This seminar was delivered to 2nd year pharmacy students as part of 2 lectures for a pharmacology & toxicology class. This material accompanies Goodman & Gilman's (12e) chapter 22.
2. Objectives
• Describe biosynthesis and elimination of
dopamine & the importance for PD symptom
management.
• Outline the rationale (pros & cons) for
different secondary treatments of PD
including MAOB-I, & DA agonists.
3. Disease Frequency in US Genetic Patho- Neuro Pharm Goal Effectiveness
physiology chem Management
Parkinson’s 500 K low nigra- DA common sym high
striatal
Alzheimer’s 5.4 million moderate diffuse ACh? common sym slight
cortex
Huntington’s 30 K high striatum ? uncommon sym small
ALS 25 K low motor Glut? common sym small
neurons
ACh: acetylcholine; DA: dopamine; Glu: glutamine; sym: symptom management
4. Ideopathic Parkinson’s Disease
• Neurodegenerative disease
characterized by:
– resting tremor
– rigidity
– bradykinesia
– a + response to PD pharmacotherapy
• Prevalence ≈ 1 million
• Risk Factors
– rural > urban
– age: > 65 1%; > 80 2.5%
– sex: 2 M : 1 F
Pill rolling (20 sec):
http://www.youtube.com/watch?v=0-t4RTQ0EsM
Parkinson’s Symptoms (1st min only):
http://www.youtube.com/watch?v=_L_WF6gv5BI
.
Van Den Eeden et al. (2003). Am J Epidemiology, 157, 1015-1022 Chen et al. (2007). Parkinson’s Disease. In DiPiro Pharmacotherapy.
9. History of
L-3,4-dihydroxyphenylalanine (1950s)
• L-DOPA (B) used to counteract reserpine (A)
• This effect corresponded with dopamine levels in the
brain
Arvid Carlsson, MD
Carlsson (2001). Science, 294, 1021-1024. 1923 -
10. History of
L-3,4-dihydroxyphenylalanine (1960s)
• Additional of a peripheral AADC inhibitor
improved response and limited nausea
11. History of
L-3,4-dihydroxyphenylalanine (1960s)
• Additional of a peripheral AADC inhibitor
improved response and limited nausea
On versus Off L-DOPA: http://www.youtube.com/watch?v=sf1N0Zf5IqA
12. Limitations of carbidopa/levodopa
(1970s)
• competition with other proteins to cross BBB
• “unawakening”
• dyskinesias occur in majority
Extreme example (1 min): http://www.youtube.com/watch?v=d1jJyk_poqE
15. Selegiline Rasagiline Tolcapone Entacapone
(L-deprenyl) (azilect) (tasmar) (comtan)
mechanism MAOB MAOB peripheral peripheral
(irreversible) COMT COMT
central COMT
monotherapy yes yes no no
other meth & amph hepatoxicity 0.5 hour
metabolites; half-life
insomnia
hallucinations
Chen et al. (2008). Parkinson’s disease. In DiPiro’s Pharmacotherapy.
16. Slowing of Further
Neurodegeneration?
• PD may occur by
– DA induced formation of free radicals (H2O2)
– apoptosis
• MAOB inhibition may act to prevent these
mechanisms but this is difficult to establish
clinically
17. PD Progression
• Early PD patients (N=520) were randomized to arm 1 (L-DOPA & AADC
inhibitor) or arm 2 (selegiline, L-DOPA, AADC inhibitor).
• Webster score, conducted non-blind) includes motor function (hand-
bradykinesia, face, speech, flexibility, rising from chair, balance).
Parkinson’s Disease Research Group British Medical Journal, 307, 469-472.
18. PD Progression
• Early PD patients (N=520) were randomized to arm 1 (L-DOPA & AADC
inhibitor) or arm 2 (selegiline, L-DOPA, AADC inhibitor).
• Mortality from a variety of causes were also recorded.
2.8% for Arm 1 & 9.6% for Arm 2.
1920 - 2005
Parkinson’s Disease Research Group British Medical Journal, 307, 469-472.
19. Thanks, home chemists!
W. Langston, M.D.
• Barry Kidston develops Parkinson’s after synthesizing
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
• Later cases were described as:
– “Three of the four patients were hospitalized with 14 days
to 6 weeks of first use of the drug. Examination in each
revealed near total immobility, marked generalized
increase in tone, a complete inability to speak intelligibly,
marked diminution of blinking, fixed stare, constant
drooling”
– Stopping L-DOPA resulted in “complete immobility &
rigidity, being only able to move his eyes”
Langston et al. (1983). Science, 219, 979-980.
