drugs Flashcards
Riluzole
Positive allosteric modulator of the Na+/K+ dependent Glutamate transporter on the plasma membrane of glial cells and neurons. Increases the Glu re-uptake, thus exerting a neuroprotective action.
Amphetamines
False substrate of the Na+/Cl- dependent transporter of biogenic amines on the nerve terminal and on the synaptic vesicles. Amphetamines are transported inside the nerve terminal and the vesicles in exchange for NA or DP therefore causing a durable build-up of the NT-level in the synaptic cleft.
Cocaine
Inhibitor of the transporter for biogenic amines and causes NT build-up in the cleft by inhibiting the re-uptake and enhances the sympathetic transmission. It has side effects on the cardiovascular level. (short acting)
Methylphenidate
Aka Ritalin; inhibits the re-uptake of DA and NA and is used to treat ADHD in children.
Fluoxetine
Selective Serotonin Re-uptake inhibitor; bind to a different binding site to the substrate and enhance serotoninergic transmission. Have side effects in the intestine as serotonin plays a major role there.
Imipramine
Tricylic antidepressant; inhibit NET competitively and have much less effect on dopamine uptake. Wide array of off-target effects: interact with muscarinic acetylcholine receptors and ion channels.
Digoxin
Cardiac glycoside; competitive inhibitors of the Na+/K+ pump in cardiac myocytes by binding to the K+ bindig site. Na+ levels inside the cells are raise, which causes the Na+/Ca2+ exchanger to change its flow and pump Ca2+ inside the cell. As a consequence a stronger heart contraction is promoted. Increased toxicity at low K+ conc and narrow therapeutic margin (causes dysrhythimas)
Omeprazole
Proton pump inhibitor; irreversible inhibitors of the H+/K+ pump on the apical membrane of gastric paretial cells. Omeprazole (racemic mixture) is a pro-drug and a weak base that accumulates in the acid environment of the canaliculi of the stimulated paretial cells where it is protonated into sulphenamide and covalently binds to SH groups of the PP.
Furosemide
loop diuretic; inhibit the Na+/K+/Cl- symporter in the ascending limb of Henle’s loop by binding to the Cl- binding site. Major side effect is the K+ loss in the collecting ducts: K+ are transported into collecting ducts by Na+/K+ ATPase on the basolateral membrane and leak into the lumen through K+ selective ion channels. Na+ passes through sodium channels in the apical membrane down the gradient generated by the ATPase. When more Na+ reaches the ducts more K+ is secreted to maintain that gradient. Have a blood pressure lowering effect by decreasing the ventricular filling.
Thiazides
Thiazide diuretics; competitive inhibitors of the Na+/Cl- symporter in distal tubule in kidney; are more potent than loop diuretics and are therefore used at lower doses. Cause a major loss of K+ in the collecting ducts, but don’t cause Ca2+ loss
K+ sparing diuretics
Aldosterone R inhibitors; compete with aldosterone for its intracellular receptor and decrease the expression of Na+/K+ ATPase and epithelial Na+ channels in the collecting ducts. Prevent hypokalemia and are therefore used in combination with other diuretics
Probenecid
non-selective inhibitor of the uric acid transporter on the apical membrane of renal proximal tubule cells and increase the uric acid secretion by preventing its reabsorption. Also inhibits SLC transporters on the basolateral membrane of renal proximal tubule cells
Lesinurad
selective uric acid transporter inhibitor for the treatment of gout
Elobixibat
inhibitor of the ilieal bile acid transporter responsible for the re-uptake of bile acids; increases the bile salt concentration in the gut and lowers cholesterol levels
Metformin
insulin sensitizer; indirectly target insulin dependent glucose transporters in insulin target tissues. GLUT-4 translocates to the membrane in response to IR activation or when energy demand is high. Metformin activates AMPK, which signals a low energy state (AMP/ATP ratio is high) and decreases hepatic glucose production and promotes glucose uptake.
Glifozins
competitive selective SGLT2 inhibitors on the apical membrane of proximal tubules responsible for the secondary active reabsorption of glucose against its concentration gradient. They cause the kidney to remove glucose from the body through the urine. Side effect: hypertension due to an osmotic effect.
