Download - Drug Discovery Process-DK
Drug Discovery and Drug Design
by
Dr. Dhurke KashinathAssistant Professor
Department of Chemistry
National Institute of Technology Warangal-506 004
E-mail: [email protected]
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Prescribed Texts:
• Foye’s Principles of Medicinal Chemistry – David Williams and Thomas Lemke
• Organic Chemistry of Drug design & Drug action-Richard Silverman,
• Practice of medicinal chemistry-Wermuth, C.
• An introduction to Medicinal Chemistry-Graham L Patrick
• Pharmaceutical chemistry: Therapeutic aspects of biomacromolecules-Bladon,
Christin
• Wilson & Giswold’s textbook of Organic Medicinal & Pharmaceutical Chemistry
John Block
• Comprehensive Medicinal Chemistry: The rational design, mechanistic study &
therapeutic application of chemical compounds Vol I– VI, Hansch
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Medicinal Chemistry Folklore/traditional usage (History)
Examples:
• Plant Ma Hung (Ephedra sinica)
– used as heart stimulant, diaphoretic agent (perspiration producer)
and to relief from cough
– Active ingredient ephedirin (a drug that raises the blood pressure
and relieves bronchial spasm; i.e. asthma )
• Papaver somniferum (opium poppy)
– 3rd centuary B.C. – opium popy juice used as an analgesic
– 10th centuary A.D. – opium pills used for coughing, mental disorders,
aches and pain
– Active ingredient – morphine (potent analgesic) and codeine (cough
suppressant)
• Bark of Cinchona trees
– Used for fever in 1600 BC is used for malaria and fever even today
– Active ingredient - quinine
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Medicinal chemistry is the science that deals with design and discovery of
the new therapeutic chemicals and their development into useful medicines to
treat diseases
Medicinal chemistry involves isolation of compounds from nature or
synthesis of new molecules, structural elucidation (spectroscopic methods) and
study of their interactions with receptors, enzymes and DNA
Introduction: Medicinal chemistry
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Objectives of Drug design:
(a) To understand the effects of synthetic/biological compounds on the basis of
molecular interaction with biological system
(b) To understand the processes by which the drugs usually produce their
pharmacological effects
(c) To understand how the drugs specifically react with the protoplasm to produce
a particular pharmacological response
(d) How the drugs usually get modified or metabolized and eliminated
from the body
(e) Probable relationship between biological activity with chemical structure
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Identification of the target
• Understanding the interactions of biomacromolecules (enzymes and receptors)
involved in a particular disease state
• Design of agonist or antagonist for a particular receptor
• Target specificity: electivity between species and body (organs and tissues)
• Design of Agonist or antagonist
Identification of bioassay:
• Choice of bioassay (finding out EC50, IC50, LD50)/therapeutic index
• In vitro and In vivo tests and Test validity
Choosing the disease:
• Diseases which are prevalent in developed countries
• Impact on the society/Geographical consideration
• Better properties than existing drugs
• Economic factors
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Modern drug discovery process
Target
identification
Target
validation
Lead
identification
Lead
optimization
Preclinical
phase
Drug
discovery
2-5 years
• Drug discovery is an expensive process involving high R & D cost (10-15
million USD) and requires extensive clinical testing
• A typical development time is estimated to be 10-15 years.
6-9 years
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Modern drug discovery process
10,000 molecules
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Early drug discovery (Preclinical)
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Drug discovery process (Clinical studies)
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Drug discovery process
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Background
View of living organisms as molecular circuit:
• Molecular circuit = biochemical processes, that form and recycle molecules in a coordinated and balanced fashion
• Intended modes of operation = healthy state
• Aberrant modes of operation = disease state
Diagnosis:
• Identify the molecular basis of disease
Therapy:
• Guide biochemical circuit back to healthy state
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Genomics - Proteomics
Mapping Sequence to Protein Structure and Dynamics
Primary SequenceMNGTEGPNFY VPFSNKTGVV RSPFEAPQYY LAEPWQFSML AAYMFLLIML GFPINFLTLY VTVQHKKLRT PLNYILLNLA
VADLFMVFGG FTTTLYTSLH GYFVFGPTGC NLEGFFATLG GEIALWSLVV LAIERYVVVC KPMSNFRFGE NHAIMGVAFT
WVMALACAAP PLVGWSRYIP EGMQCSCGID YYTPHEETNN ESFVIYMFVV HFIIPLIVIF FCYGQLVFTV KEAAAQQQES
ATTQKAEKEV TRMVIIMVIA FLICWLPYAG VAFYIFTHQG SDFGPIFMTI PAFFAKTSAV YNPVIYIMMN KQFRNCMVTT
LCCGKNPLGD DEASTTVSKT ETSQVAPA
3D Structure
FoldingThis image cannot currently be displayed.
