Anti-epilepsy Agents
Dr Andrew Mallon
Aims
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To describe the pathophysiology of epilepsy
To determine the pharmacological agents
used
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Mechanism of action
Contra-indications
Adverse effects
Patient management
Introduction
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1 person in 20 will have an epileptic seizure at some
time in their life
Epilepsy is diagnosed on the basis of two or more
epileptic seizures.
Around 450,000 people in the UK have epilepsy (40
million people worldwide)
A seizure is triggered by a sudden interruption in the
brain's highly complex electro-chemical activity
(National Society for Epilepsy UK)
Age/Incidence
Brain
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100 billion neurons
Control centre:
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Taken from OUP Illustration Resource, 2002
temperature
sensory input
motor control
emotion
thought?
body functions
Gross anatomy
Front part of the brain;
involved in planning, organizing, problem solving,
selective attention, personality
and a variety of "higher cognitive functions"
including behavior and emotions.
Gross anatomy
The parietal lobes contain the primary
sensory cortex which controls
sensation (touch, pressure).
Gross anatomy
Region in the back of the
brain which processes
visual information.
Gross anatomy
These lobes allow a person to
distinguish smells and are
believed to be responsible
for short-term memory.
Structure
Action Potential
Synapse Activity
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Seizures are a symptom of an underlying CNS
dysfunction
It is an abnormal, uncontrolled electrical
discharge from neurons
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Cell membrane disruptions (permeability)
Altered ion distributions (chemical balance)
Decreased neurotransmitters (Ach and GABA)
Everyone has seizure threshold
Classification of Seizures
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Partial:
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Simple partial seizures (no loss of consciousness)
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With motor symptoms
With sensory symptoms
With autonomic symptoms
Only involve 1 hemisphere
Dependant on which
area of the brain
Complex partial (loss of consciousness)
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Simple followed by loss of consciousness
Impaired at the onset
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Unclassified:
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Classification not possible to problems with
diagnosis – suspected
Generalised (affect whole brain with loss of
consciousness):
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Clonic, tonic (1min) or tonic-clonic (2-4min):
muscle spasm (extensors), respiration stops,
defecation, salivation, violent jerks
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Myoclonic: seizures of a muscle or group of
muscles
Absence: Abrupt loss of awareness of
surroundings, little motor disturbance, mostly
children
Atonic: loss of muscle tone/strength
Pathological Basis
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Abnormal electrical discharge in the brain
Coordinated activity among neurons depends on a
controlled balance between excitation and inhibition
Any local imbalance will lead to a seizure
Imbalances occur between glutamate-mediated
excitatory neurotransmission and gammaaminobutyric acid (GABA) mediated inhibitory
neurotransmission
Generalised epilepsy is characterised by disruption
of large scale neuro-networks in the higher centres.
Normal Processes
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Depolarising Na+ and Ca++ ionic current
shifts are activated by glutamate receptors
Repolarising K+ currents are mediated by
GABA receptors
Hyperpolarisation is mediated by GABAa
receptors creating an influx of Cl- =>
inhibition of impulse generation.
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Any defect causes the neuron to be closer to
the all or none threshold for an AP =
HYPEREXCITABLE STATE.
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Leading to instability between excitation and
inhibition => Epilepsy
Other possible causes
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Inherited mutations of proteins involved in the
ion channels
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Reduction in the activity of homeostatic
ATPase pumps within neuron cell membranes
Basis of Pharmacological Rx
Most anti-epileptic agents act either by blockade
of depolarisation channels (Na+ and Ca++)
OR
Enhancing the activity of GABA
(neurotransmission inhibition)
5 Categories of Anti-epileptic Drugs
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All classifications are based upon chemistry:
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Hydantoins
Succinimides
Benzodiazepines
Barbiturates
Miscellaneous
Hydantoins - Phenytoin (Dilantin)
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Use for pts with Tonic-Clonic seizures
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Acts to promote intracellular removal of sodium during the
refractory period
Antagonism (blocking) of Na+ channels to reduce excitability
Antagonism of Ca++ channels
Potentiation (activation) of GABA receptors to promote the
inhibitory role of GABA
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Can be used in the Rx for neuropathic pain and cardiac
arrhythmias
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Pharmacokinetics:
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Slowly absorbed from gut, use a slow IV if rapid
action is required
Avoid IM – muscle damage
Eliminated by hepatic biotransformation
Can measure amount of free agent in the saliva
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Cautions: hepatic impairment, pregnancy, breast-feeding;
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avoid sudden withdrawal;
Blood or skin disorders
