DNAP_707_Park_and Spaz_basic_2024.pptx

Drugs for treatment of Parkinson’s disease DNAP 707 Keith Shelton, Ph.D. Department of Pharmacology & Toxicology Required reading Drugs for Parkinson’s Disease – Treatment guidelines from The Medical Letters – Volume 9: Issue 101, pp. 1-6 How to access – Log into VCU library website – Search for (in...

Drugs for treatment of Parkinson’s disease DNAP 707 Keith Shelton, Ph.D. Department of Pharmacology & Toxicology Required reading Drugs for Parkinson’s Disease – Treatment guidelines from The Medical Letters – Volume 9: Issue 101, pp. 1-6 How to access – Log into VCU library website – Search for (in quotes): “Drugs for Parkinson’s Disease” AND the medical letters – The second link (at the moment) is for the correct article from Medical Letters – Select view online – Follow the links to The Medical Letter website which will recognize the VCU site license – The Feb 22, 2021 issue has the article as well as a drug comparison table. Parkinson’s disease pharmacology Learning Objectives Know the major symptoms of PD Understand the effects of PD on the dopamine system. Understand the dopamine receptor subtypes Understand the monoamine synthesis and catabolism pathways Understand the mechanisms through which PD drugs operate Know the mechanism and most common side effects of representative PD treatment drugs Dopamine Key neurotransmitter in the CNS Part of monoamine family of neurotransmitters – Dopamine, norepinephrine, epinephrine Two main families of dopamine receptors – D1-like (D1 and D5) Excitatory – D2-like (D2, D3, D4) Inhibitory Monoamine synthesis L-dopa for parkinsons. Levadopa croses the BBB Parkinson’s disease Progressive neurological disorder resulting in – Tremors in extremities – Rigidity Cogwheel, lead pipe, etc. – Bradykinesia- inability to start movement (think of sheltons moms story) – Impaired balance and coordination – Poverty of movement – Other symptoms can include cognitive deficits, cramping, sleep disruption, difficulty eating and swallowing, loss of smell (one of the ways to diagnose). Proximal Cause of PD Progressive loss of dopaminergic neurons in the substantia nigra (SN) which innervate the striatum Symptoms begin to develop at approximately 80% SN dopamine neuron loss Mid brain is necessary for movement Once 80% of neurons are dead is when you see symptoms because the brain can compensate otherwise Normal DAT response Early stage PD Late stage PD Strategies to treat symptoms of PD No currently approved treatment which can prevent loss of SN dopamine neurons Strategies involve stimulating the direct dopamine pathway between the Substantia Nigra and the Striatum – Enhance dopaminergic tone – Increase dopamine release – Directly activate dopamine receptors – Inhibit degradation of dopamine Levodopa Precursor to dopamine – Unlike dopamine it crosses the blood-brain barrier – Makes dopamine work better Oldest and most effective drug for treating PD Exogenously replaces substantia nigra dopamine input into the striatum Effectiveness gradually decreases requiring more frequent and larger dosing to maintain efficacy Levodopa Side effects – Anorexia – Nausea and vomiting – Orthostatic hypotension – Delusions, confusion and agitation in older patients – Compulsive behavior: sexual, shopping, gambling, repetitive actions because you’re activating all dopamine sites (mesolimbic system) Carbidopa Inhibitor of dopa decarboxylase Does not penetrate the CNS Prevents levodopa from being metabolized peripherally into dopamine allowing more levodopa to penetrate the CNS. Almost doubles plasma half-life of levodoparesults in lower dosages and frequency of medicating? Dopamine agonists Less effective than levodopa Used as adjuncts with levodopa or alone for early PD Ergot-derivatives – Bromocriptine (Parlodel) – no longer used in most cases Non-ergot drugs – Pramipexole (Mirapex) – Ropinirole (Requip) – Rotigotine (Neupro) – transdermal patch – Apomorphine – injected or sublingual film Bromocriptine Dopamine agonist but also acts as a serotonin receptor agonist Used for a variety of other disorders – hyperprolactinaemia, pituitary tumors, hypergonadism Side effects – Nausea and vomiting, orthostatic hypotension, headaches Non-ergot dopamine agonists Pramipexole and Ropinirole – Fairly selective dopamine agonists – Oral administration – Side effects: nausea, somnolence, orthostatic hypotension Apomorphine – Used to treat “off time” in patients with advanced PD – Administered s.c. These are used for rescue therapy because they make you throw up!! – Causes emesis requiring concurrent treatment with trimethobenzamide – Should NEVER be combined with 5-HT3 antagonists (ondansetron, granisetron) as they can produce severe hypotension and loss of consciousness COMT inhibitors Catechol-O-methyl-transferase (COMT) COMT breaks down levodopa peripherally and is upregulated when dopa decarboxylase is blocked by carbidopa treatment Inhibition of COMT prolongs the COMT inhibitors Entacapone (1st line) – Side effects: nausea, diarrhea, discolored urine Tolcapone (2nd line) – Used if entacapone is ineffective – Side effects: potential fatal hepatatoxicity (rare) Liver function tests required when beginning treatment and every 6 months thereafter MAO-B inhibitors Monoamine oxidase type B (MAO-B) Present in the brain MAO-B breaks down dopamine Inhibition of MAO-B prevents dopamine degradation- this keeps more dopamine in the brain Used as monotherapy for early PD and as adjunct for more advanced PD MAO-A have a lot of side effects MAO-B inhibitors Selegiline (Eldepryl, Zelapar, others..) Rasagiline (Azilect) Safinamide (Xadago) – MAO(B) inhibition combined with other activity including inhibition of glutamate release and dopamine and serotonin