Drug resistancy

Dr.Datten Bangun MSc,SpFKDr.Yunita Sari Pane,M Si

Dept.Farmakologi & TerapeutikFakultas Kedokteran

Universitas Sumatera UtaraM E D A N

Drug Resistancy• Bacteria or cancer cells CAN become resistant to

these antibacteria or anticancer drugs • Drug resistance occurs when medications are taken

unnecessarily.• When an illness persists, additional drugs may be

needed to kill the germ or the cancer cells

• Since some bacteria or cancer cells refuse to die, super strains can be bred by overuse/misuse of antibiotics.

New Resistant Bacteria

Mutations

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Emergence of Antimicrobial Resistance

Susceptible Bacteria

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Resistant Bacteria

Resistance Gene Transfer

Resistant StrainsRare

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Resistant Strains Dominant

Antimicrobial Exposure

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Selection for antimicrobial-resistant Strains

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Mechanisms of drug resistance

•Efflux Pumps•Hydrolysis•Reduced Uptake•Sequestering•Enzymatic Modification

The Science Creative Quarterly 2: Jan-March 2007.

Drug Resistance Acquired Resistance:>< de novo

resistance• Acquired drug resistance may result from

genomic mutations, such as the induction or deletion of enzymes involved in drug inactivation or drug activation, respectively.

Multidrug Resistance (MDR):P-glycoprotein transports many naturally occurring drugs out of neoplastic cells, and its induction may lead to multidrug resistance.As scientific understanding of the mechanisms of drug resistance increases, new treatments may be developed to counteract resistance.

Mechanism of drug resistanceA.= Genetic causes: 1. Chromosomal mutations; occur in the gene(s) that code(s) in the: - drug target,or - drug transport or - drug metabolism These mutation then be conferred to daughter cells (vertical

transmission)

2. Horizontal transmission (bacteria acquire resistance from other bacteria by: -Conjugation

- Transduction-- using bacteriophage- Transformation- naked DNA is taken up by the bacteria

GENETIC CAUSES OF DRUG RESISTANCEMechanism in Antimicrobial:

1. REDUCED INTRACELLULAR DRUG CONCENTRATION: a. Inactive drug : = Inactivation of lactam antibiotics by lactamase

b. Prevent uptake of Drug = Prevention of aminoglycoside entry by alterid porins

c. Promote efflux of drug :

= Efflux of multiple drugs by MDR membran efflux pump

2. ALTERED TARGET

= Expresion of Altered peptidoglican that no longer binds vancomycins

3. INSENSITIVITY TO APOPTOSIS : N/A4. BYPASS METABOLIC REQUIREMENT FOR TARGET; = Inhibition of thymidylate synthase bypassed by exogenous thymidine

GENETIC CAUSES OF DRUG RESISTANCE

1. REDUCED INTRACELLULAR DRUG CONCENTRATION: a. Inactivate drug : =Inactivation of antimetabolites by deaminase b. Prevent uptake of Drug : =Decreased methotrexate entry by

decreased expresion of reduced folate carrier c. Promote efflux of drug: = Efflux of multiple drugs by p170

membran efflux pump 2. ALTERED TARGET : = Expresion of mutant DHFR that no longer

binds by methotrexate (DHFR= dihydrofolate reductase)

3. INSENSITIVITY TO APOPTOSIS : =Lost of active p53 (key protein in apoptosis4. Bypass Metabolic Requirement for Target: - lost of estrogen reseptor dependent growth result in tamoxifen resistance

Mechanism in neoplastic :

REDUCED INTRACELLULAR DRUG

1. DRUGS MUST REACH THEIR TARGET : AN SUFFICIENT AMOUNT

2. WHEN INSUFFICIENT ----- RESISTANT STRAINS

( MICROBES & CELLS TUMOR HAVE DEVELOPED A NUMBER OF MECHANISMS TO INACTIVE DRUGS BEFORE DRUGS CAN BIND THEIR TARGETS)

*** Many bacteria are resistance to Penicillins and cephalosporins because they produce hydrolytic enzyme ( lactamase enzyme can hydrolyze 103 Penicillins molecules per second ---- reducing the intercellular of active drugs

NON GENETIC CAUSES OF TREATMENT FAILURE

The treatment of an infection or cancer can fail for numerous reason:

1. Drug resistance by excessive overprescription of drugs

2. Involve pharmacologic and anatomical drug barriers

3. Poor patient compliance 4. International travel promotes5. Demographic shifts and other trends created

large susceptible populations, such as immunocompromise cancer patient, AIDS patient, elderly population

Potential mechanisms involved in drug resistance

• Conversion of the drug to an inactive form by an enzyme.

• Modification of a drug sensitive site. • Increased efflux or decreased influx • Alternative pathway to bypass inhibited

reaction. • Increase in the amount of an enzyme

substrate (ie to compete with the drug). • Failure to activate the drug.

Potential mechanisms involved in drug resistance

• These modifications can arise in a population of cells by a number of mechanisms. – Physiological adaptations – Differential selection of resistant individuals

from a mixed population of susceptible and resistant individuals.

