B9 Flashcards
Paracetamol
Indirect COX inhibitor.
Effect it has:
- Analgesic.
- Antipyretic. (effects the hypothalamus, resulting in peripheral vasodilation and sweating)
Effects it doesn’t have:
- Antiplatelet.
- Anti-inflammatory.
- Gastric ulcerative.
Amoxicillin
Beta-lactam antibiotic.
MoA: Amoxicillin binds to PBP-1A and facilitates its inactivation. Penicillin-binding protein 1A (PBP-1A) is located inside the bacterial cell well. Inactivation of PBP-1A prevents the cross-linking of two linear peptidoglycan strands, inhibiting bacterial cell wall synthesis.
Use: Against wide range of gram-positive, limited range of gram-negative organisms.
Note: Amoxicillin (a beta-lactam antibiotic) combined with Clavulanic acid - a β-lactamase inhibitor to overcome bacterial antibiotic resistance mediated through β-lactamase production.
Methicillin
A transpeptidase inhibitor.
Narrow spectrum beta-lactam antibiotic.
MoA: It inhibits bacterial cell wall synthesis, via inhibition of transpeptidase enzyme used by bacteria to cross-link the peptide (D-alanyl-alanine) used in peptidogylcan synthesis in the cell wall of Gram-positive bacteria.
What does MRSA stand for?
Methicillin-resistant Staphylococcus aureus.
MRSA describes Staphylococcus aureus strains resistant to all penicillins.
Cefuroxime
Transpeptidase inhibitor (2nd gen cephaosporin) Bactericidal
Unlike most other second-generation cephalosporins, cefuroxime can cross the blood-brain barrier.
Listeria and MRSA bacterial classes are resistant to cefuroxime.
HMG-CoA-Reductase inhibitors also known as?
Statins
Competitive inhibitor of HMG-CoA-Reductase reduce hepatic synthesis of cholesterol and clearance of LDL from the blood plasma.
Fibrates
PPAR nuclear receptor agonists
Amphipathic carboxylic acids
MoA: Binding to ‘peroxisome proliferator-activated receptors’ (PPAR) and increasing lipoprotein lipase transcription, hence facilitating lipid metabolism.
PPAR = intracellular receptors that modulate carbohydrate and fat metabolism and adipose tissue differentiation.
Use: range of metabolic disorders, mainly hypercholesterolemia (high cholesterol), and are therefore hypolipidemic agents.
Note: Fibrates are structurally and pharmacologically related to Thiazolidinediones. A novel class of anti-diabetic drugs that also act on PPARs (more specifically PPARγ).
Benzylpenicillin (Penicillin G)
Transpeptidase inhibitor
Penicillin G is a beta-lactam antibiotic used to target usually gram-positive organisms
MoA: Via binding to penicillin binding proteins. That then causes the inhibition of cell wall synthesis. In addition it may inhibit the action of bacterial autolysin inhibitor
Penicillin G is stable against hydrolysis by these beta-lactamases:
- Penicillinases
- Cephalosporinases
- Extended spectrum beta-lactamases
List 3 transpeptidase inhibitors.
Methicillin
Cefuroxime
Benzylpenicillin
Oxytetracycline
30s inhibitor
Broad-spectrum antibiotic
MoA: Inhibition of bacterial cell growth by binding to the 30S ribosomal subunit. This prevents the amino-acyl tRNA from binding to the A site of the ribosome, causing inhibition of translation. It’s lipophilic so diffuses through porin channels in the bacterial.
Use: Treat many infections, including acne
Erythromycin
50S inhibitor
Macrolide group of antibiotic
It is effective only against actively dividing organisms
MoA: Reversibly binds to the 50S subunit of bacterial ribosomes, at the donor binding site. This binding blocks the translocation of peptides from the acceptor site to the donor site, inhibiting protein synthesis.
Use: Infections including: respiratory infections, syphilis, skin infections, chronic prostatitis.
Pregnancy: After absorption, erythromycin diffuses readily into most body fluids and will pass into both breast milk and placental barrier.