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Adverse effects: nausea, vomiting, mental confusion, dizziness, headache, tremor, transient
nervousness, insomnia occur commonly; rarely dyskinesias, peripheral neuropathy; ataxia,
slurred speech, nystagmus and blurred vision are signs of overdosage; rashes (discontinue; if
mild re-introduce cautiously but discontinue immediately if recurrence), gingival
hypertrophy and tenderness, coarse facies, acne and hirsutism, fever and hepatitis; lupus
erythematosus, Stevens-Johnson syndrome, toxic epidermal necrolysis, polyarteritis nodosa;
lymphadenopathy; rarely haematological effects, including megaloblastic anaemia (may be
treated with folic acid), leucopenia, thrombocytopenia, agranulocytosis, and aplastic
anaemia; plasma-calcium concentration may be lowered (rickets and osteomalacia)
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Dose:
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By mouth, initially 3–4 mg/kg daily or 150–300 mg daily (as a single dose or in 2 divided doses)
increased gradually as necessary (with plasma-phenytoin concentration monitoring); usual dose
200–500 mg daily (exceptionally, higher doses may be used); child initially 5 mg/kg daily in 2
divided doses, usual dose range 4–8 mg/kg daily (max. 300 mg)
Contraindications: increases metabolism of the contraceptive pill, anti-coagulants, and
pethidine
Succinimides – Ethosuximide (Zarontin)
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Use for pts with Absence seizures
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Acts by antagonising Ca++ channels in the
thalamocortical relay neurons => prevention
of synchronised neuronal firing => raising AP
threshold
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Pharmacokinetics:
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Almost complete absorption from the gut
Extensive metabolism in the liver with a long
half-life (2-3 days)
Plasma and salivary concentrations correlate well
for monitoring purposes
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Cautions: hepatic and renal impairment; pregnancy and breast-feeding;
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Adverse effects: gastro-intestinal disturbances, weight loss, drowsiness,
dizziness, ataxia, dyskinesia, hiccup, photophobia, headache, depression, and mild
euphoria. Psychotic states, rashes, hepatic and renal changes (see Cautions), and
haematological disorders such as agranulocytosis and aplastic anaemia occur
rarely (blood counts required if signs or symptoms of infection); systemic lupus
erythematosus and erythema multiforme (Stevens-Johnson syndrome) reported;
other side-effects reported include gum hypertrophy, swelling of tongue,
irritability, hyperactivity, sleep disturbances, night terrors, inability to concentrate,
aggressiveness, increased libido, myopia, vaginal bleeding
Dose:
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avoid sudden withdrawal
Blood disorders (review)
adult and child over 6 years initially, 500 mg daily, increased by 250 mg at intervals of
4–7 days to usual dose of 1–1.5 g daily; occasionally up to 2 g daily may be needed;
child up to 6 years initially 250 mg daily, increased gradually to usual dose of
20 mg/kg daily
Contraindications: may make tonic-clonic seizures worse
Bensodiazepines – Clorazepam
(Klonopin), Diazepam (Valium)
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Act by potentiating the actions of GABA
causing neurotransmission inhibition
(primarily in the CNS)
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Can be used to induce sleep (high dose),
anticonvulsant therapy and reduction in
muscle tone.
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Pharmacokinetics:
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Well absorbed from the gut
Lipid soluble to ensure ready prentration of the
blood brain barrier
Metabolised in the liver to create active agents
(prolonged therapeutic action)
Slow elimination from body
Eg Clonazepam
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Cautions: elderly and debilitated, respiratory disease, spinal or cerebellar ataxia; history of
alcohol or drug abuse, depression or suicidal ideation; myasthenia gravis; porphyria; hepatic
impairment; renal impairment; pregnancy; breast-feeding
Contra-indications: respiratory depression; acute pulmonary insufficiency; sleep apnoea
syndrome; marked neuromuscular respiratory weakness including unstable myasthenia
gravis
Adverse effects: drowsiness, fatigue, dizziness, muscle hypotonia, co-ordination
disturbances; also poor concentration, restlessness, confusion, amnesia, dependence, and
withdrawal; salivary or bronchial hypersecretion in infants and small children; rarely gastrointestinal symptoms, respiratory depression, headache, paradoxical effects including
aggression and anxiety, sexual dysfunction, urinary incontinence, urticaria, pruritus,
reversible hair loss, skin pigmentation changes; dysarthria, and visual disturbances on longterm treatment; blood disorders reported; overdosage:
Dose:
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1 mg (elderly 500 micrograms) initially at night for 4 nights, increased according to response over
2–4 weeks to usual maintenance dose of 4–8 mg daily in 3–4 divided doses; may be given as a
single daily dose in the evening once maintenance dose established; max. 20 mg daily; child up to 1
year, initially 250 micrograms increased as above to usual maintenance dose of 0.5–1 mg, 1–5
years, initially 250 micrograms increased as above to 1–3 mg, 5–12 years, initially 500 micrograms
increased as above to 3–6 mg
Barbiturates – Phenobarbital (Luminal)
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Used for tonic-clonic seziures.
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Act by increasing the duration of Cl- ion channel
opening by activating neuronal GABAa receptors
Causing hyperpolarisation of the AP, making it less
likely to fire again
Essentially, acts like GABA and can even potentiate
