Lecture 1 intro
Pharmaca = biologically active substances including toxins (applied for therapy).
Pharmacodynamics = what does the drug do with the body.
Pharmacokinetics = what does the body do with the drug.
The area between the minimum toxic concentration and the minimum effective concentration is called
the therapeutic window. The difference between primary and side effect is the aim for which the
medicine is administered (aspirin and blood clotting).
Placebo = a preparation without any pharmacologically active substance.
Nocebo = a placebo with unwanted (side) effects.
When a placebo has a (therapeutic) effect, you call this placebo effect (the strength of this effect can
be influenced by expectations of the patient, contribution investigated in RCT).
Lecture 2 PD-1
Four levels of drug action and drug classification;
- System: effect on system function, measure blood pressure and compare with the before.
- Tissue: effect on tissue function, metabolic activity.
- Cellular: transduction, production of second messengers (e.g. cAMP).
- Molecular: establish interaction of the drug, ion channels and receptors etc.
o What kind of drug target does a compound interfere with?
Different drug targets are receptors, ion channels, enzymes and transporters (molecular level).
A drug is called an agonist when it binds to a receptor and changes its conformation and thereby
activates the receptor (leading to effects in cell in which this receptor is expressed). Agonists
(modulators) also increase of decrease the chance of opening of the ion channel of which they bind.
An antagonist has no effect on the receptor conformation changes. Its effect on ion channels is a
blockage in permeation (blockers).
While an inhibitor inhibits normal reactions and thus has no product formation, a false substrate
does the same but leads to an abnormal metabolite product. In contrast, pro-drugs (which are inactive
by themselves) are turned into active drugs after recognition by an enzyme.
A well-known pro drug approach is the treatment of Parkinson’s disease (levodopa) and is
transformed by the enzyme thyrosinehydroxylase into dopadicarboxylase (into the active compound:
dopamine).
For transport inhibitors: cocaine prevents the transports of noradrenaline or dopamine.
False substrates will be transported into the cell, leading to an abnormal compound accumulation.
Amphetamines also act like cocaine (prevents the transports of noradrenaline or dopamine) but are
false substrates instead of inhibitors.
The biggest category of drug targets are receptors that can be divided into 4 groups:
- Ligand-gated ion channels (ionotropic receptors), for example nicotinic ACh receptor with
activation within milliseconds.
- G-protein coupled receptors (metabotropic), muscarinic ACh receptor, reacts via modulation
of second messengers in seconds, protein phosphorylation leads to cellular effects.
- Kinase-linked receptors takes hours: protein phosphorylation > gene transcription > protein
synthesis > cellular effects (autoimmune diseases, tumour types, cytokine receptors, insulin).
- Nuclear receptors are not present in membranes, takes hours: gene transcription > protein
synthesis > effect (oestrogen receptor/ vitamins). These are inactive in the cytosol and get
activated while moving into the nucleus.
NB: -Log 3. 10-7 = +7 - Log 3 = 6.5 (affinity constant, pD2?)
Occupation (total number of receptors available) is governed by affinity (EC50 or pD2), activation is
governed by efficacy (Emax). An antagonist has an overall efficacy of zero since there is no response.
Receptor-theory:
1. The agonist binds in a reversible manner to its receptor (neurotransmitter).
, 2. The agonist has a very high affinity (binding force) for its receptor.
Agonist affinity (50% of maximal effect) pD2 = - Log KdA = - Log [A]50.
3. Agonist concentration is not altered as a consequence of binding to its receptor.
4. Agonist efficacy is proportionate to the occupancy grade of its receptor at increasing drug
concentration (occupancy postulate).
Intrinsic activity is the capacity of a single drug-receptor complex to evoke a response.
The efficacy (E) of an agonist A, with intrinsic activity α, that interacts with receptor R is represented
by: EA/ Emax = α/ (1 + KDA/ A).
When EC50 = Kd (50%), we are safe within the context of the receptor theory referring to the
occupancy postulate. Lower EC50 means higher potency: you need a lower dose to reach 50% of its
maximal effect, while efficacy is the same for both drugs (graph line more to the left).
Also, when the Emax is higher for drug A, this drug also has a higher efficacy while being equally
potent.
Partial agonists which only have a partial efficacy do not reach maximum possible effect.
pA2 (affinity expression) is the negative logarithm of the concentration of a full competitive
antagonist which requires a doubling of the agonist concentration to compensate for the antagonism.
Affinity: (pA2 = log (X2/X1 -1) - log Y).
The effect of a full antagonist is visible in the graph as a rightward shift. In contrast, a non-
competitive antagonist shows a downward shift in the graph. This is because a non-competitive
antagonist causes a change the conformation of the receptor leading to less availability of a good fit
between a possible a classical agonist and its binding site on the receptor (same affinity, <efficacy).
An inverse agonist is a drug that binds to the same receptor as an agonist but induces its resting level,
opposite to that of the agonist.
Lecture 3 PK-1 What does the body do to the drug
There are 4 processes (ADME) of pharmacokinetics; absorption (gastro-intestinal tract), distribution
(systemic bloodstream), metabolism which is also called biotransformation (liver) and excretion
(kidneys). We get drugs into the body using different routes, these routes are
- By mouth: oral is swallowed, sublingual is under the tongue and buccal in the cheek pouch.
- Injection: IV (intravenous), IM (intramuscular), SC (subcutaneous), IA (intraarterial) and
intrathecal (subarachnoid space).
- Pulmonary, rectal and topical (dermatological reasons e.g. creams).