Ivacaftor
Potentiator that increases the functional activity of CFTR channels. Used in cystic fibrosis when a mutation that causes an impaired protein activity is present (G551D). Work by. increasing the open-probability of the channel
Lumacaftor
Corrector that improves the intracellular processing of channel proteins and increase the amount of cell-surface localized proteins. Used for cystic fibrosis when a mutation the causes a reduced amount of protein is present. (Phe508del)
Ataluren
production corrector that prevents premature termination of translation of CFTR channel proteins
Gabapentin
mimics GABA and is approved for epilepsy treatment. Characterized by a non-linear PK profile, since the transporter saturates at clinically used dose. Drug can be chemically modified to pro-drug that hydrolyzes to gabapentin and that is recognized by high capacity MCT-1 transporters in order to improve the PK profile
Lidocaine
local anesthetic that blocks sodium channels in peripheral nerves and prolong the refractory period by binding with high affinity to open. Bind to channel with protonated aminic group and reach the channel through the hydrophilic pathway (use-dependent). Low degree of selectivity : direct vasodilator action and absorption into systemic circulation (administered with adrenalin to avoid this)
Nifedipine
Dihydropyridine; calcium channel blocker that targets Ca2+ channels in the vessels and thus has a antihypertensive effect.
Verapamil
Phenylalkylamine; calcium channel blocker that targets Ca2+ channels in the heart and thus has an antiarrhythmic effect
Diltiazem
Benzothiazepine; Calcium channel blocker that has an intermediate actio on both heart and vessel
GIRK
K channels activated by the beta-gamma subunit of G-proteins in heart and the CNS. Opening causes hyperpolarization and slower heart rate. Indirect target GPCR antagonists or agonists
Sulphonylureas
target ABC family accessory protein of ATP regulated K channels SUR in pancreatic cells. Mimic the ATP increase and therefore cause the channel to close which leads to a depolarization of the cell membrane and the opening of Ca2+ channels that facilitate insulin secretion. Undesired side effects by targeting isoform with different SUR unit in heart and carry risk of hypoglycemia
Minoxidil
K+ channel opener; pro-drug that acts as a potent vasodilator by increasing the activity of K+ channels that leads to a hyperpolarization of the membrane. As a consequence Ca2+ channels are closed
Capsaicin
targets TRPV channels in sensory neurons that are poorly sensitive to changes in membrane potential and works by channel desensitization
tubocurarine
non depolarizing drug; competitively blocks muscle nicotinic avetylcholine receptors on the neuronal muscle junction by antagonizing Ach. Effect is reversible by the action of Ach-esterase or by sugammadex
Suxamethonium
depolarizing durg; selectively binds and activates nicotinic acetylcholine receptors. The prolonged activation with Ach-esterase resistant drugs results in channel desensitization. The block cannot be reversed.
Setrons
antagonists of serotonin 5HT3 LOCs in the chemoreceptor trigger zone and in vagal afferents. Used to control vomiting caused by chemotherapy (cytotoxics release serotonin from enterochromaffin cells). BBB in the CTZ is permeable or not present so the emetic toxins can diffuse through easily.
Benzodiazepines
positive allosteric modulators of the GABA(A) receptor; for binding BZD a His residue in the alpha subunit is required (only receptors formed by alpha 1,2,3,5 and gamma subunits + postsynaptic Rs). Doesn’t have a generalized inhibitory effect, but rather produces effects of variable extent in different areas of the brain. Bind to alpha gamma subunit interface. BZD’s effect is self limiting but they have a synergistic effect with alcohol. Side effects: tolerance, addiction, day-sleep, amnesia
barbiturates
allosteric agonists that bind in the pore of all GABA)A) receptors and are able to activate the receptor on their own. Are not self limiting
flumazenil
competitive antagonist to GABA on the GABA(A) receptor; binds to alpha beta subunit interface
beta-carbolines
inverse agonists that bind on the same spot as BZDs and produce signs of anxiety by inactivating the receptor
Suvorexant
sleep medication that blocks orexin which is produced during the day while the production is inhibited during night
Nuerosteroids
positive allosteric modulators of the GABA(A) receptors; are produced in glial cells from cholesterol and progesterone; bind to GABA with alpha 4/6 and delta subunits (extrasynaptic)
Glycomimetic drugs
Rivipansel: pan-selectin antagonist as it binds to all selectin families
Crizanlizumab: is selective for P-selectins on endothelial cells and platelets
glycomimetic drugs might interfere with intracellular interactions that are vital for homeostasis such as neutrophile migration to infected tissues; also used for the treatment of sickle cell disease by inhibiting selectin mediated adhesive interactions of circulating cells to the endothelium
Catumaxomab
