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Charles University in Prague, Third Faculty of Medicine
GENERAL MEDICINE 6-YEAR MASTER‘S STUDY PROGRAMME
Subject: General Pharmacology
Drug – enzymes interactions
Prof. M. Kršiak
Department of Pharmacology, Third Faculty of Medicine
Ruská 87, Prague 10,
Academic year 2013-2014
http://vyuka.lf3.cuni.cz
CVSE3P0012 ID9226
Four major targets for drug action:
ENZYMES
Figure 3.1 Types of target for drug action.
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© 2005 Elsevier
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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© 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
Irreversible inhibition of COX in
thrombocytes and in endothelium
• As thrombocytes (platelets)
do not have nucleus
(adequate DNA), they are
unable to synthesize new
COX once aspirin has
irreversibly inhibited the
enzyme
• Endothelial cells have
nucleus and are able to
recover synthesis of COX
MECHANISM OF ACTION OF NON-OPIOID ANALGESICS
CYKLO-OXYGENASE
COX
CONSTITUTIVE ISOENZYME
COX-1
PHYSIOLOGICAL FUNCTIONS
PROTECTION OF GASTRIC MUCOUS MEMBR.
INCREASE OF BLOOD FLOW AND SODIUM
EXCRETION IN THE KIDNEY
COX-1 inhibitors: ibuprofen,
diclofenac and other
risk of gastropathy
INDUCIBLE ISOENZYME
COX-2
INFLAMMATORY RESPONSE
INFLAMMATION
FEVER
PAIN
Selective COX-2 inhibitors:
COXIBS
lower risk of gastropathy
Selective COX-2 inhibitors (Coxibs) have
lower gastropathy but a higher risk for heart
attack and stroke
promotes clotting
has protective
anti-coagulative
effect
Arachidonic acid
COX-1
COX-2
coxibs
aspirin
tromboxan A2
promotes clotting
increases
platelet + vasoconstriction
aggregation
aspirin prevents platelet
aggregation
prostacyclin PGI2
inhibits
platelet
aggregation
+ vasodilatation
coxibs = selective COX-2 inhibitors :
higher trombotic risk
Selective COX-2 inhibitors (coxibs) increase
in the risk for heart attack and stroke through
an increase of thromboxane unbalanced by
prostacyclin (which is reduced by COX-2
inhibition)
Non-steroidal Anti-inflammatory Drugs (NSAIDs)
Major required effects:
Analgesic + Antipyretic +Anti-inflammatory
Classification of NSAIDs (by selectivity of inhibition of COX-1 and COX -2):
• Nonselective (COX-1 and COX-2) ibuprofen, diklofenac …
• Preferential (COX-2 > COX-1) nimesulide, meloxicam
• Selective (coxibs) (COX-2 only) celecoxib …
Acetylcholinesterase inhibitors
inhibit the acetylcholinesterase from breaking down
acetylcholine, thereby increasing both the level and duration
of action of the neurotransmitter acetylcholine.
REVERSIBLE
physostigmine, neostigmine, rivastigmine
Are used medicinally:
• antidote to anticholinergic poisoning
• to treat glaucoma
• to treat myasthenia gravis
• to treat Alzheimer disease
• to reverse the effect of non-depolarising muscle relaxants
IRREVERSIBLE
• Are used as weapons in the form of nerve agents
• Are used as insecticides
Monoamine oxidase inhibitors (MAOIs)
a long history originally irreversible, now withdrawn
Because of potentially lethal dietary („cheese effect“ and drug
interactions, hypertensive crisis
MAOIs have been reserved as a last line of treatment, used only when
other classes of antidepressant drugs have failed.
Monoamine oxidase inhibitors (MAOIs)
at present: reversible RIMA
MAO –A serotonin, noradrenalin (norepinephrine), tyramine moclobemid
treatment of depression
treatment of anxiety disorders (OCD, panic disorders, phobia)
dietary restrictions
serotonin syndrome
MAO –B dopamine selegiline no dietary restrictions
treatment of Parkinson‘s disease
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
Some drugs that produce active or toxic metabolites
Inactive (prodrugs)
Active drug
Active metabolite
Prednisone →
Prednisolone
Enalapril →
Enalaprilat
Toxic metabolite
Diazepam →
Nordiazepam → Oxazepam
Morphine →
Morphine 6-glucuronide
Paracetamol →
N-Acetyl-pbenzoquinone
imine
Drugs may also act as false substrates, where the drug molecule
undergoes chemical transformation to form an abnormal product
that subverts the normal metabolic pathway.
An example is the anticancer drug fluorouracil, which replaces
uracil as an intermediate in purine biosynthesis but cannot be
converted into thymidylate, thus blocking DNA synthesis and
preventing cell division
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.
Amitriptyline + fluoxetine
Fluoxetine inhibits 2D6
Amitriptyline is a substrate for 2D6
Amitriptyline + fluoxetine → increased plasma levels of
amitriptyline and prolonged t1/2 → sometimes fatal
consequences
OTHER ADVERSE CLINICAL CONSEQUENCES OF DRUG INTERACTIONS*
Profound oversedation
Profound and prolonged sedation can be brought about by inhibition of CYP3A4
enzymes that are involved in the metabolism of anxiolytics and sedatives
e.g. alprazolam, midazolam + ketoconazole/clarithromycine/grapefruit
Severe sedation due to the additive effect (summation) of drugs with
sedating properties is a particular problem in elderly and frail people,
and it can lead to falls and injuries (especially fractures of the femoral
neck).
Excessively drowsy patients are also at increased risk of venous
thromboembolism and, if confined to bed, of hypostatic pneumonia.
In people who drive, increased sedation due to drug interactions
carries a correspondingly increased risk of road traffic accidents.