DRUGS AFFECTING MOBILITY MUSCLE SPASMS SPASTICITY AND LOSS

Cholinergic Function 2 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Function of the Autonomic Nervous System • The autonomic nervous system (ANS) is an involuntary system responsible for the control of smooth muscle, cardiac muscle, and exocrine glands. • The sympathetic (SNS) and parasympathetic nervous systems (PNS) work either as complementary or oppositional systems to maintain the involuntary functions of the body. 3 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Cholinergic Neurotransmitters • Cholinergic drugs act on the parasympathetic nervous system. • Acetylcholine (ACh) is the presynaptic and postsynaptic neurotransmitter in the parasympathetic nervous system. • ACh is released in response to an action potential. It diffuses across the synaptic cleft, and binds to cholinergic receptors on the target organs or tissues – both in the brain and in the body. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 4

Types of Cholinergic Receptors • Nicotinic receptors • Activation of nicotinic. N receptors in the adrenal glands results in the release of epinephrine. • Stimulation of nicotinic. M receptors results in skeletal muscle contraction. • Useful in industrial insecticides • Muscarinic receptors • Stimulation of these receptors results in the pharmacologic response of vasodilation resulting in decreased blood pressure. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 5

Direct-Acting Muscarinic Agonists • Direct-acting muscarinic agonists are drugs that bind to the muscarinic receptors located in various tissues and organs throughout the body. • Their activation elicits a response that resembles the action of the parasympathetic nervous system. • Many drugs can have muscarinic side effects. This means that they may inadvertently lower blood pressure! 6 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Cholinergic Antagonists • The cholinergic antagonists are drugs that antagonize, or block, muscarinic or nicotinic receptors directly. • May be used to reverse toxicity of highly cholinergic drugs (e. g. insecticides) • The clinical importance is in decreasing blood pressure. Prototype drug: atropine 7 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Atropine: Core Drug Knowledge • Pharmacotherapeutics • Cardiac arrhythmias • Preoperatively, it is used to decrease respiratory secretions (“dry up” the patient) • Severe diarrhea • Pharmacokinetics • Based on route of administration • Pharmacodynamics • Competitive inhibitor of cholinergic receptors • Reduces secretions, mydriasis (eye dryness), changes in heart rate, smooth muscle (bladder and GI) contractions Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 8

Atropine: Core Drug Knowledge • Contraindications and precautions • Myasthenia gravis • Side effects • Blurred vision, dry mouth, constipation, and urinary retention • Sexual dysfunctioning (erectile and ejaculation) • Adverse effects • Confusion, agitation in higher doses • Drug interactions • Antipsychotics Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 9

Atropine: Planning and Interventions • Maximizing therapeutic effects • Assess for peptic ulcer disease. • Minimizing adverse effects • Good oral hygiene • Use sunglasses • Do not perform strenuous exercise 10 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Myasthenia Gravis • Myasthenia gravis (MG) is an autoimmune disorder that impairs the receptors for acetylcholine at the myo-neural junction. • It occurs more frequently in men over 50 years of age. • The first symptoms of MG are usually weakness of the eye muscles and ptosis. • Cholinesterase inhibitors are the drugs of choice, e. g. neostigmine. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 11

Indirect-Acting Cholinergic Agonists • After the neurotransmitter crosses the synaptic gap and binds to a receptor, the neurotransmitter is cleared from the synaptic gap. • Acetylcholine is cleared from the synaptic gap by the enzyme acetylcholinesterase. • Any drug that inhibits cholinesterase will be the functional equivalent of a cholinergic receptor. Prototype drug: neostigmine (Prostigmin) 12 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Neostigmine: Core Drug Knowledge • Pharmacotherapeutics • Myasthenia gravis: enhanced muscle contraction • Pharmacokinetics • Administered: oral and parenterally. Metabolism: liver. Excreted: kidneys. Onset: varies with the route of administration. • Pharmacodynamics • Acts as a cholinergic agent by increasing the synaptic presence of acetylcholine Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 13

