1. Describe the pathophysiology of Parkinson’s disease.
– Parkinson’s disease is a chronic, progressive disorder, affecting muscle movement. The cause is the death of the dopamine-producing neurons from substantia nigra which in normal conditions supply dopamine to the corpus striatum, a region in the brain that controls unconscious muscle movement. It is considered that for every decade of life we lose between 9 and 13% of dopamine producing neurons.
2. Describe the symptoms of Parkinon’s disease.
– Tremor of the hands, arms, legs and face; occurs in 70% of the patients
– Bradykinesia (slowness of movement)
– Rigidity or stiffness of the limbs and trunk (resistance of the passive movement of the limbs)
– Postural instability (impaired balance and coordination)
– Affective flattening (the patients have very little facial expression and blinking of the eyes)
3. Know the major groups of drugs used in the treatment of Parkinson’s disease. Be able to give an example of each. Relate the use of the drug to the pathophysiology of Parkinson’s disease.
– Drug therapy is focused on restoring functional balance between dopamine and acetylcholine within the corpus striatum.
– These drugs are classified into dopaminergic and cholinergic blockers
– Dopaminergic drugs are used to increase dopamine levels. Drug of choice is levodopa combined with carbidopa and marketed under the name Sinemet or Parcopa.
– Other approaches are used to inhibit enzymes that usually destroy levodopa and dopamine (Tolcapone, entacapone, rasagiline and selegiline). Drugs called dopamine agpnists, such as Apomorphine, bromocriptine (Parlodel), pramipexole (Mirapex) and ropinirole (Requip) directly activate the dopamine receptors.
– Cholinergic blockers or Anticholinergic drugs inhibit the effect of this neurotransmitter in corpus striatum by blocking the receptors. Benztropine (Cogentin), diphenhydramine (Bemnadryl) or biperiden (Akineton) are example of anticholinergic drugs used for Parkinsonism.
4. The combination of levadopa and carbidopa is a drug called Sinemet. Describe the functions of these two drugs in Sinemet. What is the advantage of having carbidopa given with levadopa as opposed to giving levadopa alone?
– Levodopa, a precursor of dopamine crosses the blood-brain barrier as opposed to dopamine. In the brain this chemical is transformed into dopamine. Then it is subsequently released by the brain cells allowing for improved function of the movement control centers of the brain.
– Because levodopa can be broken down by the blood enzymes called amino-acid decarboxylases before it can reach the brain, it is always combined with an enzyme inhibitor called carbidopa. Together, this combination is known under the trade name Sinemet.
– Carbidopa alone can increase the concentration of dopamine and levodopa in the brain.
5. Patients who are taking levadopa alone need to be told to avoid a certain vitamin. What vitamin is it? Does this interaction occur with the combination of levadopa and carbidopa?
– Vitamin B6 can reduce the effectiveness of levodopa. B6 can increase how quickly the body breaks down and gets rid of levodopa, thereby decreasing availability of the drug to the brain. The levodopa/carbidopa combination prevent this interaction from occurring.
6. The combination of levadopa, carbidopa and entacapone is drug known as Stalevo. What is the function of entacapone?
– By combining of levodopa with carbidopa and entacapone its enzymatic breakdown is prevented.
7. Describe the first, second and third line therapies of Parkinson’s disease.
– Medications that increase the level of dopamine in the brain
Dopamine like medications (levodopa),
Dopamine agonists (apomorphine, pramipexole, bromocriptine),
MAO-B (rasagiline and selegiline) inhibits the enzyme monoamine oxidase B that break down the dopamine in the brain
COMT inhibitors (entacapone and tolcapone) inhibits the action of catechol-O-methyltransferase enzyme that breaks down dopamine in the brain
– Medications that affect other neurotransmitters to ameliorate motor symptoms
Anticholinergics such as , benztropine or ethopropazine, reduce the action of the neurotransmitter acetylcholine and are helpful for tremor symptoms.
– Medications to help control non-motor symptoms, prescribed for various non-motor symptoms as psychoses and depression
Antipsychotics are used to treat hallucinations and delusions that some patients with Parkinson might experience (pimavanserin – blocks serotonin instead dopamine)
Homework: Study Guide for the Pharmacological Control of Pain
1. Describe the mechanism of action of the NSAIDS.
– The NSAID’s inhibit cyclooxygenase, the enzyme responsible for the formation of prostaglandins. When cyclooxygenase is inhibited, the inflammation and pain are reduced.
2. What are the functions of the prostaglandins?
– Prostaglandins activate inflammatory response, pain and fever. Also, thrombohexane, a type of prostaglandin, stimulates vasoconstriction and clotting. Certain prostaglandins are involved in GI tract (inhibit acid formation and stimulate mucus formation), induce labor or increase blood flow in kidneys. In asthma trigger the bronchial constriction.