Pharmaca = biologically active substances including toxins (applied for therapy).
Pharmacodynamics = what does the drug do with the body.
Pharmacokinetics = what does the body do with the drug.
The area between the minimum toxic concentration and the minimum effective concentration is called
the therapeutic window. The difference between primary and side effect is the aim for which the
medicine is administered (aspirin and blood clotting).
Placebo = a preparation without any pharmacologically active substance.
Nocebo = a placebo with unwanted (side) effects.
When a placebo has a (therapeutic) effect, you call this placebo effect (the strength of this effect can
be influenced by expectations of the patient, contribution investigated in RCT).
Lecture 2 PD-1
Four levels of drug action and drug classification;
- System: effect on system function, measure blood pressure and compare with the before.
- Tissue: effect on tissue function, metabolic activity.
- Cellular: transduction, production of second messengers (e.g. cAMP).
- Molecular: establish interaction of the drug, ion channels and receptors etc.
o What kind of drug target does a compound interfere with?
Different drug targets are receptors, ion channels, enzymes and transporters (molecular level).
A drug is called an agonist when it binds to a receptor and changes its conformation and thereby
activates the receptor (leading to effects in cell in which this receptor is expressed). Agonists
(modulators) also increase of decrease the chance of opening of the ion channel of which they bind.
An antagonist has no effect on the receptor conformation changes. Its effect on ion channels is a
blockage in permeation (blockers).
While an inhibitor inhibits normal reactions and thus has no product formation, a false substrate
does the same but leads to an abnormal metabolite product. In contrast, pro-drugs (which are inactive
by themselves) are turned into active drugs after recognition by an enzyme.
A well-known pro drug approach is the treatment of Parkinson’s disease (levodopa) and is
transformed by the enzyme thyrosinehydroxylase into dopadicarboxylase (into the active compound:
dopamine).
For transport inhibitors: cocaine prevents the transports of noradrenaline or dopamine.
False substrates will be transported into the cell, leading to an abnormal compound accumulation.
Amphetamines also act like cocaine (prevents the transports of noradrenaline or dopamine) but are
false substrates instead of inhibitors.
The biggest category of drug targets are receptors that can be divided into 4 groups:
- Ligand-gated ion channels (ionotropic receptors), for example nicotinic ACh receptor with
activation within milliseconds.
- G-protein coupled receptors (metabotropic), muscarinic ACh receptor, reacts via modulation
of second messengers in seconds, protein phosphorylation leads to cellular effects.
- Kinase-linked receptors takes hours: protein phosphorylation > gene transcription > protein
synthesis > cellular effects (autoimmune diseases, tumour types, cytokine receptors, insulin).
- Nuclear receptors are not present in membranes, takes hours: gene transcription > protein
synthesis > effect (oestrogen receptor/ vitamins). These are inactive in the cytosol and get
activated while moving into the nucleus.
NB: -Log 3. 10-7 = +7 - Log 3 = 6.5 (affinity constant, pD2?)
Occupation (total number of receptors available) is governed by affinity (EC50 or pD2), activation is
governed by efficacy (Emax). An antagonist has an overall efficacy of zero since there is no response.
Receptor-theory:
1. The agonist binds in a reversible manner to its receptor (neurotransmitter).
, 2. The agonist has a very high affinity (binding force) for its receptor.
Agonist affinity (50% of maximal effect) pD2 = - Log KdA = - Log [A]50.
3. Agonist concentration is not altered as a consequence of binding to its receptor.
4. Agonist efficacy is proportionate to the occupancy grade of its receptor at increasing drug
concentration (occupancy postulate).
Intrinsic activity is the capacity of a single drug-receptor complex to evoke a response.
The efficacy (E) of an agonist A, with intrinsic activity α, that interacts with receptor R is represented
by: EA/ Emax = α/ (1 + KDA/ A).
When EC50 = Kd (50%), we are safe within the context of the receptor theory referring to the
occupancy postulate. Lower EC50 means higher potency: you need a lower dose to reach 50% of its
maximal effect, while efficacy is the same for both drugs (graph line more to the left).
Also, when the Emax is higher for drug A, this drug also has a higher efficacy while being equally
potent.
Partial agonists which only have a partial efficacy do not reach maximum possible effect.
pA2 (affinity expression) is the negative logarithm of the concentration of a full competitive
antagonist which requires a doubling of the agonist concentration to compensate for the antagonism.
Affinity: (pA2 = log (X2/X1 -1) - log Y).
The effect of a full antagonist is visible in the graph as a rightward shift. In contrast, a non-
competitive antagonist shows a downward shift in the graph. This is because a non-competitive
antagonist causes a change the conformation of the receptor leading to less availability of a good fit
between a possible a classical agonist and its binding site on the receptor (same affinity, <efficacy).
An inverse agonist is a drug that binds to the same receptor as an agonist but induces its resting level,
opposite to that of the agonist.
Lecture 3 PK-1 What does the body do to the drug
There are 4 processes (ADME) of pharmacokinetics; absorption (gastro-intestinal tract), distribution
(systemic bloodstream), metabolism which is also called biotransformation (liver) and excretion
(kidneys). We get drugs into the body using different routes, these routes are
- By mouth: oral is swallowed, sublingual is under the tongue and buccal in the cheek pouch.
- Injection: IV (intravenous), IM (intramuscular), SC (subcutaneous), IA (intraarterial) and
intrathecal (subarachnoid space).
- Pulmonary, rectal and topical (dermatological reasons e.g. creams).
