Pharmacology Week 4

neurogenerative diseases

diseases characterized by the progressive loss of neuronal function in particular parts of the CNS

unknown, but heredity, autoimmunity, and environmental facts are likely involved

causes of neurogenerative diseases

Parkinson’s Disease (PD)

a neurological disorder seen when there is a loss of dopamine-producing neurons in the substantia nigra

Dopamine (DA)

normally allows for smooth, coordinated function of body muscles and movement and inhibits firing of cholinergic neurons

the neurons lose normal inhibition, resulting in an excess of cholinergic activities

loss of DA causes what

movement

less DA —→ less instructions to the brain —→ ____ problems

about 80%

Parkinson’s Disease (PD) has slow, progressive degeneration; symptoms show around a loss of _____ of the neurons

presynaptic

Dopamine is released in the ______ terminal

RAFT

In PD, remember ______

Rigidity of skeletal muscles, Akinesia, Flat Facies, and Tremor at rest

RAFT acronym

akinesia

complete or partial loss of voluntary muscle movement

flat facies

lack of facial expression

shuffling walk, muffled speech / drooling / dysphagia, depression, constipation, and incontinence

additional symptoms of PD besides RAFT

restore DA to the brain via increase in DA synthesis, inhibition of DA breakdown, and/or increasing DA release from neurons

Goal in treatment of Parkinson’s Disease

dopamine replacement therapy, dopamine agonist therapy, and anticholinergic therapy

Therapy options for PD

correct the imabalance of high levels of cholinergic neurons vs low levels of dopamine in the striatum

The ways that therapies for PD work

it is progressive, the CNS can limit medication bioavailability, and ADRs with available meds

Difficulties in treatment of PD

No; must give dopamine as a prodrug that is activated in the brain

Can dopamine cross the blood-brain barrier alone?

Levodopa (L-Dopa)

metabolic precursor of dopamine that does cross the blood brain barrier

aromatic L-amino acid decarboxylase

Levodopa (L-Dopa) is converted by what

Because of decarboxylase in periphery

Why is L-Dopa required at high does to make it into the brain?

Carbidopa and Levodopa (together because L-Dopa is required in high doses to be able to cross alone)

The mainstay treatment in PD

Carbidopa

A decarboxylase inhibitor that does NOT cross the blood-brain barrier and reduces metabolism of levodopa in periphery

more

Limiting metabolism leads to ____ drug getting to the brain

dizziness, loss of appetite, hypotension, nausea/vomiting, insomnia, AMS

ADRs of Dopamine Replacement Therapy

levodopa

As PD progresses, there is a decreased response to _____

“Wearing Off”

Describes how there are low amounts of DA in the striatum at the end of dosing interval during dopamine replacement therpay

“On-Off” Phenomena

Describes severe motor fluctuations that can occur randomly in dopamine replacement therapy

hypertensive crisis

Be aware of this interaction in Dopamine Replacement Therapy: MAOi can cause what?

antipsychotics

Be aware of this interaction in Dopamine Replacement Therapy: ______ can reduce effectiveness

bioavailability

Be aware of this interaction in Dopamine Replacement Therapy: Antacids reduce _____; avoid if possible!

plasma COMT inhibitors

used in combination with levodopa to lengthen its activity

tolcapone, entacopone, opicapone

examples of COMT inhibitors

Istradefylline

new drug in 2020; oral adenosin A2A receptor antagonist for use as an add-on therapy for patients with “off” episodes

Selegiline

MAO-Bi (B inhibitor) that slows dopamine breakdown

Selegiline

used in combination with levodopa, can cause insomnia if given late in the day

Selegiline and Rasagiline

irreversible MAO-Bis approved for PD

Safinamide

reversible MAO-Bi for use alongside carbidopa/levodopa

Amantadine

antiviral medication that appears to enhance synthesis, release or reuptake of dopamine so can be used in PD

Dopamine Agonist Therapy

Treat PD by directly stimulating the DA receptors to restore balance of inhibition and excitation in the basal ganglia

Dopamine Agonist Therapy

used in combination with levodopa/carbidopa in early stage PD

bromocriptine, pramipexole, ropinirole, rotigotine

Examples of drugs used in Dopamine Agonist Therapy

constipation, dizziness, arrhythmias, nausea/vomiting, and hypotension

ADRs of Dopamine Agonist Therapy

anticholinergics

While used less often in therapy, _______ can be used to reduce inhibited cholinergic activity (i.e. using them to decrease the tremors/dystonia)

trihexyphenidyl and benztropine

Examples of drugs used in anticholinergic therapy

dry mouth, constipation, urinary retention, drowsiness, hallucinations, confusion, and tardive dyskinesia

ADRs of Anticholinergic Therapy

Amyotrophic Lateral Sclerosis (ALS)

Also known as Lou Gehrig disease

ALS

Disorder of upper and lower motor neurons that leads to progressive weakness, muscle atrophy, spasticity, dysphasia, and respiratory difficulties

about 2.5 years

Prognosis of ALS

Riluzole

an orally active agent that extends survival 2-3 months by protecting motor neurons from neurotoxic effects - used in ALS treatments

weakness, abdominal pain, and diarrhea

ADRs of tiluzole (used for treatment of ALS)

inhibits glutamate release and voltage-gated sodium channels, blocks NMDA and KA receptors

MoA of Riluzole (used in treatment of ALS)

Baclofen (GABA-B agonist), Tizanidine (Alpha-2 agonist in the CNS), and Clonazepam (BZD)

ALS treatment drugs that primarly treat the spasticity aspect of the disease

Multiple Sclerosis (MS)

an inflammatory disease characterized by demyelination and axonal loss in the CNS that can lead to pain, spasticity, weakness, problems with speech/vision/gait/bladder function