3. Besides the treatment of pain, what are the other uses of the NSAIDS?
– They reduce fever, swelling and inflammation caused by an injury or disease. Other NSAID’s reduce blood loss (ibuprofen).
4. What are the side effects of the NSAIDs?
– NSAID’s may cause GI bleeding, abdominal pain, dizziness, light-headedness and hypotension. Acetaminophen can be hepatotoxic in large doses. Renal toxicity should be monitored by checking the urine output and periodic renal function. Aspirin and salicylates affect platelet aggregation and coagulation time. Bruising or excessive bleeding should be monitored.
5. What are some of the major side effects of the NSAIDS?
– Stomach bleeding and ulcer, fluid retention are main risks for NSAID’s use. The fluid retention can lead to heart attack, high blood pressure and stroke.
6. Who should not be taking NSAIDS? Explain the rationale.
– People who had an allergic reaction to this medication should avoid it because it can cause a life-threating reaction.
Also, patients that are using anticlotting drugs such as warfarin should not use NSAID’s during the same period because of the added anticlotting effect, that could lead to overdose.
7. Cross-sensitization can occur with the NSAIDS. What does this term mean?
– Cross-sensitization occurs when a patient is sensitive to one substance that induce another sensible reaction to another substance of similar chemical structure.
8. How does acetaminophen differ from the NSAIDS?
– Acetaminophen or paracetamol does not act as an anti-coagulation drug and it does not irritate the stomach, therefore being considered a safer drug in NSAIDS category. Can be used in pregnancy or for children. Fatal liver damage can occur with doses over 4000mg.
9. What is the mechanism of action of celecoxib (Celebrex)? What are the advantages and disadvantages of celecoxib over the more traditional NSAIDs?
– Celecoxib is an anti-inflammatory, antipyretic NSAID that inhibits cyclooxygenase type 2 (COX -2). Celecoxib provides a specific peripheral pain and inflammatory relief. This action is more specific compared to aspirin and ibuprofen, which acts toward inhibiting COX-1 and COX-2 inhibiting the formation of prostaglandins responsible for pain, inflammation and platelet aggregation.
10. What is the mechanism of action of sumatriptan (Imitrex)? Besides the triptans, what other classes of drugs can be used in the treatment of migraine headaches?
– Sumatripan acts by constricting intracranial vessels.
Another class of drugs used for migraine headaches are the ergot alkaloids (ergotamine).
Prophylactic drugs used are antiseizure drugs, beta-adrenergic blockers, calcium channel blockers or antidepressants. These drugs are used with caution due to their side effects.
11. Describe the mechanism of action of the opioid analgesics.
– Opioids exert their action by interaction with certain neuronal cell membrane receptors. Most targeted are mu, kappa and delta receptors. The pain transmission toward the brain is decreased.
12. What are the CNS and peripheral effects of the opioids? (See notes)
– The main effect on CNS is to inhibit neurotransmitter release. Effects include analgesia, mood changes and an activation of the reward center which can lead to drug abuse.
Among the peripheral effects are: inflammation reducing effects in the joints or healing wounds.
13. Describe the differences between the strong opioids, mild to moderate opioids and mixed agonist-antagonists in terms of efficacy and potential for addiction.
– Codeine is an opioid used for mild to moderate pain relief, but the side effects are very serious (nausea and constipation) and are not used for long term.
Morphine is a stronger opioid used for management of moderate to severe pain. Frequent side effects include nausea, vomiting and feelings of euphoria
Methadone has a longer duration of action than morphine.
Fentanyl is known to be a fast acting opioid, 50-100 times stronger than morphine, but is known to be highly addictive also.
14. Define the terms tolerance, withdrawal, addiction and pseudoaddiction.
– Tolerance is a state of adaptation in which the dose of the opioid needs to be increased to achieve recommended level of analgesia.
Withdrawal is a group of symptoms that occur with the abrupt discontinuation of a drug that has the capability of producing physical dependence.
Addiction is a chronic, neurobiological disease characterized by behaviors such as no control over drug use, compulsive use, continued use despite harm and craving (American society of Addiction Medicine, 2001)
Pseudoaddiction is a behavior of seeking additional medication of the patients who receive inadequate pain management. It usually stops once the pain is treated accordingly.
15. What are the side effects of the opioids?
– The most common side effects are respiratory depression, sedation, nausea, constipation and vomiting.
16. What is the clinical indication for naloxone (Narcan)? Is Narcan used in large doses or small doses? Why?
– The clinical indication for Narcan is for opioid overdose. The mechanism of action of Narcan antagonize the opioid effects by competing for opioid receptors sites in CNS. It is used in smaller doses to avoid opioid withdrawal symptoms.
REFERENCES
Adams, M., Holland N., Urban, C., (2014) Pharmacology for Nurses, A Pathophysiologic Approach 4th ed. Upper Saddle River, NJ: Pearson Education
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