Neostigmine: Core Drug Knowledge • Contraindications and precautions • Gastrointestinal and urinary tract obstruction • Side effects • nausea, vomiting, diarrhea, miosis (slowed pupillary reaction), salivation, diaphoresis (sweating) • Adverse effects • Cholinergic crisis, bradycardia, and bronchospasm • Drug interactions • Steroids, aminoglycoside, depolarizing muscle relaxants, and magnesium Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 14

Neostigmine: Planning and Interventions • Maximizing therapeutic effects • Administered at regular intervals throughout the day • Minimizing adverse effects • Availability of the antidote • If the patient has a history of chronic respiratory conditions, careful monitoring of the first few doses of neostigmine is required. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 15

Fun Quiz: 1. Identify this plant. 2. What are it’s effects if ingested or

Answers: • Datura stramonium (Jimson weed or loco weed) is a plant in the deadly nightshade family. • Tomatoes are also in this family, but are not toxic • Datura has been used as a herbal medicine to relieve asthma symptoms and as an analgesic during surgery or bone-setting. • It is also a powerful hallucinogen used spiritually for the intense visions once ingested or smoked. • However, plant is fatally toxic in only slightly higher amounts than the medicinal dosage, and careless use results in hospitalizations and deaths. • It has been responsible for sickness and death in cattle when accidentally mixed into hay cut in pastures. • It’s antidote is either atropine or pilocarpine. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 17

Drugs Affecting Muscle Spasm and Spasticity 18 Copyright © 2012 Wolters Kluwer Health |

Physiology – Muscle Spasm • The human body contains approximately 600 skeletal muscles. • Skeletal muscle movement is voluntary and is composed of two contractile proteins. • Muscle contraction is triggered by a sudden inflow of calcium ions (Ca 2+). • Muscle contraction stops when Ca 2+ is removed from the immediate environment. 19 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Muscle Fibers 20 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Pathophysiology Muscle spasm • A muscle spasm is a sudden, violent involuntary contraction of a muscle or group of muscles. • Spasms are related to a localized skeletal muscle injury or an imbalance in electrolytes. • Tonic spasm is characterized by an unusually prolonged and strong muscular contraction (think about a leg cramp). • Clonic spasms have intermittent contraction with release. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 21

Pathophysiology (cont. ) Spasticity • Spasticity is a condition in which certain muscles are continuously contracted. • This contraction causes stiffness or tightness of the muscles. • Spasticity may be associated with spinal cord injury or with cerebral palsy. 22 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Centrally Acting Muscle Relaxants • Centrally Acting Muscle Relaxants act in the central nervous system (CNS). Prototype drug: cyclobenzaprine (Flexeril) 23 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Cyclobenzaprine: Core Drug Knowledge • Pharmacotherapeutics • Manages muscle spasms associated with acute musculoskeletal disorders • Pharmacokinetics • Administered: oral. Metabolism: liver. Excreted: urine and bile. Onset: 1 hour. Duration: 12 to 24 hours. • Pharmacodynamics • Relieves muscle spasms through a central (brain) action Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 24

Cyclobenzaprine: Core Drug Knowledge • Contraindications and precautions • Hyperthyroidism • 14 days within use of MAOIs • Side effects • Drowsiness • Changes in blood pressure • Adverse effects • Cardiac arrhythmias, seizures, and MIs • Drug interactions • Tramadol (Ultram), histamine-1 blocking agents, and various herbal remedies Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 25

Cyclobenzaprine: Planning and Interventions • Maximizing therapeutic effects • Take with full glass of water at evenly spaced intervals. • Coordinate physical therapies with administration. • Minimizing adverse effects • Assess for excessive sedation. • Caution the patient about the potential for orthostatic hypotension. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 26

Centrally Acting Spasmolytics • The centrally acting spasmolytics work in the CNS to reduce excessive reflex activity. • Allow muscle relaxation Prototype drug: baclofen (Lioresal) 27 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Baclofen: Core Drug Knowledge • Pharmacotherapeutics • Relieves some components of spinal spasticity • Pharmacokinetics • Administered: oral. Distribution: crosses blood– brain barrier. Metabolism: liver. Excreted: urine and bile. Peaks: 2 to 3 hours • Pharmacodynamics • Acts specifically at the motor neurons at GABAB receptors to cause hyperpolarization – GABA is an inhibitory chemical neurotransmitter. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 28

