Module 3.5

Question 1

What are common features of neurodengerative diseases

Answer 1

• Selective areas affected
  ○ For each disease the area of the brain where the neuronal loss occurs is selective or specific for that disease while other areas of the brain are often unaffected
  • Distintic genetic forms
    ○ Each neurogenerative disease has a distinct form
    ○ Inetraction between genetic and environmental factors are important for determination of some of the featires of these diseases
  • Inappropriate protein
    ○ Deposition of a protein in a specific of the region of the brain. The beta-amyloid protein in alzeiumers
  • Increased likelihood with age
    ○ Primarily a disorder of age although recognized forms in childhood do exist
  • Treatment controls the symptoms
    Currently avaiable treatments for neurogenerative disease control symptoms but do not alter the neurogenerative proccess

Question 2

WHAT IS PARKINSONS DISEASE

Answer 2

• Affects movement, develops gradually and has 4 features
  ○ Bradykinesia - slow and poor movement
  ○ Muscle rigidity
  ○ Tremor at rest
  ○ Poor postural balance and shuffling/impaired gait
  • Most common form is idiopathtic
  • Has no known or confirmed cause
  • Other forms result from stroke or drugs sich as phenothiazimne antipsychotics
  • Irrespective of the type of parkinsons disease there is a loss of dopaminergic nerons in the region of the brain called the substantia niagra pairs
  • These dopaminergic neurons provide input into the stratium, an area of the brain involved in motor coordination and movement
  • Loss of dopaminergic function is a normal process of aging however most individuals do not lose 70 to 80% of dopaminergic function that is required for symptomatic parkinsons disease
  • While dopaminergic neurons aret he main defecit in oarkinsons otherb rain structures are also affected
    Brain stem, hippocamopis and acerebral cortext

Question 3

DRUGS USED IN TREATMENT OF PARKINSONS DISEASE

Answer 3

• Enhancing the function of remaining dopaminerguc beurons by increasing the amount of dopamine and inhibiting the breakdown of dopamine or dopamine agonists
  
  • Synthesized in the brain from dietary phenylalanine after conversion to tyrosine
  • Tyrosine is taken up into the neuron where the enzyme tyrosine hydroxylase converted into DOPA. DOPA is then converted into dopamine nad packaged into vesiccles for release
    Monoamine oxidase and catechol-o-methyltransferase break down and inactivate dopamine

Question 4

LEVODOPA/CARBIDOPA

Answer 4

• Dopamine does not corss blood brain barrier thus administering Dopamine has no effect in parkinsons disease
  
  • Levodopa is a manufacturered form of DOPA does cross the blood brain barrier and reaches the brain in sufficient concentrations to increase dopamine leevl
  • It is rapidly metabolised in oheripheral tissue
  • Using levodopa alone only 1-3% of the administered dose gets past the blood brain barrier
  • Carbidopa is to get past the pherpiphery
  • It is an inhibitor of the nezyme L-amino decarboxylase which converts levodopa into dopamine
    As a result decreases the amount of levodopa that is metabolized pheripherally increasing the concentration of levodopa that is metabolised in the pheriphery

Question 5

SELECTIVE MAO INHIBITORS

Answer 5

• Monoamine oxidase metabolizes dopamine
  
  • MAO-A and MAO-B metabolise Dopamine
  • MAO-B is the predominant form of the enzyme in the stratiym thus it oxidises the most
  • MAO-B such as seleginline inhibit the break down of dopamine to 3,4-dihydroxyphenylacetic acid
    MAO-B selective inhibitors do not interactw ith Tyramine

Question 6

CATECHOL-O-METHYL TRANSFERASE INHIBITORS

Answer 6

• Breaks down dopamine also
  
  • Administration of levodopa with carbidopa decreases the fraction of levodopa converted to dopamine pheriperally
  • Increases the amount converted to another metabolite 3-OMD by COMT
    This calss of drug inhibit peripheral COMIt reducing the peripheral metabolism of levodopa and increasing levels of levodopa reaching the critucal areas of the brain

Question 7

DOPAMINE RECEPTOR AGONISTS

Answer 7

• Alternate approach is to increasing dopaminergic activity in the substania nigra to administer synthetic dopamine agonists to supplement the decreased endogenous dopamine drugs this class are useful in patients who are not adequately controlled with levodopa adverse effects include hallucinations and confusion
  One adverse effect often not recognized is that patients receiving dopamine agonists may engage in reward seeking behaviour

