Pmcol 344 drugs Flashcards
Omeprazole
tx of ulcers - proton pump inhibitor
irreversible = long acting (T1/2 = 1 hr but effects last 2-3 days)
weak base → ionized form accumulates outside cell in acid = promotes conversion of prodrug
inhibits some CYP450 enz = potentiation of drug actions ex. warfarin phenytoin, benzos, TCAs
Cimetidine
tx of ulcers- H2 receptor antagonist (Kd H2 = 0.80 uM)
given orally, ↓ basal + stimulated acid secretion by >90% = ↑ pH above 4 (↓ pepsin activity)
promotes healing of ulcers
inhibits some CYP450 enz = potentiation of drug actions ex. warfarin phenytoin, benzos, TCAs
can cause reversible gynaecomastia in men (affinity for E Rs = ↑ prolactin secretion)
alginates
tx of ulcers- antacid
neg charged polysaccharides from algal cell walls
absorb water to form viscous gum (possibly ↑ viscosity + adherence of mucus to stomach lining)
bismuth chelate
tx of ulcers - protect mucosa
colloid
used with triple therapy to tx H.pylori → kills bacteria + prevents adherence
sucralfate
tx of ulcers - protect mucosa
complex of Al(OH)3 + sulfated sucrose
release Al in acidic envir to leave neg-charged complex = binds to proteins + glycoproteins in mucus to form gel
Misoprostol
tx of ulcers - protect mucosa
stable PGE1 analog (reduced metabolism by oxidation)
- mucosal cells: EP1/2 Rs = ↑ HCO3- ; EP4 Rs = ↑ mucus prod.
- ECL cells: EP2/3 Rs (inhibit AC) = inhibit histamine prod.
- inhibits HCl release from parietal cells
- enhances mucosal blood flow
antagonizes effects of NSAIDs = prevents damage/promotes healing
contraindicated in pregnancy (stimulates contractions)
Ipecac
emetic drug
Hyoscine
anti-emetic - mAChR antagonist
acts at vomiting centre + vestibular nuclei
given prophylactically for motion sickness + post-op emesis)
predictable side effects: dry mouth, blurred vision, sedation, constipation
Cisplatin (GIT)
chemo agent
releases 5HT from enterochromaffin cells in GIT + stimulates CTZ/visceral nerves
= chemo-induced emesis
Ondansetron
anti-emetic - 5HT3 R antagonist
acts at CTZ + visceral afferents
used for chemo-induced emesis; less effective against motion sickness
CV side effects → Long QT syndrome
Metoclopramide
anti-emetic - D2R antagonist
CTZ is primary site of action
used for chemo-induced vomiting but less effective than 5HT-3 antagonists
can cross BBB = mvt disorders
tx of constipation
↑ gastric emptying → relaxes pyloric sphincter + smooth muscle
↓ absorption of drugs normally absorbed in stomach (weak acids)
Domperidone
anti-emetic - D2R antagonist
does not cross BBB = no CNS effects
does ↑ gut motility
tx of constipation
stimulate lactation in new mothers
inhibits hypothalamic tonic DA release → pituitary lactotrophs = stimulate prolactin release
Chlopromazine
antipsychotic phenothiazine
anti-emetic
tx of severe nausea + vomiting associated with cancer, radiation therapy, cytotoxic drugs opioids, anesthetics
D2R antagonist → acts in CTZ + blocks histamine + muscarinic receptors
limited by unwanted effects = used as last resort
Nabilone
cannabinoid
anti-emetic
acts in CTZ to suppress output
Dexamethasone
glucocorticoid
anti-emetic
used with chemo; unclear mechanism
Aprepitant
NK1 R antagonist
anti-emetic
action at CTZ + vomiting centre
used in combination with dexamethasone + ondansetron for chemo-induced emesis
Atropine
tx of diarrhea - muscarinic antagonist
block action of ACh = relax gut muscle + ↓ motility
Morphine
tx of diarrhea - opiate
major unwanted effect is constipation
also Codeine, Diphenoxalate
CNS effects
Loperamide
tx of diarrhea - opiate
structurally similar to Pethidine (synthetic opioid agonist) but does not cross BBB
only peripheral effects