bi-specific antibody that targets EpCAM and CD3 cells and is therefore considered as a T-cell engager and promotes a complex immune response
Dapopotamab
antibody drug conjugate directed against TROP2 (EpCAM-like molecule), which is a transmembrane protein highly expressed in soli tumors; composed of humanized anti TROP2 mAb, a toposiomerase 1 inhibitor payload and a cleavable linker
Abciximab
Fab of chimeric antibody that targets GP IIbIIIa and vitronectin R on platelets and thus prevents platelet adhesion to EC; used in coronary angioplasty
side effect: increased risk of bleeding
Eptifibatide
heptapeptide RGD mimetic that targets GP IIbIIIa with less side effects that abciximab given the lower hemostatic function
Tirofiban
non-peptide RGD mimetic that targets GP IIbIIIa
Revacept
lesion directed antithrombotic durg that selectively targets thrombogenesis at the site of vascular injury;
dimeric fusion protein of the extracellular domain of glycoprotein VI (major platelet collagen R) and a human Fc fragment
Natalizumab
mAb that blocks integrin mediated autoreactive T cell infiltration into the CNS by targeting alpha4/beta1 integrin that binds VCAM to reduce myelin degeneration; treatment of MLS and Crohn’s disease (also targets alpha4/beta7 that binds MADCAM-1 in mucosal vessels of GI tract)
side effects: leukoencephalopathy
Vedolizumab
humanized IgG mAb to a combinatorial epitope requiring alpha 4 and beta 7 integrin subunits; binds MadCAM and has replaced natalizumab for the treatment of Crohn’s disease since it has a safer profile
Cilengitide
peptide that blocks beta 3 and beta 5 integrin and thus has a cytotoxic and pro-apoptotic effect in-vitro (did not pass phase III trial due to lack of efficacy)
etaracizumab
anti-beta3 integrin antibody (under development)
Aspirin
NSAID with antiplatelet effect at low daily doses (80mg) and thus prevents the formation of white thrombi favored by the imbalance between prostacyclin (vasodilator made mainly by COX2) and thromboxane (vasoconstrictor made by COX1); it irreversibly blocks COX1 by Ser520 acetylation (pre-systemically) which leads to the formation of salicylic acid that acts as a reversible inhibitor of COX (prior occupancy of catalytic site by other NSAIDs limits access to target serine); acteylation of COX-2 triggers the production of lipoxins with anti-inflammatory properties
Vorapaxar
competitive to thrombin for its Rhodopsin family GPCR; thrombin is a protease involved in the blood clotting cascade and cleaves the N-terminal domain of its R which generates a new ending domain that acts as tethered agonist; used in combination with aspirin to prevent thrombosis
Exenatide
Incretin mimetics=agonist of GLP1 R; GLP-1 analogue with a high sequence identity (GLP-1 is structurally similar but functionally different from glucagon); peptide hormones secreted by GI tract activate pancreatic GLP-1 R and stimulate insulin secretion (GLP1 R -> AC -> PKA -> K channel closes -> Ca channel opens).
Problem: short half life since they are quickly degraded by dipeptidyl peptidase IV
Extend exenatide’s half life
liraglutide: C-16 fatty acid chain attached that enables it to associate and bind to albumin in the bloodstream that releases it slowly
Dulaglutide: antibody composed of GLP-1 peptide linked through a linker peptide to a Fc fragment of a human IgG4
Semaglutide: first oral GLP-1 agonist exploits the use of salcaprozate sodium to neutralize the pH of the gastric fluid
Gliptins
competitive inhibitors of DPP-4 and can be given in combination with GLP-1 R agonists to extend their half-life; given orally and have pancreatitis as side effect
Maraviroc
negative allosteric modulator of the cytokine receptor CCR5 on T cells and macrophages that is a CD4 co-receptor; HIV enters the cell through the binding of its envelope gp120 to CD4 and CCR5; maraviroc binds to CCR5 and therefore blocks the binding and prevents HIV entry; is functional only against CCR-5 tropic strains od HIV
alternative: leronlimab is a humanized IgG4 mAb against CCR5 (antagonist)
clonidine
alpha 2 receptor agonist that acts as vasodilator
bivalent ligands
e.g. formed by MOPr agonists linked by a spacer to a DOPr antagonist should retain the desired analgesic effect of morphine with less respiratory depression
AT1-B2 dimer
vasodilating response to bradykinin decreases and the vasoconstrictor resoponse to angiotensin II increases (the formation of the dimer increases the sensitivity to ATII)
Erenumab
mAb raised against a fusion protein of the extracellular domain of human calcitonin like receptor and RAMP1 that includes the CGRP binding pocket and is used for the prevention of migraine since CGRP is a potent vasodilator that has a role in pain transmission
migraine treatment
triptans: old treatment and are not selective 5-HT agonists
Lasmiditan: 5-HT1 agonist that prevents CGRP release
Gepants: oral CGRP antagonists are indicated for acute migrain
mAbs: anti CGRP used fro the prevention of migraine
beta blockers
prevent the activation of beta 1 adrenergic receptors in cardiac cells (lead to calcium troponin mediated contraction); activation leads to formation of cAMP that has a direct effect on ion channels promoting membrane depolarization; PKA (activated by cAMP) indirectly activates Ca2+ VOCs and causes Ca induced Ca release;