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Genomics - ProteomicsMapping Sequence to Protein Structure, Dynamics and Function
Primary SequenceMNGTEGPNFY VPFSNKTGVV RSPFEAPQYY LAEPWQFSML AAYMFLLIML GFPINFLTLY VTVQHKKLRT PLNYILLNLA
VADLFMVFGG FTTTLYTSLH GYFVFGPTGC NLEGFFATLG GEIALWSLVV LAIERYVVVC KPMSNFRFGE NHAIMGVAFT
WVMALACAAP PLVGWSRYIP EGMQCSCGID YYTPHEETNN ESFVIYMFVV HFIIPLIVIF FCYGQLVFTV KEAAAQQQES
ATTQKAEKEV TRMVIIMVIA FLICWLPYAG VAFYIFTHQG SDFGPIFMTI PAFFAKTSAV YNPVIYIMMN KQFRNCMVTT
LCCGKNPLGD DEASTTVSKT ETSQVAPA
3D Structure
Folding
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How to design a drug in the absence of a structure?
Drug Target:Drug Target:Drug Target:Drug Target:
This image cannot currently be displayed.
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Active site: Study and design of the lignad
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General terminology used in drug discovery:
Hit
Lead compound
Lead modification
Pharmacophore
DMPK
PK/PD
In-vivo
In-vitro
ADME
IC50
EC50
LD50
Efficacy
Agonist
Antagonist
Prodrug
High throughput screening
Random screening
Therapeutic index
Drug resistance
CYPs (Cytochrome P 450)
CADD
Structure based drug design
Fragment based drug design
Hit:
A “hit” is known or confirmed compound whose biological activity is known
(which is used for the primary screening)
Lead compound:
A lead compound is a representative of a compound series with sufficient
potential activity (as measured in terms of potency, selectivity,
pharmacokinetics, physicochemical properties, no toxicity and novelty) to
progress to a full drug development program
Lead discovery:
Lead discovery is the process of identifying active new chemical entities
(NCEs), which by subsequent modification may be transformed into a
clinically useful drug
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Lead optimization:
The synthetic modification of a biologically active compound, to fulfill all
stereoelectronic, physicochemical, pharmacokinetic and toxicological properties
required for clinical use.
The new lead optimization pattern demands that companies move to parallel
processes that evaluate binding affinity, ADME, drug properties, etc. earlier in
the process in order to cut the time and costs lost in failed leads.
Pharmacophore:
Essential part of the lead molecule which is important to show bilogical
activity and has to be kept intact during lead modification
Prodrug:
A prodrug is drug which is given (taken) in an inactive form. Once administered,
the prodrug is metabolized by the body (biochemical reactions) into a
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DMPK:
Drug metabolism and pharmacokinetics
PK/PD:
Pharmacokinetics and pharmacodynamics studies of the molecules with
biological system (i. e. enzymes, receptors and nucleosides and nucleotides)
In-vitro and In-vivo studies:
In vitro studies which are performed in the laboratory on a similar (artificial)
biological system
In vivo studies which are performed on biological system (animal models)
ADME:
Administration, Distribution, Metabolism and Excretion
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Agonist:
An agonist is a chemical that binds to some receptor of a cell and triggers a
response by that cell
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Types of Agonists:
An agonist is a chemical that binds to some receptor of a cell and
triggers a response by that cell
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Antagonist:
An antagonist blocks the action of the agonist and an inverse agonist causes an
action opposite to that of the agonist
A receptor antagonist is a type of receptor ligand or drug that does not induce
a biological response itself upon binding to a receptor, but blocks or reduces
agonist-mediated responses
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IC50 (Inhibitory concentration):
Measure of the effectiveness of a compound in inhibiting biological or biochemical
function (IC50 represents the concentration of a drug that is required for 50% inhibition
in vitro)-
EC50 (Effective concentration):
The term half maximal effective concentration (EC50) refers to the concentration of a
drug, antibody or toxicant which induces a response halfway between the baseline and
maximum after a specified exposure time (the concentration of a compound where 50%
of its maximal effect is observed)-
LD50 (Lethal concentration):
In toxicology, the median lethal dose, LD50 (lethal concentration, 50%) or LCt50 (lethal
concentration & time) of a toxin, radiation, or pathogen is the dose required to kill half
the members of a tested population after a specified test duration
HTS:
High throughput screening
Penicillin
First antibiotics discovered as natural products from the mold Penicillium
1928: Alexander Fleming noticed a green mold (Penicillium notatum) growing in
a culture of Staphylococcus aureus (gram positive bacteria)
Penicillin G and V isolated; antibiotic activity discovered; new β-lactams
discovered and made through modification to give antibiotics with improved
activity.