Gentamicin
30S/50S inhibitor
Broad spectrium aminoglycoside antibiotic
MoA: Active against gram-negative bacteria, E.g. pseudomonas, acinetobacter, enterobacter. Aminoglycosides can be used to treat mycobacteria (TB) and gram-positive infections. Bind to bacterial 30S ribosomal subunit –> inhibiting protein synthesis
SE: Significant ear and kidney damage (just like other aminoglycosides)
Rifampicin
RNA/DNA polymerase inhibitor
Broad spectrum antibiotic (targets gram-positive and gram-negative organisms).
Easily absorbed and distributed within the body.
MoA: Via the inhibition of DNA-dependent RNA polymerase, leading to a suppression of RNA synthesis and cell death
Use: Rifampicin can target bacterial but not mammalian versions of the enzyme - DNA-dependent RNA polymerase. The use of rifampicin been restricted to mainly mycobacterial infections due to emergence of resistant bacteria.
Trimethoprim
Folate antagonist
MoA: Binds to (bacterial) dihydrofolate reductase
This inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid (THF). THF is an essential precursor in the thymidine synthesis pathway. Interference with this pathway inhibits bacterial DNA synthesis.
Use: UTIs, acute and chronic bronchitis
Note: Trimethoprim’s affinity for bacterial dihydrofolate reductase is greater than its affinity for the human version of dihydrofolate reductase.
Sulfamethoxazole
A sulfonamide drug (PABA analogue)
PABA - para-aminobenzoic acid
MoA: It competes with para-aminobenzoic acid (PABA) in binding to dihydrofolate synthase. It can therefore cause the inhibition of dihydrofolate synthetase, inhibiting the synthesis of tetrahydrofolic acid (THF) synthesis. THF is required for the synthesis of purines and dTMP and inhibition of its synthesis inhibits bacterial growth.
Use: Bronchitis, prostatitis, UTIs
Note: Trimethoprim and sulfamethoxazole are commonly used in combination because they target the same pathway and their synergistic effects reduce the development of bacterial resistance
Vancomycin
Peptidoglycan inhibitor
MoA: Via inhibition of incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls. In addition, vancomycin alters bacterial-cell-membrane permeability and RNA synthesis. There is no cross-resistance between vancomycin and other antibiotics.
Use: Used only after other antibiotics have failed. It’s active against Listeria monocytogenes, Streptococcus pyogenes, Streptococcus pneumoniae (indlucing penicillin-resistant strains), Streptococcus agalactiae, Actinomyces species, and Lactobacillus species.
Note: Inactive against gram-negative bacilli, mycobacteria, or fungi.
Colistin
Polymyxin antibiotic agent - A phospholipid detergent
MoA: To distrub bacterial cell membrane, changing its permeability. In addition colistins can enter the bacteria and precipitate cytoplasmic components, mainly ribosomes.
Use: Colistin is used to treat acute or chronic infections due to sensitive strains of certain gram-negative bacilli, particularly - Pseudomonas aeruginosa.
Ciprofloxacin
A broad spectrum quinolone antibiotic (Topoisomerase II inhibitor)
MoA: Inhibition of topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, strand supercoiling repair, and recombination.
Use: Used against a wide range of gram-negative and gram-positive microorganisms.
What is fusidic acid?
A translocation inhibitor - a bacteriostatic antibiotic typically used in creams and eyedrops.
MoA: Inhibition of the translocation of the elongation factor G (EF-G) from the ribosome, leading to inhibition of protein synthesis.
In addition it also can inhibit chloramphenicol acetyltransferase enzymes.
NSAIDs
Inhibition of cyclooxygenase activity.
The constitutive cyclooxygenase, COX-1, synthesizes prostaglandins necessary for normal gastrointestinal and renal function.
The inducible cyclooxygenase, COX-2, generates prostaglandins involved in inflammation.
Inhibition of COX-1 is thought to be associated with gastrointestinal and renal toxicity while inhibition of COX-2 provides anti-inflammatory activity, reduced pain, fever and swelling.
