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Charles University in Prague, Third Faculty of Medicine Cycle II, Subject: General Pharmacology 2013-2014 MOLECULAR TARGETS FOR DRUG ACTION (and other topics – a review before the final test) Prof. M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague http://vyuka.lf3.cuni.cz/ Molecular Targets For Drug Action FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES 1. RECEPTORS Channel-linked receptors G-protein-coupled receptors Cell Membrane Cellular RECEPTORS Proteinkinase-linked receptors Intracellular - Receptors linked to gene transcription (nuclear receptors) DOPAMINERGIC SYSTEM Clinical potency of antipsychotics correlates with their affinity for D2 receptors Dopamine receptors D1-5 (type D1,5, type D2,3,4 ) They differ in localization (occur mostly in the CNS, post- or presynaptically), they differ in mechanisms of transduction (some are coupled with Gs, some with Gi, some act via adenylyl cyclase, some via phospholipase C, or via ion channels – K, Ca) Synthesis of dopamine: tyrosine → L-DOPA →dopamine → noradrenalin →adrenaline Decarboxylase: L-DOPA→dopamine Decarboxylase inhibitors in combination with levodopa → antiparkinsonics Inhibitors of DA, NA, 5-HT reuptake → antidepressants Elimination of dopamine: extracellulary(in the synaptic cleft): transport protein (reuptakes DA from synapt.cleft to the presynaptic nerve ending) COMT catechol-O-methyl transferase intracellulary: MAO monoamino oxidase Inhibitors of MAO (IMAO) → antidepressants COMT inhibitors→ antiparkinsonics MAJOR DOPAMINERGIC PATHWAYS/SYSTEMS IN CNS Ac, nucleus accumbens; Am, amygdaloid nucleus; C, cerebellum; Hip, hippocampus; Hyp, hypothalamus; P, pituitary gland; SN, substantia nigra; Sep, septum; Str, corpus striatum; VTA, ventral tegmental area; Reward system Chemoreceptor trigger zone Downloaded from: StudentConsult (on 28 October 2013 06:42 PM) © 2005 Elsevier PHARMACOLOGY OF MAJOR DOPAMINERGIC SYSTEMS IN CNS System Mesocortical, mesolimbic Nigrostriatal Clinically most important drugs/ effects* ↓antipsychotics→antipsychotic effect ↓ antipsychotics → extrapyramidal adverse effects Tuberohypophyseal Note ↑ e.g.. levodopa→ psychosis ↑antiparkinsonics (dopaminergic) ↓ antipsychotics →hyperprolactinemia ↑ e.g.bromocriptine→therapy of hyperprolactinemia Reward system ↑addictive drugs (nc. accumbens) Vomiting centre ↓ antiemetics → inhibition of nausea, Chemoreceptor trigger zone in medulla, area postrema vomiting - metoclopramide, domperidon e.g. metamphetamine, morphine, nicotine, etc. ↑ e.g. apomorphine→ vomiting ↓ inhibition, ↑ stimulation * Additional neuromediator systems may participate in these effects (e.g. serotonergic, glutamatergic systems in antipsychotic effects, cholinergic system in antiparkinsonic , antiemetic effects, etc.) Antipsychotics D1 D2 alfa1 H1 mAch 5- Notes HT2A 1st generation 2nd generation chlorpromazine ++ +++ +++ ++ ++ ++ haloperidol + + ++ ++ - ± + clozapine ++ ++ ++ ++ ++ +++ Risk of agranulocytosis! Regular blood counts required. Weight gain. No EPS olanzapine ++ ++ ++ ++ ++ +++ Weight gain. Without risk of agranulocytosis, No EPS risperidone - ++ ++ ++ ++ +++ Weight gain. sulpiride - +++ - - - - Increased prolactin (gynaecomastia) quetiapine - + +++ - + + Weight gain. No EPS aripiprazole - +++ PA + + - ++ Fewer side effects [“Third generation?“dopamine stabilizers] EPS, increased prolactin, hypotension, antimuscarinic effects As chlorpromazine but fewer antimuscarinic effects Significant risk of EPS (atypical) EPS=extrapyramidal side effects, PA = partial agonist Correlation between the clinical potency and affinity for dopamine D2 receptors among antipsychotic drugs. Figure 45.1 Correlation between the clinical potency and affinity for dopamine D2 receptors among antipsychotic drugs. Clinical potency is expressed as the daily dose used in treating schizophrenia, and binding activity is expressed as the concentration needed to produce 50% inhibition of haloperidol binding. (From Seeman P et al. 1976 Nature 361: 717.) Downloaded from: StudentConsult (on 15 December 2012 09:54 AM) © 2005 Elsevier DRUG TREATMENT OF PARKINSON‘S DISEASE Normal extrapyramidal system: Nigrostriatal dopaminergic neurons inhibit cholinergic neurones in striatum Parkinson‘s disease: Death of nigrostriatal dopaminergic neurons → disinhibition of cholinergic neurons The aim of pharmacotherapy is, therefore, to enhance the dopaminergic transmission and to reduce the cholinergic transmision ANTIPARKINSONICS Dopaminergic antiparkinsonics: Levodopa (+ inhibitors of dekarboxylase in the periphery:carbidopa, benserazid) IMAO (selegiline) Agonists of dopamine (ropinirol, pramipexol) Other: amantadine, inhibitors of COMT Anticholinergic antiparkinsonics: biperiden ANTIDOPAMINERGIC ANTIEMETICS: metoclopramide, domperidone Also gastroprokinetic effect common adverse reactions: extrapyramidal akathisia, dystonia SEROTO(NI)NERGIC SYSTEM Serotonin receptors 14 subtypes (!) in 7 classes (5-HT1-7) Almost all are metabotropic: They differ in localization (occur mostly in the CNS, post- or pre-synaptically), but also in the periphery. They differ in mechanisms of transduction (are coupled with various G proteins, some act via adenylyl cyclase, some via phospholipase C, or via ion channels –Ca) Only 5-HT3 receptors are ionotropic Synthesis of serotonin/5hydroxytryptamine(5-HT): tryptofan → 5-hydroxytryptofan →5-hydroxytryptamine Reuptake inhibitors of 5-HT → SSRI and some other antidepressants Elimination of serotonin: extracellular (in synaptic cleft): transport protein (reuptakes 5-HT back in the nerve terminal) intracelular: MAO monoamino oxidase Inhibitors of MAO (IMAO) → antidepressants MAJOR SEROTONERGIC PATHWAYS/SYSTEMS IN CNS: Downloaded from: StudentConsult (on 28 October 2013 08:26 AM) © 2005 Elsevier FUNCTION OF SEROTONERGIC SYSTEM IN THE BRAIN: regulation of emotion (e.g. depression, anxiety), sleep, body temperature, eating, sexual functions, pain, perception (halucinations), nauseavomiting IN THE PERIPHERY: ↑ peristalsis in the GIT, vasoconstriction, ↑↓ BP, ↑platelet agregation CLINICALLY IMPORTANT DRUGS ACTING VIA SEROTONERGIC SYSTEM: TRIPTANS (5-HT1D agonists)- e.g. sumatriptan – ANTIMIGRAINE DRUGS „SETRONS“ (5-HT3 antagonists)- e.g. ondansetron – ANTIEMETICS SSRI (selective serotonin reuptake inhibitors) e.g. fluoxetin, citalopram, sertralin, ANTIDEPRESSANTS and in ANXIETY DISORDERS Some other antidepressant can also inhibit reuptake of seotonin IMAO (inhibitors of MAO) – ANTIDEPRESSANTS e.g.. moclobemide effective as SDA (serotonin dopamine antagonists)atypic antipsychotics e.g. risperidone HISTAMINERGIC SYSTEM Histamine receptors, H1,H2, H3, (H4) All are metabotropic They occur in the brain and in the periphery Synthesis, elimination of histamine – not utilized in applied pharmacology Drugs producing release of histamine – atracurium morphine, CLINICALLY IMPORTANT DRUGS ACTING VIA HISTAMINERGIC SYSTEM: H1 antagonists 1. generation → sedation, drowseness, e.g. promethazine, antiemetics – dimenhydrinate in motion sickness IN THE BRAIN: H1 –↑ vigility, H3 – presynaptic ↓ release of neuromediators H3 antagonist betahistine→ vasodilatation in the inner ear – antivertigo drug ( Méniere‘s disease) H1 antagonists – drugs for allergic rhinitis, urticaria - H1 antagonists 2. generation (nonsedating) - cetirizin IN THE PERIPHERY: H1 – mast cells, vasodilatation, ↑ capilar permeability, alergic reactions (itching, urticaria, allergic rhinitis), bronchoconstriction H2 – parietal cell in stomach mucose (↑ sekretion HCl) H2 antagonists – drugs for peptic ulcer disease – ranitidine, famotidine Molecular Targets For Drug Action FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES VOLTAGE-DEPENDENT CHANNELS Calcium channels Sodium channels ION CHANNELS Extracellular ligands GABA-gated Cl- chann Nicotinic receptor LIGAND-GATED CHANNELS NMDA receptor Intracellular ligands ATP-sensitive potassium chan VOLTAGE-DEPENDENT CHANNELS Calcium channels - Ca++ flows into cells, necessary for contraction of cardiac and smooth muscles, blocked by CALCIUM CHANNEL BLOCKERS : amlodipine, verapamil –used in hypertension, angina pectoris, dysrytmias Sodium channels - Na+ flows into cells, necessary for propagation of action potentials in excitable cells, blocked by LOCAL ANAESTHETICS : procaine, lidocaine, articaine, bupivacaine, some Antiepileptics: phenytoin, some Antidysrhytmics : lidocaine LIGAND-GATED CHANNELS Extracellular ligands GABA-gated Cl- channels –Benzodiazepines as modulators (ANXIOLYTICS) –, diazepam, alprazolam, midazolam GABA-gated Cl- channels Cl- GABAA receptor Benzodiazep. receptor Cl- LIGAND-GATED CHANNELS Extracellular ligands Nicotinic receptor NEUROMUSCULAR-BLOCKING DRUGS • Non-depolarising blocking agents, e.g. atracurium act as competitive antagonists at the nicotinic receptors of the motor endplate • Depolarising blocking agents - suxamethonium act by activating nicotinic receptors and thus causing persistent depolarisation of the motor endplate LIGAND-GATED CHANNELS Extracellular ligands NMDA (N-methyl-D-aspartate) receptor glutamate receptor It requires co-activation by two ligands: glutamate and either d-serine or glycine Activation of NMDA receptors results in the opening of an ion channel to Ca2+, as well as to other cations, so activation of NMDA receptors is particularly effective in promoting Ca2+ entry. NMDA receptor antagonist – ketamine (General anaesthetic – intravenous) produces 'dissociative' anaesthesia, in which the patient may remain conscious although amnesic and insensitive to pain . Sometimes psychotomimetic effects LIGAND-GATED CHANNELS Intracellular ligands ATP-sensitive potassium channels (KATP channels) K + See also Fig. 30.3 Golan et al. 2012, p. 528 ATP K + The KATP channels in pancreatic beta cells when open, allow potassium ions to flow out the cell. In the presence of increased levels of ATP, or by action of sulfonylureas (Antidiabetics) e.g. glimepiride the KATP channels close, causing the membrane potential of the cell to depolarize, thus promoting insulin release Molecular Targets For Drug Action FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES 3. CARRIER MOLECULES • „pumps“ sodium pump - Na+/K+ ATPase, „pumps“ Na+ from the cell, inhibited by cardiac glycosides proton pump - H+/K+ ATPase, „pumps“ H+ from the cell , proton pump inhibitors • transporters transporters for noradrenaline, serotonine inhibited by most antidepressants (RUI, TCA, SSRI etc) „Pumps“ sodium pump proton pump TRANSPORTERS Transport proteins transporters for noradrenaline (NA), serotonin(5-HT), dopamine (DI) P-glycoprotein (P-gp) „Pumps“ sodium pump - Na+/K+ ATPase, „pumps“ Na+ from the cell. This is inhibited by cardiac glycosides - digoxin – which lowers extrusion of Ca++ from cardiac muscle -> the intracellular concentration of Ca++ is increased -> force of cardiac muscle contraction is increased proton pump - H+/K+ ATPase, „pumps“ H+ from the cell in the stomach mucosa – increased production of HCl, inhibited by,Proton pump inhibitors omeprazol used in peptic ulcer Summary : VOLTAGE-GATED CHANNELS Calcium channelsCALCIUM CHANNEL BLOCKERS Sodium channelsLOCAL ANAESTHETICS ION CHANNELS Extracellular ligands GABA-gated Cl- channels ANXIOLYTICS - Benzodiazepines LIGAND-GATED CHANNELS Nicotinic receptor NEUROMUSCULAR-BLOCKING DRUGS NMDA receptor INTRAVENOUS ANAESTHETIC - ketamine Intracellular ligands ATP-sensitive potassium channels ANTIDIABETICS -sulfonylureas Transport proteins Transporters for noradrenaline, serotonine, dopamine inhibited by most Antidepressants – Reuptake inhibitors (RUI), TCA, SSRI etc) NERVE ENDING (presynaptic) SYNAPTIC CLEFT POSTSYNAPTIC NEURON ↓ REUPTAKE imipramin ↓ ELIMINATION by MAO moklobemid Almost all antidepressants increase supply of monoamine transmitters at postsynaptic receptors Transport proteins P-glycoprotein It is an efflux pump capable of transporting a wide range of compounds from the intracellular space into the extracellular matrix. Intestinal P-glycoprotein reduces effective drug absorption by actively transporting drugs back into the intestinal lumen. Pglycoprotein in the liver and kidneys promotes excretion of drugs from the blood stream into the bile and urine, respectively. In addition, P-glycoprotein is present at the blood– brain barrier, where it reduces drug access to the CNS. P-glycoprotein can be induced and inhibited by other drugs Inhibition of P-glycoprotein [and CYP3A4] GRAPEFRUIT-DRUG INTERACTIONS Grapefruit juice inhibits P-glycoprotein [and CYP3A4] The P-gp and CYP3A4 are located in the enterocytes (intestinal absorptive cells) → first-pass effect Grapefruit juice by inhibition of P-glycoprotein [and CYP3A4] can markedly increase the bioavailability and toxicity of some drugs, particularly (most hazardous) in: amiodarone (arrythmias) simvastatin, lovastatin (rhabdomyolysis) Summary : „Pumps“ sodium pump CARDIAC GLYCOSIDES -digoxin proton pump PROTON PUMP INHIBITORS - omeprazol TRANSPORTERS Transport proteins transporters for noradrenaline (NA), serotonin(5-HT), dopamine (DI) ANTIDEPRESSANTS- Reuptake Inhibitors P-glycoprotein (P-gp) GRAPEFRUIT-DRUG INTERACTIONS Molecular Targets For Drug Action FOUR MAJOR TARGETS FOR DRUGS: 1. RECEPTORS 2. ION CHANNELS 3. CARRIER MOLECULES 4. ENZYMES Enzyme inhibition by drugs Other drug-enzymes interactions Many drugs are targeted on enzymes and mostly act by inhibiting them: Therapeutic groups, indications Enzymes Inhibitors Cyclo-oxygenase aspirin, ibuprofen, diclofenac Monoamine oxidase moclobemide Acetylcholinesterase neostigmine, rivastigmin Parasympathomimetics, Anti-dementiadrugs Angiotensin-converting enzyme enalapril, ramipril Antihypertensives HMG-CoA reductase simvastatin, atorvastatin Lipid modifying agents; (hypercholesterolaemia) Xanthinoxidase allopurinol Drugs inhibiting uric acid production Phosphodiesterase type V sildenafil Drugs used in erectile dysfunction Dihydrofolate reductase trimethoprim Antiinflammatory and antirheumatic agents, analgesics Antidepressants Antimicrobial agents methotrexate Antimetabolites, folic acid analogues Neuroamidase oseltamivir Antivirals ( influenza virus) Thymidine kinase aciclovir Antivirals (Herpes virus) HIV protease saquinavir Antivirals (HIV), protease inhibitors An enzyme inhibitor is a molecule which binds to enzymes and decreases their activity Drugs can inhibit enzymes reversibly (usually a competitive inhibition by non-covalent binding) or irreversibly (enzyme is usually changed chemically by covalent binding) Competitive inhibition is a form of enzyme inhibition where binding of the inhibitor to the active site on the enzyme prevents binding of the substrate and vice versa. Often, the drug molecule is a substrate analogue (e.g. captopril, acting on angiotensin-converting enzyme) Irreversible inhibitors usually react with the enzyme and change it chemically (e.g. via covalent bond formation). These inhibitors modify key amino acid residues needed for enzymatic activity (e.g. aspirin, acting on cyclo-oxygenase) Reversible competitive inhibition of enzyme (inhibition of ACE by captopril):: The active site of angiotensin-converting enzyme. [A] Binding of angiotensin I. [B] Binding of the inhibitor captopril, which is an analogue of the terminal dipeptide of angiotensin I. Downloaded from: StudentConsult (on 6 November 2013 02:30 PM) © 2005 Elsevier Irreversible non-competitive inhibition of enzyme (inhibition of COX-1 or COX-2 by aspirin): Aspirin acetylates serine residue in the active site of the COX enzyme This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen, which are reversible inhibitors). Irreversible inhibition of enzyme: Recovery is possible only by synthesis of a new enzyme Drug - cytochrome P450 interactions Cytochrome P450 (CYP) enzymes The most important enzymes involved in drug interactions are members of the cytochrome P450 (CYP) system that are responsible for many of the phase 1 biotransformations of drugs. These metabolic transformations, such as oxidation, reduction and hydrolysis, produce a molecule that is suitable for conjugation. Those of importance in the metabolism of psychotropic drugs are CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, the last being responsible for the metabolism of more than 90% of psychotropic drugs that undergo hepatic biotransformation. a high affinity for one particular CYP enzyme but most are oxidised by more than one Many psychotropic drugs have Genetic effects: Genetic polymorphism The CYP enzymes that demonstrate pharmacogenetic polymorphism include CYP2C9, CYP2C19 and CYP2D6. In clinical practice, the polymorphism produces distinct phenotypes, described as poor metabolisers, extensive metabolisers (the most common type) and ultra-rapid metabolisers. Drug effects: CYP enzymes can be induced or inhibited by drugs or other biological substances, with a consequent change in their ability to metabolise drugs that are normally substrates for those enzymes. Enzymatic induction enzymatic induction can cause a decrease as well as an increase in the drug’s effect The onset and offset of enzyme induction take place gradually, usually over 7–10 days The most important are inducers of CYP3A4 and include carbamazepine, phenobarbital, phenytoin, rifampicin and St John’s wort (Hypericum perforatum). An example of an interaction in psychiatric practice is the reduced efficacy of haloperidol (or alprazolam) when carbamazepine is started, resulting from induction of CYP3A4. Enzymatic inhibition enzymatic inhibition can cause an increase as well as a decrease in the drug’s effect Inhibition is usually due to a competitive action at the enzyme’s binding site. Therefore, in contrast to enzyme induction, the onset and offset of inhibition are dependent on the plasma level of the inhibiting drug Inhibition of CYP enzymes is the most common mechanism that produces serious and potentially life-threatening drug interactions Most hazardous drug interactions involve inhibition of enzyme systems, which increases plasma concentrations of the drugs involved, in turn leading to an increased risk of toxic effects. 4. ENZYMES sites of action of about 30% of drugs Drugs inhibiting the enzyme: Cholinesterase Cholinesterase Inhibitors Non-Steroid Antiinflammatory Drugs Monoamine oxidase IMAO Cyclo-oxygenase Angiotensinconverting enzyme ACE Inhibitors HMG-CoA reduktase Statins and other - e.g. recently phosphodiesterase sildenafil (VIAGRA) degradating cGMP neuroamidase oseltamivir (TAMIFLU) stops the virus from chemically cutting ties with its host cell Molecular mechanisms of drug effects - summary FOUR MAJOR TARGETS FOR DRUGS: Examples of drugs:: Channel-linked receptors perif. muscle relaxants membr. about 45% of drugs,e.g. G-protein coupled receptors beta-blockers 1. RECEPTORS intracelul. Proteinkinase-linked receptors c. - Calcium chan. Voltage gated - Sodium chan. 2. ION CHANNELS imatinib Calcium ch. blockers lok. anaesthetetics Ligand-gated, G-prot.,… „pumps“ 3. CARRIER MOLECULES - sodium cardiac glykosides - proton PP inhibitors transporters 4. ENZYMES ACE, MAO, COX, HMG-CoA reductase antidepressants ACE inhibitors, IMAO