commonly used for travellers diarrhea (↓ frequency of cramps, ↓ duration of illness but can cause constipation)
Lactulose
tx of constipation - osmotic laxative
disaccharide of fructose + galactose, macrogols
Bisacodyl
tx of constipation - stimulant laxative
given as a suppository
can stimulate defecation in 15 minutes
Senna
tx of constipation - stimulant laxative
active component (glycoside) directly stimulates cholinergic nerves in myenteric plexus = ↑ peristalsis + defecation
used in combination with stool softeners for chronic opioin-induced constipation
Docusate
stool-softener
Cisapride
tx of constipation - 5HT4 agonist
enhancement of ACh release
blocks cardiac HERG channels = fatal cardiac arrhythmias (LQT syndrome)
also Tegaserod
Prucalopride
tx of constipation - 5HT4 agonist
not linked to ↑ risk of cardiac events
Lubiprostone
tx of constipation-dominant IBS
PGE1 analogue → EP4 receptor = ↑ cAMP to activate CFTR → Cl- efflux = stimulates fluid secretion
↑ fluid in stool → stretches gut + speeds up transit of gut contents
poorly absorbed = selective for gut
Prednisolone
tx for UC/Crohn’s
glucocorticoid
binds members of nuclear receptor superfamily = modify gene transcription = inhibit stages of inflammatory process
mild = rectal enemas (restricted action)
severe = oral
long term = ↓ immune system
Sulfasalazine
tx for UC/Crohn’s
aminosalicylate = maintenance of remission for both disorders
not well absorbed in gut; bacteria in colon release active (5-aminosalicylic acid; mesalazine)
localized anti-inflammatory agent; scavenge free radicals; inhibit PG synthesis
Infliximab
IBD biologic tx
target components of inflammatory pathway:
Anti-tumor necrosis factor-α (TNF-α)
Adalimumab
IBD biologic tx
target components of inflammatory pathway:
Anti-tumor necrosis factor-α (TNF-α)
Golimumab
IBD biologic tx
target components of inflammatory pathway:
Anti-tumor necrosis factor-α (TNF-α)
Vedolizumab
IBD biologic tx
target components of inflammatory pathway:
Anti-α4β7 integrin on T-helper lymphocytes
Ustekinumab
IBD biologic tx
target components of inflammatory pathway:
Anti-protein subunit of interleukin-12 + IL-23 → blocks interleukin binding to IL-12Rβ1 receptors on immune cells
Acetylsalicylic acid
anti-platelet drug
non-selective NSAID with anti-platelet effects
orally active, low dose enough to inhibit platelet fxn
irreversibly acetylates + inhibits COX-1 = prevent TXA2 (potent platelet aggregation stimulator) synthesis
inhibition lasts for life span of platelets
unwanted effects: GI bleeding, ↓ hemostatic fxn, hypersensitivity in asthma/nasal polyps, Reye’s syndrome, ↓ glomerular filtration rate, mild hepatitis
Ticlopidine
anti-platelet drug
first thienopyridine
can cause neutropenia + thrombocytopenia (↓ neutrophils; platelets)
largely replaced by clopidogrel
Clopidogrel
anti-platelet drug
thienopyridine
more selective for P2Y12 = less side effects
often used by ASA intolerant individuals
oral admin → quick metabolism (~5hrs) by CYP2C19
- pts with variant allele = no conversion to active form
side effects: dyspepsia, rash, diarrhea
Prasugrel
anti-platelet drug
newest thienopyridine
faster biotransformation (~30 min) to active metabolite
more efficacious as anti-platelet drug but more bleeding
Ticagrelor
anti-platelet drug
cyclo-pentul-triazolo-pyrimidine
orally active (not prodrug), reversible allosteric P2Y12 antagonist
adverse effects: dyspnea, bradyarrhythmia
Dipyridamole
anti-platelet drug
cyclic nucleotide phosphodiesterase inhibitor = prevents breakdown of cAMP/cGMP → continuous inhibition of platelet aggregation
also blocks adenosine uptake; ↓ platelet TXA2 / ↑ endothelial PGI2 synthesis
not effective alone → used with ASA to prevent TIA + stroke
Abciximab
anti-platelet drug
