a new effect

Front 28

An Experimental Apparatus to Measure Constitutive Receptor Activity

Back 28

• Isolated blood vessel preparation
• No endogenous agonist (e.g.
hormone or neurotransmitter)
present
• Vessel inner diameter = 1.0 mm

Add agonist

• Agonist dilates blood vessel
• Vessel inner diameter = 2.0 mm

Front 29

Effect of inverse agonist

Back 29

-has an independent impact upon
receptor activity
-produces an effect opposite to
agonist
-In the presence of agonist, may
appear to function as an
antagonist

-Inverse agonists reveal constitutive receptor activity

Front 30

Chemical Antagonism

Back 30

- Direct interaction of two drugs in solution such that the effect of one or
both drugs is lost

-e.g. protamine (acidic anticoagulant) and heparin (basic
anticoagulant); loss of activity of both drugs
-It depends on the charges. Protamine is negative and heparin is positive, so if you put them together, nothing happens because the drugs are opposing each other.

Front 31

Physiological Antagonism

Back 31

- Indirect interaction of two drugs with opposing physiological actions
e.g. histamine: lowers blood pressure through vasodilation
(histamine H1 receptor); epinephrine raises blood pressure through vasoconstriction (β-adrenergic receptors)

Front 32

Pharmacological Antagonism

Back 32

- Blockage of interaction of one drug with receptor by another drug!
e.g. cimetidine blocks binding of histamine to H2 receptors
resulting in lower gastric acid secretion!

Front 33

Types of pharmacological antagonists

Back 33

Competitive and Non-Competitive Antagonists

Front 34

Competitive Antagonists

Back 34

-bind reversibly to the receptor
-inhibition can be overcome by increasing agonist concentration
-primarily affect agonist potenc

Front 35

Non-Competitive Antagonists

Back 35

-bind irreversibly (e.g. covalently) to the receptor or to a site on the
receptor different from agonist
-inhibition cannot be overcome by increasing agonist concentration

-primarily affect efficacy

Front 36

How does competitive antagonism work?

Back 36

Effect = 100% when both receptors (blue) are bound by agonist (green), the maximum
biological effect can be achieved

Effect = 50% when a competitive antagonist (red) is present, it can displace the agonist from the receptor and the biological effect is reduced

Effect = 100% increasing the amount of agonist can displace the competitive antagonist and
restore the maximum biological effect

Front 37

Competitive Antagonists - Effect on Dose Response Curves

Back 37

A: -agonist with NO antagonist

-agonist has maximum
potency, maximum efficacy

B: -agonist with competitive
antagonist
-agonist now has reduced
potency, but retains maximum
efficacy

Front 38

Non-Competitive Antagonism

Back 38

Effect = 100% when both receptors (blue) are bound by agonist (green), the maximum
biological effect can be achieved

Effect = 50%! when a non-competitive
antagonist (red) is present, it can displace the agonist and bind irreversibly to the receptor; the biological effect is reduced

Effect = 50%

Increasing the amount of agonist cannot displace the non-competitive antagonist
and restore the maximum biological effect

Front 39

Non-Competitive Antagonists - Effect on Dose Response Curves

Back 39

A: • agonist with NO antagonist
• agonist has maximum
potency, maximum efficacy

B: • agonist with non-competitive
antagonist
• agonist retains maximum potency, but now exhibits
reduced efficacy

Front 40

Drug Desensitization

Back 40

• effect of a drug often diminishes when given
continuously or repeatedly
• desensitization, tachyphylaxis, refractoriness,
resistance, tolerance
• receptor-mediated and non-receptor-mediated
mechanisms

Front 41

Receptor Mediated Drug Desensitization

Back 41

- loss of receptor function
- reduction of receptor number

Front 42

Non-Receptor Mediated Drug Desensitization

Back 42

- reduction of receptor-coupled signaling components
- reduction of drug concentration
- physiological adaptation

Front 43

Simplified Model for Desensitization of G Protein-Coupled Receptor (GPCR) Signaling

Back 43

Receptor Mediated
Phosphorylation of GPCR at
sites that affect:
- coupling to G proteins
- localization on cell surface

Non-Receptor Mediated
Cellular stores of ATP can be
depleted with prolonged GPCR
activation

Front 44

Non-Receptor Mediated Desensitization:

Reduction of Receptor-Coupled Signaling Components

Back 44

-depletion of signaling molecules required for biological response
-Example: prolonged stimulation of G-protein coupled receptors can lead to depletion of intracellular secondary messengers

Front 45

Non-Receptor Mediated Desensitization:

Increased Metabolic Degradation

Back 45

-increase in the rate of metabolism and/or elimination of drug
-lowers plasma drug concentrations
-Example: barbiturates induce the expression of metabolic enzymes that degrade these drugs

Front 46

Non-Receptor Mediated Desensitization:

Physiological Adaptation

Back 46

-reduction or amelioration of drug effects due to opposing homeostatic response
-very few well characterized mechanism

Front 47

Adverse drug effects:

Side effect

Back 47

• Dose-dependent
• Not directly related to desired effect of drug
• Action of drug at other sites to produceundesirable effects

