molecular targets for drug action (and other topics – a review before the final test) prof. m....
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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
Charles University in Prague, Third Faculty of Medicine
Cycle II, Subject: General Pharmacology2013-2014
http://vyuka.lf3.cuni.cz/
FOUR MAJOR TARGETS FOR DRUGS:
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
4. ENZYMES
Molecular Targets For Drug Action
Cellular RECEPTORS
Cell Membrane
Intracellular - Receptors linked to gene transcription (nuclear receptors)
Channel-linked receptors
G-protein-coupled receptors
Proteinkinase-linked receptors
1. RECEPTORS
Dopamine receptors D1-5 (type D1,5, type D2,3,4 )
They differ in localization (occur mostly in the CNS, post- or pre-synaptically), 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
Elimination of dopamine:extracellulary(in the synaptic cleft):
transport protein (reuptakes DA from synapt.cleft to the presynaptic nerve ending)
COMT catechol-O-methyl transferaseintracellulary: MAO monoamino oxidase
DOPAMINERGIC SYSTEMClinical potency of antipsychotics correlates with their
affinity for D2 receptors
Decarboxylase inhibitors in combination with levodopa →
antiparkinsonics
COMT inhibitors→ antiparkinsonics
Inhibitors of MAO (IMAO) → antidepressants
Inhibitors of DA, NA, 5-HT reuptake → antidepressants
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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
MAJOR DOPAMINERGIC PATHWAYS/SYSTEMS IN CNS
PHARMACOLOGY OF MAJOR DOPAMINERGIC SYSTEMS IN CNS
System Clinically most important drugs/ effects* Note
Mesocortical, mesolimbic
↓antipsychotics→antipsychotic effect ↑ e.g.. levodopa→ psychosis
Nigrostriatal ↓ antipsychotics → extrapyramidal adverse effects
↑antiparkinsonics (dopaminergic)
Tuberohypophyseal ↓ antipsychotics →hyperprolactinemia ↑ e.g.bromocriptine→therapy of hyperprolactinemia
Reward system(nc. accumbens)
↑addictive drugs e.g. metamphetamine, morphine, nicotine, etc.
Vomiting centre Chemoreceptor trigger zone in medulla, area postrema
↓ antiemetics → inhibition of nausea, vomiting - metoclopramide, domperidon
↑ 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-HT2A Notes
1st generation
chlorpromazine ++ +++ +++ ++ ++ + + EPS, increased prolactin, hypotension, antimuscarinic effects
haloperidol + + ++ ++ - ± + As chlorpromazine but fewer antimuscarinic effects
2nd generation
(atypical)
clozapine ++ ++ ++ ++ ++ +++ Risk of agranulocytosis! Regular blood counts required. Weight gain. No EPS
olanzapine ++ ++ ++ ++ ++ +++ Weight gain. Without risk of agranulocytosis, No EPS
risperidone - ++ ++ ++ ++ +++ Weight gain. Significant risk of EPS
sulpiride - +++ - - - - Increased prolactin (gynaecomastia)
quetiapine - + +++ - + + Weight gain. No EPS
aripiprazole - +++ PA
+ + - ++ Fewer side effects [“Third generation?“- dopamine stabilizers]
EPS=extrapyramidal side effects, PA = partial agonist
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.)
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Correlation between the clinical potency and affinity for dopamine D2 receptors among antipsychotic drugs.
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
Dopaminergic antiparkinsonics:Levodopa (+ inhibitors of dekarboxylase in the periphery:carbidopa, benserazid)
IMAO (selegiline)
Agonists of dopamine (ropinirol, pramipexol)
Other: amantadine, inhibitors of COMTAnticholinergic antiparkinsonics: biperiden
ANTIPARKINSONICS
ANTIDOPAMINERGIC ANTIEMETICS:
metoclopramide, domperidone
Also gastroprokinetic effectcommon adverse reactions: extrapyramidal - akathisia, dystonia
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 ionotropicSynthesis of serotonin/5-hydroxytryptamine(5-HT): tryptofan → 5-hydroxytryptofan →5-hydroxytryptamine
Elimination of serotonin:extracellular (in synaptic cleft):
transport protein (reuptakes 5-HT back in the nerve terminal)
intracelular: MAO monoamino oxidaseInhibitors of MAO (IMAO) → antidepressants
Reuptake inhibitors of 5-HT → SSRI and some other antidepressants
SEROTO(NI)NERGIC SYSTEM
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MAJOR SEROTONERGIC PATHWAYS/SYSTEMS IN CNS:
FUNCTION OF SEROTONERGIC SYSTEM
IN THE BRAIN: regulation of emotion (e.g. depression, anxiety), sleep, body temperature, eating, sexual functions, pain, perception (halucinations), nausea-vomiting
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
SSRI (selective serotonin reuptake inhibitors) e.g. fluoxetin, citalopram, sertralin,
effective as ANTIDEPRESSANTS and in ANXIETY DISORDERSSome other antidepressant can also inhibit reuptake of seotoninIMAO (inhibitors of MAO) – ANTIDEPRESSANTS e.g.. moclobemide
„SETRONS“ (5-HT3 antagonists)- e.g. ondansetron – ANTIEMETICS
SDA (serotonin dopamine antagonists)atypic antipsychotics e.g. risperidone
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
HISTAMINERGIC SYSTEM
Drugs producing release of histamine – morphine, atracurium
IN THE BRAIN:H1 –↑ vigility, H3 – presynaptic ↓ release of neuromediators
H1 antagonists 1. generation → sedation, drowseness, e.g. promethazine, antiemetics – dimenhydrinate in motion sickness
IN THE PERIPHERY:H1 – mast cells, vasodilatation, ↑ capilar permeability, alergic reactions (itching, urticaria, allergic rhinitis), bronchoconstriction
H2 – parietal cell in stomach mucose (↑ sekretion HCl)
H1 antagonists – drugs for allergic rhinitis, urticaria - H1 antagonists 2. generation (nonsedating) - cetirizin
H2 antagonists – drugs for peptic ulcer disease – ranitidine, famotidine
H3 antagonist betahistine→ vasodilatation in the inner ear – antivertigo drug ( Méniere‘s disease)
CLINICALLY IMPORTANT DRUGS ACTING VIA HISTAMINERGIC SYSTEM:
FOUR MAJOR TARGETS FOR DRUGS:
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
4. ENZYMES
Molecular Targets For Drug Action
ION CHANNELS
VOLTAGE-DEPENDENT 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-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
Cl-
Cl-
GABA-gated Cl- channels
GABAA 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 Ca2+, as well as to other cations, so activation of NMDA receptors is particularly effective in promoting Ca2+ entry.