Baclofen: Core Drug Knowledge • Contraindications and precautions • Hypersensitivity and spasticity of cerebral origin • Side effects • Drowsiness, weakness, dizziness, headache, nausea and vomiting, hypotension, constipation, lethargy and fatigue, insomnia, and urinary frequency • Adverse effects • Confusion, hallucinations or delusions • Drug interactions • CNS depressants and some antidepressants Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 29

Baclofen: Planning and Interventions • Maximizing therapeutic effects • Take with full glass of water at evenly spaced intervals. • If GI distress occurs, coordinate with meals. • Minimizing adverse effects • Have patient to sit or stand slowly • Do not abruptly stop the medication. Video: Spasticity & the Baclofen Pump https: //www. youtube. com/watch? v=Shxn. YYA_s. Vg Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 30

Drugs Treating Parkinson’s Disease and Other Intentional Movement Disorders 31 Copyright © 2012 Wolters

Physiology • The extrapyramidal system (EPS) in the brain is responsible for control of voluntary muscles. • Motor activity requires integration of the actions of the cerebral cortex, basal ganglia, and cerebellum. • The regulatory neurotransmitter dopamine is produced in the brain and adrenal glands and is then transmitted to the basal ganglia. Peripherally, dopamine has circulatory and cardiac adrenergic effects Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 32

Dopamine: Core Drug Knowledge • Pharmacotherapeutics • Used to correct the hemodynamic imbalances present in shock. Only given in acute care settings and only given IV. • Pharmacokinetics • Distribution: throughout the tissues. Metabolism: kidney, liver, and plasma. Excreted: kidneys. Onset: 5 minutes. Duration: 10 minutes. • Pharmacodynamics • Stimulates alpha-1 and beta-1 receptors: increased cardiac output Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 33

Dopamine: Core Drug Knowledge • Contraindications and precautions • Pheochromocytoma (excessive blood iron), uncorrected cardiac arrhythmias, and ventricular fibrillation • Side effects • nausea and vomiting, headache • Rapid heart rate (tachycardia) • Shortness of breath (dyspnea) • Hypotension • Adverse effects • Ectopic beats (extra heart beats), arrthymias • Angina 34 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Pathophysiology Major pathological disorders that are centrally-driven but affect the peripheral nervous system include: ØParkinson’s disease ØAmyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) ØMyasthenia Gravis ØMultiple sclerosis ØHuntington’s disease ØGilles la Tourette’s syndrome (Tourette’s disorder) Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 35

Parkinson’s Disease • Parkinson disease generally afflicts patients aged 50 years and older and progresses slowly. • This disease is naturally occurring in that an external stimulus, such as a virus or trauma, does not trigger it. 36 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Parkinson’s Disease (cont. ) • In PD, degeneration of the neurons that supply dopamine to the striatum occurs, resulting in reduced dopamine in the nerve terminals of the nigrostriatal tract. • Dopamine is the neurotransmitter that sends information to the parts of the brain that control movement and coordination. • As the disease progresses, messages from the brain telling the body how and when to move are delivered more slowly. Video: http: //www. youtube. com/watch? v=IHDFQfmk. Klg Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 37

Parkinson’s Disease: An imbalance of DA and ACh 38 Copyright © 2012 Wolters Kluwer

Antiparkinson Drugs • The reduction in dopamine combined with the relative excess of ACh causes the symptoms of Parkinson disease. • The goal of therapy is to restore the balance between dopamine and acetylcholine. • Drugs used to treat Parkinson disease increase dopamine levels, stimulate dopamine receptors, extend the action of dopamine in the brain, or prevent the activation of cholinergic receptors. Prototype: 39 carbidopa-levodopa (Sinemet) Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Carbidopa-Levodopa: Core Drug Knowledge • Pharmacotherapeutics • Combination drug used in treating Parkinson disease • Pharmacokinetics • Administered: oral. Metabolism: peripherally. Onset: 1 to 2 months. T 1/2: 1 to 2 hours • Pharmacodynamics • Diffuses levodopa into the central nervous system (CNS), where it is converted to dopamine 40 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Carbidopa-Levodopa: Core Drug Knowledge • Contraindications and precautions • Caution in psychotic disorders, e. g. schizophrenia • Side effects • Teeth grinding (bruxism), nausea, vomiting loss of appetite • Adverse effects • Orthostatic hypotension • Abnormal movements • Drug interactions • Dilantin, some antidepressants and all antipsychotics 41 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Carbidopa-Levodopa: Planning and Interventions • Maximizing therapeutic effects • Take on an empty stomach. • Monitor diet for high protein and pyridoxine (B 6) as this drug competes with protein and B 6 for absorption. • Minimizing adverse effects • Administer carbidopa-levodopa at evenly spaced intervals. • Titrate the dose. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 42