Drug Discovery Without a Lead: Serendipitous discovery
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– Penicillin-G ( R = benzyl), is the most potent of all penicillin derivatives
• effective only against gram-positive bacteria
• Undergoes metabolism in the stomach by gastric acids and is poorly and
irregularly absorbed into the blood stream
• many disease producing staphylococci are able to produce an enzyme
capable of inactivating penicillin-G.
– Other semi-synthetic derivatives:
• Phenethicillin (Penicillin-V, R=PhOCH2) : Powerful electron-attracting
groups attached to the amino acid side chain prevent acid attack.
• Methicillin (R=2,6-di-OCH3-C6H3-): A bulky group attached to the amino
acid side chain provides steric hindrance which interferes with the
enzyme attachment which would deactivate the penicillin
• Ampicillin or Carbenicillin (R=C6H4NH2-): Increased polar character
imparts a greater activity against Gram-negative bacteria.
R = Ph/
substituted Ph
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Increased polar character
imparts a greater activity
against Gram-negative
bacteria
A bulky group attached to the
amino acid side chain
provides steric hindrance
which interferes with the
Electron-attracting groups
attached to the amino acid side
chain prevent acid attack
-OH group at 4-position
better absorbed, following oral
administration
Penicillin-G: Effective only against
gram-positive bacteria. Undergoes
metabolism in the stomach by gastric
acids and is poorly and irregularly
absorbed into the blood stream many
disease producing staphylococci are
able to produce an enzyme capable of
inactivating penicillin-G
Drug Discovery Without a Lead: Librium (Chlordiazepoxide)
• Benzodiazepine tranquilizer (discovered while searching for anxiety drugs)
• 1957: Dr Leo Sternbach (Roche; Switzerland based company)
LibriumBenzheptoxdiazine
Originally planned to synthesizeQuinazoline 3-oxide
X=7-Cl, R1=CH2NHCH3,
R2=C6H5
Submitted for
pharmacological
evaluation and found to
be Librium
Benzodiazepine 4 -oxide
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Screening of natural products (plant kingdom, microbial world, marine
world, animal sources, venoms and toxins)
• Medical folklore or Existing drugs
• Screening synthetic compounds (series of compounds/libraries)
• Starting from natural ligand or modulator (natural ligands for receptors,
enzymes, enzyme products as lead compounds, natural modulators as
lead compounds)
Finding a lead compound
– Drug Discovery without a lead
• Penicillin
• Librium
– Approaches for lead identification• Random Screening
• Nonrandom Screening
• Drug Metabolism Studies
• Clinical Observations
• Rational Approaches to Lead Discovery
Drug Discovery – lead identification
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Lead Modification
Identification of the Active Part of the molecule: The Pharmacophore
Pharmacophore: The relevant groups on a molecule that interact with a receptor (or an
enzyme) and are responsible for the activity are collectively known as pharmacophore
(Other atoms not part of the pharmacophore are part of the auxophore)
The pharmacophore can be used as a tool to design new drug molecules that can
interact with the same receptor
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High blood pressure
(hypertension)
Losartan
(reference compound)
Lead Modification
Which part has to be modified to improve drug action ???