– Spontaneous mutations followed by selection. – Changes in gene expression. (gene

amplification)

Resistance Mechanisms

B-lactamases :B-lactamases cleave B-lactam rings from penicillin

Modification of Drugs :Some enzymes have the ability to phosphorylate, adenylate, or acetylate antibiotics-chloramphenicols and aminoglycosides

Resistance Mechanisms

Efflux Pumps and Prevention of Uptake :• Enzymes actively pump out drugs or the drug

is not taken into the cell at all-tetracycline

Enzymes with Altered Shapes :• Enzyme proteins with altered shapes are

produced so that the drug no longer fits to inhibit-Rifampin and Quinolones

Some Factors Involved in Resistance

Chromosomal Resistance :Tends to involve modification of the target drug

R-Plasmids (R-Factors) :Tend to involve inactivation of drugsCan be shared with many different strains and speciesMulti-resistant R-plasmids have several genes which encode for different enzymes

• Many different mechanisms may account for this chemoresistance:

= including reduced blood supply to the tumor,

= up-regulation of antiapoptotic pathways, = enhanced DNA repair mechanisms, and = increased metabolic inactivation and subsequent elimination of the applied drugs

Resistance to Cancer Chemotherapy

Moreover: = in recent years, the expression and function of ATP-driven export pumps of the ATP-binding cassette (ABC) protein superfamily have been extensively studied in cancer cell lines, in in vitro models, and in tissues. Besides transporting a variety of physiologic substrates, several of these transporters also confer resistance to cytotoxic and antiviral drugs = Entry of many hydrophobic cationic drugs into the brain is decisively limited by multidrug resistance 1 (MDR1) P-glycoprotein (symbol ABCB1) in the blood-brain barrier = The presence of other ABC family members in the blood-brain barrier of human brain, including breast cancer resistance protein, ABCG2 and = efflux proteins of the ABCC subfamily which have other substrate specificities than MDR1 P-glycoprotein may add to the resistance

Specific causes:

decreased import of drug into cell (1); e.g. Methotrexate- transporter

nucleoside-transporter increased inactivation of drug (2); e.g. overexpression of bleomycin-hydrolase or cyclophosphamid-aldehyd dehydrogenase

decreased activation of drug (3); e.g. decreased activity of hypoxantine-guanin-phosphoribosyltransferase which activates mercaptopurine.

increased DNA-repair after use of alkylating drugs (4);

cancer cell modifies substrate of drug (5); e.g. changes of topoisomerase II after use of podophyllotoxins.

overexpression of target protein (6); e.g. overexpression of dihydrofolate-reductase (methotrexate) or thymidylate-synthase (5-fluorouracil).

increased export of drug outof target cell (7); multidrug resistance genes; ATP-dependent transporter.

(7) multidrug resistance:

1. tumor cells can become resistant simultaneously to several drugs with apparently different modes of action (anthracyclines, vinca alkaloids, epipodophyllotoxins, actimomycin)

2. correlates with the overproduction (due to gene amplification) of a membrane glycoprotein (“P-glycoprotein:)

3. P-glycoprotein is an energy-dependent drug efflux pump (structural similarities to bacterial membrane transport proteins)

4. other drug efflux pumps may be involved in MDR ; some MDR cells have mutant topoisomerases

5. several drugs have been used in an attempt to overcome MDR: verapamil, cyclosporins, quinoline derivatives, calmodulin inhibitors

Resistance to antihypertension

A= debrisoquine = metoprolol (β-adrenergic blocker) -------metabolize by CYP2D6 ----- ada keluarga yang extensive metabolizer ---- resistant to these drugs,genetically

B.Proses up-regulation to β-adrenergic blocker)

B= ACE-Inhibitor; = lisinopril; genetically polymorphism in receptor

Diuretic Resistance1. Compensatory Mechanisms (RAAS, SNS)2. Failure to reach tubular site of action

a - Decreased G.I. absorptionb - Decreased secretion into tubular lumen (e.g. uremia, decreased kidney perfusion)c - Decreased availability in tubular lumen (e.g. nephrotic syndrome)

3. Interference by other drugs (e.g. NSAID’s)4. Tubular adaptation (chronic Loop diuretic use)

Can Use Combination of Diuretics to Induce a Synergistic Effect

RESISTANCE TO ANTIEPILEPTIC

Many antiepileptic drugs (AEDs) prevent seizures by blocking voltage-gated brain sodium channels.

However, treatment is ineffective in 30% of epilepsy patients, which might, at least in part, result from polymorphisms of the sodium channel genes.

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It has been shown that alterations in voltage-gated sodium channels and GABA-A receptors are responsible for resistance to some epileptic drugs.

These changes may be constitutional (genetically

determined) or acquired (as a consequence of the seizures themselves or disease progression) and may seem alone or combined with each other (pharmacodynamic hypothesis)

Associations have been shown between certain genetic polymorphisms and resistance to epileptic drugs

It is currently known that= membrane transporter proteins are increased

in brain tissue of refractory epileptic patients and in animal models of epilepsy ;and

= that overexpression of these transporters and their inhibition are correlated with a reduction epileptic drugs and an increase in epileptic tissue (pharmacokinetic hypothesis)