Drug – enzymes interactions

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 2013-2014

GENERAL MEDICINE 6-YEAR MASTER‘S STUDY PROGRAMME

http://vyuka.lf3.cuni.cz

CVSE3P0012 ID9226

Figure 3.1 Types of target for drug action.

Downloaded from: StudentConsult (on 5 November 2013 05:28 PM)© 2005 Elsevier

Four major targets for drug action:

ENZYMES

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.

Downloaded from: StudentConsult (on 6 November 2013 02:30 PM)

© 2005 Elsevier

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

• 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

Irreversible inhibition of COX in thrombocytes and in endothelium

CONSTITUTIVE ISOENZYME INDUCIBLE ISOENZYME

COX-1 COX-2PHYSIOLOGICAL FUNCTIONS INFLAMMATORY RESPONSE PROTECTION OF GASTRIC MUCOUS MEMBR. INFLAMMATIONINCREASE OF BLOOD FLOW AND SODIUM FEVER EXCRETION IN THE KIDNEY PAIN

CYKLO-OXYGENASE

COX

MECHANISM OF ACTION OF NON-OPIOID ANALGESICS

Selective COX-2 inhibitors: COXIBS

lower risk of gastropathy

COX-1 inhibitors: ibuprofen, diclofenac and other

risk of gastropathy

Selective COX-2 inhibitors (Coxibs) have lower gastropathy but a higher risk for heart attack and stroke

COX-1

tromboxan A2

increases platelet

aggregation+ vasoconstriction

Arachidonic acid

COX-2

prostacyclin PGI2

inhibits platelet

aggregation+ vasodilatation

aspirin

aspirin prevents platelet aggregation

coxibs = selective COX-2 inhibitors :

higher trombotic risk

coxibs

has protective anti-coagulative

effect

promotes clotting

promotes clotting

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

• Nonselective (COX-1 and COX-2) ibuprofen, diklofenac …

• Preferential (COX-2 > COX-1) nimesulide, meloxicam

• Selective (coxibs) (COX-2 only) celecoxib …

Classification of NSAIDs (by selectivity of inhibition of COX-1 and COX -2):

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.

serotonin syndrome

MAO –A serotonin, noradrenalin (norepinephrine), tyramine moclobemid

treatment of depression

treatment of anxiety disorders (OCD, panic disorders, phobia)

MAO –B dopamine selegiline no dietary restrictions

dietary restrictions

Monoamine oxidase inhibitors (MAOIs)

at present: reversible RIMA

treatment of Parkinson‘s disease

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:

Inactive (prodrugs) Active drug Active metabolite Toxic metabolite

Prednisone → Prednisolone  

Enalapril → Enalaprilat  

  Diazepam → Nordiazepam → Oxazepam

  Morphine → Morphine 6-glucuronide

  Paracetamol →N-Acetyl-p-benzoquinone imine

Some drugs that produce active or toxic metabolites

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

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

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

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.

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