MedChem Exam I

• Chloramphenical
• Carrier Linked Prodrug, drugs that are attached through a metabolically labile chemical linkage to another molecules designated as the promoiety

• Esterase or water cleaves off the sodium succinate making it an active drug
• serious infections, monitor for blood dyscrasiasfac

Alcohol hydroxyl oxygen gluconrides

Estermustine Sodium Phosphate

Mutual Prodrug, Carrier linked prodrug in which the promeity is also a drug

The products are sodium phosphate and nornitrogen mustard --> Aziridine

Used to treat of progressive or metstatic carcinoma of the prostate

• Antobiotic used to treat upper and lower respiratory infections, legionnaire's disease skin infections
• Very bitter substance and easily destroyed at acidic pH

Add two functional groups

Prodrug

Propionate ester to increase lipid solubility

Lauryl sulfate salt, absorption not affected by food, less bitter after taste and is acid stable

Penicillin have the beta lactam ring with the r group as the prodrug, with the r being ethyl, propyl, butyl, phenyl group that needs to be cleaved for it to be active

Esterase cannot cleave by itself needs to be be an double ester for esterase to act on it, cleaves the carbonate and then the ester spontaneously leaves leaving the active drug

Taking with food increases absorption

Amine derivatives as prodrugs

Tetracycline with increased water solubility

Tetracycline Reacts with formaldehyde to form rolitetracyline

• Sulfasalazine
• Azolinkage as a prodrug
• Sulfoamide antibiotic and anitinflammatory used to treat ulcerative colitis, rheumatoid arthritis
• Bacterialreductase lead to reductive cleavage releasing 2 amine compounds
• occurs in the colon: discourages small intersinte systemic absorption and concentrates the drug at the desired site of absorption

• Methenamine hippurate
• Carboonyl compound derivative as prodrugs
• USed for prophylaxis or suppression/elimination of frequent UTI espeially for long term use
• The lower the pH the faster the rate of formation of formaldehyde in the urine in the blood sream

• Nabumetone
• Bioprecursor prodrugs, oxidation example, do not contain promeity, they contain latent functionality that is metabolically or chemically transformed into an active drug
• Non-steroidal antiinflammatory, arthritis
• Active form of drug that inhibits prostaglandin biosynthesis by cyclooxygenase

• Mitomycin
• Bioprecursor prodrug, reduction example
• Oncology for use in Adenocarcinoma of the stomach and pancreas
• A quinone, reduction, to hydroquinone, loss of OCH3, loss of H+, Loss of CO2 and NH3, Further alkylation for the active drug

• Iodoxuridine
• Bioprecursor prodrug phosphylation example
• Has halogen makes it lipid soluble
• Opthalmic product for herpes simplex keratitis, higher affinity for viral kinases than mammalian kinases but some toxcity

Two mechanisms of actions: inhibits DNA polymerase, causing incorrect base pairing

• Anti-Parkinsonism agent
• Dopamine does not cross the blood brain barier efficiently is rapidly metabolized bu oxidatvie deamination and can cause peripherial side effects

Methylation conjugation

how the drugs are processed by the body

how the drug works on the body

• compounds that enhance metabolism
• phenobarbitol, carbamazepine, rifampin

• A piperidine based sedative hypnotic
• two different enatiomers with different effects

Phenytoin

• Steroselective that is an oxidative process hydroxylation
• there are two different enatiomers 90%of one and 10%of the other

• Papaverine
• Regioselective metabolism: refers to selective meabolism of one or 2 or more of the same functional group within a part of a molecule: has four OMe groups for the demethylation to occur, the methyl group that is next to the heteroatom
• Smooth muscle relaxer used as a peripherial vasodilator

• Primarily oxidative with functional group changes mediated principally by Cytochrome P450
• Addition of a polar functional group

• Conjugating enzymes that usually add a hydrophilic molecules o drug o a phase 1 etabolite
• to increase water solubility

Efflux pump systems that facilitate the remval of the meabolites from cells to the urine or bile

With normal amount of drug there is very low concentration of drug needs to saturate the first pass effect, once the first pass effect enzymes are saturated then normal concentration of drug are seen

• Lidocaine
• First pass effect exampl of de-ethylation, oxidative dealkylation
• Not useful for treatment of ventricular arrhythmias since activity is lost upon first pass effect throught the liver due to inactivityof the two de ethylated metabolites
• Tertiary aliphatic and alicyclic amines

• Diazepam
• Oxidation reactions
• Selectivity: oxidation occurs at the most electron rich carbon, on the benzene ring

Oxidation at alpha carbon loated next to carbonyls and imines



Oxidation of Amides- Hydroxylation alpha to the amine nitrogen product of desmethylDiazepam

• Carbamazepine
• Oxidation of carbon carbon double bonds: OLEFINS
• Leading to epoxides, then 1,2 diols
• Subjuct to glutathione conjugation
• Primary drug for partial and clonic tonic seizures
• 30% urinary metabolites with the balance as glucuronide conjugates
• POtent anticonvulsant activity

• Secobarbitol
• Olefinic Oxidation
• both process via an intermediate epoxide
• Two metabolites Secodiol, P450 Heme Nitrogen
• The P450 Heme Nitrogen has irreversible destruction and leads to liver failure

• Metoprolol
• Benzylic oxidation
• Beta adrenergic blocker

• Tolmetin
• Benzylic oxidation
• Anti-inflammatory analgesic

• Pentazocine
• Oxidation at Allylic Carbons: allylic carbon is the carbon adjacent to carbon-carbon double bound
• Narcotic used for pain or pre/post operative anesthesia

• Quinidex Extentabs (sulfate salt)
• Quinagulate Dura-Tabs (sulfate salt)
• Quinalan (gluconate salt)
• Cardioquin (gluconate salt)
• Oxidation at allylic carbons
• antiarryhthmic

oxidation at allylic carbons

• Oxaepam
• Oxidation at alpha carbon located next to carbonyls and imines
• antianxiety

• Oxidation at alpha carbon located next to carbonyls and imines
• 3-7days for insomnia Schedule II

• Chlorpropamide
• Oxidation at aliphatic carbons

• Ibuprofen
• Oxidation at aliphatic carbons
• Non-steroidal antiinflammatory

Acetohexamide

• Oxidation at alicyclic carbons
• Oral antidiabetic agent
• a sulfonylurea

• Minoxidil
• Oxidation at alicyclic carbons
• Severe unresponsive hypertension
• Male pattern baldness

• Chlorpromazine
• Tertiary aliphatic and alicyclic amines

• Tertiary aliphatic and alicyclic amines
• antiemetic, antivertigo, antipsychotic
• bad n/v

• Propranolol
• Oxidation of secondary and primary amines
• a non selective beta0adrenergic blocking agent

• Methylphenidate
• Oxidation of secondary and primary amines
• USed for atentiondeficit disorders and narcolepsy

• Ionamin, Adipex-p, Zantryl, Fastin
• Oxidation fo secondar and primary amines
• Managemnt of obesity

• Oxidation of secondary and primary amines
• Attention deficit disorder
• narcolepsy
• Remember n-hydroxy compounds are chemicaly unstable

• Trimethoprim
• Oxidation of NItrogen Hetercycles
• Dihydrofolate reducatase inhibitor

• Oxidation of Amides- Hydroxylation alpha to the amine nitrogen
• Alkylating agent

• Thiopental
• Oxidation of carbon sulfur bonds
• INduces anethesia to get you through tage 1 of anesthesia
• MEtabolite pentobarbitol

• THrioridazine
• Sulfur oxidation
• antipsycotic, tranuilizer
• Metabolite: mesoridazine = serentil

• Halothane
• Oxidative dehalognations
• General anethetic
• Hepatic Damane

• Oxidative aromatization or dehydration
• A progstin used in OC's
• AROMATASE

• Warfarin
• Bioreduction fo ketones is often sterospecific or steroselective for one isomer over the other
• Has two diasteromer a major and minor
• Anticoagulant

Enol oxygen glucuronides

• Dantrolene
• REduction of NItro and Azo compounds
• Direct acting skeletal muscle relaxant

• Disulfiram
• Disulfate bond cleavage
• Treatment of chronic alcoholism

• Sulindac
• Cleavage of sulfoxide group
• Non-steroidal antiinflammatory

• Clofibrate
• Hydrolysis of esters
• Antihyperlipidemic agent

• Prazosin
• Hydrolysis of amides
• Amides are more difficult to hydrolyze relative to esters
• Antihypertensive, alpha1 adrenergic blocker

• APAP, N-acetyl-p-aminophenol
• Phenol hydroxyl glucuronides

• Fenoprofen
• Carboxylate hydroxyl glucuronide
• Non-steroidal anti-inflammatory

• N-hydroxy metabolite
• N-hydroxyl glucuronide
• USed in treatment of leprosy, pneumocystis carinni pneumonia

BROWN RECLUSE SPIDER BITES

• alpha-methyldopa
• Sulfate conjugation
• antihypertensive

• Albuterol
• Sulfate conjugation
• A sympathomimetic bronchodilator
• USed for treatment for bronchospasms in COPD

• Isoniazid
• Conjugation with glycine
• Antituberculosis

• glutathione nuclephilic displacement conjugation
• A nitrate vasodilator for the treatment and prophylaxis of angina pectoris

• Azathioprine
• glutathione nucleophilic displacement conjugation
• Immunosuppressant for the treatment of transplantation and rheumatoid arthritis

• Ethacynic Acid
• Glutathione Michael Addition conjugation
• Loop diuretic used edema from CHF renal nd hepatic disease

Clonazepam

• N-acetylation conjugation
• anticonvulsant benzodiazepine

• Hydralazine
• N-acetylation conjugation
• Antihypertensive vasodilator

• Terbutaline
• Methylation conjugation
• Asympathomimetic brchodilator

• Amantadine HCL
• N-methylation conjugation
• Anitparkinsonism and antiviral

• S-methylation conjugation
• Used for hyperthyroidism mainly by preventing T3 and T4 synthesis