Pharm - FINAL CNS drugs I

Chemical
Neurons using distinct NTs are organized functionally in CNS
Some drugs may only affect one pathway
Other drugs may cause a more general response (ie. overall excitability of CNS)

A function of CNS capillaries; tight junctions btw endothelial cells, as well as astrocytes and bsmt membrane make it difficult for substances to diffuse into CNS
The BBB isn't something physical that you can see under a microscope - it is a function of the selective tight junctions of the capillaries

1. Pre-snyaptic potential
2. Synthesis of NT
3. Storage of NT
4. Release
5. Reuptake
6. Degradation
7. Postsyaptic receptor
8. presynaptic autoreceptors
9. Membrane effects

Drug blocks propoagation along neural axons so AP fails to reach snyapse

Drugs can block synthesis of NT

Usually a certain amt of NT is stored in presynaptic vesicles
Drugs dec this storage dec the ability of the synapse to continue to transmit info

Drugs inc synaptic activity by directly increasing release of NT from presynaptic terminal
Can also impair the release by directly decreasing the amt of NT released during each AP

Reuptake = send NT back to presynaptic terminal
Block this and NT is allowed to remain in cleft and exert its effect

Inhibit the enzyme that causes degradation of the NT (ie. cholinesterase inhibitors for MG or MAO inhibtors for depression)

Antagonist can block receptor
Allosteric modulators can bind to receptor and inc effect of NT (ie. valium)

During high levels of synaptic activity, the accumulation of NT in the cleft may allow binding to the presynaptic receptors and limit futher release of NT
This a form of negative feedback
Certain drugs appear to be able to bind to these presynaptic autoreceptors and dec NT release.. or you could block these autoreceptors which would result in more NT

Drugs can alter transmission by affecting membrane organization and fluidity
Allow vesicles to dock
Change presynaptic poential

Chronic neurological d/o characterized by recurrent seizuers

Episode of sudden, transient disturbances in cerebral excitation
Sufficient # of neurons begin to fire rapidly in synchronized bursts
A group of hyperexcitable nerves intitiate the seizure

Incident: CVA, TBI, brain tumor
Genetic or birth trauma
We dunno

Inhibit firing of cerebral neurons thru...
Inc inhibitor effects of GABA
Dec effects of excitatory NTs (glutamate)
Alter Na and Ca movt across membranes

Seizure recurrence causes more damage to already injured nerves, and may also injure healhty ones

1. Partial
2. Generalized (absence, myoclonic, clonic, tonic, tonic-tonic)
3. Status epilepticus

Only part of brain is involved vs. whole brain involvement

Petit mal: sudden, brief LOC, may or may not have mo. signs

General seizure: mm contraction in part of the body, may or may not LOC

Grand mal: mm contraction t/o body and LOC

Series of seizures without recover of conscioussness bw attacks: life-threatning
May stem from numerous factors: ischemic CVA, systemic or intracranial infection, drug/alcohol withdrawl?

1. Barbiturates (phenobarbital {Solfoton}): back up/adjunct drug
2. Benzodiazepines (diazepam {valium} and Lorazepam {ativan}): Status epilepticus
3. Carboxlic acids (Valproic acid {Depakote}): partial, tonic-clonic, absence, and myoclonic
4. Hydantoins (phenytoin {Dilantin}): tonic-clonic and partial
5. Iminostilbenes (carbamazepine {Tegretol}): Tonic-clonic and partial
6. Succinimides (ethosuximide {Zarontin}): absence
7. Neurontin (gabapentin): parital

Drug of choice for controlling seizures in infants, may be used in adults (particularly for hard-to-control seizures)
Phenobarbital (Solfoton)
Inc inhibition of GABA and inhibit Ca entry into presynaptic terminal = dec release of Glutamate
Drowsiness and sedation

Tx status epilepticus, Klonotin treats absence seizures
Diazepam (valium), lorazepam (Ativan), Clonazepam, Klonotin
Inc Gaba inhibition
Sedation and behavioral changes

Short term: diazepam (valium) or Lorazepam (Ativan) via IV for acute problem
Long term: Clonazepam or Klonotin used for absence seizures

Valproic acid (Depakote)
Unclear, likely multiple
GI distress
Bipolar

Hydantoins: phenytoin (Dilantin)
Iminostilbenes: carbamazepine (Tegretol)