LIGAND-GATED CHANNELSExtracellular 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 (KATP channels)
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
The KATP channels in pancreatic beta cells when open,
allow potassium ions to flow out the cell.
K+
K+
ATP
See also Fig. 30.3 Golan et al. 2012, p. 528
FOUR MAJOR TARGETS FOR DRUGS:
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
4. ENZYMES
Molecular Targets For Drug Action
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)
TRANSPORTERS
„Pumps“
Transport proteinstransporters 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
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
„Pumps“
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 :
ANXIOLYTICS - Benzodiazepines
NEUROMUSCULAR-BLOCKING DRUGS
INTRAVENOUS ANAESTHETIC - ketamine
ANTIDIABETICS -sulfonylureas
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-glycoproteinIt 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)
TRANSPORTERS
„Pumps“
Transport proteinstransporters 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 :
FOUR MAJOR TARGETS FOR DRUGS:
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
4. ENZYMES
Molecular Targets For Drug Action
Other drug-enzymes interactions
Enzyme inhibition by drugs
Enzymes Inhibitors Therapeutic groups, indications
Cyclo-oxygenase aspirin, ibuprofen, diclofenacAntiinflammatory and antirheumatic
agents, analgesics Monoamine oxidase moclobemide Antidepressants
Acetylcholinesterase neostigmine, rivastigmin Parasympathomimetics, Anti-dementia-
drugsAngiotensin-converting
enzymeenalapril, ramipril Antihypertensives
HMG-CoA reductase simvastatin, atorvastatinLipid modifying agents; (hypercholesterolaemia)
Xanthinoxidase allopurinol Drugs inhibiting uric acid production
Phosphodiesterase type V
sildenafil Drugs used in erectile dysfunction
Dihydrofolate reductase trimethoprim
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
Many drugs are targeted on enzymes and mostly act by inhibiting them:
Drugs can inhibit enzymes reversibly (usually a competitive inhibition by non-covalent binding) or irreversibly (enzyme is usually changed chemically by covalent binding)
An enzyme inhibitor is a molecule which binds to enzymes and decreases their activity
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)
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)
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.
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Reversible competitive inhibition of enzyme (inhibition of ACE by captopril)::
Irreversible non-competitive inhibition of enzyme (inhibition of COX-1 or COX-2 by aspirin):
This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen, which are reversible inhibitors).
Aspirin acetylates serine residue in the active site of the
COX enzyme
Irreversible inhibition of enzyme:
Recovery is possible only by synthesis of a new enzyme
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.
Cytochrome P450 (CYP) enzymes
Many psychotropic drugs have a high affinity for one particular CYP enzyme but most are oxidised by more than one
Drug - cytochrome P450 interactions
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.
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.
Genetic 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.
Drug effects:
Enzymatic inductionenzymatic 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 inhibitionenzymatic inhibition can cause an increase as well as a decrease in the drug’s effect
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.
Inhibition of CYP enzymes is the most common mechanism that produces serious and potentially life-threatening drug interactions
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
4. ENZYMESsites of action of about 30% of drugs
Drugs inhibiting the enzyme:
Cholinesterase Cholinesterase Inhibitors
Cyclo-oxygenase Non-Steroid Antiinflammatory Drugs
Monoamine oxidase IMAO
Angiotensin- converting enzyme
ACE Inhibitors
HMG-CoA reduktase Statins
and other - e.g. recently phosphodiesterase
neuroamidase
sildenafil (VIAGRA) oseltamivir (TAMIFLU)
degradating cGMP
stops the virus from chemically cutting ties with its host cell
G-protein coupled receptorsmembr.
Voltage gated- Calcium chan.
- Sodium chan.
„pumps“- sodium
- proton
transporters
cardiac glykosides
PP inhibitors
lok. anaesthetetics
Calcium ch. blockers
about 45% of drugs,e.g. beta-blockers
antidepressants
ACE inhibitors, IMAO
perif. muscle relaxants
Examples of drugs::
Proteinkinase-linked receptors
c.intracelul.
Ligand-gated, G-prot.,…
ACE, MAO, COX, HMG-CoA reductase
Channel-linked receptors
1. RECEPTORS
2. ION CHANNELS
3. CARRIER MOLECULES
Molecular mechanisms of drug effects - summaryFOUR MAJOR TARGETS FOR DRUGS:
4. ENZYMES
imatinib