20. MPTP= Parkinson’s model
Immunocytochemistry for
tyrosine hydroxylase in rhesus
monkeys
Parkinson’s Disease Normal
Masilamoni et al. (2011). Brain, 134, 2057-2073.
24. Compulsive Behaviors with
Dopamine23 Agonists
• sexual
• gambling
• other repetitive behaviors
Bostwick et al. (2009). Mayo Clinic Proceedings, 84(4), 310-316.
3 min: http://www.youtube.com/watch?v=3oNkYNVdsio
25. PD Progression with D agonist
benserazide: peripheral DOPA decarboxylase inhibitor
bromocriptine: D234 agonist
Rang et al. (2007). Pharmacology. p. 519.
26. Muscarinic Antagonists
• Trihexyphenidyl (Artane) and Benztropine (Cogentin)
• Rationale
– Muscarinic Receptors on striatal neurons mediate cholinergic
tremor
– May cause presynaptic inhibition of dopamine release
• Adverse effects
– “atropine-like”: dry mouth, inability to sweat, impaired vision,
urinary retention, constipation, drowsiness, confusion
27. Summary
Pro Con
L-DOPA awakening unawakening
dyskinesia
MAOB-I delay time until L- long-term
DOPA outcomes*
dopamine agonists reduced dyskinesia compulsions
sleep attack
*needs additional study
28. Caffeine & Decreased PD Risk
• Dietary habits were obtained
from middle aged men
(N=8,000) in 1965.
• Subjects were monitored for
30 years for incidence of PD.
• Mechanisms
– 3rd variable
– antioxidant
Ross, G. W. et al. (2000). JAMA, 283, 2674-2679.
29. Smoking & Decreased PD Risk
• A meta-analysis of 44 studies (6,814 cases,
11,791 controls) has revealed a highly
consistent reduction.
• Current smokers are 60% less likely to
develop PD than non-smokers.
• Ex-smokers are 40% less likely to develop
PD than non-smokers
• Potential mechanisms
– third variable?
– ↑ dopamine
– Inhibition of MAOB
Relative Risk = Probability Exposed
Probability Unexposed
Hernan (2002). Annals of Neurology, 52, 276-284.
30. Pesticides & Increased PD Risk
• origin of rural > urban for PD is unclear
• Rotenone is an insecticide & piscicide and
causes MPTP like neurodegeneration (animals)
• Paraquat is one of the most common
herbicides in the world.
Tanner et al. (2011). Environmental Health Perspectives, 119, 866-872.
32. Terminology Refresher
bradykinesia: slowed movement
dyskinesia: involuntary movement involving head, neck, or upper extremeties
dystonia: abnormal tone of any tissue, sustained muscle contractions
Pronunciation: http://dictionary.reference.com/browse/dyskinesia?s=t
http://dictionary.reference.com/browse/idiopathic
Editor's Notes
Lou Gehrig: 1st baseman for Yankees
The artificial sweetener Aspartame is a dipeptide (phylalanine/aspartic acid) & is found in many (6000?) foods.
PKU is fairly rare (1/15,000)
PD involves a selective degeneration of the nigrastriatal pathway. Transplantation of somas into the striatum produces limited improvements.
Carlsson found that L-DOPA (iv) could very quickly reverse the profound sedation caused by reserpine. This would was completed in the 1950s when: 1) people still believed neurocommunication was exclusively electrical and 2) dopamine was just a precursor to norepinephrine.
Peripheral dopamine acting on the brainstem (area postrema) causes nausea,vommitting, anorexia.
George Cotzias, MD, a Greek clinician scientist working at Brookhaven National Labs, gradually titrated the oral L-DOPA dose. Motor ratings (tremor: ++++ prevents use of limb, + barely perceptible) were made. Note response on an individual level! 13/28 patients were able to go from inpatient to outpatient & return to work! Side-effects included nausea/vomiting/anorexia & anxiety.
L-DOPA has to compete with other amino acids on the large neutral amino acid transporter to pass the Blood Brain Barrier. This can be overcome by taking the pills on an empty stomach. A larger concern is that the effects of L-DOPA wear off and that L-DOPA causes dyskinesias, involuntary movements of the head, trunk, upper & lower extremities.
Selegiline (se-LE-ji-leen) isMAOBselective at moderate doses. Adverse effects of selegiline are minimal but may include insomnia (especially if taken at bedtime), hallucinations, & jitteriness. The benefits of selegiline are modest with upto 1 hour longer of “on time”. The breakdown products include methamphetamine and amphetamine. Interestingly, Selegiline is a controlled substance in Japan (but not U.S.).Rasagiline produces side effects at rates equivalent to placebo.Hepatoxicity is a rare but serious effect of Tolcapone.Entacaponeɛntəkəˈpoʊn/has a very short half-life which results in many (8x) doses/day.