Note: Paracetamol (acetaminophen) is generally not considered an NSAID because it has only little anti-inflammatory activity
Examples:
Aspirin - irreversible
Ibuprofen - reversible
Naproxen
Acetylsalicylic acid’s antirheumatic actions are a result of what?
Its analgesic and anti-inflammatory mechanisms.
Irreversible inhibition of COX prevents the formation of the aggregating agent thromboxane A2 in platelets.
Platelets cannot produce more COX enzyme and thus, the effects of aspirin persist for the life of the exposed platelets (7-10 days).
Aciclovir
DNA polymerase inhibitor
MoA: Aciclovir in an antiviral agent activated by viral thymidine kinase.
Aciclovir –> (alot of steps) –> aciclovir triphosphate.
Aciclovir triphosphate competitively inhibits viral DNA polymerase and competes with the natural deoxyguanosine triphosphate, for incorporation into viral DNA. Once incorporated into DNA, aciclovir acts as a termination signal.
Note: Aciclovir is selective and low in cytotoxicity as the cellular thymidine kinase of normal, uninfected cells does not use aciclovir effectively as a substrate
Amantadine
Viral ion channel disruptor
Antiviral drug which also acts as antiparkinsonian agent
MoA: Inhibition of a viral protein, M2 (an ion channel) - which is needed for the viral particle to become “uncoated” once it is taken inside the cell by endocytosis. The moa ‘of amantadine in the treatment of Parkinson’s disease is not known.
Diamorphine
A mu-opiate receptor agonist (analgesic)
MoA: Heroin reduces and sometimes stops production of endoenous opiods (Beta-endorphin, Dynorphin, Leu-enkephalin, Met-enkephalin)
Adminstration:
- Taken orally, heroin is totally metabolized in vivo into morphine before crossing the blood-brain barrier; so the effects are the same as oral morphine.
- Taken by injection, heroin crosses into the brain, where it is rapidly metabolized into morphine by removal of the acetyl groups. It is the morphine molecule that then binds with opioid receptors and produces the subjective effects of the heroin high.
Heroin targets which 4 endogenous neurotransmitters?
Beta-endorphin
Dynorphin
Leu-enkephalin
Met-enkephalin
Amprenavir
A protease inhibitor - used to treat HIV-1
MoA: to inhibit HIV-1 protease, which is required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. This inhibition of the protein cleavage results in the formation of immature non-infectious viral particles.
Use: Anti-HIV drug
Phenoxymethylpenicillin
a.k.a. Penicillin V
Transpeptidase inhibitor
MoA: Penicillin V moa is through the inhibition of bacterial cell-wall biosynthesis by binding to specific penicillin-binding proteins (PBPs) located inside the bacterial cell wall. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins.
Use: Narrow spectrum antibiotic used to treat infections caused by susceptible gram-positive aerobic organisms -
such as Streptococcus pneumoniae, groups A, B, C and G streptococci, nonenterococcal group D streptococci, viridans group streptococci, and non-penicillinase producing staphylococcus.
Zidovudine
Thymidine analogue
Nucleoside reverse transcriptase inhibitor (NRTI)
MoA:
- Zidovudine is a structural analogue of thymidine, and as such competes for incorporation into viral DNA
- The incorporation of the analogue, inhibits HIV-1 reverse transcriptase via DNA chain termination, terminating viral FDNA growth.
- Zidovudine is also a weak inhibitor of cellular DNA polymerase α and γ.
Use: Treat HIV-1
What is the overall effect of zidovudine (a structure analogue of thymidine)?
Incorporates into the viral DNA and terminates viral DNA replication thus growth
What class of drugs are clotrimazole, fluconazole, nystatin, amphotericin?
Anti-fungals
Clotrimazole
A Fungal Ianosine Demethylase inhibitor
MoA: An imidazole derivative with a broad spectrum of antimycotic activity. It inhibits biosynthesis of the sterol ergostol, an important component of fungal cell membranes, via the inhibition yeast 14-α demethylase, a cytochrome P-450 enzyme that converts lanosterol to ergosterol, an important component of fungal cell membranes.