used for hypertension; non-selective antagonists cause bronchoconstriction by affecting beta2 Rs as well (bisoprolol, carvedilol …)
Beta 2 receptor agonists
used for asthma since the cAMP/PKA pathway mediates relaxation in SMC by inhibiting MLCK and its phosphorylation of MLC;
asthma
distinguish chronic inflammatory disease of airways (treated with corticosteroids) or a recurrent reversible airway obstruction in response to several stimuli (treated with broncodilators)
SABA: short acting used on demand (e.g. salbutamol)
LABA: longer acting used in combined therapies with glucosteroids
side effect: tachycradia due to vasodilation
theophylline
used for asthma; inhibitor of phosphodiesterase
side effect: arrhythmias since it is a competitive antagonist of adenosine receptor (enprofylline is a PDE inhibitor devoid of adenosine antagonism)
sildenafil
aka viagra; targets PDE5 competitively in vascular smooth muscle cells to address erectile dysfunction; PDE5 breaks down cGMP; NO is a vasodilator released from the endothelium and bind to guanylyl cyclase Rs increasing cGMP levels and causing vasodilation
Fasudil
Rho kinase inhibitor; acts as a vasodilator used in pulmonary hypertension; Rho kinase is responsible for the inhibition of MLC-phosphatase (dephosphorylation of MLC results in relaxation); downstream of GPCRs coupled to G12/13 (calcium independent contraction)
Bosentan
Endothelin R antagonist (coupled to both Gq and G12/13);
endothelin levels increase up to ten fold in patients with pulmonary arterial hypertension -> vasoconstriction and proloferation of pulmonary VSMCs that is inhibited by ET-A R antagonists
biased agonists
agonists that show preference for an effector pathway over another downstream tha same GPCR; R coupled to the same G protein do not show sequence homology in the regions involved in G protein binding: G protein binding is dependent on specific 3D conformation that is selectively stabilized by a biased agonist
opioid R activation: analgesic effect induced by G coupled signal while the side effects (respiratory depression) are driven by beta-arrestin signals that are responsible for R desensitization and internalization -> selective Gi based MOR agonists have been identified (TRV130) for treatment of pain
carvedilol: is a arrestin biased agonist that drives the nitric oxide production and is able to stabilize the R conformation that is uncoupled to the G protein
sotarasib
KRASG12C OFF inhibitor; able to bind a cysteine in KRAS with G12C mutation (normally KRAS has a very smooth surface that does allow binding pockets); locks KRAS in the inactive GDP conformation by binding to it in an allosteric manner and therefore requires GTP hydrolysis for inhibition; RGS3 proteins are able to enhance the GTPase activity of mutant and wild type KRAS;
approved for non-small-cell-lung cancer
vemurafenib
targets the oncogenic V600E RAF involved in metastatic melanoma and induces cell proliferation and survival;
resistance occurs after 6 months of treatment due to constitutive active RAS or mutations in MEK or activation of PI3K/AKT/mTOR pathway
dabrafenib is a more potent V600E RAF inhibitor
trametinib is a mek inhibitor
imatinib
binds a cytoplasmic mutated kinase encoded by the Abl proto-oncogene by competing with ATP for it binding site;
is a tyrosine kinase inhibitor; used in adults diagnosed with philadelphia chromosome positive myeloid leukemia (generation of constitutively active fusion protein Bcr-Abl) and patients with Kit positive malignant gastro intestinal stromal tumors (cKIT is receptor responsible for signaling in GISTs)
side effects: edema, myelosupression
alternatives: dasatinib, nilotinib
VEGF
bevacizumab: binds VEGF-A and prevents R activation
aflibercept: fusion protein of VEGFR1 and VEGFR2 and an Fc fragment = soluble R that traps VEGF-A
ramucirumab: mAb against VEGF-R
side effects: bleeding, wound healing defects, hypertension
trastuzumab
targets HER2 oncoprotein by binding to the extracellular domain and thus prevents proteolysis of the EC segment and aggregation -> induction of phagocytosis through Fc of IgG1 and cytokine release leads to downregulation of R
side effect: increased risk of heart problems, since HER-2/HER-4 signaling is relevant in the heart for the maintenance of contractile function
Ado-trastuzumab-emtansine is an armed antibody that delivers a cytotoxic agent to the target cell (DM1 is a strong antimicrotubular agent)
Pertuzumab
humanized mAb that binds to the HER2 extracellular domain (domain II) in a different manner than trastuzumab (domain IV) and specifically inhibits dimerization
Tyrosine kinase inhibitors of HER-2
lapatinib: reversible, approved for breast cancer with HER2 overexpression
neratinib: irreversible
also inhibit the truncated R
anti HER-1 agents
cetuximab: EGFR expressing tumors (colorectal cancer) negative for KRAS mutation
osimertinib: irreversible inhibitor of T790M mutated EGFR approved for non small metastatic non small cell lung cancer
