Pharm: Psych-antiepiletpics-abuse-gen/local anesthetics
Terms in this set (161)
• Iproniazid and isoniazid, used for TB, were found to lift depression of chronically ill patients.
• They were later shown to inhibit MAO.
• So, monoamine depletion leads to depression and monoamine preservation leads to mood elevation.
• These data led to the monoamine hypothesis:
"Depression may be due to lowered monoamine neurotransmitter at brain synapses. Treatment of depression may be achieved by restoring the monoamine levels or actions to normality"
• The monoamine hypothesis was reinforced by the actions of antidepressants.
• Tricyclics block monoamine reuptake.
• MAO inhibitors block degradation of monoamine neurotransmitters.
Weaknesses of the hypothesis:
• The pharmacological actions of both tricyclic and MAO inhibitor classes of antidepressants are immediate.
• But the clinical effects of the drugs take weeks.
• This discrepancy between biochemical and therapeutic effects suggests that the drugs trigger longer term changes.
• Depression may be linked to a deficiency in signal transduction.
• Such a deficiency could lead to a deficient response of target neurons to neurotransmission and thus, depression.
• Antidepressants may take 2-4 weeks to produce any improvement and 6-8 weeks to achieve substantial benefit.
• All antidepressant drugs enhance monoamine neurotransmission by one of several mechanisms.
• The most common mechanism is the inhibition of the serotonin transporter (SERT), the norepinephrine transporter (NET), or both.
• Monoamine oxidase inhibitors were the first modern class of antidepressants.
• Introduced in the 1950s.
• MAO is a mitochondrial enzyme that functions as a "safety valve".
• It in activates excess norepinephrine, dopamine, and serotonin that may leak out of synaptic vesicles when the neuron is at rest.
MAO inhibitors inactivate the enzyme: neurotransmitter molecules escape degradation.
• This causes activation of norepinephrine and serotonin receptors.
MAO inhibitors are now rarely used in clinical practice due to toxicity and potentially lethal food and drug interactions.
Used in the tx of depression unresponsive to other antidepressants
Drowsiness, orthostatic hypotension, blurred vision, dry mouth, dysuria, constipation
MAO Inhibitor drug interactions
Associated with 2 classes of serious drug interactions
Serotonin syndrome- combo of a MAO inhibitor with a serotonergic agent such as SSRIs, SNRIs or TCAs or meperidine, may result in a life-threatening serotonin syndrome
• The syndrome includes hyperthermia, muscle rigidity and myoclonus.
• Serotonin syndrome is the result of overstimulation of 5-HT1A and 5-HT2 receptors.
• An irreversible MAO inhibitor with a serotonergic agent is the most toxic reported combination.
• Any drug or combination that increases serotonin can cause serotonin syndrome.
The Cheese reaction:
Tyramine is contained in certain foods, such as aged cheeses, chicken liver, soy products, pickled fish and red wines.
Tyramine is normally inactivated by MAO in the gut
Patients on MAO inhibitors can't degrade tyramine.
Tyramine causes release of catecholamines resulting in tachycardia, hypertension arrhythmias, seizures and possibly, stroke.
Sympathomimetic drugs may also cause significant hypertension when combined with an MAO inhibitor.
OTC cold preps that contain pseudoephedrine and phenylpropanolamine are contraindicated in patients taking MAO inhibitors.
TCAs block SERT and NET
This leads to increased Monoamine concentration in the cleft.
There is variability in affinity for SERT vs. NET
For example: clomipramine has very little affinity for NET but potentially binds SERT
On the other hand, desipramine and nortriptyline are more selective for NET
• Additionally, TCAs block α-adrenergic, muscarinic, histamine and 5-HT receptors.
• Blockade of these receptors are responsible for many of the adverse effects of the TCAs.
Blockade of M rc leads to blurred vision, xerostomia, urinary retention, constipation, and aggravation of narrow-angle glaucoma.
Increased catecholamine activity results in cardiac overstimulation
TCAs slow cardiac conduction similarly to quinidine, which may precipitate arrhythmicas.
Blockade of alpha1 adrenoceptors causes orthostatic hypotension and reflex tachycardia. Most serious problem in the elderly.
H1 blockade causes sedation and weight gain.
Sexual effects are common, particularly with highly serotonergic agents such as clomipramine.
Precautions- TCAs have a narrow therapeutic index.
Depressed pts who are suicidal should be given only limited quantities of these drugs and be monitored closely.
OD can cause lethal arrhythmias.