glycoprotein IIb/IIIa antagonist
mouse/human chimeric monoclonal antibody against receptor protein
Eptifibatide
anti-platelet drug
glycoprotein IIb/IIIa antagonist
synthetic cyclic heptapeptide based on Arg-Gly-Asp sequence
Tirofiban
anti-platelet drug
glycoprotein IIb/IIIa antagonist
synthetic non-peptide based on Arg-Gly-Asp sequence
Warfarin
anti-coagulant
derived from sweet clover, developed as rat poison
oral vitamin K reductase antagonist = stops coagulation cascade
interferes with carboxylation of glutamic acid residues in clotting factors II, VII, IX, X
leads to accumulation of inactive clotting factors that cannot bind to neg surfaces via Ca2+
lots of problems
unfractionated Heparin
anti-coagulant
favours thrombin inhibition
low molecular weight Heparin
anti-coagulant
favours Xa inhibition
more favourable pharmacokinetics - longer elimination half-life = less frequent dosing + more predictable anticoagulation effects
Ribaroxaban
anti-coagulant
reversible, direct competitive inhibitor of factor Xa (high selectivity)
orally active drug, once daily dosing
unwanted effects: bleeding; contraindicated in pts with renal failure
+ Apixiban + Edoxaban
Dabigatran Etexilate
anti-coagulant
reversible direct competitive inhibitor of thrombin
orally active prodrug; once/twice daily dosing
rapidly converted by plasma esterases to dabigatran
unwanted effects: bleeding; contraindicated in pts with renal failure
Hirudin
anti-coagulant
from medicinal leech
specific inhibitor of thrombin
7 KDa protein (65 amino acids)
does not need ATIII
slowly reversible
Lepirudin
anti-coagulant
recombinant hirudin (thrombin inhibition)
Bivalirudin
anti-coagulant
shortened (20aa) hirudin-based synthetic peptide (thrombin inhibition)
Alteplase, Duteplase, Reteplase
thrombolytic/fibrinolytic drug
recombinant tissue-plasminogen activator
IV admin
converts plasminogen to plasmin → breaks down fibrin = clot lysis
tx of stroke
Streptokinase
thrombolytic/ fibrinolytic drug
non-enzymatic protein from hemolytic streptococci
allows plasminogen to gain enzymatic activity by forming stable complex to induce conformational change + expose active site) → breakdown fibrin
inactivated by anti-streptokinase antibodies
Mechlorethamine
Nitrogen mustard (alkylating agent)
myelosuppression
Hodgkin’s lymphoma
Chlorambucil
Nitrogen mustard (alkylating agent)
myelosuppression
Chronic lymphocytic leukemia
Melphalan
Nitrogen mustard (alkylating agent)
myelosuppression
multiple myeloma
Cyclophosphamide
Nitrogen mustard (alkylating agent)
prodrug (metabolized by hepatic cytochrome oxidase) active = acrolein + phosphoramide mustard
myelosuppression + immunosuppression + hemorrhagic cystitis
lymphoid + myeloid malignancies
Acrolein
metabolite of cyclophosphamide
cytotoxic = lung irritant + hemorrhagic cystitis
doesn’t target cancer cells, causes side effects
Ifosfamide
Nitrogen mustard (alkylating agent)
myelosuppression
hemorrhagic cystitis → always given with MESNA
lymphoid + myeloid malignancies
Mesna
mercaptoethanesulfonate
given with cyclophosphamide/ ifosfamide to prevent hemorrhagic cystitis
inactivates acrolein → detoxification
Carmustine
Nitrosourea (bifunctional alkylating agent)
activated in liver
myelosuppression + leukemogenic + hepatoxicity
Lomustine
Nitrosourea (monofunctional alkylating agent)
activated in liver
myelosuppression + leukemogenic + hepatoxicity
Busulfan
Alkyl sulfonate (bifunctional alkylating agent) = intra-strand crosslinks
myelosuppression
used in high doses for bone marrow transplants
Dacarbazine
Triazine (alkylating agent)
active
myelosuppression
glioblastomas + melanomas
Temozolomide
Triazine (alkylating agent)
prodrug → metabolized to Dacarbazine
myelosuppression
glioblastomas + melanomas
Thiotepa
Ethylenimine (alkylating agent)
myelosuppression
lymphomas; breast, ovary, bladder cancer; malignant effusions
Cisplatin
bifunctional alkylating agent
forms intrastrand crosslinks
nephrotoxicity (generation of ROS)
testicular, ovarian, solid tumour cancers
cell-cycle non-specific
Methotrexate
anti-folate (antimetabolite)
blocks DHFR of folate cycle
polyglutamated = also blocks TYMS (↑ efficacy)
cytotoxicity = S phase
myelosuppression + GI ulcers + pulmonary effects
breast cancer, childhood acute lymphoblastic leukemia, osteogenic sarcoma
Leucovorin
rescues normal tissue from MTX toxicity
DHFR-independent conversion to FH4
only taken up in normal cells = used for tx of osteosarcoma
Fluorouracil
pyrimidine analogue (antimetabolite)
nucleobase analogue → becomes FdUMP = inhibits TS (similar anti-folate effect as MTX)
cytotoxicity = S phase
myelosuppression + GI toxicity
breast cancer + colorectal cancers
IV admin
Capecitabine
prodrug of 5-FU
selectivity: enzyme for metabolism is upreg in tumor cells = higher levels of 5-FU produced
oral admin
= replace for tx of gastric cancers
Raltitrexed
specific thymidylate synthase inhibitor
inhibits DNA synthesis → deplete dTMP
cytotoxicity = S phase
tx of colorectal cancer
Cytarabine
pyrimidine analogue (antimetabolite)
nucleoside analogue
prodrug
rapid deamination + clearance
competitive inhibitor of DNA polymerase
cytotoxicity = S phase
myelosuppression
acute myeloid leukemia (combined with an anthracycline drug)
long IV infusions
Gemcitabine
pyrimidine analogue (antimetabolite)
nucleoside analogue
prodrug
inhibits DNA polymerization, inhibits ribonucleotide reductase
cytotoxicity = S phase
myelosuppression
solid tumors - pancreas, lung, breast
Fludarabine
purine analogue (antimetabolite)
nucleotide analogue
inhibition of DNA polymerase + ligase, ribonucleotide reductase, RNA polymerase = prevents elongation of DNA
cytotoxicity = S phase (but also resting cells)
immunosuppression
CLL
6-Mercaptopurine
purine analogue (antimetabolite)
nucleobase analogue → converted into fraudulent nucleotides
inhibits enzymes
cytotoxicity = S phase
myelosuppression
acute lymphoblastic leukemia
6-Thioguanine
purine analogue (antimetabolite)
nucleobase analogue → converted into fraudulent nucleotides
inhibits enzymes
cytotoxicity = S phase
myelosuppression
acute lymphoblastic leukemia
Camptothecin
topoisomerase Ib inhibitor
binds to topI-DNA complex = prevent DNA religation by top
causes DNA ss breaks → apoptosis
problems: low solubility + adverse drug reactions
Irinotecan
topoisomerase Ib inhibitor
semisynthetic analog of camptothecin (substitution of A ring to ↑ solubility)
prodrug: activated by carboxyesterase to SN-38
colon cancer
Topotecan
topoisomerase Ib inhibitor
semisynthetic analog of camptothecin (substitution of A ring to ↑ solubility)
prodrug
ovarian + lung cancer
Doxorubicin
topoisomerase II inhibitor (anthracyclin)
Daunorubicin
topoisomerase II inhibitor (anthracyclin)
solid tumors, leukemia, lymphoma
Idarubicin
topoisomerase II inhibitor (anthracyclin)
AML
Epirubicin
topoisomerase II inhibitor (anthracyclin)
breast cancer
Valrubicin
topoisomerase II inhibitor (anthracyclin)
bladder cancer
Dexrazoxane
type II topoisomerase inhibitor (anthracyclin)
inhibit ATP hydrolysis and DNA release at last step
reduce adverse CV effects for doxorubicin breast cancer tx → iron chelating (antioxidant) activity
Carvedilol
adrenoceptor blocker
antioxidant in cardiac tissue
co-admin with doxorubicin to ↓ cardiotoxicity
Anthraquinones
act like anthracyclines but with fewer adverse effects/toxicities
Etoposide
podophyllotoxin derivatives (topoisomerase inhibitor)
late S/early G2
*myelosuppression
testicular, lung cancer; acute myeloid leukemia
Teniposide
podophyllotoxin derivatives (topoisomerase inhibitor)
late S/early G2
*myelosuppression
testicular, lung cancer; acute myeloid leukemia
better cell accumulation
Vinblastine
antimicrotubular agent (vinca alkaloid)
myelosuppression
Hodgkin’s lymphoma, non-small cell lung cancer
Vincristine
antimicrotubular agent (vinca alkaloid)
peripheral neuropathy
ALL, Hodgkin’s lymphoma, pediatric solid tumors
Paclitaxel
antimicrotubular agent (taxane)
ovarian, breast cancer; lung cancer
Docetaxel
antimicrotubular agent (taxane)
higher affinity for tubulin binding site than Paclitaxel (↓ dose needed)
myelosuppression
ovarian, breast cancer
Noscapine
antimicrotubular agent
sigma opioid receptor agonist
used orally
↓ side effects + ↓ efflux (less resistance)
Tamoxifen
competitive inhibitor of estradiol binding to the ER in breast tissue
prodrug, metabolized in liver by CYP2D6 (higher indiv variability)
tx of ER+ and PR+ breast cancer
prophylaxis for high risk of breast cancer development
side effects: hot flashes (treated with SSRIs), ↑ risk of endometrial cancer, thrombosis
Raloxifene
non steroidal selective estrogen receptor modifier
anti-E action on uterus and breast = tx for ER+ breast cancer w/o ↑ risk of endometrial cancer
agonist action on bone → tx / prevention of osteoporosis in post-menopausal women
Anastrazole
selective aromatase inhibitor = ↓ E2 in body
2nd line hormonal therapy for breast cancer
Leuprolide
GnRH agonist
R desensitization = block the secretion of LH from pituitary = inhibition of testosterone synthesis in testis
Degarelix
GnRH antagonist
Abiraterone
androgen synthesis inhibitor
inhibits CYP17A1 (expressed in testicular, adrenal, and prostatic tumor tissues)
blocks conversion of pregnenolone into 17ahydroxy derivative + subsequent formation of DHEA and antrostenedione
used in castration-resistant prostate cancer
Flutamide
non-steroidal antiandrogen
prodrug → metabolized to 2-OH flutamide = blocks binding of androgens at AR
adverse effects: diarrhea, nausea, vomiting; liver function abnormalities
usually administered with leuprolide
Enzalutamide
androgen receptor antagonist
prevents binding of AR to DNA + AR coactivator proteins
tx of castration-resistant prostate cancer
Herceptin
binds extracellular domain of HER2 R → blocks receptor dimerization + downstream signaling
arrest cells in G1 phase
suppresses angiogenesis
used in combo with chemo
Cetuximab
MCAB against extracellular domain
stimulates EGFR internalization
Panitumumab
MCAB against extracellular domain
fully monoclonal antibody to EGFR
Imatinib
targets BCR-ABL tyrosine kinase
tx of chronic myeloid leukemia
competitively binds to site = inhibits protein → substrate cannot enter kinase site = tumor cell cannot proliferate
Nilotinib
second gen tyrosine kinase inhibitor
active against imatinib-resistant patients
Gefitinib (Iressa)
ATP site competitive inhibitor of EGFR TK activity
effectively inhibits HER1-HER2 heterodimers
non-small cell lung cancer → low efficacy = no longer used as first line tx
Erlotinib (Tarceva)
EGFR inhibitor
more effective for non-small cell lung cancer
Lapatinib
dual EGFR/ErbB inhibitor
Avastin (Bevacizumab)
angiogenesis inhibitor
tx of metastatic colorectal cancer
administered with chemo ex. 5-FU
Bortezomib
proteasome inhibitor
B atom binds catalytic site of proteasome with high affinity + selectivity
prevents degradation of pro-apototic factors = cell cycle arrest + apoptosis
tx of relapsed multiple myeloma
*myelosuppression + peripheral neuropathies
Marizomib
irreversible proteasome inhibitor
less myelosuppression and peripheral neuropathy