Question 8

ALZEIHMERS DISEASE

Answer 8

• Progressive loss of memory and cognitive function
  
  • Early stages someone may become forgetful but as the disease progresses there is a loss of cognitive function that affects daily activities
    Can result in a vegetative state

Question 9

PATHOLOGY OF ALZEIHMERS DISEASE

Answer 9

• Amyloid plaques
  ○ Deposition of betal amyloid proteins
  ○ Into certain regions of the brain
  ○ They are called amyloid plaques
  ○ They are collected between neurons in the brain and disrupt cell function
  • Neurofibrillary tangles
    ○ Occurs later in disease progression than amyloid plaques
    ○ More closely associated to cognitive impairment
    ○ Tangles are resultof aggregated tau protein which normally supports micortubules
    ○ In alzeihmers tau proteins disassociate and stick togeyher instead of forming threats

Question 10

TREATMENT OF ALZEIHMERS

Answer 10

• Amyloid plaques and neurofibrillary tangles lead to progressive loss of neurons within the brain espeically cholinergic neurons
  
  • No disease modifying drugs are avaiable for alzheimers disease
  • Current theory is aimed at symptom controk
    Most drugs used to treat the condition modify cholingergic transmission or attempt to enhance transmission in the remaining cholinerguc neurons
  • Cholinesterase inhibitors
    ○ Block enzyme acetylcholinesterase reducing the rate of breakdown of acetylcholine
    ○ Enhances the activity of acetylcholune at the receptoos and potentially improve memory and cognition
    ○ Response is a modest improvement in symptoms including a decreased rate in the decline of memory
    ○ Adverse effects are GI and muscle cramping and abnormal dreams
  • Memantine
    ○ Antagonist for specific glutamate receptor called NMDA
    ○ Slow the rate of destruction of neurons by inhibiting the excitatory responses to glutamate preventing glutamate induced excitatory neuronal death
  • Other drugs
    ○ Other drugs are used in treatment of alzeiherms like anti psychotics and mood stabilizers for the symptpmoms

Question 11

NON OPIOD ANALGESIC DRUGS

Answer 11

• Aspirin
  
  • Tylenol
  • They alleviate pain and the low potential for misuse and withdrawal
  • They all functiom by inhiniting cyclooxygenase and or COX2 reducing the amount of prostoglandins. They are endogenous substances that sensitize the nerve endings to mediators of pain
    Reducing fever and inhibiting the propagation of inflammation

Question 12

NON STERIODAL ANTI INFLAMMATORY DRUGS

Answer 12

• Have analgesic effects
  
  • Antipyretics - reduce fever and anti inflammatory effects
  • Acetylsalicylic acid is the protipical NSAID
  • Ibuprofen and naproxen were developed
  • Most NSAIDs are well absorbed and highly metabolized by CYP450 enzymes in the liver and excreted in the kidney
  • Adverse effects
    ○ GI, abdominal pain, nausea, vomiting, and ulcers
    ○ Hepatic liver function abnormalities and liver failure
    ○ Renale - renal insufficency renal failure
    ○ Pulmonary - Individuals with astham are at higher risk for expeirencing allergic reactions
    ○ Cardiovascular - fluid retention edema, hypertension
    ○ CNS - Headache, tinnitus, dizziness
    Skin - Rashes

Question 13

NON SELECTIVE NSAIDS

Answer 13

• Determined by patient characteristics and the adverse effects of the specific drug for instant diclofenac would not be used in patients who already has liver damage
  
  • ASA acetylsalicylic acid
    ○ For mild to moderate pauin and fever
    ○ Prevention of strokes and myocardial infarcts
    ○ Low dose ASA has been shown to reduce the risk of serious diseases by inhibiting olateket aggregation and hence clot formation
    ○ Key adverse effect of ASA is associated with the develop of Reyes syndrome that affects the CBS
    ○ Causes brain and liver damage when given to children with fevers
  • Ibuprofen
    ○ 200 mg dose of ibuprofen is more effective than 325 dose of ASA in number of conditions
    ○ Including dental pain and menstraul pain
    ○ As an anti inflammatory it is the most efficacious over the counter agents on the market
    ○ It can be used to close patent ductus arteriosis - a heart defect
    ○ Mechanism of action is reversible COX1 and COX2 enzyme
  • Naproxen
    ○ Was available with perscription until very recently
    ○ It is an over the counter analgesic
    ○ Useful for rheumatologic indications such as rheumatoidarthritis
    ○ Naproxen is also available as an opthalmic solutions and a topucal preparation

Diclofenac
* Only available with perscription
* Used as an opthamic preparation for prevention of post operative opthalmic inflammtory and topical gel for solar keratosis
Can be used as a rectal suppository