Tx includes cardiac monitoring, airway support and gastric lavage. Sodium bicarbonate is useful in reversing conduction block.
SSRIs are the DOC in treating depression
INcreased serotonergic activity in the gut is associated with nausea, GI upset and diarrhea.
Increased serotonergic tone at the level of the spinal cord and above is associated with diminished sexual function and interest.
Some patients gain weight when taking SSRIs, particularly paroxetine
SSRI Drug interactions
OD: the likelihood of fatalities from SSRI overdoses is extremely low.
Overdoses may cause seizures.
Block reuptake of serotonin and norepinephrine
Differ from TCAs by their lack of blockade of H1 muscarinic and alpha1 receptors.
May be effective in treating depression in patients in whom SSRIs are ineffective
Have relatively fewer CYP450 interactions than the SSRIs.
Potent inhibitor of 5HT uptake.
At higher doses inhibits NE uptake
Also inhibits reuptake of dopamine very weakly.
Inhibits serotonin and norepinephrine reuptake at all doses.
Inhibits norepinephrine and dopamine uptake
Increases norepinephrine and dopamine release.
Not associated with sexual dysfunction problems which occur with SSRIs because it lacks the serotonergic component
OD is associated with seizures
• When 5HT reuptake is blocked by SSRIs, all 5HT receptors are stimulated byin 5HT.
• Stimulation of 5HT1A receptors in raphe may help depression.
• But stimulation of 5HT2 receptors in forebrain may cause agitation or anxiety, and stimulation of 5HT2 receptors in spinal cord may cause sexual dysfunction.
SARIs combine 5HT reuptake blockade with 5HT2 antagonism
• This decreases undesired actions of stimulation of 5HT2 receptors
The main action of both nefazodone and trazodone is blockade of the 5-HT2A receptor.
• Inhibition of this receptor is associated with antianxiety, antipsychotic, and antidepressant effects
Noradrenergic and specific serotonergic antidepressants
TCAs and SSRIs Chart
Tx of Depression and anxiety disorders
Tx of chronic pain
Tx of eating disorders
Antidepressants are helpful for bulimia, but not anorexia
Fluoxetine is approved for treatment of bulimia
Tx of premenstrual dysphoric disorder
SSRIs are beneficial to many women with PMDD
Fluoxetine and sertraline are approved for this indication
Tx of smoking cessation
Tx of enuresis
TCAs are effective, but not commonly used because of their adverse effects.
Used prophylactically in treating manic-depressive patients and in treatment of manic episodes. Also effective in 60-80% of patients with mania and hypomania
The inositol depletion theory is the most widely accepted explanation for the actions of lithium
LIthium inhibits inositol polyphosphatase and monophosphatase, thus blocking the regeneration of inositol.
Free inositol is essential for the synthesis of PIP2, therefore lithium blocks the phosphatidylinositol signaling cascade in the brain
Inositol circulates freely in blood, but it can't cross the blood-brain barrier.
The two mechanisms of inositol synthesis in CNS neurons: regeneration from IP3 and de novo synthesis from glucose-6-phosphate, are inhibited by lithium.
By blocking the regeneration of PIP2, lithium inhibits central adrenergic, muscarinic and serotonergic neurotransmission.
Inhibition by lithium is UNCOMPETITIVE- means that ONLY NEURONS WITH ACTIVE RECEPTORS WILL BE AFFECTED BY LITHIUM.
Narrow therapeutic window
Acute lithium toxicity results in neurological effects, progressing from confusion and motor impairment, to coma, convulsions and death if the plasma concentration reaches 3-5mM.
Adverse neurologic effects of lithium include tremor, sedation, ataxia, and aphasia.
The use of lithium during pregnancy may increase the incidence of congenital cardiac anomalies. Category D
Contraindicated in nursing mothers.
Alternatives to lithium
Valproate and carbamazepine are widely used.
Olazapine and aripiprazole are approved for maintenance treatment
Quetiapine, risperidone, and ziprasidone are approved for treatment of acute mania or mixed episodes.
A combination of olanzapine and fluoxetine is approved for the treatment of depression associated with bipolar disorder.
Lamotrigine is approved for maintenance treatment.
A set of symptoms in which a person's mental capacity, affective response and capacity to recognize reality, communicate, and relate to others is impaired
Positive sx: reflect an excess of normal functions
Delusions, thought disorder, perceptual disturbances, incongruous mood, increased motor function
Positive psychotic symptoms are believed to be linked to overactivity of dopamine neurons in the mesolimbic dopamine pathway.
