Drugs Acting on CNS - National University · 2020. 7. 9. · Antiseizure Drugs •The primary use of antiseizure drugs is in the prevention and control of epileptic seizures. •Theoretically,

Drugs Acting on CNS

Dr. Amged SirElkhatim 1

Depressant Drugs


Antiepleptic Drugs

(AEDs)


• An epileptic seizure is a transient symptom of

excessive or synchronous neuronal activity in

the brain.

• Brought about by a disturbance of

physicochemical function and electrical

activity of the brain.

• Manifested as an alteration in mental state,

tonic or clonic movements, convulsions, and

various other psychic symptoms.

• The outward effect can be as dramatic as a

wild thrashing movement or as mild as a brief

loss of awareness.Dr. Amged SirElkhatim 4

• Two possible mechanisms for convulsive

disorders have been suggested:

- A loss of the normal inhibitory control

mechanism.

- A chemical supersensitivity that increases

excitability of neuronal elements.


Seizure Classification:



General Mechanism of Action of Antiseizure Drugs

• Enhancement of GABA-mediated inhibition.

• Suppression of rapid repetitive firing through

inactivation of Na+ channels.

• Reduction of current through T-type Ca++

channels.

• Reduction of excitatory glutaminergic

neurotransmission.



Antiseizure Drugs

• The primary use of antiseizure drugs is in the

prevention and control of epileptic seizures.

• Theoretically, the ideal antiseizure drug

should:

- Completely suppress seizures in doses that do

not cause sedation or other undesired CNS

toxicity.


- It should be well tolerated and highly

effective against various types of seizures.

- Be devoid of undesirable side effects on vital

organs and functions.

- Its onset of action should be rapid after

parenteral injection for control of status

epilepticus.

- Have a long duration of effect after oral

administration for prevention of recurrent

seizures.


Antiseizure Drugs Having Ureide Structure


Non-Ureide Antiseizure Drugs


Hydantoins

• Imidazo-2,4-dione structure.



• Prototype.

• pKa is in the range of 8.06 to 8.33.

• Water soluble sodium salt (pH > 11).

• CO2.

• Erratic absorption (IM, pH< 11).Dr. Amged SirElkhatim 16

• Prototype.

• pKa is in the range of 8.06 to 8.33.

• Water soluble sodium salt (pH > 11).

• CO2.

• Erratic absorption (Intramuscular route).Dr. Amged SirElkhatim 17

• Pro-drug (t1/2 = 8–15 minutes).

• Freely soluble in aqueous solutions.

• IV.

• IM (rapidly absorbed).


Bio-activation of Fosphenytoin


Barbiturates


Benzodiazepines


Oxazolidinediones

• Potential side effects!


Succinimides

• Less toxic than oxazolidinediones!


Iminostilbenes

• Carbamazepine is highly effective and

relatively less toxic.

• Carbamazepine 10,11 epoxide is an active

metabolite (trans-dihydroxy metabolite).

• Oxacarbazepine is a prodrug!Dr. Amged SirElkhatim 27


Eslicarbazepine Acetate

• Improved efficacy and safety.

• Prodrug for (S)-licarbazepine.

• For partial-onset seizures (FDA, 2009).Dr. Amged SirElkhatim 29

Bis-Carbamates: Felbamate

• Approved by the U.S. FDA in 1993.

• Aplastic anemia and severe hepatotoxicity.




Gabapentin

• No direct GABA-mimetic activity.

• It raises brain GABA levels in patients with

epilepsy.Dr. Amged SirElkhatim 33

Valproic Acid

• pKa of valproic acid is 4.7, the drug is

completely ionized at physiologic pH.

• Discovered serendipitously.


Documents

Drugs Acting on CNS - National University · 2020. 7. 9. · Antiseizure Drugs •The primary use of antiseizure drugs is in the prevention and control of epileptic seizures. •Theoretically,