M&C Exam 3 - Drugs

Lidocaine

Blocks Na+ channels that are rapidly and repeatedly activated and inactivated through state-dependent binding that penetrates deep into the channel via hydrophilic pore or hydrophobic cell membrane and attaches on the inner face (local analgesic/pain relief - short duration)

Tetrodotoxin (TTX), Pufferfish Toxin

Physically blocks channel due to bulky occlusion - has a guanidinium group that blocks the superficial binding site on the extracellular end of the pore (VERY POTENT AND DIFICULT TO CONTROL TOXICITY)

Capsaicin

Targets transient receptor potential channels - prolonged use can increase conductance for large cations and may lead to larger pore diameter

Scorpion venom/ toxin

Activates the voltage gated Na+ channel Nav1.7 but has no effect on Nav1.8, although earlier studies with grasshopper mice showed Nav1.8 is important in pain signaling (potential analgesic/pain relief target)

Suzetigine (VX-548, Journayx)

First in class non-opioid analgesic for acute pain in adults as it selectively inhibits the Nav1.8 voltage gated Na+ channel expression in pain sensing neurons

Caffeine

Effects calcium entry and exit by reversibly disrupting calcium channels (voltage gated, L-type, and Ryanodine receptors)

TZD Drug Class

Insulin sensitizing drugs that act as PPAR gamma agonists (effective in improving insulin sensitivity and treating T2D)

Troglitazone

The first TZD in the clinic, PPAR-gamma agonist for T2D - taken off the market due to drug-induced liver damage

Rosiglitazone (Avandia)

PPAR-gamma agonist used for T2D - increased risk of myocardial infarction and cardiovascular events

Pioglitazone (Actos)

Targeted PPAR-gamma but was shown to be associated with an increase in serious heart failure, although at a significantly lower risk of myocardial infarction and death 

Muraglitazar

PPAR-alpha /gamma dual agonist for T2D - found to be associated with major cardiovascular events and increased incidence of death

Elafibranor

PPAR-alpha and delta agonist to increase lipid oxidation for treatment of primary biliary cholangitis (PBC)

Estradiol

A natural oestrogen

SERMs (Raloxifen, Tamoxifen)

Selective estrogen receptor modulators and partial agonists in some tissue but antagonists in others

MDV3100 (Enzalutamide)

Androgen receptor inhibitor used for mCRPC and non-mCRPC

Abiraterone

Oral androgen/CYP17 inhibitor used for advanced prostate cancer

Ketoconazole

A broad-spectrum imidazole anti-fungal that has inhibitory effects on gonadal and adrenal steroidogenesis - used for second line treatment of prostate cancer

Androgen deprivation therapy (ADT)

Involves the use of luteinizing hormone-releasing hormone (LHRH) drugs, resulting in a 90-95% reduction in circulating levels of testosterone - can also be called ligand-reduction therapy

Oestrogens

Acts in association with progesterone by decreasing oestrogen receptor expression - balances between expression of ER alpha and ER beta and used as a contraception replacement therapy

Tamoxifen

anti-oestrogen SERM used for oestrogen-sesitive breast cancer to inhibit the expression of ER alpha target genes that regulate cell cycle and apoptosis

Raloxifene

Anti-oestrogen SERM that is less used but results in less bone loss

Clomiphene

Anti-oestrogen used for treatment of infertility by blocking oestrogen binding in the anterior pituitary to induce ovulation

Androgen

Actions similar to testosterone used for hormone therapy 

Anti-androgens

Receptor therapy used for mCRPC (ex. Galeterone)

Aspirin

Non-selective COX inhibitor that has side effects of gastric mucosal damage and erosions 

Acetaminophen

Non-selective COX inhibitor that doesn’t have a well known mechanism - correlated with liver toxicity but may be mediated by Cytochrome P450 1A2 (excellent at analgesic and antipyretic, but anti-inflammatory activity is slight and selective)

COXIBs

COX-2 inhibitors that suppress prostanoid synthesis in inflammatory cells and have three major actions: anti-inflammatory (decrease E2), analgesic (decreases sensation in nerve endings), and antipyretic (prevent IL-1 releasing prostaglandins into CNS)

Celecoxib (Celebrex)

Selective COX-2 inhibitor (COXIB) that has a potential to enhance clotting due to cardiac issues

Rofecoxib (Vioxx)

Selective COX-2 inhibitor (COXIB) that was voluntarily withdrawn from market since it had the potential to increase heart attack and stroke

Sulindac

NSAID used for arthritis and also effective in colon cancer prevention - believed to be a dual COX-1/2 inhibitor (reducing prostaglandins)

NSAIDs

Inhibition of arachidonic acid oxidation by the fatty acid COXs - include asprin and acetaminophen

Curcumin

Non-specific antioxidant from turmeric, thought to inhibit lipoxygenases and COX-2 (causes NFKB to remain dormant, reducing inflammation)

Licofelone, Flavocoxid

Dual inhibitor targeting COX and 5-LO (5-lipooxgenases in leukotrienes) - used for treating inflammation in osteoarthritis

Casgevy

Ex-vivo gene therapy for sickle cell disease and beta thalassemia (CRISPR/Cas9 mediated)

Lyfgenia

Ex-vivo gene therapy for sick cell (lentivial mediated)

Zynteglo

Ex-vivo gene therapy for beta thalassemia (lentiviral mediated)

Luxturna

In vivo direct targeting treatment for retinal dystrophy - mediated by modified AAV vector

Zolgensma

In vivo direct targeting treatment for spinal muscular atrophy - mediated by modified AAV vector

Hemgenix

In vivo direct targeting treatment hemophelia B - mediated by modified AAV vector

Elevidys

In vivo direct targeting treatment Duchenne muscular dystrophy - mediated by modified AAV vector

Anti-oestogens

Compete with natural oestrogens for receptors in target organs (SERMS)