Dopamine breakdown results in the formation of free radicals like hydrogen peroxide which have an unpaired electron. The formation of these free radicals can result in tissue damage specifically to DNA, proteins, & lipids.
Arm 1 received L-DOPA (dose increased from 62.5 mg, tid) & benserazide, a peripheral AACD inhibitor not approved for use in the U.S.Arm 2 received selegiline (5 mg once per day for once week, then twice per day).An extension of the Webster score is described at: http://www.dwp.gov.uk/publications/specialist-guides/medical-conditions/a-z-of-medical-conditions/parkinsons-disease/rating-scale-pd.shtml
Note that an appreciable portion of both groups did not complete the study (arm 1 lost 51.8%, arm 2: 45.4%).On 31 March 2005 following a urinary tract infection,Pope John Paul II developed septic shock, a form of infection with a high fever and low blood pressure. Interestingly, the miracle that made him a saint was Sister Marie Simon-Pierre had lasting relief from her PD following a prayer to John Paul II.
Bromocriptine is an older agent that is not used very much. Ratings of motor behavior were made. These findings show that MPTP does not cause dyskinesia, only MPTP & L-DOPA.
Sleep attack refers to strong desire to quickly goto sleep. This has resulted in some car accidents. This has occurred in patients with clean driving records and was verified by passengers. This resembles narcolepsy.Apomorphine is used during the “off” periods in patients with variable response to L-DOPA. Apomorphine has high affinity for D4 and moderate affinity for D2, D3, D5 and adrenergic alpha 1D, 2B, & 2C receptors. Apomorphine & ondansetron can result in profound hypotension. This combination is contraindicated.
Extreme changes in behavior have been documented by chart-review to occur in about 5% of dopamine agonist patients. The true # may be as high as 20%. This reported noted 7/28 or 18.4%.After 3 years of parkinsonism, a 46-year-old married man was diagnosed as having PD, and ropinirolemonotherapy was initiated, with the dosage gradually increased to 15 mg/d. He subsequently developed “excessive libido” that “occasionally causes arguments with my wife.” Later carbidopa/levodopa was added, and the hypersexuality persisted for the next 2 years, with the patient or wife mentioning this to physicians at least 2 other times. Ultimately, with the hypersexuality “becoming a marital issue,” the dose of ropinirole was tapered and replaced with entacapone (COMT inhibitor), leading to reduction of problematic libido. A 49-year-old married man with an 8-year history of PD developed a compulsive gambling habit a month after increasing his ropinirole dosage from 15 to 21 mg/d. Initially regarded as a psychiatric problem, the compulsive gambling was managed with counseling and attendance at Gamblers Anonymous meetings, which controlled the urge but did not eliminate it. A year later, his wife told the neurologist that he had “an excessive sex urge,” later necessitating a call to the police after her husband chased her when she refused sex. Other new-onset compulsions included intense focus on his hobby of making stained glass windows, often staying up all night to work on these. His appetite and alcohol intake also increased. Quetiapine (atypical antipsychotic) was initiated at dosages up to 300 mg/d without effect on his sexual demands. He was diagnosed as having bipolar disorder, and his medical regimen was switched from quetiapine to carbamazepine (anticonvulsant)without benefit. Not until the dosage of ropinirole (then 24 mg/d) was tapered and carbidopa/levodopa substituted did his pathologic behaviors remit, with his wife reporting a “complete transformation” with the levodopa and entacapone. “I have my husband back,” she said. “It was like I was married to an alien.”
Bromocriptine very strongly binds to D2 and strongly binds to D3 & D4 receptors. There were approximately 250 participants/group at start of trial.Percent Not Completing Studybromocriptine: 68.8% versus less than half-that for other groups!
Pronunciation:trye hex ee fen' idilThe reason that muscarinic antagonists are useful for symptom management is unclear but they have been used for decades. Tryhexyphenidyl targets M1. Because of potential confusion, these may not be the best agents for use with very old/Alzheimer’s patients.
An example of relative risk is if 20 smokers/100 developed a disease versus 1 non-smoker/100 or .20/.01 = RR of 20. See also: http://en.wikipedia.org/wiki/Relative_risk
Piscicide is used to kill fish. Rotenone is also found in some plants so may be used in “organic” foods. Rotenone is used for fish management.Paraquat can be used to generate free radicals in the laboratory, especially superoxide (O2-)A case-control study of farm workers in North Carolina & Iowa revealed elevated PD with rotenone (OR =2.5) & also paraquat (OR = 2.5)