Use: Has a broad spectrum of antimycotic activity, with its primary action against dividing and growing organisms
Name 2 fungal ianosine demethylase inhibitors.
Clotrimazole
Fluconazole
Fluconazole?
A synthetic antifungal agent, used to treat vaginal candidiasis
MoA: Inhibition of 14-α demethylase, a cytochrome P-450 enzyme that converts lanosterol to ergosterol, an important component of fungal cell membranes; this inhibition leads to increased membrane permeability and possibly disruption of membrane bound enzymes
Nystatin
An anti-fungal, effective against a wide variety of years and yeast-like fungi.
MoA: Via binding to ergosterol in fungal cell membranes; this binding to ergosterol causes the formation of pores in the membrane, leading to potassium and other cellular constituents’ leakage causing cell death
Amphotericin
Ionophore
A chemical species that reversibly binds ions.
Many ionophores are lipid-soluble entities that transport ions across a cell membrane.
MoA: Via binding to ergosterol in fungal cell membranes. This binding to ergosterol causes the formation of pores in the membrane, leading to potassium and other cellular constituents leakage causing cell death.
Fusidic acid
A bacteriostatic antibiotic typically used in creams and eye drops
MoA: Inhibition of the translocation of the elongation factor G (EF-G) from the ribosome, leading to inhibition of protein synthesis. In addition it also can inhibit chloramphenicol acetyltransferase enzymes
Griseofulvin
A fungal mitosis inhibitor (a fungistatic)
An anti-parasitic compound, used as an adjunct in the treatment of uncomplicated, chloroquine resistant, P. falciparum malaria and toxoplasmosis
MoA: Unkown
Pyrimethamine
Folate antagonist
An anti-parasitic compound, used as an adjunct in the treatment of uncomplicated, chloroquine resistant, P. falciparum malaria and toxoplasmosis
MoA: Inhibition of the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver. This activity is highly selective against plasmodia and Toxoplasma gondii.
Note: The action of pyrimethamine against Toxoplasma gondii is greatly enhanced when used in conjunction with Sulphonamides
Quinine
Haem polymerase inhibitor
Use: Quinine is used parenterally to treat life-threatening infections caused by chloroquine-resistant Plasmodium falciparum malaria
How do schizonticidal drugs compare with chloroquine?
As a schizonticidal drug, it is less effective and more toxic than chloroquine
Artemether
A peroxide antimalarial (reactive metabolite generator)
Active metabolite of artemether is dihydroartemisinin.
MoA: The interaction of the peroxide-containing drug with heme in the parasite food vacuole results in the formation of a range of potentially toxic oxygen and carbon-centred radicals
Name 3 antimalarial drugs?
Pyrimethamine
Quinine
Artemether
Clobetasone
Glucocorticoid nuclear hormone receptor agonist
Use: Anti-inflammatory, antipruritic, vasoconstrictive effects
MoA: It binds to receptors causing the formation of a receptor-ligand complex, which translocates into the cell nucleus, where it binds to glucocorticoid response elements, causing the increase/decrease in expression of specific target genes (such as cytokine genes)
What are the anti-inflammatory actions of corticosteroids thought to involve?
♣ Induction of lipocortin-1 (annexin-1) synthesis
• Lipocortin-1 prevents phospholipase A2 from inducing eicosanoid production from arachidonic acid.
♣ COX-1 and COX-2 expression is also suppressed, potentiating the effect of reduced eicosanoid production.
♣ Lipocortin-1 escapes to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events e.g. epithelial adhesion, chemotaxis, and phagocytosis.
Dacarbazine
An alkylating agent
MoA: unknown – appears to exert cytotoxic effects via its action as an alkylating agent. Dacarbazine is not cell cycle-phase specific.
Use: A chemotherapy drug
Cyclophosphamide
An alkylating agent
MoA: Cyclophosphamide must be activated in the liver to its metabolite, Aldophosphamide
Use: Antineoplastic used to treat various forms of cancer. A chemotherapy drug.
SE: Sterility, birth defects, mutations, cancer
Alkylating agents work by 3 mechanisms. Name them.