Negative sx: reflect a diminution or loss of normal functions: poverty of speech, loss of emotional responsiveness, reduced motor function, social withdrawal
The dopamine hypothesis of schizophrenia
• The evidence suggests that excessive dopaminergic activity plays a role in the disorder.
• Drugs that increase dopaminergic activity increase or produce positive psychotic symptoms.
• Drugs that decrease dopaminergic activity decrease or stop positive symptoms
Amphetamine and cocaine if given repeatedly can cause a paranoid psychosis indistinguishable from schizophrenia.
• Antipsychotic drugs are blockers of D2 receptors.
4 well-defined dopamine pathways in the brain:
1. Mesolimbic pathway
2. Nigrostriatal pathway
3. Mesocortical pathway
4. Tuberoinfundibular pathway
Projects from brainstem to limbic areas
Thought to have important role in emotional behaviors
Hyperactivity is thought to account for positive psychotic symptoms
Blockade of D2 receptors in this pathway is believed to mediate the antipsychotic effects of antipsychotic drugs
Reduce hallucinations and agitation.
Have a calming effect.
Do not depress intellectual function
Motor incoordination is minimal.
Onset of antipsychotic action is <=24hrs
With the exception of aripiprazole and thioridazine, most neuroleptics have antiemetic effects.
Mediated by blockade of D2 receptos of the chemoreceptor trigger zone of the medulla.
The efficacy of the traditional neuroleptic drugs correlates closely with their ability to block D2 receptors in the mesolimbic pathway
Atypical antipsychotic drugs
Common properties of atypicals:
Dual antagonism at 5-HT2A and D2 receptors.
Exert part of their action by blocking 5HT receptors.
Less likely to cause EPRs than classical agents.
Less likely to cause tardive dyskinesia
Less likely to cause increases in prolactin
More effective at treating negative symptoms
Effective in refractory populations
Properties of some atypical antipsychotic agents
Most antipsychotic drugs are almost completely metabolized, mainly by CYP2D6, CYP1A2 and CYP3A4
Antipsychotics do not interfere with the metabolism of other drugs.
EPRs are also less likely to occur with conventional agents with strong anticholinergic activity, such as thioridazine and chlorpromazine.
Atypical antipsychotic drugs have low potential for causing EPRs
EPRs include typical Parkinson's syndrome, akathisia, and acute dystonic reactions.
Parkinsonism can be treated with antimuscarinic drugs like benztropine or trihexyphenidyl, with diphenhydramine, or with amantadine.
Levodopa should never be used in these patients.
Dystonia can be controlled with benztropine, trihexyphenidyl, or diphenhydramine
Management of akathisia typically requires reduction of dosage or a change of the antipsychotic drug.
The drugs most commonly used to manage akathisia are clonazepam or propranolol
EPR risk of antipsychotic agents
Tardive Dyskinesia and APS
Late-occurring syndrome of abnormal choreoathetoid movements.
Most important unwanted effect of antipsychotics
May be due to dopamine receptor up-regulation
Neuroleptic malignant syndrome and APS
Sedation and Seizures and APS
Especially common with chlorpromazine and clozapine
Autonomic effects and Toxic or allergic reactions of APS
Clozapine causes agranulocytosis in 1-2% of patients.
Regular blood cell counts are mandatory
Prolactin secretion and APS
Weight gain and APS
Cardiac toxicity, ocular complications and APS
Chlorpromazine causes deposits in the cornea and lens
Thioridazine causes retinal deposits
APS, clinical potency, EPR, Sedation, hypotension
Nausea and vomiting
Droperidol is used in combination with fentanyl in neurolept-anesthesia
APS Drug choices
Antipsychotic drugs are category C.
Only clozapine is category B
The risk of hyperglycemia and weight gain, which may be problematic in pregnancy, are greater with atypical antipsychotics
Sedative-hypnotics a cause a graded dose-dependent depression of CNS functions.
Individual drugs differ in the relationship between drugs differ in the relationships between the dose and the degree of CNS depression
• Older sedative-hypnotics show a linear dose- response curve.
• An increase in dose above that needed for hypnosis may lead to a state of general anesthesia.
• At still higher doses they may depress respiratory and vasomotor centers in the medulla, leading to coma and death.
• Benzodiazepines show a non-linear dose- response relationship. They are safer drugs.
Sedative hypnotics flow chart
• Benzodiazepines are the most widely used anxiolytic drugs.
• They have largely replaced barbiturates in the treatment of anxiety, because they are safer and more effective.
• The benzodiazepines bind to GABAA receptors in neuronal membranes in the CNS.
• The GABAA receptor functions as a chloride channel, and is activated by the inhibitory neurotransmitter GABA.
The Binding sites for GABA are located between adjacent alpha and beta subunits
• Benzodiazepines bind to a site located between an α subunit and the γ subunit.
• These binding sites are sometimes called benzodiazepine receptors.
• Two benzodiazepine receptor subtypes commonly found in the CNS have been designated BZ1 and BZ2.
• GABA is the major inhibitory neurotransmitter in the CNS.
• Binding of GABA to its receptor opens the chloride channel, leading to an increase in chloride influx.
• Benzodiazepines enhance GABA's effects allosterically.
• This enhancement takes the form of an increase in frequency of channel opening events.
Benzodiazepines enhance GABA-induced chloride influx
Agonists- • Are positive allosteric modulators of receptor
• These are the clinically useful benzodiazepines, which exert anxiolytic and anticonvulsant effects.
• Flumazenil: blocks actions of benzodiazepines.
• Negative allosteric modulators of GABA
• They can cause anxiety and seizures.
Actions, absorption/distribution and duration of action of the benzodiazepines
• Reduction of anxiety.
• Sedative and hypnotic actions.
• Muscle relaxant.
ABSORPTION AND DISTRIBUTION
• Benzodiazepines are lipophilic and are rapidly and completely absorbed after oral administration and are distributed throughout the body.
• The half-lives of the benzodiazepines are very important clinically: duration of action may determine the therapeutic usefulness.
• Benzodiazepines can be divided into short-, intermediate- and long-acting groups.
• Longer acting agents form active metabolites with long half-lives.
Metabolism of Benzodiazepines
Most benzodiazepines undergo phase 1 reactions, mainly by CYP3A4
The metabolites are then conjugated to form glucuronides that are excreted in the urine
Desmethyldiazepam, with a half-life of over 40 hours, is an active metabolite of several benzodiazepines used clinically.
Desmethyldiazepam is then metabolized to the active compound oxazepam
Oxazepam, lorazepam and temazepam are conjugated directly and are not metabolized by the P450 system.
Flurazepam is oxidized by liver enzymes to active metabolites with half-lives ranging from 30 to 100 hours.
Clorazepate is a prodrug that is decarboxylated to desmethyldiazepam in gastric juice.
Therapeutic uses of Benzodiazepines
Recommended only for short-term or intermittent use in anxiety disorders
Diazepam is useful in the treatment of skeletal muscle spasms and treating spasticity from degenerative disorders, like MS and cerebral palsy.
Clonazepam: used for some types of epileptic seizures
Lorazepam and diazepam: used in status epilepticus
Diazepam and oxazepam: useful in the management of withdrawal from ethanol
• Certain benzodiazepines are used as components of anesthesia protocols.
• The three most prescribed for sleep disorders are:
• long-acting flurazepam
• intermediate-acting temazepam
• short-acting triazolam
• Drowsiness and confusion. The two most common side effects.
• Cognitive impairment.
Adverse Psychological Effects
• Benzodiazepines may cause paradoxical effects: Anxiety, irritability, hostility and rage, paranoia, depression and suicidal ideation.
• The incidence of such reactions is rare and appears to be dose-related.
• Psychological and physical dependence can develop if high doses are given over prolonged period.
• Abrupt discontinuation leads to withdrawal symptoms: confusion, anxiety, agitation, restlessness, insomnia, tension.
Benzodiazepine antagonists: Flumazenil
• Only benzodiazepine receptor antagonist available for clinical use.
• It blocks effects of benzodiazepines.
• Approved for reversing the CNS depressant effects of benzodiazepine overdose and to hasten recovery following use of these drugs in anesthetic and diagnostic procedures.
• Rapid onset.
• Short duration: half-life about 1 hour, due to rapid hepatic clearance.
• Frequent administration may be necessary to maintain reversal of long-acting benzodiazepines.
• May precipitate withdrawal in physiologically dependent patients or may cause seizures if a benzodiazepine is used to control seizures.
• Replaced by the benzodiazepines as sedative- hypnotics.
• Barbiturates induce tolerance, drug-metabolizing enzymes, physical dependence and cause very severe withdrawal symptoms.
• They can cause coma in high doses.
• Barbiturates also act on GABAA receptors, and enhance GABAergic transmission.
• The binding site of barbiturates is different from that of the benzodiazepines.
• Barbiturates increase the duration of the GABA- gated chloride channel openings.
• