CNS brain and spinal cord

Brain disorders may result from structural or functional disturbances of the sensory, integrative or motor activities of CNS Associated with a variety of disease processes e.g. degenerative, ischaemic and physiologic disturbances Role of drugs mainly to relieve the symptoms of brain dysfunction, but usually do not correct the underlying disorder Drug therapy for many brain disorders is therefore a lifelong process. Short term Rx may be effective in relieving acute symptoms e.g. pain and insomnia

General mechanism of action

Drugs act by affecting the synthesis, storage/release, reuptake or degradation of neurotransmitters; or by activating receptors causing various changes in the brain Common NTs Acetylcholine Amino acids GABA,glutamate/aspartate, glycine

Biogenic amines
Dopamine, norepinephrine, serotonin(5HT), histamine

Peptides opiods,enkephalins, neurokinins, substance P

Others-NO, CO, purines

Sedative hypnotic and anxiolytic drugs

Sedative-reduces a response to external stimuli and causes drowsiness Hypnotic-induces sleep Anxiolytic -reduces anxiety Management of anxiety d/orders Acute anxiety
benzodiazepines e.g. diazepam or lorazepam-short term relief

Panic d/order-characterized by impending sense of doom

psychotherapy + benzodiazepines or antidepressants

Phobic d/oders-overly fearful about certain condition

benzodiazepines or antidepressants

Obsessive d/orders-Antidpressants+psychotherapy Generalized anxiety d/order-Persistent state of fear

Benzodiazepines-short term Buspirone-long term

Sleep disorders
Insomnia-may not require Rx, melatonin

Insomnia due to medical conditions which interfere with sleep

Benzodiazepines, zolpidem (hypnotic)

Others hypersomnia Narcolepsy Enuresis nightmares

Management by antidepressants or CNS stimulants

Classification of sedative-hypnotic and anxiolytic drugs

Sedative-hypnotic drugs
Benzodiazepines
Alprazolam, diazepam, flurazepam, lorazepam, mildazolam, oxazepam, temazepam, triazolam, chlorodiazepoxide

Barbiturates
Phenobarbital, phenobarbital, thiopental

Antihistamines
Diphenhydramine, hydroxyzine

Other sedative hypnotic drugs

Chloral hydrate, melatonin, zolpidem

Non-sedating anxiolytic drugs

Buspirone, propanolol

Benzodiazepines
Most widely used sedative hypnotic drugs MOA-bind to GABA receptors (omega receptors) leading to opening of GABAA chloride channels Pharm. effects dose dependent but limited depression of CNS
Low doses-sedative, high-hypnosis and anaesthesia.

Orally administered do not produce respiratory depression unless with other CNS depressants e.g. alcohol May cause autoretrograde amnesia (patient does not remember what happened from when drug administered to time effects disappear). Have anticonvulsive effects and therefore used to Rx seizure d/orders

Benzodiazepines
A/effects
motor inco-ordination, dizziness and excessive drowsiness Respiratory depression when administered as I/V Mild euphoric effect in manner similar to alcohol Long term use may produce physical dependence with withdrawal symptoms on abrupt discontinuation C/I in pregnancy except zolpidem

Rx of side effects
Flumazenil a benzodiazepine receptor antagonist to counteract effects e.g. resp. depression due to IV dosages

 Rx of anxiety d/orders, insomnia, muscle spasms, seizure d/orders and spasticity Alprazolam(med. dur. o/action)-anxiety, panic disorder Chlorodiazepoxide, diazepam-converted to longer acting metabolites
May be used to Rx alcohol detoxification, muscle spasms and spasticity associated with neurological d/orders

Indications

Lorazepam-anxiety, seizures Oxazepam-anxiety Temazepam-insomnia Flurazepam, triazolam-insomnia, confusion, delirium esp. in old patients but may produce rebound insomnia Mildazolam-used as IV in anaesthesia

Barbiturates
MOA-bind to GABA increasing affinity for GABA receptors Higher doses progressively depress CNS causing resp. depression coma and death. They therefore have lower margin of safety cf. to benzodiazepines May cause tolerance + dependence Indications Phenobarbital/pentobarbital-Rx of seizure d/orders e.g. epilepsy Thiopental-Administered I/v to induce anaesthesia

Contd.
Antihistamines
Produce sedation and may be used to Rx mild insomnia and anxiety d/orders e.g. diphenhydramine Sedation before surgery

Other sedative-hypnotic drugs

Chloral hydrate-may be used as pre-anaesthetic medication Melatonin-Rx of jet lag and insomnia Zolpidem-sedative with less S/E. Used for insomnia and in pregnancy

Non-sedating anxiolytic drugs

Buspirone-Partial agonist at serotonin 5HTA receptors used in Rx of chronic anxiety Propranolol-beta blocker-may be used to prevent physiologic manifestations of stage fright or performance anxiety

Antiepileptic drugs
Pathophysiology
Seizures-episodes of abnormal electrical activity in the brain causing involuntary movements, sensations or thought. Recurrent seizures are seen in patients with epilepsy and are preceded by an aura accompanied by characteristic changes in the EEG

2 main types of seizures

Partial(focal seizures)-no alteration of consciousness or thought Generalized seizures
Grand mal Petit mal

MOA Antiepileptic drugs suppress the formation and spread of abnormal electrical discharges in the brain via different mechanisms

Classification
Drugs for partial seizures and generalised tonic-clonic seizures
Carbamazepine,phenobarbital,phenytoin,primodone, valporate(primodone has two active metabolitesphenobarbital and phenylethylmalonamide[PEMA])

Adjunt drugs for partial seizures

Gabapentin,Lamotrigine, topiramate

Drugs for generalised (grand mal), myoclonic, atonic or absence(petit-mal) seizures

Clonazepam, ethosuxemide, lamotrigine, valporate

Drugs for status epilepticus

Diazepam, lorazepam(IV), phenobarbital, phenytoin

Carbamazepine
Orally administered, metabolized to active metabolites

MOA
Blocks voltage sensitive Na+ channels and inhibits spread of abnormal electrical discharges A/effects drowsiness, ataxia

Indications
Partial seizures, generalised tonic-clonic seizures and trigeminal neuralgia

 Orally or parenterally administered MOA as carbamazepine (blocks Na+ channels) A/effects Gingival hyperplasia, ataxia and blurred speech Interferes with folate metabolism and may cause megaloblastic anaemia-may cause malformation of the fetus (teratogenic) Interacts with several drugs Indications Partial seizures and generalised tonic-clonic seizures Kinetics- highly plasma bound, hepatic enzyme inducer. Metabolized to inactive metabolites, excreted in urine.

Phenytoin

Valporate
Formulations valporic acid, valporate Na MOA inhibits voltage sensitive Na+ channels, increases GABA synthesis and decreases degradation A/effects Reversible hepatic toxicity, in few instances fatal hepatic toxicity, nausea, vomiting and heartburn. Interactions-increases serum levels of phenobarb., primodone 90% protein bound, displaces phenytoin. Indications Has the broadest spectrum of activity-partial seizures and all forms of generalized seizures, may be given in combination with other drugs

Contd.
Adjunt drugs: Gabapentin, lamotrigine, Topiramate Used in combination with other drugs especially for Rx of partial seizures Drugs for generalised, absence, myoclonic or atonic seizures Ethosuxemide MOA: inhibits T-type Ca2+ channels in the thalamic neurons A/effects: Has relatively less S/E Indications: Highly effective and safe in Rx of generalized and absence seizures in children Others Clonazepam-absence, myoclonic or atonic seizures

Vigabatrin
MOA
Inhibition of metabolism of GABA by irreversibly inhibiting GABA transaminase enzyme.

Indications
Rx resistant epilepsy. It is also indicated as monotherapy for paediatric patients one month to two years with in infantile spasms due to Wests syndrome.

A/effects
headache, depression , somnolence (drowsiness), confusion and speech disorders.

D/interactions
Increases plasma clearance of carbamazepine and phenytoin

Choice of drugs for Rx of seizure d/orders

Attempt for use of single drug with low dose gradually increasing the dose to effective levels Use of 2 drugs with different MOAs if single drug ineffective If patient has had no seizures for several yrs it may be possible to withdraw drugs by slowly tapering Consideration of cost of drugs

Status epilepticus
Medical emergency managed by I/V administration of diazepam or lorazepam sometimes followed by I/V phenytoin or phenobarbital

Drugs for neurodegenerative diseases

Parkinsons disease
Drugs that increase dopamine levels Amantidine, carbidopa,levadopa, selegiline, tolcapine Dopamine receptor agonists Bromocriptine,pergolide,pramipexole, ropinirole Acetylcholine receptor antagonists:Benztropine, trihexylphenidlyl (benzhexol)

Huntingtons disease
diazepam, haloperidol

Alzheimers disease Donazepil, tacrine (cholinesterase inhibitors) Drugs for multiple sclerosis Beclofen,inteferon beta-ib, prednisone Drugs for amyotrophic lateral sclerosis Beclofen, gabapentin, riluzole

Parkinsons disease
Results from degeneration of dopaminergic neurons arising from substantia nigra and projecting to other parts of the basal ganglia Characterized by resting tremor, rigidity and bradykinesia Rx by drugs that either increase dopaminergic activity or inhibit cholinergic activity at the basal ganglia

Drugs for Rx of Parkinsons disease

Drugs that inc. dopamine levels Levadopa (L-dopa)-precursor of dopamine and inc. levels of dopamine
conc. in the brain thus alleviating motor dysfunctions (Dopamine is not effective since it doesnt cross the b/b/b)

MOA-converted to dopamine in the brain and efficacy dependent on

availability of dopaminergic neurons; as they decrease then the effects wear off.

A/effects-nausea, vomiting, orthostatic hypotension and cardiac

arrhythmias due to peripheral dopamine effects which are reduced when combined with carbidopa. Dyskinenesis-involuntary muscle movements due to xcess dopamine

Interactions-MAO inhibitors and antipychotic drugs Indications-most forms of Parkinsons disease

Carbidopa Inhibits the conversion of L-dopa to dopamine in peripheral tissues and facilitates entry to the brain Does not cross b/b/b and therefore doesnt inhibit dopamine actions in the brain and combination useful to decrease S/E Amantidine Antiretroviral drug that inc. dopamine levels used in adjunct with L-dopa Selegiline Inhibits MAOB thereby preventing oxidation of dopamine. Function still controversial Indications Early or mild Parkinsons disease as adjunct to L-dopacarbidopa

Tolcapone Inhibits COMT an enzyme that converts DOPA to 30MD in GIT and liver, hence increasing L-dopa effects via a protective mech; and therefore reduction in dosage regimens of L-dopa Dopamine receptor agonists MOA-by directly activating the dopamine D2 receptors and therefore may be useful in advanced Parkinsons disease Bromocriptine and pergolide-ergot alkaloids Pergolide stronger since has longer duration of action Uses: Adjunct to L-dopa in patients with wearing off effects Pramipexole and ropinirole Not ergot alkaloids but act on D2 receptors. Uses: as above

Others Benztropine
Improves tremors and rigidity but not bradykinesia

Huntingtons disease
Due to degeneration of GABA neurons in the brain Symptoms associated with xcessive dopaminergic activity Rx: by drugs which block dopamine receptors e.g. haloperidol Diazepam and other benzodiazepines since the potentiate GABA and therefore reduce xcessive movements

Alzheimers disease
Progressive dementia without cure Due to destruction of cholinergic and other neurons that have role in memory Rx: central acting cholinesterase inhibitors e.g. donezepil or tacrine to improve cholinergic neurotransmission and slow disease progression.

Multiple sclerosis Characterized by demyelination of neurons Rx: Goal is to reduce target CNS dysfunction and prevent relapses and progression by such drugs as baclofen Acute progression may be Rx by corticosteroids eg progesterone Interferon-beta-1b may reverse effects due to immunomodulation or halt the process Amyotrophic lateral sclerosis Progressive disease of motor neurons characterized by muscle wasting, weakness and resp. failure, cause unknown Rx: symptomatic with baclofen and riluzole that is believed protect neurons and increase life by a few months.