Stabilize neuronal membrane so it is less likely to be excited
Hydantoins: Confusion and ataxia
Iminostilbenes: Dizzy, water retention, anemia.. but NO SEDATION

Absence seizures
Ethosuximide (Zarontin)
Reduce Ca currents, which limits spontaneous neuronal firing (so vesicle can't bind to the membrane)
GI deistress and other membrane effects

Partial seizures
Also a spasmolytic and usedful for treating neuropathic pain

Second-generation which is used an adjunct therapy or alternative to first line drugs
Unclear, but may inc GABA release
Sedation, ataxia, dizziness

Mothers on antiseizure drugs have inc risk of fetal malformations
Don't know if it the disease or the meds

Tapered to avoide inc seizure frequeny or severeity

Primary prevention

Alter quantity of NT released
Affect stimulation of postsynaptic receptors

Does not cure underlying pathology
Can alleviate the mo. s/s and dementia to improve quality of life

Dec dopamine
Inc Ach

Levodopa
Dopamine agonist
Anticholinergics
Amantidine
Monoamine oxidase inhibitors (MOA)
COMT inhibitors

Levodopa. Converted to dopamine after crossing BBB

PROs: effective
CONs: vast majority converted to dopamine outside CNS

Peripheral Decarboxylase Inhbitor (Carbadopa) to inhbit premature conversion - Called Sinemet
ORALLY for this and levadopa

Gi (espec if given without carbidopa)
CV (Postural hypotension) - careful with pts with hx or CVD
Dyskinesisas
Behavioral changes (especially when given with carbadopa)
Diminished response over years
Fluctuations in response (on-off phenomenon)

Phychoses pt... maybe jsut levadopa by itself

Pose inc risk of immobility and associated conditions b/c back to PD's s/s

Directly stimulate dopamine in BG
N/V, postural hypotension

Bromocriptin (Parlodel)
Pergolide (Permax)
Ropinorle (Requip)
Pramipexole (Mirapex)
Last two are being used early

Fewer side effecs than levodopa
Effective in early PD
Possible neuroprotective (dx-slowing)

Apomorphine (Apokyn) used for temporarily relief of Off periods from levadopa tx
Number of side effects/complications: severe N/V and potential complications

Block AcH receptors
Dec the ACh influence, to more closely match the dec dopamine influence
TREMORS

Benztropine mesylate (Cogentin)
Procyclidine (Kemadrin)
Trihexyphenidyl (Artane)

Useful if used in comb with other drugs
CONS: nonselective, not as effective as other drugs when used alone
Side effects: mood changes, GI disturbances, dry mouth , urinary retention, others
Can also be used to tx dementia associated with PD

Anti-viral drug taht blocks glutamate receptor (NMDA) and may have other neuro-transmitter effects
Research is on-going; may be antichilinergic and may enhance dopamine's effects

PROs: milder side effects than some PD drugs
CONs: Effective for short term (several wks)
Side effects: orthostatic hypotension, CNS/mood disturbances

Selegiline (Deprenyl) and Rasagline (Azilect)
Inhibit MAO enzyme that breaks down dopamine

Pros minor side effects at low doses, seems to help in early PD
Cons: unclear if effective long term, drug-drug interactions
MINOR side effects

Prevents breakdown of levadopa in periphery to an inactive metabolite
Tolcapone (Tasmar)
Entacapone (Comtan)

Sinemet plus entacapone
= levadopa, carbadopa, entacapone in one preparation

Pros: can use lower levels of levadopa, may reduce fluctuations in levadopa response
Cons: side effects
Side effects: Iniital inc in dyskinesias, Gi disturbances, mm cramps
Tasmar - liver toxicity

Conezyme Q10... levels seem to be low in PD, but not clear if inc' these levels helps s/s

Hydantoins (Phenytoin)
Iminostilbenes (Tegretol)
Valproic acid (Depakote)

Succinimides (Zarontin)
Valproic acid (depakote)
Klonotin

Valproic acid

Hydantoins and iminiostilbenes

1. Sedation-- need to find a balance bt one and off meds so pt wont be too tired for treatment but also wont get a seizure

2. Fall risk secondary to ataxia

3. Withdrawal sx's

4. GI disturbances can affect PT

5. When pts hx and what brings on seizure when treating

6. Low light environment

7. Modalities often bring on seizure