PCOL PREFI

• Pharmacologic intervention for Alzheimer's disease is only palliative and provides modest short-term benefit
• None of the currently available therapeutic agents have been shown to alter the underlying neurodegenerative process.
• three distinguishing features of alzheimer's

  1. accumulation of senile plaques (amyloid accumulations)
  2. formation of numerous neurofibrillary tangles, and loss of cortical neurons particularly cholinergic neurons.
• MOA


  aimed at either improving cholinergic transmission within the CNS or preventing excitotoxic actions resulting from overstimulation of N-methyl-D-aspartic acid (NMDA)-glutamate receptors in selected brain areas
• AChE INHIBITORS


  It is postulated that inhibition of acetylcholinesterase (AChE) within the CNS will improve cholinergic transmission, at least at those neurons that are still functioning
• memory loss that is a hallmark symptom of Alzheimer's disease
• four reversible AChE inhibitors are approved for the treatment of mild to moderate Alzheimer's disease. They are donepezil, galantamine, rivastigmine, and tacrine
• galantamine, which is competitive, all are uncompetitive inhibitors of AChE
• Galantamine may also be acting as an allosteric modulator of the nicotinic receptor in the CNS and, therefore, secondarily increase cholinergic neurotransmission through a separate mechanism
• tacrine is associated with hepatotoxicity
• Stimulation of glutamate receptors in the CNS appears to be critical for the formation of certain memories;
• overstimulation of glutamate receptors, particularly of the NMDA type, has been shown to result in excitotoxic effects on neurons and is suggested as a mechanism for neurodegenerative or apoptotic (programmed cell death) processes.
• Binding of glutamate to the NMDA receptor assists in the opening of an associated ion channel that allows Na+ and, particularly, Ca2+ to enter the neuron
• excess intracellular Ca2+ can activate a number of processes that ultimately damage neurons and lead to apoptosis.
• Memantine is a dimethyl adamantane derivative.
• Memantine acts by physically blocking the NMDA receptor associated ion channel, but at therapeutic doses, only a fraction of these channels are actually blocked
• Anxiety is an unpleasant state of tension, apprehension, or uneasiness a fear that seems to arise from a sometimes unknown source
• The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation.
• Because many of the antianxiety drugs also cause some sedation, the same drugs often function clinically as both anxiolytic and hypnotic (sleep-inducing) agents. In addition, some have anticonvulsant activity.
• Benzodiazepines are the most widely used anxiolytic drugs.
• They have largely replaced barbiturates and meprobamate in the treatment of anxiety, because the benzodiazepines are safer and more effective
• The targets for benzodiazepine actions are the aminobutyric acid (GABAA) receptors.
• GABA is the major inhibitory neurotransmitter in the central nervous system
• Binding of GABA to its receptor triggers an opening of a chloride channel, which leads to an increase in chloride conductance.
• The influx of chloride ions causes a small hyperpolarization that moves the postsynaptic potential away from its firing threshold and, thus, inhibits the formation of action potentials.
• The benzodiazepines are also useful in treating the ANXIETY THAT ACCOMPANIES SOME FORMS OF DEPRESSION AND SCHIZOPHRENIA
• These drugs should not be used to alleviate the normal stress of everyday life. They should be RESERVED FOR CONTINUED SEVERE ANXIETY, AND THEN SHOULD ONLY BE USED FOR SHORT PERIODS OF TIME BECAUSE OF THEIR ADDICTION POTENTIAL
• ANXIETY DISORDERS: THE LONGER-ACTING AGENTS, SUCH AS CLONAZEPAM, LORAZEPAM, AND DIAZEPAM, ARE OFTEN PREFERRED IN THOSE PATIENTS WITH ANXIETY THAT MAY REQUIRE TREATMENT FOR PROLONGED PERIODS OF TIME
• The antianxiety effects of the benzodiazepines are less subject to tolerance than the sedative and hypnotic effects
• For panic disorders, ALPRAZOLAM IS EFFECTIVE FOR SHORT- AND LONG-TERM TREATMENT, although it may cause withdrawal reactions
• MUSCULAR DISORDERS: DIAZEPAM IS USEFUL IN THE TREATMENT OF SKELETAL MUSCLE SPASMS
• AMNESIA: The shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant procedures, such as endoscopic, bronchoscopic, and certain dental procedures as well as angioplasty
• Midazolam is an injectable-only benzodiazepine also used for the induction of anesthesia.
• SEIZURES: Clonazepam is occasionally used in the treatment of certain types of epilepsy, whereas diazepam and lorazepam are the drugs of choice in terminating grand mal epileptic seizures and status epilepticus
• Due to cross-tolerance, chlordiazepoxide, clorazepate, diazepam, and oxazepam are useful in the acute treatment of alcohol withdrawal and reducing the risk of withdrawal-related seizures
• Not all benzodiazepines are useful as hypnotic agents, although all have sedative or calming effects. THEY TEND TO DECREASE THE LATENCY TO SLEEP ONSET AND INCREASE STAGE II OF NON-RAPID EYE MOVEMENT (REM) SLEEP
• Flurazepam: This long-acting benzodiazepine SIGNIFICANTLY REDUCES BOTH SLEEPINDUCTION TIME AND THE NUMBER OF AWAKENINGS, AND IT INCREASES THE DURATION OF SLEEP
• Temazepam: THIS DRUG IS USEFUL IN PATIENTS WHO EXPERIENCE FREQUENT WAKENING. However, the peak sedative effect occurs 1 to 3 hours after an oral dose; therefore, it should be given 1 to 2 hours before the desired bedtime
• Triazolam: This benzodiazepine has a relatively short duration of action and, therefore, is used to induce sleep in patients with recurring insomnia.
• triazolam is effective in treating individuals who have difficulty in going to sleep.