Question 14

SELECTIVE NSAIDS

Answer 14

• They inhibit both Cox1 and Xo2
  
  • Inhibit production of inflammtory prostoglandins
  • Only contribute to adverse effects of the drug
  • They have been developed to inhibit Cox-2
  • Celecoxib
    ○ Approximately 10-20x more selective for COx2 than COX1
    ○ Clinically perscribed to relieve paun and unflammation caused by arthitic conditions
    ○ Such as osteoarthritis and rheumatoid arthritis
    ○ Also treat post surgical pain
  • Meloxicam
    ○ Inhibits CO2
    ○ Not to the same exten as Celecoxib
    ○ They have been developed
    ○ Clinical datat suggested that patients taking these drugs had increased incidence of cardiobascular thrombiotic events
    ○ Such as heart attack or stroke
    ○ Resulting in withdrawal

Question 15

WHAT ARE SOME OTHER NON PERSCRIPTION DRUGS

Answer 15

• Acteminophen is not an NSAID
  
  • Its punctions as an analgesic and antipyretic but not as an antiflammatory
  • Mehcnaism of action
    ○ Inhibition of protogralandin formation COX I and COX II responsible for the analgesic and antipyretic effects - does not have anti inflammtory or anti platelet action
  • Therapeutic uses
    ○ Very well tolderated at therapeutic doses and drug of choice where ASA causes GI and in ferbile conditions in children and the young
    ○ Can also lead to liver injury
  • Liver injury
    ○ Overdose can lead to liver failure
    ○ Individual will consume 5 to 10 grams 20 tablets or more of acteminophen
    ○ There is some evidence that alrge therapeutic doses can result in liver injury as well
    ○ Individuals with liver dosease are more suspectiple to the liver toxocity
    ○ Cirrhosis is a common condition where the liver does not function properly due to long term damange
    This is characterized as the repalcement of normal liver tissue by scar tissue

Question 16

WHAT IS HEPATOXICITY THAT RESULTS FROM ACETOMINOPHEN

Answer 16

• Related to metabolism and depletion of gluthionine
  
  1. Acetaminophen can undergo glucorondiation or sulfation (PhaseII reactions)
  2. Although 5% will undergo hydroxylation and struuctural arrangement to produce intermediate known as NAPQI
     NAPQI can be effectively detoxified by gluthionine conjugation although the bodys limited amount of gluthinione. Acetaminophen overdose can ddelpeet gluthionine toxicity

Question 17

TREATMENT FOR ACETAMINOPHEN OVERDOSE

Answer 17

• Give the antidote N-acetylcysteine with supportive measures
  
  • It is a source of luthionine which decreases the amount of NAPQ1 (Liver damaging component)
    It is effective if administered within 8 hours

Question 18

WHAT ARE THE OPIOD TERMINOLOGIES

Answer 18

• Opiate - Derived form the word opuim
  
  • Opioid - Any natural or synthetic substance that exerts actions on the body similar to those induced by morphine and are antagonized by the drug Naloxone
  • Examples
    ○ Opiates - Morphine
    ○ Substances tsructurally related like horin
    ○ Synthetic drugs with dufferent form of morphine like methadone
    Endogenous brain peptides that exert analgesic actions like endorphins

Question 19

WHAT ARE Mu OPIOID RECEPTORS

Answer 19

• Present in brain and spinal cord
  
  • Primarily mediate analgesia
  • Depression of brain stem which includes depresion of respiration
  • They are involvedi n the compulsive behaviour demonstrated by opiate users
    Endogenous ligands are endorphin 1 and 2

Question 20

WHAT ARE THE KAPPA OPIOID RECEPTORS

Answer 20

• Involved in analgesia, dysphoria and miosis (pin point pupils)
  
  • Mixed opioid agonists/antagonists like pentazocine
    The endogenous ligands are dynorphins although endorphines have some activity on these receptors

Question 21

WHAT ARE THE DELAT OPIOID RECEPTORS

Answer 21

• Inolved in anaglesia at the spinal cord and brain
  
  • May also modulate emotional response to opioids
    Endogenous ligands are enkephalins

Question 22

WHAT IS THE MECHANISM OF ACTION OF OPIOIDS

Answer 22

• Block pain pathways in the spinal cord and brain
  
  • Primarily through MOPs
  • Reduced release of presynaptic chemical trabsmittered mobilized by pain impulse
  • Blockade of postsynaptic effect
  • Activator of descending inhitory pathways
  • Reduced emotional reaction to pain by acting on limbic area of the brain