♣ Attachment of alkyl groups to DNA bases, resulting in the DNA fragmentation by repair enzymes preventing DNA synthesis and RNA transcription from affected DNA
♣ DNA damage via the formation of cross-links preventing DNA uncoiling for synthesis or transcription
♣ The induction of mispairing of the nucleotides leading to mutations
Rituximab
B cell CD20 antibody
Rituxan is a genetically engineered chimeric murine (light and heavy chain variable region)/human (constant region) monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes
MoA: Upon binding, rituximab mediates cell lysis, via either complement dependent cytotoxicity (CDC) or antibody dependent cell mediated cytotoxicity
Use: Treatment for Non-Hodgkin’s lymphoma, Chronic lymphocytic leukaemia, and alongside methotrexate for Rheumatoid Arthritis
Doxorubicin
A DNA/RNA synthesis inhibitor
MoA: Doxorubicin is a cytotoxic anthracycline antibiotic. It has antimitotic and cytotoxic activity and is an important class of antitumor drugs against a wide spectrum of tumours, either grafted or spontaneous.
Paclitaxel
A microtubule stabilisation agent (toxoid antineoplastic agent)
MoA: Paclitaxel binds to the β subunit of tubulin causing hyper-stabilization of the microtubule; this prevents the cell from undergoing disassembly and therefore reorganising the microtubule cytoskeleton; this adversely affects cell function, as a dynamic microtubule network is key to effective cellular transport
5-fluorouracil
A pyrimidine analogue
MoA: Anti-metabolites masquerade as purine or pyrimidine and become incorporated into DNA, during the S phase of the cell cycle, stopping normal development and division
Use: Treatment of cancer, breast, colon, stomach and head and neck cancer
Etoposide
DNA Topoisomerase II inhibitor
MoA: Inhibition of DNA topoisomerase II, thereby inhibiting DNA re-ligation; this causes critical errors in DNA synthesis and can lead to apoptosis of the cancer cell.
Etoposide is cell cycle phase specific, which affects S and G2 phases of cell division.
Use: Treatment of lung and testicular cancer
Vinblastine
A vinca-alkaloid
MoA: Primarily the inhibition of mitosis at metaphase; vinblastine causes the crystallisation of the microtubules at the mitotic spindle, leading to mitotic arrest or cell death.
Use: Treatment of bladder cancer, but is also used to treat breast, testicular, and kidney cancer. In addition to its anticancer properties it also has some immunosuppressant effect.
Rituximab
A monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes
MoA: Upon binding rituximab mediates cell lysis, via either complement dependent cytotoxicity (CDC) or antibody dependent cell mediated cytotoxicity
Use: Treatment of Non-Hodgkin’s lymphoma, Chronic lymphocytic leukaemia, and alongside methotrexate for Rheumatoid Arthritis.
Imatinib
Tyrosine kinase inhibitor
MoA: Targets the Bcr-ABL tyrosine kinase; This mutated kinase is formed by the Philadelphia chromosome abnormality in chronic myeloid leukaemia (CML), leading to the constitutive activation of the kinase; The effect of imatinib is to inhibit the cell proliferation driven by Bcr-Al positive cells, whilst at the same time inducing apoptosis
Use: Imatinib is a small molecule kinase inhibitor used to treat chronic myelogenous leukaemia, gastrointestinal stromal tumours, and several other malignancies
Tamoxifen
A selective oestrogen receptor modulator (SERM)
MoA: Tamoxifen is via binding to the oestrogen receptor (ER), leading to a conformational change in the receptor and therefore altering the expression of oestrogen dependent genes. Acts as an oestrogen antagonist.
Use: Breast cancer treatment + infertility
Tretinoin
A naturally occurring derivative of vitamin A and is an important regulator of cell reproduction, proliferation, and differentiation
MoA: Tretinoin binds to alpha, beta, and gamma retinoic acid receptors (RARs). RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukaemia. Furthermore, it induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo
Uses: Acne treatment, photo damaged skin and keratinization disorders (ichthyosis and keratosis follicularis). In addition is used as an anticancer drug to treat acute promyelocytic leukaemia.
