Transcript FOUR MAJOR TARGETS FOR DRUGS

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
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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.)
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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:
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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.
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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