PHAR 736 Final Exam Structures Flashcards
Acetylcholine
Muscarine
Nicotine
Physostigmine | Reversible AChE Inhibitor
Plant Natural product - used in 1877 for Glaucoma
Carbamoylated intermediate 10^10 fold more stable to hydrolysis than acetylated intermediate | AChE half-life for regeneration 3-5 minutes
Neostigmine Bromide | Reversible AChE Inhibitor
Two Important Gruops: Quaternary ammonium, dimethylcarbamate
Half-life for regeneration 30-60 minutes
Used for Myasthenia Gravis
Edrophonium Chloride | Reversible AChE Inhibitor
No group to transfer to active site serine | Can’t covalently modify the active site
Important groups: Quaternary ammonium
Short duration of action | often used to diagnose Myasthenia Gravis
Donepezil | Non-covalent Reversible AChE | Alzheimer’s
Structure Importance: Two aromatic rings bind aromatic residues in AChE channel giving more affinity; structure developed base on crystal structue of AChE
Good AChE selectivity over BuChE
T1/2 greater than 70 hours | Once daily dosing | O-demethyl active metabolite (from 2D6 and 3A4) | significant aount excreted unchanged
Rivastigmine | Reversible AChE Inhibitor | Alzheimer’s
Structure: Carbamate group (covalent modifier), S-enantiomer active
Lacks selectivity for AChE over BuChE
T1/2 = 1.5 hr | Extended, 10 hour duration of action | Dosed BID or QD as transdermal patch
Galantamine | Non-covalent modifier | Isolated from daffodils | Alzheimer’s
Features help provide affinity for AChE | Some selectivity for AChE over BuChE
T1/2 = 7 hours | Dosed BID or QD as an ER formulation
Huperzine A | Natural product form Chinese Club Moss | Reversible, non-covalent modifier | AChE Inihibitor
Structure: Primary amine that can be protonated | Aromatic ring
Considered a natraceutical | Unregulated in dietary and herbal supplements | Has pharmacological properties
Echothiophate Iodide | Organophosphate | Irreversible AChE Inhibitor
Has thiocholine group
Phosphorylated-Serine (Di-ethyl) intermediate has half-life of regeneration of 8 hours | Aging can occur and results in resistance to hydrolysis and inactivation of AChE
Limited to use in eye for glaucoma and other conditions | Effects last days to weeks
Sarin | Nerve Gas | Irreversible AChE Inhibitor
Bulkier group than O-Et
Slow regneration | Significant aging
Malathion | Pro-drug Pesticide | Irreversible AChE inhibitor
Used to treat lice
Metabolism: Oxidized (slow in humans and insects) to Malaoxon, an effective AChE inhibitor, followed by breakdown with phosphatases (occuring slowly in insects); Plasma-carboxyesterases break cleave to inactive product fast in mammals
Pralidoxime Chloride | AChE Reactivator
Aromatic ring and (+) charge give high selectivity for AChE | Hydroxylamine-like nucleophil needed to access modified serine
Can’t reactivate aged enzymes
Verenicline | Nicotinic Partial Agonist | Full agonist at a7 containing receptors
Cytisine
Plant natural product from Cytisus sp. | Used in Eastern Europe for Smoking Cessation
SuccinylCholine | Depolarizing Neuromuscular Blocking Agent (all are symmetrical or dimer-like molecule)
Causes muscle paralysis | Rapid onset (1 minute) short duration (10 minutes)
Rapid hydrolysis by BuChE and plasma cholinesterases
Undesirable Side Effects: Hyperkalemia
Tubocurarine | Non-depolarizing, competitive antagonist and Neuromuscular Blocking Agent
Plant natural product component of Curare
Contains Benzyl-isoquinolones
Long duration (80-120 minutes) | SEs include histamine release
Cisatracurium Besylate | Nondepolarizing neuromuscular blocking agent
Protons alpha to carbonyl slightly acici, leading to easier deprotonation for the elimination reaction | 1R-cis 1’R-cis most effective enantiomer of original product, Atracurium
Intermediate duration (30-40 minutes) | No histamine release
Main route of inactivation is non-enzymatic Hofmann elimination | Some ester hydrolysis
Pancuronium Bromide | Nondepolarizing Neuromuscular Blocking Agent (Ammonio Steroid)
Steroid backbone provides spacing between positive nitrogens
Long duration of action (2-3 hours) | Has 3-desacetyl metabolite, retaining some activity
Vecuronium Bromide | Nondepolarizing Neuromuscular Blocking Agent (Amonnio Steroid)
Intermediate Duration (60-90 minutes) | Has 3-desacetyl metabolite
Rocuronium Bromide | Nondepolarizing Neuromuscular Blocking Agent (Ammonio Steroid)
No 3-acetyl group | No active metabolites
Sugammadex | SRBA (Selective Relaxant Binding Agent)
Positive charges on ammonio steroids (Rocuronium and Vecuronium) interact with negative charges lining the cavity of the cyclodextrin | Complex is excreted | Pancuronium has little affinity
Dorzolamide | Carbonic Anhydrase Inhibitor
Designed to fit active site of Carbonic Anhydrase
Structure: Thiophene group; Aryl sulfonamide group (potential for hypersensitivity/sulfa reaction)
Used topically in the eye 2-3 times daily
Brinzolamide | Carbonic Anhydrase Inhibitor
Structure: Thiophene group; Aryl sulfonamide group (potential for hypersensitivity/sulfa reaction)
Used topically in eye 2-3 times daily
Prostaglandin F2a | Endogenous
Increases outflow of aqueous humor, lowering intraocular pressure
Limitations: Poor penetrance due to negatively charged carboxylate, Rapid metabolism (oxidized at C-15 hydroxy followed by further beta and omega oxidation)
Latanoprost | Prostaglandin Analog Prodrug
Isopropyl ester and aromatic ring slow oxidation and increase penetrance into the eye
Long duration in eye with minimal side effects | T1/2 in plasma 17 minutes (beta oxidation)
Latanoprostene bunod | Prostaglandin Analog | Dual-action Prodrug
Butanediolnitrate group cleaved to active | Latanoprost Acid + Nitric Oxide regulates IOP
Travoprost | Prostaglandin Analog | Ester prodrug
Has trifluoromethyl
T1/2 in plasma (45 minutes)
Bimatoprost | Prostaglandin Analog | Ethyl Amide Derivative (Prostamide)
Amide Prodrug
T1/2 Plasma (45 minutes)
Tafluprost | Prostaglandin Analog | Isopropyl Ester Prodrug
Short Plasma T1/2 Due to Beta Oxidation
All prostaglandin analogs to treat glaucoma are dosed once daily