Amyotrophic Lateral Sclerosis (ALS) “Lou Gehrig’s Disease” • ALS is a progressive neurologic disorder that affects motor function. • The cause of ALS is unknown. • ALS affects both the upper motor neurons in the cerebral cortex and the lower motor neurons in the brain stem and spinal cord. • One of its classic features is that it spares the sensory system. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 43

Amyotrophic Lateral Sclerosis (cont. ) • The disease begins in the distal neurons. • The loss of upper motor neurons results in spastic paralysis and hyper-reflexia. • The loss of lower motor neurons results in decreased muscle tone and reflexes and flaccid paralysis. 44 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Centrally Acting Anticholinergic Drugs • The centrally acting anticholinergic drugs work by blocking the access of acetylcholine to cholinergic receptors in the striatum. • Centrally acting anticholinergic drugs are less effective than carbidopa-levodopa. • Historically, there has not been specific pharmacotherapy for treating ALS. In December 1995, the FDA approved riluzole (Rilutek), as the first drug for treatment of ALS. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 45

Multiple Sclerosis • 4 types of MS: relapsing-remitting, primary progressive, secondary progressive, and progressive -relapsing. • More than one area of inflammation and scarring of the myelin in the brain & spinal cord occurs. • Messages between the brain and other parts of the body are affected. • Most common symptoms of MS include fatigue, weakness, spasticity, balance problems, bladder and bowel problems, numbness, vision loss, tremor, and vertigo. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 46

Anti–Multiple Sclerosis Drugs • There is no cure for MS but various drugs are available to modify the disease course, treat exacerbations, and manage symptoms. • Pharmacotherapy for MS uses a multilayered approach. • Drugs are: • interferon beta-1 a (Avonex), • interferon beta-1 b (Betaseron), and • glatiramer (Copaxone). 47 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Huntington’s Disease • Huntington’s disease is a genetically inherited disorder. • The two main symptoms of the disease are progressive mental status changes and choreiform muscle movements. • The inhibitory neurotransmitter GABA is depleted in the basal nuclei and substantia nigra of the brain. • There is currently no effective treatment to prevent or delay the progression of Huntington disease. • Newer drug treatments block multiple neurotransmitters to delay deterioration. Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 48

Gilles de la Tourette Disease “Tourette’s disorder” • Tourette’s is an autosomal dominant inherited tic disorder appearing in childhood. • Motor and vocal tics from this disease may respond to haloperidol (Haldol) or other dopamine-blocking antipsychotic drugs e. g. , aripiprazole (Abilify) • Pimozide (Orap) is another drug used for TS. • Another drug useful in treating TS is clonidine (Catapres). 49 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Case Study Bill is a 72 -year old farmer who started to have a very flat facial expression and seemed to be staring intently (masked face) and he walked very slowly with a shuffling gait and very little arm swinging. At times he seemed to have difficulty in initiating movement (bradykinesia). His hand head movements were very pronounced and they had an irregular, jerking quality (cogwheel rigidity). When sitting, Bill was rocking back and forth slowly and clutching the arms of the chair, and it was noted that his fingers curled in and out in a rhythmic manner (pill-rolling tremor). On further examination, Bill had reduced DTR’s (deep tendon reflexes), difficulty with handwriting (dysgraphia, micrographia) and a low, monotonous voice (hypophonia). Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 50

Case Study Write out your answers and turn in for 10 in-class activity points: 1. What type of neuro-muscular disorder does Bill probably have? 2. What is the drug-of-choice for this disorder? 3. What are some typical side effects of this medication? 4. What dietary education is important for this medication? 51 Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins