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Description : Check out this medical presentation on Pharmacology, which is titled "General Pharmacodynamics", to know about the general pharmacodynamics.

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GENERAL PHARMACO- DYNAMICS Assoc. Prof. I. Lambev Medical University of Sofia www.medpharm-sofia.eu
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1. PHARMACO- DYNAMICS OF DRUGS - DEFINITION
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Pharmacodynamics: (1) How the drugs act on the body? (2) The mechanism of action of drug and its effects.
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The mechanism of action represents the interaction between drug molecules and biological structures of the organism.
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The effect represents the final results from the drug action. The effect can be observed and measured, but not the action.
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50 100 150 1 min (Effect or action?) ... Blood pressure {mm Hg} ACh 2 mg i.v. ACh 50 mg Hypotensive effect of acetylcholine (ACh) ACh
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2. SITES OF DRUG ACTION They can be divided into: specific and non-specific
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osmotic diuretics Mannitol osmotic laxative drugs Duphalac MgSO4 antiacids (antacids) NaHCO3 Non-specific action have:
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Specific action It is connected with interaction of the drug with specific site(s) on the cell membrane or inside the cell.
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3. MOLECULAR ASPECTS OF SPECIFIC DRUG ACTION How drugs act?
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Main specific targets for drug actions are:  DNA  microbial organelles  target macroproteins
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Alkylating agents bind covalently to sites within the DNA such as N7 of guanine and block DNA-replication.  DNA
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Doxy- cyclin Peni- cillins Nystatin Rifampicin  Microbial organelles
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receptors (> 150 types with many subtypes) ion channels enzymes carrier molecules  Target macroproteins
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P. Ehrilch (1854-1915) “Corpora non agunt nisi fixata” (a drug will not work unless it is bound).
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are the regulatory macroproteins – sensitive elements in the system of chemical commu- nications that coordinates the function of the different cells in the body. A. Receptors
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Receptors bind to Endogenous ligands (such as): - neurotransmitters (mediators) - hormones - autacoids (tissue mediators) - grouth factors - inhibitory factors, etc. Exogenous ligands: - many (but not all) drugs - some other xenobiotics
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Partial Agonist (unfull antagonist) The main receptor ligands are agonists - activate the receptors antagonists - block the receptors (Full) (Full)
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The interaction between the ligand and the receptor does not involve covalent bonds but weaker, reversible forces, such as: Ionic bonding Hydrogen bonding Hydrophobic bonding Van der Waals forces.
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The receptors have a three-dimensional organization in space and require the different aspects of a ligand to be pre- sented in the correct 3-D configuration (like fitting a hand into the glove).
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The numbers of receptors may be altered during chronic drug treatment, with either an increase in receptor numbers (up-regulation) or a decrease (down-regulation). The therapeutic effect of b-blockers develops slowly. This is probably related to adaptive regulation of receptor numbers.
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There are pre- and postsynaptic receptors. Presynaptic receptors may inhibit or increase transmitter release (feedback mechanism: +/-)
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a Presynaptic receptors in adrenergic synapse and their role in the regulative negative and positive feedback
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There are 4 main types of recep- tors, according to their molecu- lar structure and the nature of receptor-effector linkage. The location of type 1, 2 and 3 receptors is on (into) the cell membranes; type 4 - into the cell nucleus.
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 Ionotropic receptors (ligand-gated ion channel receptors) These receptors are involved mainly in fast synaptic transmission. They are proteins containing several transmembrane segments arranged around a central channel. Ligand binding and channel opening occur on a millisecond time-scale.
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Ligand-gated ion channel receptors Effector Coupling Time scale Examples ion channel (Ca2+, Na+, K+, C–) direct milliseconds nACh-receptors GABAA-receptors 5-HT3-receptors
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N-receptor: 5 subunits
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GABAA- receptors
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Antiseizure drugs, induced reduction of current through T-type Ca2+ channels. Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006) (-) (-)
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 G-protein-coupled receptors All comprise 7 membrane-spanning segments. One of the intracellular loops is larger than the others and interacts with G-protein.
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The G-protein is a membrane protein comprising 3 subunits (, , ). The alpha-subunit possessing GTP-activity. When the agonists occupy a receptor, the alpha-subunit dissociates and is then free to activate a target (effector): - enzyme (AC, GC, PLC) - Ca2+ ion channels
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AC (adenylate cyclase) catalyses formation on the intracellular messenger (cAMP). cAMP activates various protein kinases (PKA and others) which control cell function in many different ways by causing phos- phorylation of various enzymes, carriers and other proteins.
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b-ad- reno- ceptor 7 sub- units
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Regulation of Intracelullular calcium
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Ryanodine receptors (RyRs) form a class of intracellular calcium channels in various forms of excitable tissue like muscles and neurons. They regulate the releasing of calcium in animal cells. There are multiple isoforms of RyRs: RyR1 is expressed in skeletal muscle RyR2: in myocardium (heart muscle) RyR3: in the brain.
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RyRs are named after the plant alkaloid ryanodine, to which they show high affinity. Ryanodine is a poisonous alkaloid found in the South American plant Ryania speciosa. Ryanodine
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Adrenaline (b1&b2) Gs AC ATP cAMP PKA Effects Ex In (+)
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PLC (phospholipase C) catalyses the formation of two intracellular messen- gers - InsP3 and DAG, from memb- rane phospholipids. InsP3 (inositol-triphosphate) increases free cytosolic calcium by releasing Ca2+ from the endoplasmic reticulum. Free calcium initiates contractions, se- cretion, membrane hyperpolarization DAG activates protein kinase C (PKC).
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Noradrenaline (a1) PLC PIP2 IP3 Ca2+ DAG PKC ADP ATP Ex In (+) Gs
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Effector Second messenger Protein- kinase AC cAMP PKA PLC IP3 DAG PKC GC cGMP PKG
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Effector Coupling Time scale Examples Enzyme (AC, GC, PLC); Ca2+ channels G-protein seconds AT1-receptors mACh-receptor Adrenoceptors (a, b) H1 – H5-receptors Opioid receptors (m, k, d) G-protein-coupled receptors
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ppt slide no 42 content not found
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Incorporate thyrosine kinase in their intracellular domain. These receptors are involved mainly in events controlling phosphorilation, cell growth and differentiation.  Tyrosine-kinase receptors
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Kinase-linked receptors Effector Coupling Time scale Examples thyrosine kinase direct minutes (to hours) Insulin receptor ANP receptor growth factors rec.
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They are nuclear proteins, so ligands must first enter cells. Receptors have DNA-binding domain. Stimulation of these receptors increase protein synthesis by the activation of DNA transcription.  Nuclear receptors
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Nuclear (steroid/thyroid) receptors Effector Coupling Time scale Examples gene transcription via DNA hours steroid receptors thyroid receptors vitamin D receptors
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a) Cytoplasmic receptors: Steroid hormones, Calcitriol Steroide hormone diffuse into the cell. When activated, the receptors translocate to the nucleus where they can upregulate gene transcription by action on specific DNA response elements and recruiting co-activator proteins.
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b) Directly at nuclear receptors: Thyroid hormones (T3, T4) T3 or T4 penetrate the nucleus Combine with their receptors Alters DNA-RNA mediated protein synthesis
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Types of receptor-effector linkage (R = receptor; G = G-protein; E = enzyme)
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B. Ion channels Ex In LAH+ (local anaesthetics) block Na+ channels.
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C. Enzymes Drug Action on enzyme Galantamine (-) ACh-esterase Digoxin (-) Na+/K+-ATP-ase Aspirin (-) COX-1/COX-2 Obidoxim (+) ACh-esterase
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Na+/K+ АТФ-аза Na+/Ca2+ обмен Ca2+ 3Na+ 3Na+ 2K+ DIGOXIN Ex In (–)
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D. Carrier molecules
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4. DOSE-RESPONSE RELATIONSHIPS (introduction)
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Most drug produce graded dose-related effects, which can be plotted as a dose response curve. Such curves are often hyperbolic (a), but they can be conveniently plotted on semi-logarithmic paper to give sigmoidal shape (b).
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Plotted dose- response curves: (a) arith- metically (b) semi- logarith- mically Sigmoidal shape (b) Hyperbolic shape (a)
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The method of plotting dose-response curves facilitates quantitative analysis of: full agonists, which produce graded responses up to maximum value; antagonists, which produce no response on their own but antagonize the response to an agonist; partial agonists, which produce some response but to a lower maximum than that of a full agonist and antagonize its effect.
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The affinity of a drug is its ability to bind to the receptor. The intrinsic activity of a drug is its ability after binding to the receptor to produce effect. The efficacy of a drug is its ability to produce maximal response. The selectivity of a drug is the extent to which it acts preferentially on particular receptor types.
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Affinity Intrinsic Efficacy Selec- activity tivity Agonists + + ++ + + (Morphine) Antagonists + - - + (Naloxon) Partial agonists (Pentazocine) + + - + Drugs
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Bisoprolol Metoprolol Nebivolol Propranol 1/2-blocking activity -blockers 50 25 293 1,9 S e l e c t i v i t y
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Dose-response curve of two full agonists (A, B) of different potency, and a partial agonist (C).
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In the clinical situation dose-response curves are influenced by many factors including genetic, as well as age, weight, nutrition; psychological and social factors (that strongly influence compliance and placebo effect).
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5. FACTORS, AFFECTING DRUG CONCENTRATION AT THE SITE OF ITS ACTION
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