the effects of GABA when present.
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Pharmacokinetics:
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Almost complete absorption
Elimination is by heptic and renal (25% excreted
unchanged)
Biotransformed in the liver into 2 active
metabolites
Plasma concentrations relate poorly to seizure
control, use only for monitoring of patient
compliance.
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Adverse effects:
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CNS effects (sedation and fatigue)
Restlessness/Hyperactivity
Folate deficiency
Tolerance
Dependence with physical withdrawal reactions
Adverse drug-drug reactions (contraception and warfarin).
Contraindications: Do not use with patients with respiratory
depression, children or elderly.
NOTE: low therapeutic index means more toxic and
overdose can have serious consequences
Miscellaneous Agents – Carbamazepine
(Tegretol)
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Used in most epilepsy types.
MoA not fully understood but believed to be
related to:
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Antagonist action of Na+ channels to inhibit
repetitive neuronal firing
Decreasing the production (or release) of
glutamate (excitatory chemical)
Can also be used in the Rx of neuropathic
pain
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Pharmacokinetics:
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Slow and incomplete absorption
Metabolised in the liver – creates an expoxide metabolite
that can have a weak therapeutic effect
Relatively long half-life (1-2 days)
Potency decreases overtime therefore need to increase
dose to ensure adequate control of seizures
Plasma and salivary concentrations correlate well to
clinical effectiveness
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Adverse effects:
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Nausea & vomiting (especially early Rx),
constipation, diarrhoea and anorexia
Skin irritation
CNS toxcity – dizzy, drowsy, confusion
Bone marrow depression (rare)
Drug-drug reactions (contraception, warfarin)
Contraindications: see drug-drug reactions.
Sodium Valproate
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Use in all forms of epilepsy, as it suppresses
the initial seizure discharge and its spread.
Clinical actions are:
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Antagonism of Na+ and Ca++ channels
Potentiation of GABA
Attenuation of Glutamate
Can be fast acting due to Na+ MoA, although
the full Rx effect usually takes weeks.
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Pharmacokinetics:
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Well absorbed from gut (should be taken with
food to counteract gastric irritation)
Extensively metabolised in the liver
Rapidly transported across the blood brain barrier
Monitor plasma concentration for patient
compliance only
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Adverse effects:
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GI upset (Nausea, vomiting, anorexia, abdominal pain and diarrhoea)
Weight gain (appetite stimulation)
Transient hair loss
Tremor
Coma (rare)
Thrombocyptopenia (platelets)
Oedema
Severe hepatotoxicity (liver damage)
Contraindications: People with liver damage or a history
hepatic dysfunction
Vigabatrin
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Only used in conjunction with other agents when pt
becomes resistant (due to tolerance) or poorly
tolerates
Effective in partial epilepsy but with restricted used
due to severe adverse effects (vision)
MoA: completely different to other agents as it is a
structural analogue of GABA that the enzyme that
normally inactivates GABA will degrade instead of
GABA.
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More GABA available to inhibit neuron transmission
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Pharmacokinetics:
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Rapidly absorbed from the gut
Unchanged by renal processes
Intermediate half-life (hrs)
Blood concentrations are of no value.
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Adverse effects:
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Sedation, fatigue, dizziness, nervousness,
irritability, depression, impaired concentration.
tremor (CNS effects)
Psychotic reactions (check pt history)
Visual defects after prolonged use
Weight gain and oedema
Lamotrigine (Lamictal)
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Used for partial seizures in adults only
Acts by the inhibition (antagonism) of
neuronal Na+ channels but is highly selective
(onlu neurons that synthesise glutamate and
aspartate)
Additionally, decrease glutamate release
Pharmacokinetics: well absorbed, extensively
metabolised in the liver and has a long halflife.
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Adverse effects:
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Fever, influenza-like symptoms
Skin irritation
GI disturbances (vomiting, diarrhoea)
CNS effects (drowsiness, headache, dizziness,
double vision)
Contraindications: Pts with hepatic
impairment
Gabapentin (Neuronitin)
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Used for partial seizures in adults
Designed to be a structural analogue of
GABA but it does not mimic GABA in the
brain.
Acts via:
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Increased synthesis and release of GABA
Decrease degradation of GABA
Inhibition of Ca++ channels
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Pharmacokinetics:
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Adverse effects:
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Incompletely absorbed in the gut
Excreted unchanged via kidney processes
Short half-life
CNS effects (dizzy, drowsy, fatigue, headache, double
visions)
Nausea and vomiting
Contraindication: be careful with sudden withdrawal
in the elderly due to kidney effects and alterations in
acid-base balance.
Anti-Parkinson Drugs
