Lecture 1

Why Pharmacology?
1. Pharmacodynamic: What is the drug doing to the
organism?
2. Pharmacokinetic: What does the organism do with the
drug?

Classification of Drugs
mostly descriptiv :
 Analgetics – painkillers
 Antipyretis – lowering the body temperature (fever)
 Antiphlogistics – anti-inflammatory
 Antibiotics – inhibit or kill bacteria
 Cytostatics – inhibit or kill tumor cells
 Antihypertensives – suppress elevated blood pressure

Drugs work via inhibition or activation of following proteins:

 Receptor (membran or nuclear)
 Ion-Channel
 Encymes
 Transporter & Pumpen

Receptors
• Makromolecule, characterised by a specific binding side for ligands; specific for a certain
structure, high affinity and stereoselectivity for a distinct ligand
• Transduction of signals per se or to „effector"-protein by conformational or functional changes of
the receptor molecule

Classification of Receptors
1. Cytosolic receptors: sexual hormones, glucocorticoids
2. G Protein coupled receptors epinephrine, serotonine, glucagon
3. Ion channel receptors acetylcholine receptor
4. Tyrosine kinase-linked receptors cytokine-receptor family
5. Receptors with intrinsic enzymatic activity the receptor has intrinsic catalytic activity receptor
tyrosine kinases

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1. Cytosolic Receptors
nuclear localisation, binding to DNA,
transcriptionfactors

steroid hormomes:
 glucocorticoides. estrogens, progesteron,
testosteron,
 Vitamin A and D,
 Thyroid hormones

Examples:: Dioxin PXR (Pregnan-X ), Rifampicin

2. G protein coupled receptors

Seven-helices or Seven Transmembrane Receptrr (7TMR = GPCR), largest
group of receptors (>1000), 50% of all available drugs are targeting GPCRs

-Blocker: eg Propranolol, Bisoprolol, Atenolol, Metoprolol, high

blood pressure, heart failure
Agonisten at the Opioid-Receptoren: (Morphin)

3. Ion channel receptor

Ligand associated ion-channels

 Nicotin: activates the n-Cholinoceptor

 Curare blocks the n-Cholinoceptor

Diazepam (Valium) agonist at the GABAA receptor

Odansetron: Inhibition at the 5-HT3 receptor

4. Tyrosine kinase linked receptors

Dimerisation upon activation by a ligand (cytokine), tyrosine kinase associated, JAK-kinase
Erythropoetin

EPO: Erythropoetin is used to increase of red blood cells

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5. Receptors with intrinsic enzymatic activity

 Guanylatcyclase: GTP -> cGMP
ANP: peptide hormone, atrium of the heart upon rising blood pressure – decreases vascular
resistance via a cGMP dependent kinase
 serin-threonine kinases: TGF –ß superfamily, growth inhibition, bone formation,
 receptor tyrosine phosphatases: CD45, expressed on B and T lymphocytes
 ReceptorTyrosineKinases: EGFR, Insulin, VEGFR

Specific Points of Actions of Drugs

• Binding to defined Receptors
• Binding to enzymes(most painkillers work on enzymes)  popular targeting of COX
• Binding to transporter proteins
• Bindung to DNA

Phenacetin (example)
Was first painkiller, side effect was kidney failure. When it is metabolized to paracetamole (in overdose
also kidney failure)  which is metabolized to NAPQI  Glutathione. If there is too much NAPQI
(overdose) it searches for other Sulphur groups at cysteine’s, mainly in the liver and it kills the livers.

2) Enzyme binding drugs:

 Cyclooxygenase: non-selective COX-Inhibition: Acetylsalicylacid, Paracetamol, Diclofenac,
Indomethacin
 COX-2 selektiv: Celecoxib, Rofecoxib, Valdecoxib/Parecoxib
 Dihydrofolat-Reduktase: human = Methotrexat
bacterial= Trimethoprim

 bacterial Enzyme: s. Antibiotics

Acetylsalicylacid
Arachidonic acid is produced by all cells.

• Prostaglandine inhibits paine (look in CNS)

• Prostacyclin blood coagulation system is inhibited
• Thromboxan blood clotting by platlets activated

Most pain killes block COX1 and COX2, most side effects
also from COX1 inhibition.

Non selective Cox inhibitors:

Non selective, many side effects

COX2 specific:
Should have less side effects. But COX2 is important for
production for Prostacyclins  heart attack risk

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3) Binding to transporter proteins

Transport-proteins
 Voltage-gated Ion-Channels:
voltage- dependant L-Typ Ca2+-channels: inhibition by “Calcium-Channel-blockers“

 Transporter:
Na -,K+-,2Cl- -Cotransport and Na+-,Cl-Cotransport inhibited by diuretics (Furosemid, Bumetanid,
+

Piretanid, Ethacrynsäure ...

Neurotransmitter transporters  inhibited by antidepressants (Citalopram)

 Ion-pumps:
H+/K+-ATPase in the stomach:  inhibited by Omeprazol, Pantoprazol,

4) Binding to DNA

Interaction with DNA  only very limited structural specificity compared to binding of drugs to a
particular protein

Alkylierende Zytostatika: eg cyclophosphamid - covalent incorporation

Effects by Drugs not mediated by interaction with proteins

Antacida Neutralisation of H+
Carbo medicinalis Adsorption to big surface
Laxans exerts effects by osmotic pressure

Quantification of receptor/drug interaction

• Dose-Response curve may be determined experimentally: Potency (ED50) and maximal effects
(Emax)
• Dose-Response curve may be determined clinically: (Alternativ way) individual sensitivity
towards a drug (ED50) and response-rate

Agonist high intrinsic activity

Partial Agonist low intrinsic activity
Antagonist no intrinsic activity, high affinity

Cumulative Dose-Response
• Used for clinical effects that are determined by an all or nothing effect (convulsions or
arrythmias)
• The dose of the drugs is increased till all individuals have reacted: -> Gauss'sche distribution
• ED50 : Dose, where 50% of the individuals have reacted.

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• TD50 : Dose, where 50% of the individuals react with

toxic effects
• Steepness of the curve: correlates with the variability of
the response to the drug (may differ between desired and
non desired effects!)
• TD5 /ED95 : "therapeutical Index„-comparison between
dose where 95% have reacted vs Dose where 5% have a toxic
effect.
• TD50/ED50 is therapeutical with

Important:
Emax : "efficacy"
EC50 : "potency"

Advantage of partial agonist/antagonist:

- At high concentration of agonist it works as antagonist
- At low concentration of agonist it works as agonist

The effects of a partial Agonist depends on the concentration of the endogenous ligand. In the presence
of endogenous ligands partial agonists exert antagonistic effects. In the absence of endogenous ligands
partial agonists exert agonistic effects

Antagonists some in different flavours

 Competitive antagonist
Drug and endogenous ligand compete for the same binding site
In Diagram_
Emax remains constant
EC50 shifts to the right

 Non competitive antagonist:

Drug inhibits independently from binding of the ligand to the receptor

Irreversible inhibition of the receptor due to covalent binding of

the antagonist to the receptor itself
Inhibition of a receptor by blocking a downstream signaling
cascade or dowmsteam effector protein

Emax ; EC50 remains constant