Front 48

Adverse drug effects:

Toxic reaction

Back 48

• Dose-dependent
• Directly related to desired effect of drug
• Excessive action of drug at intended target
site

Front 49

Adverse Reaction: Allergic Reaction

Back 49

• Not dose-dependent
• Not related to desired effect of drug
• Immunologic response to drug (largely unpredictable)

Front 50

Example: Beneficial versus Adverse Effects of Cyclosporine:

Desirable Beneficial Therapeutic Effect

Back 50

– Promotes survival of transplanted organs
• Consequence of intended pharmacological action (immunosuppression)
• Magnitude of effect is dose-dependent

Front 51

Example: Beneficial versus Adverse Effects of Cyclosporine:

Adverse effects

Back 51

– Increased susceptibility to infection and increased risk for some cancers
• Consequence of intended pharmacological action (immunosuppression)
• Magnitude of effect is dose-dependent
• Toxic reaction
– Kidney damage
• Not related to intended pharmacological activity

• Magnitude of effect is dose-dependent
• Side Effect
– Rash, hives, itching, breathing difficulties
• Not related to intended pharmacological activity
• Magnitude of effect is usually not dose-dependent
• Allergic effect

Front 52

Therapeutic Index

Back 52

• A measure of drug safety
• Considers dose required for a toxic or other adverse drug effect versus that required for the desired beneficial effect

Therapeutic Index (T.I.) =
Toxic ED50
Beneficial ED50

• In general, a larger T.I. indicates a clinically safer drug

Front 53

Therapeutic Window – Relationship to Blood Levels

Back 53

A measure of drug safety that considers the range of blood concentrations of a drug that are
associated with toxic (other adverse drug effects), therapeutic benefit or lack of effect within a
population.

A larger therapeutic window makes a safer drug.

Front 54

Pharmacokinetic Differences are a Major
Determinant of Patient Response to Drugs

Back 54

Same drug, same diagnosis, same dose can have different effects for the different people because their bodies may respond to drugs differently.

Front 55

Pharmacokinetics

Back 55

Drug absorption, administration, metabolism and excretion etc

Front 56

Pharmacodynamics

Back 56

Clinical response, adverse effect, therapeutic benefit

Front 57

Enteral drug administration

Back 57

-desired effect is systemic(non-local), substance is given via the digestive tract

Oral is the most convenient route, but not ideal if the drug has a quick first pass metabolism as the bioavailability can be reduced

Other methods include gastric feeding tube and rectal

Front 58

Parenteral drug administration

Back 58

desired effect is systemic (non-local), drug is given by route other than digestive tract

This method has 100% bioavailability

Bypass first pass effect

But may be more expensive and require professional assistance

• Transdermal (nicotine patches)
• Transmucousal
• Buccal (nitroglycerine)
• Insufflation (cocaine)
• Inhalational (general anesthetics)

Front 59

Topic Drug Administration

Back 59

local effect, substance is applied directly where its action is desired
• epicutaneous (application onto the skin)
- local anesthesia
• inhalational
- asthma medications
• eye drops
- antibiotics for conjunctivitis
• ear drops
- antibiotics and corticosteroids
• intranasal
- decongestant nasal sprays
• vaginal
- topical estrogens, antibacterials

Front 60

Oral Drug Absorption

Back 60

• The process by which a drug moves from the
site of administration (gastrointestinal tract) to
the site of measurement (usually blood)
• Requires passage across membranes of
cells (enterocytes) that comprise intestine wall
• Most oral drugs absorption occurs by
passive diffusion across membranes

Front 61

Physiochemical Factors that Affect Oral Drug Absorption

Back 61

– Concentration difference across membrane

– Size
• Larger drugs are less efficiently absorbed

– Polarity!
• Highly polar drugs are less efficiently absorbed
• Variable depending on drug structure (e.g. -OH, C=O)

Ionization
• Highly ionized drugs are less efficiently absorbed

• Dependent upon environmental pH
– Stomach: 1-3
– Duodenum: 5-7
– Rest of small intestine: 7-8

Front 62

Passive Drug Absorption in the Small Intestine

Back 62

• The majority of absorption for
most drugs occurs in the small
intestine
• Why?
– Extremely large surface area
• ~250 m2
• 1000x > stomach
• Villi, microvilli (brush
border)
– Extremely high blood flow

Front 63

Physiological Factors That Affect Oral Drug Absorption

Back 63

1) Gastrointestinal Motility
– Decreased stomach emptying slows onset and/or rate of drug absorption
– Can be decreased by food, disease, drugs (opioids)
2) Metabolism

– Many drugs are metabolized by enzymes in enterocytes
– Contributes to “first-pass effect”
3) Changes in pH of Gastrointestinal Tract
– Affects ionization (charge) of acidic and basic drugs
– Can be altered by food, disease, other drugs (e.g. antacids)

Front 64

First pass effect

Back 64

The first-pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. It is the fraction of lost drug during the process of absorption which is generally related to the liver and gut wall. Notable drugs that experience a significant first-pass effect are imipramine, morphine, propranolol, buprenorphine, diazepam, midazolam, demerol, cimetidine, and lidocaine.