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' Corpora non agunt nisi fixata ‘ „a drug will not work unless it is bound ” (Ehrlich). Pharmacodynamics Mechanism of drug action Dependent and structure – independent drug action Definition and classification of receptors Quantitative aspects of drug receptor interaction.
„a drug will not work unless it is bound”
Mechanism of drug action
Dependent and structure – independent
Definition and classification of receptors
Quantitative aspects of drug receptor
(Major Types of Drug Receptors)
-Ligand-gated ion channels (1/1)
-G-protein–coupled receptors (1/2)
-Receptor-activated tyrosine kinases (1/3)
-Intracellular nuclear receptors (1/4)
(Major Types of Drug Receptors)
Ligand-gated ion channels
Acetylcholine interacts with a nicotinic receptor that is a nonspecific Na+/K+ transmembrane ion channel.
Nicotinic receptors are localizedat
-the motor endplate of the myoneural (neuromuscular) junctions of somatic nerves and skeletal muscle (NM),
-autonomic ganglia (NG), including the adrenal medulla, and
-certain areas in the brain.
- ACh interacts with nicotinic receptors
- open channels
- permit passage of ions, mostly Na+
- Na+ current
- membrane depolarization
- resulting in the release of Ca2+
- muscle contraction
- hydrolysis of ACh by AChE results in muscle cell repolarization
The biologic activity of the receptors is mediated via interaction with a number of G (GTP binding)-proteins.
Gαs(Gαstimulatory)-coupled receptors (2/1/1)
Gαi (Ginhibitory)-coupled receptors (2/1/2)
Gq (and G11)-coupled receptors (2/1/3)
Epinephrin (adrenalin) binds its receptor, that associates with an heterotrimeric G protein. The G protein associates with adenylate cyclase that converts ATP to cAMP, spreading the signal.
β-adrenoceptor, which when activated by ligand binding (e.g., epinephrine) exchanges GDP for GTP. This facilitates the migration of Gαs (Gαstimulatory) and its interaction with adenylyl cyclase (AC). Gαs-bound AC catalyzes the production of cAMP from ATP; cAMP activates protein kinase A, which subsequently acts to phosphorylate and activate a number of effector proteins. The γ dimer may also activate some effectors. Hydrolysis of the GTP bound to the Gα to GDP terminates the signal.
- H2-receptors are found in the brain, heart, vascular smooth muscles, leukocytes, and parietal cells
- response of H2-receptors is coupled via Gαs
- activation of H2-receptors increases gastric acid production, causes vasodilation, and generally relaxes smooth muscles
Gαi (Ginhibitory)-coupled receptors
Ligand binding (e.g., somatostatin), to Gαi (Gαinhibitory)-coupled receptors, similarly exchanges GTP for GDP, but Gαi inhibits adenylyl cyclase, leading to reduced cAMP production.
- α2-receptors are located primarily in prejunctional adrenergic nerve terminals
- prejunctional inhibition of release of norepinephrine and other neurotransmitters (α2)
- α2-Receptorsactivate (Gi) (like muscarinic M2-cholinoceptors)
Gq (and G11)-coupled receptors
Gq (and G11) interact with ligand (e.g., serotonin)-activated receptors and increase the activity of phospholipase C (PLC). PLC cleaves the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG activates protein kinase C, which can subsequently phosphorylate and activate a number of cellular proteins; IP3 causes the release of Ca2+ from the endoplasmic reticulum into the cytoplasm, where it can activate many cellular processes.
- H1-receptors are found in the brain, heart, bronchi, gastrointestinal tract, vascular smooth muscles, and leukocytes.
- H1-receptors activation causes an increase in diacylglycerol and intracellular Ca2.
- Activation of H1-receptors in the brain increases wakefulness.
- Activation of H1-receptors in vessels causes vasodilation and an increase in permeability.
- α1-receptors are located in postjunctional effector cells, vascular smooth muscle (mainly excitatory)
- α-adrenoceptors mediate vasoconstriction (α1), gastrointestinal relaxation (α1), mydriasis (α1)
- α1-receptorsactivate (Gq) (like muscarinic M1 and M3 cholinoceptors)
Receptor-activated tyrosine kinases
Many growth-related signals (e.g., insulin) are mediated via membrane receptors that possess intrinsic tyrosine kinase activity. Ligand binding causes conformational changes in the receptor. The liganded receptors then autophosphorylate tyrosine, and activated.
Intracellular nuclear receptors
Ligands (e.g., cortisol) for nuclear receptors are lipophilic and can diffuse rapidly through the plasma membrane. In the absence of ligand, nuclear receptors are inactive because of their interaction with chaperone proteins such as heat-shock proteins like HSP-90. Binding of ligand promotes structural changes in the receptor that facilitate dissociation of chaperones, entry of receptors into the nucleus, hetero- or homodimerization of receptors, and high-affinity interaction with the DNA of target genes.
(2) Alteration of the activity of enzymes
Neostigmine and physostigmine are indirect-acting parasympathomimetic agents inhibit AChE and increase ACh levels at both muscarinic and nicotinic cholinoceptors.
(3) Antimetabolite action
(4) Nonspecific chemical or physical
Antacids are weak bases that partially neutralize gastric acid.Antacids reduce the pain associated with ulcers and may promote healing.
Antacids, which are used to treat peptic ulcer disease. Unlike antiulcer agents that bind to receptors involved in the physiologic generation of gastric acid, antacids act nonspecifically by absorbing or chemically neutralizing stomach acid. Examples of these agents include bases such as
-Sodium bicarbonate (NaHCO3)
-Magnesium hydroxide (Mg(OH)2)
Osmotic agents include both salt-containing and salt-free agents.
-Salt-containing osmotic agents: magnesium sulphate, magnesium citrate, magnesium hydroxide, sodium phosphates.
-Salt-free osmotic agents: glycerine, lactulose.
One class of diuretics, alters water and ion balance not by binding to ion channels or G protein-coupled receptors, but by changing the osmolarity in the nephron directly. The sugar mannitol is secreted into the lumen of the nephron and increases the osmolarity of the urine to such a degree that water is drawn from the peritubular blood into the lumen. This fluid shift serves to increase the volume of urine while decreasing the blood volume.
Metal-chelating agents. Metal-chelating agents usually contain two or more electronegative groups that form stable coordinate-covalent complexes with cationic metals that can then be excreted from the body.
-EDTA (ethylenediamine tetraacetic acid). EDTA is an efficient chelator of many transition metals. Because it can also chelate body calcium, EDTA is administered intramuscularly or by intravenous (IV) infusion as the disodium salt of calcium.
-Deferoxamine is a specific iron-chelating agent that binds with ferric ions to form ferrioxamine; it also binds to ferrous ions.