MS

Relapses and remission are common with this disease

anti-CD20 B-cell antibodies

first line for MS treatment

Ocrelizumab (ocrevus) and Ofatumumab (Kesimpta)

first line drugs for MS treatment (anti-CD20 B-cell antibodies)

Immunomodulators for CD20/CD52/Integrin Alpha-4 and Sphingosine 1-phosphate (S1P) modulators

Other treatments for MS that aren’t the first line ones

Interferon Beta-1b

immunomodulator that makes natural killer cells and macrophages more effective thus halting progression and reducing relapse

chills, diarrhea, fever, pain

ADRs of Interferon Beta-1b (in treatment of MS)

Glatiramer Acetate

synthetic protein that mimin myelin basic protein to significantly reduce relapse frequency

oral drugs to treat relapsing MS

S1P modulators

Fingolimod, Siponimod, and teriflunomide

Examples of S1P modulators (in treatment of MS)

Duchenne Muscular Dystrophy

A progressive X-linked neuromuscular disorder characterized by decreasd levels of dystrophin

Antisense oligonucleotides

Synthetic DNA or RNA that binds to affect protein production

Antisense oligonucleotides

For patients with specific mutation in the dystrophin gene that helps produce a useful, truncated dystrophin protein. Examples include Golodirsen and viltolarsen

Delandistrogen moxeparvovec (Elevidys)

A new drug that is a one-time adeno-associated virus based gene therapy that can aid in motor function (used in Duchenne Muscular Dystrophy)

liver injury, myositis, and myocarditis

ADRs of Duchenne Muscular Dystrophy

Spinal Muscular Atrophy

An autosomal recessive disorder causing muscle weakness in atrophy

copies

Severity of Spinal Muscular Atrophy is based on number of ____ of function gene present

Nusinersen (Spinraza)

antisense oligonucleotide that increases production of SMN protein (used with Spinal Muscular Atrophy)

Onasemnogene abeparvovec (Zolgensma)

A one-time virus-based gene therapy for children under 2 years old

Zolgensma (used for Spinal Muscular Atrophy)

Most expensive drug in the world (about $2.125 million / dose)

increased liver enzymes, vomiting, decreased appetitie, fever, and rash

ADRs of Zolgensma

spasticity

increased deep tendon reflexes, loss of supraspinal inhibition (ex: flexed elbow, clenched fist, and flexed wrist)

spasms

result from injury to a muscle or a region; tonic (rigid/tense) and painful (think cramping/Charley Horse)

direct and central acting

Two different flavors of skeletal muscle relaxants

exert effect at all muscle cells; botox and dantrolene

direct acting skeletal muscle relaxants: what are they and what are examples?

exert effect at the brain or spinal cord, decrease alpha motor neuron excitation; all the rest

centrally acting skeletal muscle relaxants: what are they and what are examples?

muscle weakness, drowsiness, dizziness/vertigo, nausea/vomiting, and impaired vision

Whether direct or central, skeletal muscle relaxant agents tend to display these similar ADRs as a class:

additive

Since skeletal muscle relaxants are CNS depressants, _____ effects are seen when combining with alcohol, BZDs, opioids, etc.

Botulinum Toxin A

more official name for botox

inhibits presynaptic ACh release, thus blocking nerve impulses and causing muscle paralysis

MoA of Botox

spastic

botox is a direct acting skeletal muscle relaxant that usually lasts 1-3 months and is given as localized injections for generalized ____ disorders

inhibits the release of calcium from the sarcoplasmic reticulum in muscle fibers and directly relaxes skeletal muscle

MoA of Dantrolene

severe spasticity (malignant hyperthermia, neuroleptic malignant syndrome, etc.)

uses for dantrolene, a direct acting skeletal muscle relaxant

severe muscle weakness and hepatotoxicity

ADRs of Dantrolene

baclofen, tizanidine, carisoprodol, methocarbamol, cyclobenzaprine, metaxalone, and diazepam

examples of centralling acting skeletal muscle relaxants

GABA-B receptor agonist

MoA for Baclofen, a centrally acting skeletal muscle relaxant

spinal cord spasticity, quadriplegia, MS, and ALS

use for Baclofen as a centrally acting skeletal muscle relaxant

Alpha2-adrenergic agonist, presynaptic inhibition of spinal motor neurons

MoA for Tizanidine - a centrally acting skeletal muscle relaxant

relieves spasticity due to neurological injury

use of Tizanidine - a centrally acting skeletal muscle relaxant

muscle weakness, drowsiness, and hypotension

ADRs of Tizanidine - a centrally acting skeletal muscle relaxant

not clearly established, all work centrally as CNS depressants

MoA for carisoprodol, methocarbamol, cyclobenzaprine, and metaxalone - centrally acting skeletal muscle relaxants

for spasms ONLY, not for spasticity

Use of carisoprodol, methocarbamol, cyclobenzaprine, and metaxalone - centrally acting skeletal muscle relaxants

muscle weakness, sedation, vertigo, and ataxia

ADRs, of carisoprodol, methocarbamol, cyclobenzaprine, and metaxalone - centrally acting skeletal muscle relaxants

diazepam

centrally acting skeletal muscle relaxant that is a BZD, used for spasticity from cord lesions, Cerebral Palsy (CP), and overuse muscle spasms

seizures

synchronous neuronal discharges within a particular group of neurons, usually within the cerebral cortex

abnormal movements/thoughts/sensations

The synchronous neuronal discharges during seizures spread to other areas of the brain and produce what?

epilepsy

A chronic disorder where the patient has excessive, recurrent discharges