Dr Andrew Mallon
Aims
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To review pathogenesis of Parkinson's
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To review clinical presentation
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To identify treatment drugs
Prevalence
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1.5 million in USA and 120,000 in the UK –
accounts for about 10% of all acute hospital
admissions
Effects 2 in 1,000 people; aged 80+ incidence is 1 in
50.
Mainly affects adults in later life
Slightly more common in men, Afro-Caribbean's and
people from the Indian subcontinent
Affects the quality of life of about 500,000 (family,
carers etc)
Causes
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Unclear, but is a number of factors:
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Environmental – toxins
Free Radicals – there is a increase in post-mortem
brain sections
Aging – age related decline in dopamine
production
Genetic – possible, no single gene identified
Parkinson’s Disease
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A degenerative and progressive disorder
Associated with neurological consequences of
decreased dopamine levels produced by the basal
ganglia (substantia nigra)
Dopamine is a neurotransmitter found in the neural
synapses in the brain
Normally, neurones from the SN supply dopamine to
the corpus striatum (controls unconscious muscle
control)
Initiates movement, speech and self-expression
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Balance, posture, muscle tone and involuntary
movement depends on the roles of dopamine
(inhibitory) and acetylcholine (Ach: excitatory)
If dopamine missing, Ach produces more of an
effect on muscles
Basis to exploit by drugs:
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Restore dopamine function
Inhibit Ach within corpus striatum
Consequences of dopamine reductions
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Tremors – hands and head develop involuntary
movements when at rest; pin-rolling sign (finger and
thumb)
Muscle rigidity – arthritis-like stiffness, difficulty in
bending or moving limbs; poker face
Brandykinesia – problems chewing, swallowing or
speaking; difficulty in initiating movements and
controlling fine movements; walking becomes
difficult (shuffle feet)
Postural instability – humped over appearance,
prone to falls
Additional symptomology
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Anxiety
Depression
Sleep disturbance
Dementia
Disturbance of ANS (difficulty in urinating)
Clinical Presentation
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Altered body image (depression)
Poor balance
Bradykinesia (slow movement)
Bradyphrenia (slowness of
thought)
Constipation
Dribbling/drooling
Dyskinesias (involuntary
movements)
Dysphagia (difficulty
swallowing
Dystonia (pain spasms)
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Excessive sweating (impaired
thermoregulation)
Festinating gait
Hullucinations (visual)
Postural hypotension
Restless leg syndrome (leg
aches, tingle, or burn)
Rigidity
Sleep disturbance
Slurring/slowing of speech
Tremor
Ref: Noble C (2000) Parkinson’s Disease – the challenge. Nursing Standard, 15 (12), 43-51
Videos
GO TO MEMORY STICK
Treatment (early stage)
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Clinical judgements based upon level of disability,
age, cognitive status, concurrent medial problems
Initial pharmacological therapies are titrated to
determine optimal dose per person
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Agent used: Levodopa
Social support and health education vital
Referrals to other professional groups (SLT, PT, OT
etc)
Treatment (maintenance stage)
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Speech therapist is prophylactic and deals with
swallowing problems (recommend exercises etc)
Impaired thermoregulation – use beta-blockers
Disturbance in sleep – can be side effects of
medication; change time of intake or use a controlled
release drug delivery system
Continued health education and liaison with other
professionals
Treatment (complex stage)
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Function has deteriorates to such a level a
combination of drugs are prescribed
Dyskinesias and Dystonia – can be associated with
long-term Levodopa use and it can be difficult to
manage these effects – co-agent is co-beneldopa
Restless-leg – dopamine agonists
Anxiety – relaxation, distraction, CBT
Depression – alterations in dose of anti-parkinson’s
drugs
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Cognitive problems – referral to clinical
psychologist and prescription of anti-dementia
agents
Hallucinations - ?anti-psychotics
Essentially, a multidimensional approach to
pharmacological treatment combined with a
multidisciplinary approach
Medication Rational
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Replace depleted levels of dopamine
Stimulate the nerve receptors enabling
neurotransmission
Increase the effect of dopamine on nerve
receptors (agonist)
Counteract the imbalance of Ach and
Dopamine
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The Drugs:
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Dopaminergic drugs (improving dopamine
functioning)
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Levodopa
Dopamine receptor agonists
Amantadine
Selective monoamine oxidase B inhibitors
Catechol-O-methyltransferase inhibitors
Antimuscarinic drugs (Ach inhibitors)
Levodopa (or Levodopamine)
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Can not administer dopamine directly, as it does not
cross the blood brain barrier
A natural amino acid that the brain converts into
dopamine (replacement therapy) used since the
1960’s
To make it slow release, combined with benserazide
(an enzyme inhibitor) to create co-beneldopa or cocareldopa (Sinemet)
Dose = 50, 100 or 200mg (12.5, 25 or 50mg)
Source: Adams et al (2006). Pharmacology for Nurses –
A Pathophysiologic Approach. Prentice Hall Publishers

Pharmacokinetics:
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Absorbed by the small intestine by an active
transport system
Decarboxylation occurs in peripheral tissues (gut
wall, liver and kidney
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decrease amount available for distribution – 1% of an
oral dose
Extracerebral dopamine amounts causing unwanted
effects (benserazide)
Short half-life
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Cautions: pulmonary disease, peptic ulceration, cardiovascular disease, diabetes
mellitus, osteomalacia, open-angle glaucoma, history of skin melanoma (risk of
activation), psychiatric illness (avoid if severe); warn patients about excessive
drowsiness; in prolonged therapy, psychiatric, hepatic, haematological, renal, and
cardiovascular surveillance is advisable; warn patients to resume normal activities
gradually; avoid abrupt withdrawal;
Contra-indications: closed-angle glaucoma; pregnancy breast-feeding
Adverse effects: anorexia, nausea and vomiting, insomnia, agitation, postural
hypotension (rarely labile hypertension), dizziness, tachycardia, arrhythmias,
reddish discoloration of urine and other body fluids, rarely hypersensitivity;
abnormal involuntary movements and psychiatric symptoms which include
hypomania and psychosis may be dose-limiting; depression, drowsiness,
headache, flushing, sweating, gastro-intestinal bleeding, peripheral neuropathy,
taste disturbance, pruritus, rash, and liver enzyme changes also reported;
syndrome resembling neuroleptic malignant syndrome reported on withdrawal
Dose:
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Initially 125–500 mg daily in divided doses after meals, increased according to
response (but rarely used alone, see notes above)
HOMEWORK: WHAT DRUGS INTERACT WITH LEVODOPA?
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Adverse effects:
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As a result of the amount of peripheral dopamine
levels
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Nausea, vomiting
Postural hypotension
As a result of the amount of CNS dopamine
levels
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Dyskinetic involuntary movements (face & neck)
Hallucinations and confusion
Dopamine receptor agonists
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Apopmorphine (APO-go):
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SC administration
Rescue therapy – rapid onset with a short
duration of action (~50mins)
Bromocriptine (Parlodel); Pergolide
(Celance); Ropinirole (Requip)
Direct agonists of dopamine receptors in the
brain

?longer lasting therapeutic effects that Levodopa

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Start a pt on this alone, then combine with
levodopa to ‘smooth out’ control when PD is
getting progressive (especially young)
Pharmacokinetics:
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Incompletely abosrbed need extensive first-pass
metabolism (biotransformed in liver)
Pergolide & Ropinirole have higher
bioavailability (distribution)
Short to medium half life (Potency)
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Adverse effects:
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Use gradual dose titration
N + V (particularly Apomorphine)
Dyskinesia
Hallucinations and confusion
Peripheral vasospasm (Raynaunds)
Respiratory depression (Apomorphine
Amantadine (Symmetrel)
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Originally an antiviral drug, now used as conjucntive therapy
for dyskinesis effects produced by Levodopa
MoA:
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Pharmacokinetics:
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stimulates/promotes the release of dopamine stored in the synaptic
terminals
Reduces reuptake of released dopamine by pre-synaptic neuron
Well absorbed, long half-life, excreted unchanged by the kidney
Adverse effects:
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Not many
Ankle oedema, postural hypotension, nervousness, insomnia,
hallucinations (high dose)
Other Disease Modifying Drugs

Selective monoamine oxidase B inhibitors
(selegiline – Trade name Eldepryl/Zelapar):
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MoA: prolongs the effects of levodopa as MAO-B
degrades dopamine
Pharmacokinetics: completely absorption, short half-life
Adverse effects: N, V, Dia, Constipation; dry mouth, sore
throat; transient dizziness; insomnia, confusion and
hallucinations
Early stage – prescribed on it is own to delay need for
levodopa and there is good evidence for its slowing down
of PD progression

Catechol-O-methltransferase inhibitors - COMT
(entacapone, Trade name Comtess)
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MoA: inhibits the breakdown of levodopa
Pharmacokinetics: variability of absorption, extensive
first-pass metabolism, short half-life
Adverse effects: dyskinesias, hallucinations; N, V, Dia
and abdominal pain
New combination – Levodopa/carbidopa/entacapone
(Stalevo) as 1 tablet (50, 100, 150mg)

Antimuscarinic/Anticholinergic Drugs:
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Trihexyphenidyl (Broflex, Artane, Agitane); Benztropine
(Cogentin); Orphanadrine (Disipal); Procycline
(Kemadrin, Arpicolin)
Less common drugs but they affect Ach based interactions
MoA: blocking cholingeric (Ach) receptors to restore
balance
Pharmacokinetics: fairly well absorbed, extensive hepatic
metabolism, intermediate to long half-lifes
Adverse effects: dry mouth and confusion
Disease Modifying Drugs Overview
Symptom Management Drugs

PD is multidimensional, therefore there are a
number of clinical presentations that require
supplementary agents


Drug-Drug reactions is the problem
Major area is depression
Antidepressants




Amitriptyline (Tryptizol), imipramine (Tofranil),
Nortriptyline (Allegron), Iofepramine (Gamanil)
MoA: block re-uptake of noradrenaline and
serotonin => Sedative actions, can help with
drooling and loss of appetite
Adverse effects: sleepiness, dry mouth, increased
hunger, cardiac arrhythmias and changes in BP
Can interfere with the effects of levodopa!
Other Drugs to Avoid
Generic Name
Brand Name
Prescribed for
Prochlorperazine
Prephenazine
Flupentixol
Stemetil
Triptafen
Fluanxol/Depixol
Chlorpromazine
Largactil
Pimozide
Sulpiride
Orap
Dolmatil
N +V, Dizziness
Depression
Confusion,
Hallucinations
“
“
“
Video Sites


HealingWell.com
Birmingham Teaching Tutorials (hopefully)

The Neuron Connection


www.bio.davidson.edu/projects/neuron/video.asp
Useful Websites:

Parkinson’s Disease Society


http://www.parkinsons.org.uk/
Nursing Standard (CPD)

http://www.nursing-standard.co.uk/
Pathophysiology of Pain
Dr Andrew P Mallon
Context

“It is easier to find men who will volunteer to die,
than to find those who are willing to endure pain”
Julius Caesar

“We all must die. But if I can save (a person) from
days of torture, that is what I feel is my great and
ever new privilege. Pain is a more terrible lord of
mankind than even death itself”
Albert Schweitzer, 1953
Aims
To define pain and
develop an operational
definition.

To explore the
physiological processes
involved (from cause
to perception).


To examine the role of
opioids in pain
modulation
Can we define pain?





‘Noxious stimuli via nociceptors which are free nerve
endings found in skin, muscle and joints which transmit
impulses the brain’ (Bakal 1974)
‘Abnormal experience evoked by abnormal, harmful or
noxious stimuli’ (Wyke 1981)
‘A subjective combination of sensory, emotional and
cognitive factors’ (Bond 1984)
‘Sensory and emotional experience of discomfort, which is
usually associated with threatened tissue damage’ (Sander
1985)
‘Pain is whatever the patient says it is’ (Sternbach &
McGaffey 1974)
What is Pain?

Pain is an unpleasant
sensory and emotional
experience associated with
actual or potential tissue
damage, or described in
terms of such damage.

International Association
for the Study of Pain
(1991).
What is Pain?

Pain is an unpleasant
sensory and emotional
experience associated with
actual or potential tissue
damage, or described in
terms of such damage.






International Association
for the Study of Pain
(1991).
Aspects…..
Physiology
Psychology
Social
Relates to:



sensory
cognitive
affective (emotion)
Pain Classification

Acute and Chronic


Underlying cause transitory or protracted/ongoing
Fast and Slow Pain

Sharp and dull/throbbing
Pain = Sensation
1.
Transduction of noxious stimuli by sensory
receptors
2.
Transmission of nociceptive information
3.
Perception of noxious information
4.
Modulation of the incoming noxious
information
Basic pathway

Periphery

Enters spinal cord

Travels up towards the
tertiary
Interneuron
Secondary
Interneuron
brain

Medulla

Thalamus (processor)

Cerebral cortex
Primary
Interneuron
Nociceptive pathways (Walsh, 1997)
Somatosensory cortex and limbic system
Perception
Supraspinal structures:
Thalamus
Midrain/Pons/Medulla
Basal Ganglia
Spinal Cord:
Pain pathways
Dorsal horn synapses
Peripheral Nerve Fibres:
A-delta
C-fibres
Cortical Level
Supraspinal Level
Spinal Segmental
Level
Nociceptor:
Detection
Transduction
Nociception
Peripheral Level
Noxious Stimulus
Peripheral Level

Noxious stimulus:






Bradykinin
Histamine
Potassium/ Protons
(H+)
Prostaglandins
Substance P
Serotonin

Nociceptor
Activation:
 Transducer to
convert the stimulus
 Receptor potential
=> Action potential
 Activity in
ascending sensory
pathways
(Tortora & Grabowski, 2004)
Peripheral Nerve Fibres
Name
Diameter
NCV
AP
Sensory
Duration Function
A-Alpha 20 micron 70-120
½ ms
Proprioms
ception
A-Beta 10 micron 30-70
½ ms
Touch
ms
A-Delta 3 micron
12-30
1 ms
Sharp
ms
Pain
C-fibres 0.5 micron ½-2 ms
2 ms
Slow
Pain
(Tortora & Grabowski, 2004)
Afferents into
laminas 1,2,5,
plus motor
Afferents into
laminas 1,2,5,
plus motor &
autonomic
Ascending Nociceptive Pathways

Lateral Spinothalamic:





arises in Lamina I & V
peripheral input from
A units
respond to high
threshold noxious
stimuli & non-noxious
stimuli
synapses in thalamus
collateral's to midbrain

Multi-synaptic





spinoreticular
arises in lamina VII &
VIII
input from most other
lamina
Collateral's to brain
stem reticular formation
projects to thalamus
Spinothalamic Tract
(Almeida et al., 2004)
Spinoreticular Tract
(Almeida et al., 2004)
Limbic System
Nociceptors
Hypothalamus
Frontal Lobe
Somatosensory
Cortex/Insular
Thalamus
Reticular
Formation
C fibres
Spinal Cord
Medulla/Pons
A delta fibres
(Adapted from Johnson, 1997)
Pain Modulation





Ability by either external or internal
influences or “interference” to alter the
perception of a painful experience
Non-pharmacological (physical therapy,
acupuncture etc)
Pharmacological
“Mind over matter”
Placebo?

Therapist interaction effect
Gate control (spinal level)
LDA
+
-
-
T
+
SDA
Gate Control System
Action
system
Supraspinal Descending Pain
Inhibitory Pathways

The inhibitory interneurones in the substantia
gelatinosa may also be influenced by
descending inputs from higher centres.
Gate control (spinal level)
Reticular formation/
Thalamus
LDA
+
-
-
-
T
+
SDA
Gate Control System
Action
system
Descending Pain
Pathways
Descending inhibitory control
LDA
+
T
SDA
Gate Control System
Action
system
Endogenous Pain Modulating
System

Opioid Peptides



enkephalins
dynorphins
endorphins

Opioid Receptors





widely distributed
role in pain modulation
role in neural tissue
growth & in formation
of new central synaptic
connections

variation in types of
receptors
variation in activity
(agonist/antagonist)
3 major subtypes:



μ (mu): PAG & SC
κ (kappa):
Peripheral
δ (delta):
Throughout
Exogenous Opioids

Work by binding to CNS endorphin receptors

Activate descending pain pathways

Specific site of action is at second order
neuron level

Each analgesic agent have different pattern of
affinities => different effects/pain experiences
Role of Opioids
Exogenous Opioids
Endorphin
Binding to brain
stem receptors
AP to Dorsal Horn
Enkephalin Release
Inhibition
Pain Medication

Weak Opioids (MSk Pain):



Codine: 10% converted into morphine by liver, therefore
used with paracetamol
Tramadol: stimulation of the descending nerves from the
brain which inhibit the dorsal horn of the spinal cord
Strong Opioids:

Morphine: is the "gold standard". It is a potent stimulator
of morphine receptors, blocking pain impulses at several
sites:



in inflamed peripheral tissues (e.g. knee osteoarthritis),
in the dorsal horn of the spinal cord,
centrally in the brain.
Hydromorphone: 7.5 times more potent
Cognitive Control
Descending inhibitory control
LDA
+
T
SDA
Gate Control System
Action
system
Summary





Pain is multidimensional
Physiologically it is sequence of events from
cause to perception
There are 2 main pain fibres (a-delta and C)
and 2 corresponding path pathways in the
spinal cord (Spinothalamic and
Spinoreticular)
Pain modulation can occur endogenously and
exogenously.
Key concept: inhibition at the dorsal horn.
Key References

Almeida TF, Roizenblatt S, Tufik S (2004) Afferent pain pathways: a neuroanatomical
review. Brain Research 1000: 40-56.

Johnson MI (1997) The Physiology of the Sensory Dimensions of Clinical Pain.
Physiotherapy 83(10): 526-536

Kidd BL (1996) Problems with pain - is the messenger to blame? Annals of the
Rheumatic Diseases 55:275

Kidd BL, Morris VH, Urban L (1996) Pathophysiology of joint pain. Annals of the
Rheumatic Diseases 55:276-283

Kidd BL (1999) What are the mechanisms of regional musculoskeletal pain?
Bailliere’s Clinical Rheumatology 13(2):217-230

Wells P, Frampton V, Bowsher D (1994) Pain: management by physiotherapy. 2nd
edn, Butterworth Heinemann, Oxford.