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Charles University in Prague, Third Faculty of Medicine
GENERAL MEDICINE 6-YEAR MASTER‘S STUDY PROGRAMME
Subject: General Pharmacology
Drugs acting via ion channels and
transporters
Prof. M. Kršiak
Department of Pharmacology, Third Faculty of Medicine
Ruská 87, Prague 10,
Academic year 2013-2014
http://vyuka.lf3.cuni.cz
CVSE3P0012 ID9258
Four major targets for drug action:
Ion Channels
Transporters
Figure 3.1 Types of target for drug action.
Downloaded from: StudentConsult (on 11 November 2013 07:28 PM)
© 2005 Elsevier
VOLTAGE-GATED CHANNELS
Calcium channels
Sodium channels
ION CHANNELS
Extracellular ligands
GABA-gated Cl- channels
Nicotinic receptor
LIGAND-GATED CHANNELS
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-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+
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
„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
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 I:
VOLTAGE-GATED CHANNELS
Calcium channels
Sodium channels
ION CHANNELS
CALCIUM CHANNEL BLOCKERS
LOCAL ANAESTHETICS
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
ANXIDIABETICS -sulfonylureas
Summary II:
„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