Pharmacodynamics

Question 1

What is pharmacology?

Answer 1

Pharmacology (“Science of drugs”):
Science of the effects of drugs on healthy or sick organisms
In a broader sense:
Study of the interactions between chemicals and biological systems.
-> Pharmacodynamics deals with the interactions of chemicals with receptors.
-> Pharmacokinetics deals with the four stages by which chemicals pass through the body: absorption, distribution, metabolism and excretion.

Question 2

Paracelsus, the Father of Toxicology

Answer 2

Paracelsus wrote: “Alle Ding’ sind Gift, und nichts ohn’ Gift; allein die Dosis macht, daß ein Ding kein Gift ist.”
“If you want to explain any poison properly, what then is not a poison? All things are poison, nothing is without poison; the dose alone causes a thing not to be poison.”
Or, more commonly “The dose makes the poison.”
No substance as such is toxic!
To assess the risk of toxicity, knowledge is required of:
(1) the effective dose during exposure;
(2) the dose level at which damage is likely to occur.

Question 3

Relationship between dose and effect

Answer 3

Emax, EC50, ED50, LD50, potency (pD2)
Dose-response curves, Therapeutic Range: Therapeutic Ratio, Therapeutic Index

Question 4

Receptor theory

Answer 4

Types of action: specific and non-specific effects
Pharmacological receptors
Physiological receptors: ligand-gated ion channels, G-protein-coupled receptors, receptor protein kinases, intracellular receptors

Question 5

Agonists and antagonists

Answer 5

Relative intrinsic activity: full and partial agonists
Types of inhibition: competitive antagonists, non-competitive antagonists
Functional antagonism, physiological antagonism, chemical antagonism

Question 6

Individual Sensitivity of an Organism to Drugs

Answer 6

The sensitivity of an organism for pharmacological substances depends on
- age
- gender
- hereditary factors (genes)
- rythms
- diseases
- tolerance (Habituation)
- Tachyphylaxis (rapid decrease in sensitivity)

Question 7

Dose

Answer 7

The dose is the applied quantity of a drug. The empirically determined therapeutically effective values usually refer to an adult Central European of 70 kg of body weight

ED - Effective (single) dose
LD - Lethal dose

Standard dose (generally corresponds to the ED)
Maximum single dose
Maximum (daily) dose (maximum allowable dose in 24 h)

Initial dose and maintenance dose

Question 8

Which characteristics of a Drug can be read from the Concentration-Effect Curves?

Answer 8

The maximally possible effect (Emax)
The concentration which gives the half-maximum effect (EC50).

Question 9

Concentration-Effect Curves for Acetylcholine Analogues as Parasymthathetic Drugs studied at the isolated Rat Intestine

Answer 9

Agonists are compared regarding their potency (pD2) and their maximally possible effect Emax (“efficacy”).

pD2 = -log(EC50)

Question 10

Dose-Response Relationship

Answer 10

Depending on the concentration, the intensity of an effect is measured in an individual.
Depending upon the dose, the frequency of an effect is studied within a collective.

Question 11

Incidence of Effect as a Function of the Dose

Answer 11

Relationship between the frequency of animals responding and the dose given
-> higher dosage -> more animals are responding

Question 12

Dose-Frequency Relationship

Answer 12

ED50 (Effective Dose 50) is called the dose at which 50% of the group show the observed effect.

Question 13

ED50-LD50

Answer 13

ED50 (Effective Dose 50) is the dose at which 50% of the group show the observed effect.
Similarly, a cumulative frequency curve can be created for the lethal effects of a substance in animal experiments.
The LD50 (Lethal Dose 50) then corresponds to the dose at which 50% of the group would die with a statistically validated likelihood.
Lethality is not determined in human clinical trials. Instead, the dose that produces an adverse effect in 50% of the population is used (Toxic Dose 50 - TD50).

Question 14

LDLo-TDLo

Answer 14

LDLo bzw. LCLo (Lethal Dose/Concentration low)
Lowest dose/concentration of a substance for that a lethal effect has been described.
TDLo bzw. TCLo (Toxic Dose/Concentration low)
Lowest dose of a substance for that a toxic effect in humans, or carcinogenic, neoplastic or teratogenic effects in animals or humans has been described.

Question 15

Therapeutic Range and Therapeutic Ratio

Answer 15

Therapeutic Ratio: LD50/ED50

Therapeutic Range: Abstand zwischen ED50 and LD50 Range Curve

Question 16

Therapeutic Index

Answer 16

LD25/ED75 oder LD10/ED90

In humans, TD50, TD25, and TD10 are used to calculate the Therapeutic Ratio/Index (also called Protective Ratio/Index).

Question 17

Structure-specific and Structure-independent Effects

Answer 17

Unspecific substances are characterized in that
* they do not react specifically with certain biological structures and, therefore, act only in relatively high doses or concentrations,
* they produce similar effects despite differences in structure, * changes in structure barely change their effect.
Examples: anesthetics (nitrous oxide, halothane), disinfectants, anti-metabolites (cytostatic drugs, purine and pyrimidine antagonists)
Specifically acting substances act at very low concentrations. Their effect strongly depends on their structure!
The vast majority of drugs can be based on specific mechanisms that describe cellular structures / sites of action.

Question 18

Targets for Drug Action (Drug-Receptors)

Answer 18

A drug is a chemical applied to a physiological system that affects its function by binding specifically (chemically) to a receptor.
Four main kinds of regulatory proteins are commonly involved as primary drug targets, namely:
* Receptors
* Ion channels
* Enzymes
* Carrier molecules (neurotransmitter/electrolyte transporters)

Question 19

Receptor theory I

Answer 19

The classic concept of drug actions:
-> The Key and Lock model:
“To use a picture, I would like to say that enzyme and glucoside have to fit to each other like a lock and key in order to exert a chemical effect on each other.“ (Emil Fischer, 1894)
-> Nicotine and curare act by binding at receptive substances (John N. Langley, 1905)

Question 20

Receptor theory II

Answer 20

-> „Corpora non agunt nisi fixata“ – „Bodies do not act if they are not bound“ (Paul Ehrlich, 1913)

Question 21

Drug-Receptor Interaction (I)

Answer 21

Pharmacological receptors are membrane-bound or intracellular proteins, which cause an effect after binding of a specific ligand (L) to a binding site at a receptor (R):
[L] + [R] <-> [LR] -> -> Effect
Consequently, pharmacological receptors have a dual function:
1.They bind a drug with high affinity to form a ligand-receptor complex: -> signal detection
2. By conformational change they trigger a follow-up response: -> signal transduction
Pharmacon (P) Receptor (R) Interaction:
[P] + [R] <-> [PR] -> Effect (Agonists)
[P] + [R] <-> [PR] -> no Effect (Antagonists)

Question 22

Drug-Receptor Interaction (II)

Answer 22

Simple Occupancy Model (Alfred Joseph Clark, 1926)
Clark related occupancy to response with a direct linear relationship .The more receptors are occupied with an agonist, the greater the effect of the agonist . After the law of mass action the following applies:
KA = (Pf)(Rf)/(PR)
(Rt) = (Rf) + (PR)
Ka = (Pf)((Reiten)-(PR))/(PR)
-> KA(PR) = (Pf) * (Rt) - (Pf) * (PR)
-> KA * (PR) + (Pf) * (PR) = (Pf) * (Rt)
-> (PR) * (KA + (Pf)) = (Pf) * (Rt)
-> (PR) = ((Pf) * (Rt))/(KA + (Pf))

Theoretical relationship between occupancy and ligand concentration -> Michaelis Menten Kinetik

Question 23

Extended Occupancy Model (E. J. Ariens, 1954)

Answer 23

Ariens maintained the linear relationship, but introduced a proportionality factor termed the intrinsic activity (alpha) that allowed a partial agonist to produce a reduced response at maximal receptor occupancy:
EA/Emax = (alpha*(PR))/(Rt)
EA = effect triggered by A
Emax = maximal effect possible
alpha = intrinsic activity
[PR] = concentration of receptors occupied with A
[Rt] = concentration of the total receptors
f = proportional factor

Question 24

Induced-fit Theory (Daniel E. Koshland, 1958)

Answer 24

• Agonists are capable of causing a conformational changes in the receptor, which leads to signal transduction.
• Although antagonists bind to the receptor no conformational change is caused and no signal transduction occurs.

Question 25

Radioligand Binding

Answer 25

Different IC50 values for Losartan in the kidney medulla and adrenal cortex
-> Different AT1-Receptor subtypes!

Question 26

Ligand-gated Ion Channels

Answer 26

• Nicotinic ACh receptor
• Ionotropic glutamate receptor
• GABAA receptor
• Glycine receptor
• 5-HT3 receptor

Question 27

G-Protein-coupled Receptors (GPCRs)

Answer 27

• Muscarinic ACh receptors
• Adrenoceptors
• Dopamine receptors
• Metabotropic Glu-R
• Histamine receptor
• Opiate receptors
• Serotonin receptors (except 5-HT3)
• Adenosine receptor
• Many peptide receptors

Question 28

Receptor Protein Kinases (Kinase-linked Receptors)

Answer 28

• Insulinreceptor
• Immunoglobulin E receptor
• Low-density lipoprotein (LDL) receptor
• Cytokine receptors (e.g., interleukin)

Question 29

Intracellular (nuclear) Receptors

Answer 29

• Steroid hormone receptors
• Vitamin D receptor
• Retinoid receptors
• Thyroid hormone receptors
• Peroxisome proliferator- activated receptor (PPAR)

Question 30

Agonists/Antagonists

Answer 30

Agonists bind to a receptor to change its conformation, thus leading to signal transduction.
Agonists have both affinity and “intrinsic activity”.

Antagonists bind to a receptor, but do not result in conformational change.

The “intrinsic activity” is defined as “relative intrinsic activity” alpha: alpha = EA/EM

EA: effect triggered by the drug A
EM: the maximum possible effect

For full agonists is alpha = 1
For antagonists is alpha = 0
For partial agonists is alpha < 1

Question 31

Antagonists

Answer 31

Antagonists can be divided into:
- competitive antagonists
- noncompetitive antagonist
- functional “antagonist” and physiological “antagonist”
- chemical antagonists

Question 32

Competitive Antagonists

Answer 32

• Competitive antagonists compete with agonists for the same receptor.
• According to the law of mass action one substance can be displaced from the receptor by increasing the concentration of the other substance.

Dose-response curves of an agonist in the absence (a) and the presence (b, c) of increasing doses of an competitive antagonist:
- Competitive antagonists lead to a parallel shift in the dose-response curve of the agonist (ED50 will increase).
- The Emax of the agonist is not affected.

Question 33

Non-competitive Antagonists

Answer 33

• Non-competitive antagonists bind allosterically to the receptor.
• This leads to a conformational change, which alters the binding conditions/signal transduction of the agonist.

Dose-response curves of an agonist in the absence (a) and the presence (b, c) of increasing doses of an non-competitive antagonist
- Non-competitive antagonists lead to a decrease in the Emax of the agonist.
- The ED50 of the agonist is not changed.

Question 34

Functional antagonism

Answer 34

An agonist reverses the effect of a second agonist in the same cell system / organ. The effects are mediated by different receptors (e.g. sympathetic - parasympathetic activation).

Question 35

Physiological antagonism

Answer 35

An agonist will reverse the effect of a second agonists at a different cell system / organ. Opposing effects are triggered in the overall system (e.g. increase in cardiac stroke-volume by glycosides - peripheral vasodilatation by Dihydralazine).

Question 36

Chemical antagonism

Answer 36

If a substance prevents the effect of another substance through, e.g., complex formation, there is chemical antagonism.
Characteristically, this reaction takes place independently of an organism (e.g. EDTA with Ca2+ and heparin with protamine).