Lecture 7: Pharmaceutical development of drugs to treat neurological and neurodegenerative disorders Flashcards
What is the primary use of anti epileptic drugs?
The prevention and control of epileptic seizures
What would an ideal anti epileptic drug do?
Completely supress seizures whilst showing minimal sedation or other undesirable CNS toxicity. It should have a rapid onset of action following parenteral injection for control of status epiplticus - when one fit follows another without regaining consciousness. It should also have a long duration of effect following oral administartion for prevention of recurrent seizures
What was the first effective anti epileptic?
Potassium bromide, it works by activating GABA receptors, due to the adverse side effects on CNS and the skin, it was replaved by phneobarbital.
What are the characteristics of barbirates?
- Characterised by their barbituric acid core - six membered ring system consisting of alternating amide carbonyl and nitrogen aotm.
- To be pharmacologically Rb and Rc should be alkyl or aryl.
- Most barbiturates are substitued with an ethyl group
- The nature of Rc substitution determines the onset, duration of action and the indictaion
What are the properties of phenobarbitol?
- Low lipophilocity 1.67, so less drug to peripheral tissues
- The lone pair on the nitrogen is not available for reaction with protons so it is not basic it behave as weak acid in solution
- pKa 7.3
- Usually administered in the form of the sodium salt to increase water solubility.
- Phenobarbital bioavailability is greater than 90% when given orally in tablet or elixir form.
- Phenobarbital metabolised by CYP2C9 and C19 also it is inducer of CYP2C9, C19 and CYP3A4 which is responsible for many drug- drug interactions with other AED and non anti convulsant such as hormonal contraceptive.
What are the properties of phenytoin?
- Structuarally relates to phenobarbotol but it doesnt have sedative properties
- Inhibits Na channles
- Slow onset of action
- Long duration of action
- Metabolised by CYP2C9 and C19
- pKa 8.3
- Cyclic amide
- Usually administed as a sodium salt to increase water solubility
- Displays tautomerism
What is the hyantoin family?
- Hydantoin isnt a drug, its derivatives are
- 5 membered ring derived from functional groups urea and amide so has a ureide structure.
What are the structure activity relationship (SAR) requirements for anticonvulsant activity of hydantoin derivatives?
- Substitution in position 5 of the hydantoin molecule is critical with a phenyl group being a preferred substitution;
- Two phenyl moieties at position 5 led to maximal anticonvulsant activity;
- Substitution of a phenyl with an alkyl group broadened the anticonvulsant spectrum; and
- Substitution of a methyl or an ethyl group in position 3 of the hydantoin molecule increased the anti-scMet activity (subcutaneous metrazole seizure test).
- Removal of the phenyl group or substitution with larger aryl groups (e.g. benzyl) decreases or eliminates the anticonvulsant activity.
What can the substitutes on the ureide structure be and what are the drug names?
- Barbiturates eg phenobarbitol
- Hydantoins - phenytoin
- Oxazolidinediones eg trimethadione
- Succinimides eg ethosuximide
What are the most commonly prescribed member of the hydantoin family?
Phenytoin
What are the properties of valproate?
- Achiral short branched fatty acid with eight carbons that does not contain a nitrogen atom or a cyclic ring in its chemical structure
- Water insoluble
- Weak acid
- pKa 4.8
- Sodium salt is freely water soluble and very hygroscopic
- Valproate sodium is converted to its active form, valproate ion, in the blood
- Limited by two rare serious side effects - teratogenicity and hepatotoxicity
What is the structure actovity relationship of valproate?
Increasing the size of the aliphatic group attached to a carboxylic acid fragment also increased anticonvulsant potency.
The results from the tests shows that both anticonvulsant activity and sedation increase with volume and lipophilicity.
What are the properties of Gabapentin?
Belongs to a class of organic componds known as GABA amino acid derivatives. These are amino acids having a (-NH2) group attached to the gammacarbonatom and contain a carboxylic acid so at pH7 it exist as zwitterionic
Water soluble amino acid
Gabapentin was formed by the addition of acyclohexyl groupto GABA, which allowed this form of GABA to cross theblood–brain barrier.
Raises brain GABA levels in patients with epiplesy
Binds to calcium channels
Also used for treating spasticity arising in MS
What is the 2-ene analogue of valproate?
A known metabolite of valproate with similar pharmacological profile. It has similar binding affinity but poorer brain permeation so less effective
What is lamotrigine?
6-phenyl-1,2,4-triazinederivative often used as monotherapy or as an adjunct for partial seizures. It produces a blockage of Na channel reptitive firing. Valproate significantly increases the half life of lamotrigine by inhibiting the N-glucuronidation process which produces lamotrigines major metabolite
What is topiramate?
A sulfamate subtitued monosaccharide derived from fructose with a broad range of anti epileptic activity.
Induced CYP3A4 and inhibits CYP2C19 which results in increased plasma phenytoin levels if co-administed.
Children 4 to 17 can have 50% increase in clearance compared to an adult
Relatively hydrophilic and polar
What is parkinsons disease
Brain disorder that leads to difficulty walking, stiffness and shaking
What is the main treatment for parkinsons disease?
Treatment aims to replace dopamine deficeincy in striatum. This can be accomplished by; augmentation of the synthesis of brain dopamine, stimulation of dopamine release from presynaptic sites, direct stimulation of dopamine receptors, decreasing reuptake at presynptiv sites, decreasing metabolism of dopamine or its precursor L-DOPA, or a combination of these
What is co-beneldopa?
A combination treatment which combines levadopa and benserazide. Dopamine cant cross the blood brain barrier, so the dopamine precurser levodopa is able to cross the blood brain barrier. It is converted into the neurotransmitter dopamine by dopa decarboxylate. To reduce the peripheral side effects of levodopa, it is administered with DOPA decarboxylase inhibitor such as benserazide and carbidopa. These compounds dont cross the blood brain barrier, but selectively prevent the peripheral side effects
What is Co-careldopa?
A combination treatment which combines levodopa with carbidopa
Decarboxylase inhibitors (DCIs) greatly increasel-dopa concentrations that reach the brain by increasing the availability ofl-dopa available to cross the BBB up to 4-fold.(7)This effect allows for administration of lowerl-dopa concentrations in a particular dose to obtain equal therapeutic effects for patients, and it decreases the side effects attributed to peripherall-dopa metabolism, specifically, nausea and vomiting.
Hence the administration of carbidopa is essential to prevent the transformation of externallevodopato dopamine before reaching the main action site in the brain.
What are the properties of levodopa
- 4 hydrogen bond doners
- 5 hydrogen bond acceptor
- logP -2.7
How is L-DOPA peripheral decarboxylation inhibted?
By coadministration of carbidopa or benserazide
What are the properties of Carbidopa?
- Similar structure to L dopa: amine group replaced by hydrazine while the absolute stereochemistry retained and the hydrazine further substituted with methyl group
- It is acarbohydrazide, a member of catechols (Acatecholis an unsaturated six-carbon ring (phenolicgroup) with two hydroxylgroupsattached to adjacent carbons (dihydroxyphenol))
- It is a conjugate base of a benserazide
- Polar
- Inhibitors of extra-cerebral decarboxylase inhibitors
