Hypnotics drugs used in treating motor disorders



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HYPNOTICS DRUGS USED IN TREATING MOTOR DISORDERS

  • J. Mojžiš

Hypno-sedative drugs

  • terminology
  • Sedation
  • can be defined as a supression of responsiveness to a constant level of stimulation, with decreased spontaneous activity
  • Hypnotic effects
  • involve more pronounced depression of the CNS than sedation, and this can be achieved with most sedative drugs simply increasing the dose.

Hypno-sedatives

  • generation – barbiturates (obsolete)
  • generation – benzodiazepines (BZD)
  • generation – zolpidem, zaleplon

Benzodiazepines

  • act selectively on gamma-aminobutyric acid (GABAA) receptors, which mediate fast inhibitory synaptic transmission through the CNS
  • they bind specifically to a regulatory site of the receptor, distinct from the GABA binding site and act allosterically to increase the affinity of GABA for the receptors
  • by facilitating the opening of GABA activated chloride-channels BZ enhance the response to GABA

Benzodiazepines – Mechanism of Action

  • GABA-A receptors – highly variable (i.e., consist of different complements of alpha, beta, and gamma subunits).
  • = different sensitivities to benzodiazepines.
  • = 2 subunit is critical in sedative effects.
  • Benzodiazepines do NOT activate the receptor directly.
  • = increase frequency of chloride-channel opening produced by GABA.
  • GABA Receptor

Benzodiazepines

  • absorption: well absorbed if given orally , Cmax reached in about 1 h
  • binding: strongly bound to plasma proteins
  • distribution: large Vd: accumulation in body fat (high lipid sol.)
  • metabolism: hydroxylation, conjugation with glucuronic acid

Benzodiazepines

  • Pharmacological effects and uses
  • The main effects
  • reduction of anxiety and agression
  • sedation and induction of sleep
  • reduction of muscle tone and coordination
  • anticonvulsant effects

Benzodiazepines

  • Indications
  • reduction of anxiety and agression
  • Note: BZD may paradoxically produce an increase
  • in irritability and aggression in some individuals
  • (particularly if short- acting drugs are given (triazolam)
  • sedation and induction of sleep
  • BZDs decrease the time taken to get to sleep
  • increase the total duration of sleep (only in subjects who normally sleep for less than about 6 hours each night)

Benzodiazepines

  • Non-rapid eye movement(NREM) sleep: 70%-75%
  • Rapid eye movement(REM) sleep
  • REM sleep ( rapid eye movement) is less affected if compared with the same effect of other hypnotics.
  • Is that important? Yes, artificial interruption of REM sleep causes irritability and anxiety even if the total amount of sleep is not reduced.

Benzodiazepines

  • reduction of muscle tone and coordination
  • may be clinically useful: increased muscle tone is a common feature of anxiety states and may contribute to pains (headache). Influence of manual skills (!)
  • anticonvulsant effects
  • clonazepam to treat epilepsy
  • diazepam (i.v.) status epilepticus to control life-threatening seizures

Pharmacological Effects of Benzodiazepines are Concentration-Dependent.

  • Nanomolar Concentrations
    • Anxiolytic sedation – via 2 subunit.
    • Action effectively blocked by flumazenil.
  • Micromolar Concentrations
    • Anesthesia – diazepam, midazolam, lorazepam.
    • Activity due to binding of benzodiazepines to low-affinity site on GABA-A receptor.

Benzodiazepines

  • Unwanted effects
  • effects occuring during normal therapeutic use
  • acute overdosage
  • tolerance and dependence
  • Unwanted effects occuring during therapeutic use
  • Influence of manual skills (such as driving performance) due to drowsiness, confusion, amnesia and impaired coordination
  • enhance of depressant action of other drugs (in a more than additive way)

They vary greatly in duration of action, and can be roughly divided into

  • They vary greatly in duration of action, and can be roughly divided into
    • Short-acting compounds: triazolam, oxazepam(t1/2 2-3 h)
    • Medium-acting compounds: estazolam, nitrazepam (t1/2 5-8 h)
    • Long-acting compounds: diazepam (biphasic half-life of about 1–3 and 2–7 days for the active metabolite desmethyldiazepam), flurazepam (50h)

Benzodiazepines

  • acute overdosage (BZs are relatively safe in overdose)
  • - BZs produce prolonged sleep, without serious depression of respiration or cardiovascular function
  • - severe even life-threatening respiratory depression may appear in BZ combination with other CNS depressants, particularly alcohol.
  • - acute overdosage can be counteracted with flumazenil

Benzodiazepines

  • tolerance, dependence
  • tolerance occurs with all BZs; it appears to represent a change at the receptor level
  • Discontinuation of benzodiazepine therapy in tolerant patients MUST be gradual.
  • dependence – in human subjects and patients, stopping BZ treatment after weeks and months causes an increase in symptoms of anxiety, together with tremor and dizziness.
  • Addiction (craving -severe psychological dependence) is not a major problem.

New drugs

  • Zolpidem
  • binds selectively to the 1 subtype of BZ receptors and
  • facilitates GABA-mediated neuronal inhibition
  • like the BZs, the actions of zolpidem are antagonised by
  • flumazenil
  • minimal muscle relaxing and anticonvulsant effects
  • the risk of development of tolerance and dependence
  • with extended use is less than with the use of other BZs
  • Zaleplon
  • rapid onset and short duration of action are favorable properties for those patients who have difficulty falling asleep.
  • ANTIPARKINSONICS
  • History of Parkinson´s disease (PD)
  • First described in 1817 by an English physician, James Parkinson, in “An Essay on the Shaking Palsy.”
  • The famous French neurologist, Charcot, further described the syndrome in the late 1800s.
  • Epidemiology of PD
  • The most common movement disorder affecting 1-2 % of the general population over the age of 65 years.
  • 2.5% of the population older than 85
  • The second most common neurodegenerative disorder after Alzheimer´s disease (AD).
  • Parkinsonism:
  • degenerative disease of CNS
  • symptomatic
  •  hypokinesia
  •  muscle rigidity
  •  tremor
  •  postural lability

Etiology

  • Parkinson disease is caused by the death of the nerve cells in the substantia nigra, which produce the neurotransmitter dopamine.

Famous Faces of Parkinson

  • Michael J. Fox
  • Muhammad Ali
  • Katharine Hepburn
  • Pope John Paul II
  • Johnny Cash
  • Mao Tse Tung
  • Imbalance primarily between the excitatory neurotransmitter Acetylcholine and inhibitory neurotransmitter Dopamine in the Basal Ganglia
  • ACh
  • DA

Pharmacotherapy (strategy)

  • dopamine saturating agents:
  • levodopa
  • dopamine receptor agonists
  • bromocriptine, ropinirol, pramipexol
  • agents increasing dopamine effect:
  • selegiline, tolcapon, entacapon
  • agents increasing dopamine release:
  • amantadine
  • acetylcholine bloking agents:
  • biperiden, procyclidine, trihexyfenidil

Dopamine-saturating agents

  • Levodopa
  • 1. choice drug
  • Dopamine doesn´t cross BBB

Mechanism of action

  • dopamine receptors D1 a D2
  • dopaminergic antiparkinsonics – stimulation of D2 receptors

Pharmacokinetics

  • L-DOPA - rapid GIT absorption
  • brain distribution - 1-3% only
  • majority metabolised to dopamine in extracerebral tissues

Clinical use

  • L-DOPA can change all symptoms of parkinsonism
  • effective mainly in rigidity, hypokinesia
  • 65-70% patients answer in the begining of therapy
  • decreased effectiveness – after few years

Side effects 1

  • GIT
  • - about 80% of patients - nausea, vomiting
  • - divide doses, apply with meal
  • - tolerance – after few weeks
  • - application with dopa-decarboxylase inhibitors –
  • about 20% vomiting
  • CVS
  • - increase in catecholamine production in periphery:
  •  arrhythmias
  •  orthostatic hypotension
  •  hypertension

Side effects 2

  • Diskinesia
  • Behavioral changes
  •  depression
  •  anxiety, agitation
  • insomnia
  •  euforia
  • - mainly in L-DOPA + carbidopa combination
  • Other
  •  mydriasis
  •  taste or smell abnormality

Dopamine receptor agonists or agents increasing dopamine effect

  • Bromocriptine
  • Ergot alcaloid derivative
  • Claviceps purpurea

Mechanism of action

  • 2. choice drug
  • acts as partial agonist on presynaptic D2 - receptors

Clinical use

  • can be combined with L-DOPA
  • therapeutic level should be reached in 2-3 months
  • the dose of L-DOPA should decrease

Side effects

  • GIT
  • nausea, vomiting, anorexia, constipation
  • CVS
  • hypotension, vasospasms (fingers), arrhythmias
  • Diskinesia
  • Mental disorders
  • - confusion, halucinations

II. generation of dopamine receptor agonists

  • Ropinirol - D3/D2 agonist:
  • - similar effects as L-DOPA
  • Carbegoline - D2 agonist
  • Pramipexol - D3/D2 agonist
  • - monotherapy, in severe forms combination with L-DOPA

MAO-inhibitors

  • Selegiline
  • inhibits MAO B
  • prolongs L-DOPA effect  dose diminution
  • additional therapy
  • weak therapeutic effects alone

COMT- inhibitors

  • Entacapon
  • peripheral COMT- inhibitor
  • additive to L-DOPA+carbidopa
  • L-DOPA dose diminution
  • nausea, vomiting, hallucination
  • Tolcapon
  • strong peripheral  central COMT inhibitor
  • similar as entacapon (in patients with weak response to L-DOPA+carbidopa
  • possible severe hepatotoxicity (nausea, vomiting, abdominal pain, unusual fatigue, loss of appetite, yellow skin or eyes, itching, dark urine; death)

Agents increasing dopamine release

  • Amantadine
  • antiviral agent
  • increases dopamine release from nerv endings
  • short action, disappears after few weeks
  • positive effects on rigidity, tremor
  • can induce CNS disorders - depressions, sleep disturbancies

Acetylcholine blocking agents

  • Biperiden, procyclidine, trihexyfenidil
  • progressive begining of therapy
  • influence rigidity, tremor
  • important side effects
  • continual discontinuation of therapy
  • ANTIEPILEPTICS

Epilepsy

  • Etiology:
  • symptomatic epilepsy
  • idiopatic epilepsy (mainly in young adults - 75%)
  • ideal antiepileptic drug – nonsedative!

Trigger mechanisms of epilepsy

  • hyperpyrexia (infections)
  • CNS infections
  • metabolic disorders (hypoglycemia, phenylketonuria)
  • toxic agents (strychnine, lead, alcohol, cocaine)
  • brain hypoxia
  • expansive processes (tumors, bleeding)
  • CNS developmental disorders
  • brain trauma
  • anaphylactic reactions

Attack classification

  • partial attacks
  • simplex partial attacks
  • complex partial attacks
  • generalised attacks
  • generalized tonic-clonic attacks (grand mal)
  • absences (petit mal)
  • tonic attacks
  • atonic attacks
  • clonic  myoclonic attacks

Barbiturates

  • Phenobarbital
  • belongs to the oldest antiepileptics (OBSOLETE)
  • acts through inhibitory neurotransmitters (GABA)
  • inhibits the effect of excitatory neurotransmitters (glutamate)
  • in high doses  blocks Ca2+ channels

Clinical use

  • rarely used (sedative effect)
  • partial seizures
  • grand mal

Side effects

  • sedative
  • allergic reactions
  • megaloblastic anemia
  • increased porphyrine synthesis (CI in porphyria)
  • overdose, intoxication
  • tolerance, dependence

Other barbiturates

  • Primidon
  • metabolised to phenobarbital
  • Clinical use
  • - partial seizures
  • - grand mal
  • Side effects
  • - as phenobarbital

Hydantoin derivatives

  • Phenytoin
  • introduces in 1938
  • significantly influences the movement of ions across the membrane (Na+, K+, Ca2+)
  • binds to membrane lipids  membrane stabilization

Clinical use

  • partial attacks
  • generalised tonic-clonic seizures
  • antidysrrhythmic

Side effects

  • nystagmus (early side effect)
  • diplopia, ataxia, headache – dose adjustment
  • hyperplasia of gums, hirsutism
  • chronic application  avitaminosis (D)  osteomalatia
  • folic acid metabolism disorders  megaloblastic anemia
  • allergic reactions  skin
  • teratogenic effects

Iminostilbens

  • Carbamazepine
  • chemically similar to tricyclic antidepressants
  • effect similar to phenytoin
  • blocks sodium channel
  • inhibits synaptic transmission

Clinical use

  • drug of choice in partial attacks
  • effective also in grand mal
  • neuralgia trigemini
  • painful seizures in diabetic neuropathy

Side effects

  • diplopia  ataxia
  • GI intolerance
  • restlessness, sleepness
  • in elderly - fatal aplastic anemia, agranulocytosis
  • inducer of microsomal enzymes

Suxinimides

  • Ethosuximide
  • Mechanism of action
  • calcium channels T-type
  •  calcium current responsible for induction of cortical impulses in petit mal
  • Clinical use
  • - petit mal

Side effects

  • GIT disorders (start therapy with low doses)
  • fatigue
  • headache, vertigo, euphoria (rare)

Valproic acid

  • Valproic acid  sodium valproate
  • mechanism of action - not fully understood
  • inhibits GABA-transaminase
  •  aspartate level in brain
  • possible change in membrane permeability for K+  hyperpolarisation

Clinical use

  • absences
  • myoclonic seizures
  • generalised tonic-clonic seizures
  • partial seizures (rarely)

Side effects

  • nausea, vomiting, abdominal pain
  • (progressive dose increase)
  • weight   alopecia
  • (about 10 % of patients)
  • hepatotoxicity !!!
  • (liver function monitoring)
  • possible teratogenic effect
  • ( incidence of spina bifida)

Benzodiazepines

  • diazepam – drug of choice in acute epileptic
  • attack (10 mg i.v.)
  • lorazepam - as diazepam, more effective
  • clonazepam – long acting, absences, myoclonic seizures, highly effective antiepileptic drug
  • nitrazepam – some forms of myoclonic seizures

Side effects

  • important sedative effect (use limitation)
  • tolerance

Newer antiepileptics

  • GABA transaminase inhibitor: vigabatrin
  • Na+ channel blocker: lamotrigine
  • GABA analogue: gabapentine
  • Aspartate excitatory effects antagonist: felbamate
  • As phenytoin with less side effects: topiramate

GABA transaminase inhibitor

  • Vigabatrin
  • - irreversible inhibitor of GABA-transaminase
  • -  concentrations of GABA
  • Clinical use
  • - drug of choice in complex partial seizures
  • Side effects
  • - sleepness, weight gain
  • - vertigo, confusion

Na+ channel blocker

  • Lamotrigine
  • - inhibits also release of EA in brain cortex
  • Clinical use
  • - broad spectrum antiepileptic
  • - drug of choice in partial  generalised tonic-clonic seizures
  • - preferentially in non responders to other therapy
  • Side effects
  • - ataxia, vertigo, headache, diplopia, skin affections

GABA analogue

  • Gabapentine
  • - easily crosses blood-brain barrier, enhances GABA release
  • Clinical use
  • - drug of choice in partial seizures
  • - first line for pain due diabetic neuropathy an postherpetic neuralgia
  • Side effects
  • - well tolerated
  • - fatigue, vertigo, headache, nausea,

Aspartate excitatory effects antagonist

  • Felbamate
  • - in non-responders to other therapy
  • Clinical use
  • - in partial seizures
  • - in children in seizures in Lennox-Gaustat sy
  • (generalised myoclonic epilepsy with mental retardation)
  • Side effects
  • - nausea, insomnia, irritability – low incidence
  • - aplastic anemia  hepatopathia – very rare but fatal

Na+ channel block, GABA potentiation

  • Topiramate
  • - similar as phenytoin, less side effects
  • - inhibits also glutamate receptors
  • - in children and adults
  • Clinical use
  • - in partial seizures (simplex, complex)
  • - in children in seizures in Lennox-Gaustat sy
  • Side effects
  • - CNS depression
  • - suspect teratogenic effect

Therapeutic choices

  • Seizure type 1st choice alternative or add-on
  • Tonic-clonic carbamazepine clobazam
  • phenytoin lamotrigine
  • valproic acid topiramate
  • Absence ethosuximide clobazam
  • valproic acid lamotrigine
  • topiramate
  • Partial (simple carbamazepine clobazam
  • or complex) phenytoin lamotrigine
  • valproic acid
  • phenobarbital
  • Acute epileptic attack: diazepam, lorazepam

Antiseizure drugs

  • Use of antiseizure drugs in other non-seizure conditions
  • Carbamazepine
  • mania, trigeminal neuralgia (possibly behavioural disturbances in dementia)
  • Gabapentin
  • neuropathic pain (possibly mania)
  • Lamotrigine
  • (possibly mania, migraine)
  • Phenytoin
  • (possibly neuropathic pain, trigeminal neuralgia)
  • Valproic acid
  • Mania, migraine (possibly behavioural disturbances in dementia)

Status epilepticus

  • 0-5 min - history, physical examination, intubation?, ECG
  • 5-10 min – start 2 large bore IV saline, dextrose, thiamine, lorazepam or diazapam IV
  • 10-30 min - Phenytoin or phenobarbital IV
  • 30-60 min - If seizures persist after phenytoin, use phenobarbital or vice versa. Admit to CCU, get EEG, consider thiopental, propofol
  • The Virgin Mary as advocate for a girl with epilepsy
  • (portrayed having a tonic seizure)



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