Drugs acting via ion channels and transporters Prof. M. Kršiak Department of Pharmacology, Third Faculty of Medicine Ruská 87, Prague 10, Subject: General Pharmacology Charles University in Prague, Third Faculty of Medicine Academic year GENERAL MEDICINE 6-YEAR MASTER‘S STUDY PROGRAMME CVSE3P0012 ID9258

Figure 3.1 Types of target for drug action. Downloaded from: StudentConsult (on 11 November :28 PM) © 2005 Elsevier Four major targets for drug action: Ion Channels Transporters

ION CHANNELS VOLTAGE-GATED CHANNELS LIGAND-GATED CHANNELS Extracellular ligands Calcium channels Sodium channels GABA-gated Cl- channels Nicotinic receptor NMDA receptor Intracellular ligands ATP-sensitive potassium channels

VOLTAGE-GATED CHANNELS Calcium channels - Ca++ flows into cells, necessary for contraction of cardiac and smooth muscles, blocked by CALCIUM CHANNEL BLOCKERS : amlodipin, 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, 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 A receptor Benzodiazep. receptor

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 act by activating nicotinic receptors and thus causing persistent depolarisation of the motor endplate Depolarising blocking agents - suxamethonium

to Ca 2+, as well as to other cations, so activation of NMDA receptors is particularly effective in promoting Ca 2+ entry. LIGAND-GATED CHANNELS Extracellular ligands NMDA (N-methyl-D-aspartate) receptor glutamate receptor Activation of NMDA receptors results in the opening of an ion channel It requires co-activation by two ligands: glutamate and either d-serine or glycine 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 (K ATP channels) In the presence of increased levels of ATP, or by action of sulfonylureas (Antidiabetics ) e.g. glimepiride the K ATP channels close, causing the membrane potential of the cell to depolarize, thus promoting insulin release The K ATP channels in pancreatic beta cells when open, allow potassium ions to flow out the cell. K+K+ K+K+ ATP

TRANSPORTERS „Pumps“ Transport proteins transporters for noradrenaline (NA), serotonin(5-HT), dopamine (DI) P-glycoprotein (P-gp) sodium pump proton pump

sodium pump - Na + /K + ATPase, „ pumps“ Na + from the cell. This is inhibited by c ardiac 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 „Pumps“

Transporters for noradrenaline, serotonine, dopamine inhibited by most Antidepressants – Reuptake inhibitors (RUI), TCA, SSRI etc) Transport proteins

NERVE ENDING (presynaptic) SYNAPTIC CLEFT POSTSYNAPTIC NEURON ↓ ELIMINATION by MAO moklobemid ↓ REUPTAKE imipramin Almost all antidepressants increase supply of monoamine transmitters at postsynaptic receptors

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. P- glycoprotein 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 Transport proteins

Inhibition of P-glycoprotein [and CYP3A4] Grapefruit juice inhibits P-glycoprotein [and CYP3A4] GRAPEFRUIT-DRUG INTERACTIONS 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)

ION CHANNELS VOLTAGE-GATED CHANNELS LIGAND-GATED CHANNELS Extracellular ligands Calcium channels Sodium channels GABA-gated Cl- channels Nicotinic receptor NMDA receptor Intracellular ligands ATP-sensitive potassium channels CALCIUM CHANNEL BLOCKERS LOCAL ANAESTHETICS Summary I: ANXIOLYTICS - Benzodiazepines NEUROMUSCULAR-BLOCKING DRUGS INTRAVENOUS ANAESTHETIC - ketamine ANXIDIABETICS -sulfonylureas

TRANSPORTERS „Pumps“ Transport proteins transporters for noradrenaline (NA), serotonin(5-HT), dopamine (DI) P-glycoprotein (P-gp) sodium pump proton pump CARDIAC GLYCOSIDES -digoxin PROTON PUMP INHIBITORS - omeprazol ANTIDEPRESSANTS- Reuptake Inhibitors GRAPEFRUIT-DRUG INTERACTIONS Summary II: