Parkinsons Major clinical SX

1
Parkinsons Major clinical SX

• Bradykinesia slowness of mvt, diffic
  initiationg movt
• Muscular rigidity increase in mm tone
• Resting tremor pill rolling
• Stooping posture
• Festinating gait shuffling gait, once initiate,
  rapid acc.
• Due to deficit in DA in NSP, which contains 80
  DA in brain, SX appear after 80-90 DA depleted
• Cause Unknown, genetics? Free-radicals?
• Extrapyramidal System fine motor mvts, mm tone,
  posture
• Cell bodies SN PC project fibers to
• Nerve terminals NSP StriatumCaudatePutamen
• NSP modifies output of desc motor pathway to
  turn gross mvt into fine mvt.

2

• Indirect No-Go Cortex sends Glu to
  Caudate-Putmamen (Striatum), Glu excites Ach,
  which excites the GABA neuron going to LGP, which
  sends GABA to Subthalamic Nucleus, which sends
  Glu neuron to MGP/SNr, which sends GABA to
  thalamus, which inhibits Glu neuron leaving
  thalamus and going to Cortex. Result Mvt
  inhibited
• Direct Cortes sends Glu to Striatum, which sends
  GABA to MGP/SNr, which sends GABA to thalamus,
  which sends Glu to Cortex. The GABA leaving the
  striatum inhibits the GABA leaving the thalamus,
  so that mvt is promoted, or disinhibited.

3

• Nigrostriatal Pathway modifies mvt. Cortex
  sends neuron to SNc, which secretes Glu, which
  excites neuron w/in wihc secretes GABA, which
  inbigits neuron w/in which goes to Striatum, and
  has two branches w/in Striatum, both secreting
  DA. D2 secretes DA-, D1 secretes DA. THE DA-
  inhibits the No-Go pathway, and the D1 excites
  the Go pathway.
• In PARK, NSP degenerated, causing DA deficit
  No-Go pathway predominates, Ach increases with
  breakdown of NSP

4

• Most antipsychotics are D2R blockers, if you
  decrease DA, you increase Ach
• Why Dopamine agonists, anti-muscarinics work with
  PARK.
• Physiologic Tyrosine conc saturates toyrosine
  hydroxylase
• L-tyr ? L-Dopa ? DA ? NE ? Epi
• Enz tyrosine hydroxylase (RLS), Dopa
  Decarboxylase DA doesnt cross BBB, enzymes for
  NE, Epi not in brain
• 10 neurons remaining are enough, takes several
  mos to see effects, degen continues, so effect
  diminishes with time. If tyrosine ?, l-dopa
  doesnt work as well

5

• On-off effect fluctuation in response to l-dopa
  due to
• DZ progression
• Duration of TX, the longer youre on, the more
  likely
• Fluctuations in dietary AAs, esp aromatics
• 90 l-dopa converted to DA in periph, need large
  doses, ? SEFX
• NV Stim Chemo-receptor Trigger Zone, in area
  postrema, floor of 4th ventricle, not portected
  by BBB
• Many anti-emetics are phenothiazines,
  (prochlorperazine) D2 antagonists interfere w
  TX of l-dopa
• Minimize with CARBIDOPA periph decarboxylase
  inhibitor keeps L-dopa from being converted to
  DA in periph,
• LODOSYN Carbidopa alone

6

• SINEMET 25mb Carbidopa/100 mg l-dopa 3X a day
  PRVN NV
• SINEMET CR minimizes on-off effect
• Also 5HT-3 antagonists
• DOLASETRON
• ONDANSETRON
• GRANISETRON
• Anti-histamines
• BENZTROPINE
• MECLIZINE
• EMETROL phophrylated carbo soln, OTC
• Can take l-dopa with food/milk, ? absorp, delay

7

• DA can also stimulate alpha and beta R
• Transient tachycardia CXN CV problems
• DA stimulates B1 in heart
• Give Propanalol beta blocker
• Orthostatic hypotension changes in BP due to
  changes in posture
• L-dopa psychosis elderly, meso-limbic pathway,
  cant use typical anti-psychs block DA R,
  interfere with TX.
• Atypical CLOZAPINE, QUETIAPINE block 5HT-2
  receptors (Serotonin)
• Orofacial dyskinesias tongue, face,
  supersensitive D2 Rs Degen of presyn term ?
  upregulation postsyn Rs,
• Lactation ? DAPIF, TX with CARBIDOPA

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RX Interactions w L-dopa

• PYRIDOXINE Vit B6 Co-fctr for tyr Hase
• PHENOTHIAZINES BYTYROPHENONES D2 Antagonists
• NON-SELECTIVE MOA-Is MAO A, B
• Phenelzine
• Tranylcypromine
• Isocarbozaxid
• MAO-A in gut NE, EPI, 5-HT
• MAO-B in brain DA
• Tyramine, found in cheese, beer, metab by MAO-A,
  ? plasma levels enters NE terminals and adrenal
  medulla, metab to
• NE, which is ? due to MAO-I,
• Octopamine displaces NE
• Net effects vasoconstriction, hypertensive
  crisis, () Inotropic/Chronotropic EFX

9

• SELEGILINE relatively selectively INH
  MAO-B??HTN crisis Dose-dependent
• Blocks DA uptake
• ? activity catalase super oxide dismutase ?
  free radical scavenging
• Metab to amphetamine and methamphetamine ?
  anxiety and insomnia
• RX Interactions
• MEPERIDINE(Demerol) Serotonin Syndrome stupor,
  rigidity, agitation, hyperthermia Mech blocks
  5HT uptake ??Serotonin transmission, perhaps
  Selegine also Inh MAO-A
• TCAS AND SSRIS block Serotonin re-uptake
• SELEGILINE gen taken with l-dopa or SINEMET

10
COMT Inhibitors

• TOLCAPONE adjunct to l-dopa, selective inh of
  COMT ?DA
• Do NOT use with non-select MAOI eliminates all
  mech of metab of catecholamines
• Problem with Seleginine will INH MAO-B, so ? DA
• SEFX 3 cases FATAL LIVER FAILURE
• USE adjunct to l-dopa/carbidopa for On-Off
  phenom
• ENTACAPONE Selective INH of COMT short t1/2
  2 hrs, so used onle with L-D/C
• No sig HEPATOXICITY with this RX

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Direct Acting DA Agonists

• Conversion not required, longeracting drups, so
  no ON-OFF
• BROMOCRIPTINE Ergot deriv LSD
• Strong D2 agonist, partial D1 Agonist
• Fewer dyskinesias stim D2 Rs but blox D1 Rs.
  Must stim D1 D2 to get full motor effect.
  Blocking D1 Rs diminishes dyskinesias
• SEFX NV, Stim D2 in CTZ, confusion,
  hallucinations, hallucinosis persistent halluc.,
  HTN titrate dose slowly
• TX Galactorrhea Acts on PIF

12

• PERGOLIDE Ergot weakly stim D1 D2, adjunct
  for serious dyskinesias and On-Off phenom
• SEFX ? Hallucinosis, ? Prolactin release
• PRAMIPEXOLE non-ergot, D2 Selective
• ROPINIROLE Non-ergot, D2 selective
• Both do not cause HTN, but both cause SUDDEN
  SLEEP ATTACKS

13

• MISC DAergic RX
• AMANTADINE Sole agent in mild cases, anti-viral
  for flu
• Mech ?DA release, ?DA uptake, Anti-muscarinic
  axn bc I PARK - ?Ach
• CNS SEFX Confusion, dizziness, anxiety
• PNS Constipation, dizziness, anxiety, LIVEDO
  RETICULARIS (1-5) benign red or blue patches on
  extremities

14

• Anticholinergics block Ach-R, so ?Ach doesnt
  harm muscarinic antagonists
• Nicotinic NMJxn, ganglia, adrenal medulla
• Muscarinic others
• TRIHEXYPHENIDYL prototype
• BENZTROPINE
• PROCYCLIDINE
• BIPERIDIN
• DIPHENHYDRAMINE Benadryl, anti-hist
• SEFX CNS elderly confusion, depression,
  hallucinations PNS sedation, dry mouth, blurred
  vision, constipation, tachycardia all anti-PARA
  SX
• CXN Narrow angle glaucoma PARA constricts
  ciliary mm, widens angle, block ciliary relaxes,
  no drainage, IOP up.

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Barbituates

• Sedative ? anxiety, calming effect w/o altering
  mental/motor fxn.
• Hypnotic produce drowsiness
• Into disfavor
• Low TI (TITD50/ED50) Suicide
• Tolerance RAPID work 3-4 nights MAX
• Pharmacodynamic fxnal tolerance body changes
  hemoestoci mechs
• Cross tolerance to ROH, opiods, benzodiazepies
  via down regulation receptors
• Pharmcodynamic way body metab and disposes of
  drug Quick response enzyme indxn
  P450/microsomal enz
• High abuse liability controlled substance DEA
  - withdrawl SX - FATAL
• ?? Drug intrxn from Enz Indxn

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Sleep cycles

• 4 stages plus REM (paradoxical/fast wave)
• Each stage deeper, REM subset of 1
• Barbs supress REM, 1, 3, 4, but ? 2, ? total
  sleep time
• Spontaneous awakening from REM
• External Stimuls awakening non-REM, no brain
  filtering
• Prolonged sleep latency cant fall asleep,
  shorter duration drug used for TX
• Early morning awakenings cant sleep long
  enough longer action drug used for TX
• Sudden discont BARBS REM-rebound ?nightmares
• Tolerance due to sedative-hyponotic EFX, get
  hangover

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Site of axn for BARBS

• GABA A Receptor Complex ionotropic R directly
  linked to ion channles
• 5 different subunits from total of 8 diff types
• Each subunit exists in multiple isoforms
• Min receptor requirements for BARB a, ß
• ? subunit has 2 sites GABA and BARB
• Binding GABA ? ? gCl ? hyperpolarization
• Binding BARB ?GABA binding ? ? gCl ? etc
• Benzos ? frequency channel opening
• Net effect BARB prolong duration opening
• All BARB anticonvulsant, but too sedating
• TX doses REQUIRE GABA, Toxic directly open Cl
  channels
• block Glu AMP Rs, allows inb ctrs to put brain to
  sleep

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• Ultra-short acting BARBs 20 min
• Thiopental IV rapdi indxn, rapid recovery from
  anesthesia, pass by delirium (stage 2)
• Venodilates ? venous capacitance ? ? BP by 20-30
  mm Hg ? ? HR (reflex)
• Resp depression normally leads to ? ICP, but
  not with BARBs due to venodilation
• Hyperalgesia - ? pain sensitivity.
• HIST release
• METHOHEXITAL
• No Hist release still get bronchospasm
• No venodilation thiopental only venodilator

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• Short-acting barbituates 3-4 hoursSedative-hypno
  tics, pre-anesthesia
• PENTOBARBITAL anticonvulsant
• SECOBARBITAL
• Good for prolonged sleep latency
• Intermed acting barbs 6-8 hours
• Early morning awakening
• AMOBARBITAL
• BUTABARBITAL
• Tuinal Secobarbital Amobarbital both

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Long-acting 24 hoursnot good sedative too long

• PHENOBARBITAL Antiepileptic, Status epilepticus
  (series of grand mals)
• MEPHOBARBITAL N-methyl phenobarbital,
  demthylated by liver to phenobarb, contra liver
  DZ, not used much use sedative for anxiety,
  tension
• BARBS Weak Acids so you alkalinize the urine
  to ionize the weak acid, so it can clear

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SEFX BARBS

• Paradoxical excitement inbibition of inhibitory
  process
• Enzyme Indxn Pharmacokinetic ?p450
• Leads to ?metab ??drug interxns
• Resp depression depresses neurogenic drive with
  only 3X dose. Higher doses depress hypoxic and
  chemical drives to resp
• Hangover effect daytime sedation
• RX Interxn additive with other CNS depressants
• CONTRA acute intermittent porphyria
  neuropathis, enzyme indxn toxic precursors

22
Benzodiazapines (BZ)

• Uses S/H, anxiolytics, anesthetics,
  pre-anesthetics, anticonvulsants, musc relax
• BZs do NOT cause
• CNS depression
• ENZ Induction leads to ?? drug
• BZs have
• High TI (LD50/ED50)
• No signif resp depression
• Caveats alcoholic, COPD BZs cause resp
  acidosis
• Pts w OSA exaggerated EFX on albeolar hypoxia,
  pulmonary HTN, ventricular load
• BZ snoring to OSA (Obstruc Sleep Apnea)
• BZs suppress REM and all stages except stage 2,
  ?
• ?Stage 4 Night terrors wake screaming from
  deep sleep, acts on RAS

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Mech of axn of BZs

• BZs bind at interface of a and b subunits of
  GABA-A Rcx, gama subunit REQUIRED. Binding to BZ
  site enhances binding of GAMA to beta subunit
  hyperpolarization
• Net effect ? frequency
• Without GABA, no effect on gCl
• 2 types receptors omega BZ-1, BZ-2
• Determined by Isoform of a subunit
• BZs sed-hyp hi affinity BZ-1 Rs with a-1
  isoform
• BZ-2 a-5 isoform anticonvulsant, mm relaxant
• BZs nonselective unless otherwise stated, BZ -1,
  2
• In proper dose ALL HAVE SED-HYP ACTIVITY
• Allosteric relationships bt sites

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BZs used as SED-HYPs

• TRIAZOLAM t½ lt6h PSL
• Quick tolerance, try intermittent use, amnesia
• TEMAZEPAM - t½ 6-24 h, EMA
• ESTAXOLAM -
• FLURAZEPAM - t½ gt24h
• Active metabolite desalkylflurazepam
• Hangover effect, NIGHTMARES
• QUAZEPAM long acting 2-oxo-quazepam
• Both selective for BZ-1 receptor
• MIDAZOLAM IV-preanesth, only anesth in some
  cases

25

• FLUMAZENIL
• only BZ Antagonist used clinically
• Reverse the sedative effects of BZs
• Pre-op or post-op
• TX BZ OD
• Clonidine Anti-HT
• Causes sedation
• ?2 agonist
• Decrease sympathetic outflow

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Misc sedative-hypnotics

• ZOLPIDEM NON-BZ
• Binds to BZ-1 sites on a subunit of GABA-A R Cx
  ?gCl-
• Rapid onset, short dura PSL,
• Doesnt alter sleep stages, not good for night
  terrors
• ZALEPLON BZ-1 site, t½1hr, PSL
• CHLORAL HYDRATE knock-out drug
• Sed-Hyp, act metabtrichloroethanol,
• BARB-like effect on GABA-A Receptor
• NV, Hangover effect, sleep cycle like BARB, less
  ? in REM
• PARALDEHYDE intox, tolerance, phys depen
• Sedation in
• Delirium tremors drug withdrawals
• ER TX convulsions
• DEXMEDETOMIDINE IV ICU mech vent
• a2 agonist does not interfere w GABA,
• ?1- Rap IV hypoTN, brdcardia, sinus arrest, ?
  vagal tone, barorflx

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• Factors governing sensitivity of nerve fibers to
  local anesthetic
• Small diameter appear more sensitive
• Pain fibers more sensitive
• Non-myelinated more more susceptible
• Myelinated blocked before non same diameter
• Critical length length of neuon that must be
  exposed to Rx
• 3 successive nodes must be blocked
• The larger the fiber, the greater the the CL
• Frequency and use dependance of neuron
• ? Rx access to site of axn
• MOA block voltage sensitive Na channels
• Binding site for Rx inside a subunit.
• The more frequently used, the more likely to be
  open

28

• Na channel has 3 subunits, ß1, 2, a req for
  activity, 4 domains form ion channel w/in memb
  as neuron deopolarizes, ea domain will change
  charge and conform, causing channel to either
  open or close
• After opening, channel enters inactivated state
  which is desensitized.
• Local anesthetics prefer binding to OPEN and
  INACTIVATED states.
• Binding to prefered states
• STATE DEPENDENCE
• Lipid soluble drugs go right in
• Cationic form of Rx greatest affinity for R which
  must be accessed from intracellular side of
  channel must pass thru open channel

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2 categories local anesth

• Esters metab by plasma exterases shorter acting
• Amides metab by LIVER longer acting
• Hydrophillic grp 2ary or 3ry amine
• Hydrophobic grp aromatic ring

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Procaine short acting 15 min

• Infiltration anesth minor surgery, dental
• DX nerve blocks block plexus
• Musc relax
• DX spinal anesth
• Intrathecal subarachnoid space lumbar level
• Blocks sensory motor fibers below diaphragm
• Control spread of anesth w/in SAS by
• Adjusting specific gravity
• Hyperbaric 10 glucose added
• Hypobaric sterile water added
• Adjusting tilt of patient
• Many pts sensitive to esters, amides preferred
• TOXIC EFX Resp ? - blocking Na channels

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CHLOROPROCAINE

• Rapid onset, short duration ? Toxicity
• Uses infiltration, peripheral and epidural nerve
  block
• Epidural associated with ? incidence of muscular
  back pain, possibly from tetany due to chelaiton
  of Ca2 by EDTA

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COCAINE Intermediate acting

• Topical use on mucous membranes
• 4 and 10 solutions available
• Vasoconstrictor blocks NE uptake
• Advantages
• ? systemic EFX from ? blood flow
• ? duration
• Control bleeding
• CXN can slow wound healing
• Other locals add vscnstr epi, phen
• Systemic EFX
• EUPHORIA block DA uptake mesolimbic
• Tremors and convulsions ? excit tone, NE
• Resp ?, death block Na channels
• CV block NE uptake, beta at high dose
• Hyperpyrexia block NE vasocon hypothal
  disrupt

33
TETRACAINE long acting 2-3 hours

• CXN
• Cardiotoxicity ext block Na chan
• Vasodilates block Ca channels
• ? risk to system
• Uses No longer used
• Pot SYS EFX all locals
• Sys absorption from vasodilation via blocking Ca
  channels
• Reflex ? HR, palpitations, chest pains,
• Phenylephrine prfer bc no ß efx
• Profound vasoconstriction reflex ? HR

34
PROPARACAINE Ophtalmic

• Ester and ester link
• Does not exhibit cross-sensitivity to other
  esters
• Uses
• Ophthalmic surgery
• Removal of sutures
• Removal foreign objects

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Amide locals int act 30-90 min

• LIDOCAINE
• faster onset, longer than procaine
• Topical pain, itch minor burns, hems, rash
• Injexn infiltration, spinal, NN blocks,
• Ventricular arrythmias block Na channels
• SEFX seizures, coma, resp ?, resp arrest
• MEPIVACAINE infiltr, epidural
• Not OB lower Ph in neo blood ion trapping
• PRILOCAINE 1.8 ML Dental cart only
• Systemic TOX met Hbemia
• Tx methylene blue

36
Long acting amides

• BUPIVACAINE 2 4 hrs,
• Varoius strengths w, w/o epi
• Can be cardiotoxic
• Uses similar to LIDOCAINE
• LEVOBUPIVACAINE
• Levorotary isomer of bupivacaine
• Purified isomer
• Uses
• local and regional surgical anesthesia
• Post-op pain management

37
Topical use skin, mucosa only, no eyes

• DUBUCAINE cream, sunburn, rash, bites
• DYCLONINE 2 ether links
• Endoscopic procedures mucosa
• PRAMOXINE 2 ether links sunburn
• BENZOCAINE procaine wo NH2 grp
• ?H2O solubility, ? systemic absorp
• Topical dir to wound, sunburn, orajel lg area
  oral cav
• BUTAMBEN OTC mucosa mouth sores
• OPIODS morphine epi, intrathecal
• ABSOLUTE ETOH
• near NN trunks for intratractable pain Tic Delou

38

• What are the four symptoms seen in Horners
  Syndrome?
• Anhydrosis
• Ptosis
• Pigment changes (Lighter colored Iris) esp.
  congenital
• Miosis
• What is the most important part of the visual
  examination?
• Visual acuity test

39

• How would you treat a patient with orbital
  cellulitis?
• Get them to the emergency room
• Hospitalization
• Massive I.V. antibiotics
• Warm compresses to increase blood flow
• Get sinus x-rays
• Why is it important to get the patient to the ER
  quickly?
• Patient can develop meningitis and die
• Why do you need to hospitalize patients with
  orbital cellulits?
• Because they need to start massive I.V.
  antibiotics and this is the only location that
  they can do this.
• Why would you want to get sinus x-rays in orbital
  cellulitis?
• Because infection can spread from the sinuses

40

• Herpes Zoster if nose tip involved, elevated
  IOP, inflammation inside eye iritis,
• Retinal detachments flashes, floaters,
  peripheral loss of vision,
• Corneal abrasions Ab ointment, pressure patch,
  check the NEXT DAY, and the NEXT DAY, until it
  heals.

41

• What are the two ocular changes seen in herpes
  zoster (vesicles seen on face)?
• Ocular inflammation, also on nose
• Secondary glaucoma (increase IOP) (so check eye
  pressure w/herpes-zoster pts)
• What is the other name for ocular inflammation?
• Iritis
• What is the most common type of glaucoma?
• Open-angle
• What is not functioning properly in open-angle
  glaucoma?
• Trabecular meshwork
• Is the eye pressure in open angle high or
  moderate?
• Moderate

42

• Will the patient with open angle glaucoma
  typically have early symptoms?
• No only after many years
• Do patients with open angle usually lose
  peripheral or central vision?
• Peripheral
• How would a non-ophthalmologist measure eye
  pressure?
• With a Shiots Stenometer
• Where is aqueous humor produced?
• Ciliary bodies
• What of the population has open angle glaucoma?
• 1 ½ gt 40 years of age

43

• What is the high limit of normal eye pressure?
• 21 mmHg (gt 21 look into a problem)
• Where do the axons of the ganglion cells project?
• They follow a course to the optic nerve
• Which part of the eye has a more direct route to
  the optic nerve?
• Macula
• What happens (damage) with IOP?
• Decreased blood flow to the optic nerve and you
  see cupping or indentation of the optic nerve
  which results in loss of vision (retrograde
  degeneration)
• If the patient has inferior retinal loss, what
  area of the eye field is lost?
• Superior eye field

44

• What is the easiest way to lower IOP?
• Eye drops timoptic (timolol)- a beta blocker
  that decreases aqueous production.
• If patient is taking eye drops for glaucoma and
  continues to lose visual field, what is the next
  appropriate step?
• Use laser surgery on the trabecular meshwork (
  open and stretch) allows aqueous to flow out
• If laser surgery is not effective, what is the
  next appropriate step?
• Perform a trabeculectomy

45

• How is the trabeclulectomy performed?
• Create a flap in the conjunctiva, then a
  superficial cut into the sclera then a full
  thickness cut into the second layer of sclera,
  and then remove a piece of the iris. Then suture
  the superficial flap followed by the conjunctiva
  flap. Aqueous flows under the trap door created
  instead of the trabecular meshwork.
• Which type of glaucoma is rare but more serious?
• Narrow angle or closed angle glaucoma

46

• Instead of moderate pressure as in open angle,
  these patients can have pressure in the 70-80
  range. Besides acute pain, what else happens at
  these pressures?
• 1. Cornea becomes cloudy or hazy (poor vision
  quickly)
• 2. Eyes become very red
• 3. Pupil no longer responsive
• 4. Very often nauseated
• 5. Eyes dilated
• Is narrow angle glaucoma more common in men or
  women?
• Women ( 3 fold higher)

47

• What happens if the pressure in the eye stays at
  70 for more than 24-48?
• Permanent vision loss if untreated
• What are the two medical emergencies in
  opthamology?
• 1. Alkaline burns
• 2. Central retinal artery occlusion
• Do vasoconstrictor eye drops alone work well in
  narrow angle glaucoma?
• Not really ( dont penetrate the cornea)

48

• How would you treat narrow angle glaucoma?
• 1. Start on I.V. meds that pull fluid out of the
  eye via surrounding blood vessels (Mannitol or
  Diamox)
• 2. Vasoconstrictor eye drops
• 3. If patient is diagnosed ? laser surgery to
  burn a hole through the iris, to prevent likely
  reoccurrence. (patient no longer requires eye
  drops)