reuptake. Safinamide should not be combined with COMT inhibitors Side effects: – Unlike nonselective MAO inhibitors they are generally safe with tyramine-rich foods (in moderation) – Should not be used concurrently with: Tricyclic antidepressants, SSRIs, meperidine, dextromethorphan, propoxyphene, tramadol or methadone can produce serotonin syndrome Safinamide is expressly contraindicated with opioids for this reason Serotonin Syndrome Combining MAO inhibitors with other drugs that increase serotonin can produce a potentially fatal drug interaction. – Agitation, diarrhea, myoclonus, tremor, tachycardia, hypertension, hyperthermia, confusion, delirium Despite the therapeutic target of opioids at mu opioid receptors, off-target activity can cause this interaction. Should be considered possible with any opioid but appears to be more likely with some (Tramadol, tapentadol, meperidine, dextromethorphan, methadone, propoxyphene, fentanyl). – Some opioids increase serotonin levels Those with least likelihood of causing the serotonin syndrome appear to be hydrocodone, morphine and codeine. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safetycommunication-fda-warns-about-several-safety-issues-opioid-pain-medicinesrequires Other PD adjunct drugs Anticholinergics – Used for the treatment of PD tremors – Trihexyphenidyl, benztropine, procyclidine, others. – Side effects include dry mouth, constipation, urinary retention, worsening of glaucoma Amantadine – Weak NMDA antagonist, dopamine releaser and reuptake blocker – Late stage PD adjunct – Controls tremors, effects can be short-lived – Many CNS side effects Istradefylline – Adenosine A2A receptor antagonist – Indirectly stimulated dopamine – Used for treatment of OFF time Combination drugs for PD As disease progresses drug combination therapy is utilized to maintain symptom control Carbidopa+Levadopa – Sinemet, Sinamet CR, Parcopa, Rytary – CLES (Duopa) c0ntinuous gastic infusion pump Combination of carbidopa, levodopa and entacapone – Stalevo Deep brain stimulation Used to treat PD patients which can no longer be successfully managed by drug therapy Permanent electrodes implanted into one of two brain areas – Subthalamic nucleus or Globus pallidus Primarily improves motor function and “off time” High Intensity Focused Ultrasound (FUS) Ultrasound is used to lesion the ventral intermediate nucleus of the thalamus or more recently the Globus pallidus. Non-surgical Improves tremors and rigidity Parkinson’s mediations – anesthesia considerations Long pre-surgical NPO periods in which PD medications are withheld will worsen symptoms and delay recovery Consideration should be given surgical timing and necessity of strict NPO regime. Some common pre, peri and post-operative medications should be avoided in PD patients – Dopamine antagonist antiemetics: Droperidol Metoclopramide Prochlorperazine Promethazine – Opioids associated with serotonin syndrome: See prior slide Patients with advanced Parkinson’s disease may have swallow dysfunction which may be exacerbated by anesthesia. Parkinson’s patients are also prone to urinary dysfunction, UTIs and constipation. Drugs for treatment of spasticity and musculoskeletal diseases and injuries Spasmolytic/Skeletal Muscle Relaxant pharmacology Learning Objectives Know the symptoms and causes of spasticity Understand how drugs can interact with the stretch reflex arc Understand the mechanism of action and major side effects of the common spasmolytic drugs Symptoms of spasticity Stiff or rigid muscles resulting in – Abnormal posture – Carrying shoulder, arm, wrist and/or finger at abnormal angles due to muscle tightness – Exaggerated deep tendon reflexes – Repetitive jerky motions (clonus) most pronounced when touched or moved – Scissoring (crossing the legs like scissors closing) Causes of spasticity CNS injury (ischemia, trauma, etc.) Adrenoleukodystrophy Cerebral palsy Multiple sclerosis Stroke Others.. Stretch reflex arc Drugs which modify the reflex may negatively modulate excitatory or positively modulate inhibitory synapses. Dantrolene Peripheral action Prevents calcium release by selectively blocking the RyR1 ryanodine receptor Also used for treatment of malignant hyperthermia by blocking calcium release in the sarcoplasmic reticulum in muscle cells. Baclofen GABAB receptor positive modulator Produces presynaptic hyperpolarization inhibiting release of glutamate Sedation at low doses and some respiratory suppression at higher doses Oral or IT administration Benzodiazepines GABAA receptor positive modulators Diazepam primary treatment drug for spasticity due to long duration of action Effects mediated by interaction at level of brain and spinal cord Produce sedation at doses required to reduce muscle tone (tolerance develops to this effect) Tizanidine Adrenergic alpha2 agonist Relative of clonidine with fewer CV side effects Produces minimal hypotension Restores alpha2 mediated inhibitory activity of spinal interneurons Side effects: drowsiness, dizziness, dry mouth, hepatotoxicity Botulinum Toxin Used for post-stroke focal spasticity Local administration into affected muscle – Long duration inhibition of acetylcholine release Free of CNS side effects produced by systemic treatments Drugs for acute local muscle spasms (antispasmodics) Carisoprodol (Soma) Methocarbamol (Robaxin) Orphenadrine (Norflex, Flexon, others..) Cyclobenzaprine (Flexeril) Metaxalone (Skelaxin) Tizanidine Others…. Clinically beneficial mechanisms of action poorly understood Probably act at the level of the spinal cord but some may also act at higher brain areas. Most can produce dizziness, drowsiness and headaches. Some produce anti-muscarinic side effects such as dry mouth, confusion and visual hallucinations