Pharm: CNS (parkinson's, alzheimer's, multiple sclerosis)

CNS drugs

drugs that act in the brain and spinal cord

how many nuerotransmitters are in the CNS

at least 21, and we do nit fully understand the function of all of them

what can pass the Blood brain barrier

• only lipid-soluble drugs

• protein bound or ionized drugs cannot

prolonged drug exposure In the CNS

• prolonged drug exposure can lead to different effects

• many psych drugs must be taken for several weeks before therapeutic effects develop

• side effects may decrease but the therapeutic effects will not

Tolerance

decreased response occurring during the course of prolonged use

physical dependance

state in which abrupt discontinuation of drug use will precipitate a withdrawal syndrome

process of developing new psychotherapeutic drugs

• structural analogs synthesized (modifying existing drugs)

• biochemical and physical screening tests

• serious toxicity ruled out then tested in humans

• small advances vs major breakthroughs

what is parkinsons

neurodegenerative disorder of the Extrapyramidal system (controls involuntary movement, posture and tone)

• gets worse over time, there is no cure

motor symptoms of Parkinsons

• tremors at rest

• rigidity

• postrural instability

• bradykinesda

non-motor symptoms of parkinson’s

• autonomic disturbances

• depression

• psychosis and dementia

what causes parkinson’s

• the degradation of neurons that supply dopamine to the striatum

• balance of ACh and dopamine disrupted.

• the disrupted balance balance causes overactivity of gamma-aminobutyric acid

• causing motor symptoms

what 2 drug categories are used to treat Parkinsons

• dopaminergic drugs - more commonly used

• anticholinergic drugs

goal of treatment for PD

• no cure exists to prevent further degradation of dopamine nuerons

• goal is to improve ability to carry out ADLs

dopamine replacement drug

• levodopa - precursor to dopamine

• crosses BBB (which dopamine cannot do) and converts into dopamine in the brain

• first line for severe symptoms

drawback to levodopa

• beneficial effects diminish over time

• may cause dyskinesias

how are levodopa induced dyskinesias managed

• reduce the dose

• give amantadine - NMDA agonist

• last resort - surgery and electrical stimulation

carbidopa

• decarboxylase inhibitor of levodopa in intestine and peripheral tissues

• makes more levodopa available to the CNS

• cannot cross BBB

• has no therapeutic effect on its own, only with levodopa

Dopamine agonists

• directly activate dopamine receptors in the striatum

• first choice for mild-moderate symptoms

• 2 groups: ergot derivative and nonergot derivative

drawbacks of dopamine agonists

• side effects: hallucinations, daytime sleepiness, orthostatic hypotension

• usually only given to younger patients as they tolerate side effects better

DA: non ergot derivative

• apomorphine

• highly selective for dopamine receptors

• preferred over ergot derivatives

apomorphine

• non ergot DA

• approved for hypo mobility during “off“ episodes of patients with advanced Parkinsons

DA: ergot derivative

• bromocriptine

• less selective

• causes adverse effects bc it block serotonin and alpha receptors

bromocriptine

• direct acting dopamine agonist

• ergot derivative

• when combined with levodopa, it can prolong therapeutic response and reduce motor fluctuations

MAO inhibitor

• seligine

• selective irreversible inhibition of MOA-B (the enzyme that breakd down dopamine in the striatum)

• considered first line, though improvement of motor functions are modest

• reduces the wear off effect when combined with levodopa

NMDA receptor agonist

• amantadine

• helps manage levodopa induced dyskinesia

• promotes release of dopamine, but we are unsure of the mechanism

• only NMDA antagonist approved for parkinson’s

alzhiemers disease

• progressive memory loss

• impaired thinking

• neuropsychiatric symptoms

• inability to perform routine ADLs

physiology of AZ

• degrading nuerons

• reduced cholinergic transmission (ACh 90% below normal)

• beta-amyloid and neurotic plaques for outside of neurons

• nueorfibrillary tangles and tau from inside neurons

how do neurons degenerate in AZ

• the degenerate early in the hippocampus affecting memory

• later in the cerebral cortex affecting speech, perception, reasoning and higher functioning

Donazepil

• indicated for mild, moderate and severe stages of AZ

• reversible Cholinestrase inhibitor

• causes enhanced transmission of cholinergic nuerons that have not yet been destroyed

• does stop stop progression of AZ

Memantine

• indicated for moderate and severe stages of AZ

• NDMA receptor antagonist

• firs drug in new class

what Is multiple sclerosis

• chronic inflammatory autoimmune disorder that damages myelin sheaths in the CNS

• causes variety of sensory and motor deficits

• unknown cause, but may be linked to Epstein-barr virus

demyelination causes

slowed or blocked axonal conduction

inflammation mechanism in MS

• lymphocytes (T cells ) and macropahges, stick to CNS blood vessels

• they then migrate across the BBB and initiate the inflammatory process

• destroys myelin, axonal membrane and ogliodendrocytes

after an acute inflammatotion effect

• some degree of recovery occurs

• partial remyelination

• functional axonal compensation

• brain developed alternate circuits that bypass damaged region

• the more episodes = the less recovery , irreversible injury

what happens to the myelin sheaths in the PNS

they are unaffected by MS bc they are made by Schwann cells not ogliodendrocytes

S/S of multiple sclerosis

• parestesia

• mucscle/ motor issues

• visual impairment

• bladder and bowel issues

• sexual dysfunction

• fatigue

• cognitive impairment / depression

• slurred speech

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relapsing - remitting MS

• clearly defined episodes

• periods of partial or full recovery

• 85%-90% have this form initially

• affects 2x as many women as men

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secondary progressive MS

• pt with relapsing -remitting MS develops steadily worsening dysfunction without occasional plateaus, acute exacerbations, or minor remissions

• within 10-20 years 50% of people with relapsing -remitting MS develop secondary progressive MS

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primary progressive MS

• symptoms grow progressively more intense from the onset

• 10% of MS

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progressing-relapsing MS

what 2 drug categories are used to treat MS

• immunomodulators

• immunosuppressants - more toxic

immunomodulators

• tysabril - blocks adherence of leukocytes to CNS blood vessels, so they can’t cross BBB

• interferons

interferons

• naturally occurring glycoprotein with antiviral, anti proliferative and immunomodulatory actions

• inhibits migration of inflammatory leukocytes across BBB

• suppresses T-helper cell activity

Avonex (interferon beta 1a)

• IM injection

• contains 166 amino acids and glycoprotein

• identical to human interferon data

Betaseron (interferon beta 1b)

• SubQ injection

• contains 156 amino acids and has no glycoproteins

risks of immunomodulators

• formation of neutralizing antibodies (body sees as foreign substance)

• hypersensitivity/ allergic reactions

• infections

• hematologic changes (low WBCs)

• liver injury

• vaccines are less effective