• Some of the atoms are essential to maintain the integrity of the molecule & hold the
pharmacophoric groups in their appropriate positions
• While some are interfering with the binding of the pharmacophore, they need to be
excised/modified from lead compound
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Morphine (X)
(Reference compound)
Levorphanol (4X)
Excising
the
dihydrofuran
ring
Benzomorphan (<X)
Removal of half
of cyclohexene ring
Cutting away
methylene group
(Not much change)
Removal of all
fused ring
Mepiridine (<X)
Acyclic analog
Dextropropoxyphene (X/2)Methadone (X)
Benzomorphan based drugs: Morphine as reference compound
Lead Modification:
Branching, isomerization, replacement of the rings, bioisosterism
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Lead compounds from natural receptor agonists
Examples:
Steroidal hormone progesterone (weakly active) acted as the lead compound
for contraceptive (+)-norgestrel
Serotonin (neurotransmitter) was used as a lead for anti-inflammatory
drug indomethacin [non-steroidal anti-inflammatory drug (NSAID)]
Anti-inflammatory drug sulindac is inactive, its metabolite is active
Drug Metabolism Studies:
• Drug metabolites are degradation products generated in vivo
• Drug metabolites are screened to determine if the activity is due to drug
candidate or from a metabolite
Antibacterial drug sulfanilamide is a metabolite of prontosil
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Pharmacokinetics (ADME)
Absorption – movement of drug from
site of administration to blood [Rate of
dissolution, Surface area, Blood flow,
Lipid solubility, pH partitioning
Distribution (systemic circulation and
body tissues of the body)
Metabolism (generation of active species
and metabolites through enzymatic
biochemical reactions in the body:
cytochrome P450, hepatic microsomal
enzyme system)
Excretion
(Absorption, Distribution/Transportation, Metabolism and Excretion)
1910: Paul Ehrlich and Sahachiro Hata developed Salvarsan
(Arsphenamine) against syphilis (Starting of chemotherapy)
1928: Fleming discovered penicillin
1932: Sulfa drugs (sulfanilamide) discovered against Gram+ bacteria
1940: Howard Florey and Ernst Chain performed first clinical trials of
penicillin
The History of Chemotherapy
Inhibited area
Normal bacteria
Penicillinium colony
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Features of antimicrobial Drugs
• Selective toxicity (species): Drug kills pathogens without damaging the host
• Therapeutic index: ratio between toxic dose and therapeutic dose or ratio of
LD50 to ED50 (High therapeutic index)
• LD50 (low) vs. MIC and/or MBC (high)
• Four major sites:
– Cell wall, Ribosomes, DNA,
• Antimicrobial action – Bacteriostatic (inhibits the growth) vs
Bactericidal (kills bacteria)
• Activity Spectrum:
Broad Spectrum Antibiotics: Effective against many types (E.g. Tetracycline);
Narrow Spectrum Antibiotics: Effective against very few types (E.g. Penicillin)
• Antimicrobial drugs: Synthetic material, interfere with the growth of microbes within the host
• Antibiotic: Biological origin/produced by a microbe, inhibits/kills other microbes
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e.g. Bacteriostatic, Bactericidal
The Action of Antimicrobial Drugs
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The Action of Antimicrobial Drugs
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Mechanism of action: Gram +Ve bacteria
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Mechanism of action: Gram –Ve bacteria
Retention of Penicillin G (Dose response curve)
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Inhibition of Protein Synthesis by Antibiotics
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Cephalosporins
Structure and mode of action resembles penicillins
1. More stable to bacterial ββββ-
lactamases than penicilins
2. Broader spectrum ⇒⇒⇒⇒ used
against penicillin-resistant
strains
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Vancomycin
– Glycopeptide from Streptomyces
– Inhibition of cell wall synthesis
– used for Penicillin resistant Gram +Ve bacteria
– Used to kill Methionine Sulfoxide Reductase A gene
– Vancomycin resistance: Vancomycin-Resistant
Enterococcus (VRE) and Vancomycin-resistant
Staphylococcus aureus (VRSA)
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Antibiotic Resistance
A variety of mutations can lead to antibiotic resistance including the following
1. Enzymatic destruction of drug
2. Prevention of penetration of drug
3. Alteration of drug's target site
4. Rapid ejection of the drug
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Resistance to Antibiotics
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Antibiotic Resistance
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Misuse of antibiotics:
– Using outdated or damaged antibiotics
– Using antibiotics for the common cold and other problems in
inappropriate condition
– Failing complete the prescribed regimen
– Using someone else's leftover prescription
Antiviral Drugs: Acyclovir DNA polymerase inhibitor
Nucleoside analogs inhibit DNA synthesis
Acyclovir and newer derivatives: Selective inhibition of herpes virus replication.
Acyclovir converts in to nucleotide analog only in virus infected cells ⇒⇒⇒⇒ very little harm to uninfected cells!
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Herps simplex virus
Antiviral Drugs: Acyclovir DNA polymerase inhibitor
Mechanism of Action of Acyclovir
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HIV protease cleaves viral polypeptide into functional proteins
Protease inhibition ⇒⇒⇒⇒ HIV cannot mature and noninfectious viruses are
produced.
Antiviral Drugs for Treating HIV/AIDS:
HAART: Highly active antiviral therapy
1. NRTIs and NNRTIs
2. Protease Inhibitors
3. Fusion Inhibitors
4. Integrase Inhibitors
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Antifungal Drugs
• Polyenes, such as nystatin and amphotericin B, used for systemic fungal infections involve inhibition of ergosterol synthesis ⇒⇒⇒⇒ fungicidal
• Griseofulvin from Penicillium. Systemic/oral. Binds to tubulin ⇒⇒⇒⇒ used for theTineae
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• Fungal infections classification:
– Superficial infections: Ringworm (tinea) → skin and mucous
membrane. Incidence rate is high.
– Systemic infections: Candida albicans → opportunist infections.
Fatality rate is high.
• Antifungal agents classification:
– Antibiotics: Amphotericin B;
– Azole: Ketoconazole;
– Allylamine: Terbinafine;
– Pyrimidine: Flucytosine.
Antifungal Drugs
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Antiprotozoan and Antihelminthic Drugs
Examples of Antiprotozoan:
• Chloroquine: Malaria (Plasmodium falciparum)
• Metronidazole (Flagyl): Vaginitis, skin, joints infections and respiratory tract
caused by anaerobic bacteria
Examples of Antihelminthic:
• Niclosamide and praziquantel: Tapeworm
• Mebendazole: broadspectrum antihelmintic
• Ivermectin: nematodes, mites, lice . . .
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Anti inflammatory drugs: How NSAIDs Help Relieve Pain ?
• Block the effects of special enzymes called Cox-1 and Cox-2 enzymes
• These enzymes play a key role in making prostaglandins
• By blocking the Cox enzymes, NSAIDs stop body from synthesizing many
prostaglandins
• Thus, less swelling and less pain
NSAIDs available over-the-counter drugs:
Aspirin (Bufferin, Bayer, and Excedrin)
Ibuprofen (Advil, Motrin, Nuprin)
Ketoprofen (Actron, Orudis)
Naproxen (Aleve)
NSAIDs are available by prescription:
Daypro, Indocin, Lodine
Naprosyn
Relafen
Voltaren
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Main Diseases of the Cardiovascular System
• Hypertension: Increased sympathetic activity and sodium overload increase
blood pressure (BP)
• Congestive heart failure: CHF due to weakening of the contractile function
of the heart. Blood and fluid accumulate in the heart, lungs, abdomen etc.
• Coronary artery disease: Chest pain due to coronary artery disease (CAD)
and myocardial ischemia. Exertional angina (pain) usually occurs during physical
exertion or stress
• Myocardial infarction: Caused by complete blockage of one of the coronary
arteries. Heart cells deprived of blood/oxygen become ischemic, die, and form
an infarct
• Cardiac arrhythmias:
Disturbances in the normal electrical activity of the heart. Can be detected
on a recording of the electrocardiogram (ECG)
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Drug Classes Used to Cardio Vascular diseases:
• Diuretics
• Sympatholytic drugs
• Vasodilator drugs
• Calcium antagonist drugs
• Angiotensin-converting enzyme inhibitor and angiotensin receptor blocking
drugs
• Nitrites and nitrates
• Beta adrenergic blocking drugs
• Calcium antagonists, also referred to as calcium channel blockers
• Cardiac glycosides
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Carcinogenesis
DNA mutation: Inactivation of tumor
supressor genes, binding to a virus
protein or binding to a mutated
cellular protein
Activation of protooncogenes to
oncogenes: point mutation (single
nucleotide polymorphisms-SNPs),
gene amplification, chromosome
translocation, virus interaction
Hereditary
Acquired: radiation, viruses, chemicals,
drugs
Characteristics of tumour cells:
• Uncontrolled proliferation
• Dedifferentiation &&&& loss of function
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Types of cancers
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