Question 23

WHAT ARE THE SHORT TERMS EFFECT OF OPIOIDS

Answer 23

• Analgesia
  ○ Including morphine nad heroin produce analgesia
  ○ Which is an indifference to intensity of pain
  ○ Or reaction to it
  ○ Respiratory depression is the limiting factory
  • Sedation
    ○ All opioids produce sedation
    ○ Those with analgesics
  • Supression through cough center
    ○ Relief or prevention of cough occurs through supression of the cough centers in the medulla
  • Respiratory depression
    ○ Opioids supress the repsiratory center in the brain stem
    ○ The response to respiratory drive by CO2 id blunted
  • Decreased GI motility
    ○ All opioids cause constipation
  • Endocrine effects
    ○ Reduce release of hormones responsible for regulating sex hormones from the hypothalamus
    ○ Reduction of testosterone and estrogen production
    ○ Drop in libido in men and mestrual irregulatiries in women
  • Miosis
    ○ Constriction of the pupils
    ○ All opioids gain acces the CNS so this is a sign of an opioid user
  • Heart rate and thermoregulation
    ○ With high doses the heart rate is ireegular
    Body temperature is low and the skin is cold and clammy

Question 24

WHAT ARE THE LONG TERM EFFECTS OF OPIOIDS

Answer 24

• Physioligical deterioration or psychological impairment does not seem to occur
  Long term use includes mood instability, pupillary constriction ( Impairs night vision), constipation, reduced libido, mestrual irregularity and respiratory impairment

Question 25

WHY ARE OPIOIDS THE MOST COMMONLY MISUED DRUG

Answer 25

* Create and indifference to pain * There is no limit to the intensity of pain that can be reduced * Those who suffer severe injuries may be perscribed opioids for the pain and take more than the recommended dose * Or take if no longer needed Many people addicted to opioids have at;least 1 psycholoigical commorbidty

Question 26

WHAT ARE THE THERAPEUTIC USES OF OPIOIDS

Answer 26

* Relief of severe pain (post surgical). Analgesia for the major use for the opiates * Treatment of diarrhea. Diphenoxylate(lomotil) is an over the counter opioid which is not an anaglesic does not produce the opioid use disorder * Supression of cough - All opioids are effective at this Treatment of opioid use dusorder. Naloxone and methadone

Question 27

WHAT IS OPIOD WITHDRAWAL

Answer 27

* Tolerance, withdrawal and addiction develops to all opioid analgesics * Small number of opioids have become problematic in terms of producing opioud use disorder * While tolerance develops to most pharm effects of the opiopids does not develop to the constriciton or the constipation * Cross tolerance between opioid analgesics occurcs provided they all act on the same receptor Methadone as a bothdrugs bind to the opiod receptors

Question 28

WHAT IS NEONATAL OPIOD WITHDRAWAL

Answer 28

* Individual with opioid use disorder who is pregant faces increased risk of premature delivery and low brith weight infant * Infant undergoes premature termination of drug supply * Newborn will face withdraswal reactiom Withdrawal may last 2 weeks to months

Question 29

WHAT IS OPIOID OVERDOSE

Answer 29

* Medical ermergency * All opioud drugs cause repsirtaory deppression * Which cause of death Treatment consists of opioid anatgonists such as naloxone and support of respiratrion

Question 30

HOW ARE OPIOID OVERDOSES TREATED

Answer 30

* Bupnorphine/naloxone * First line tretament * Methadone is second line * Psycosicla supports and counselling and tretament are also considered * Buprenorphine/ Naloxone ○ Long acting synthetic opioid ○ Partial MOP receptor ○ Halflife os 24-42 hours ○ Bupnorphine provides enough opioid agonist activity to prevent withdrawal ○ IF injected naloxone acts as an opioid antaginist ○ If taken orally naloxone is not absorbed to any significant degree due to first pass effect ○ It is used to deter people from misuing naloxone through injectio * Methadone ○ Synthetic opioid ○ Effective following oral administration and has a long hald life Abuse positional is much lower than morphine and heroin

Question 31

**WHich statement regarding non steriodial anti inflammatory drugs is correct** * A) The reduce only pain and fever * B) They inhibiy production of prostagalandins * C) Inhibit COX-1Enezyme * D) They are not available over the counter medications

Answer 31

B

Question 32

**Which statement regarding morphine is correct** * It causes mydriasis (Dillation of pupil) * B) Causes respiratory depression * C) Binds to muscarinic receptors * D) Does not cause dependence

Answer 32

B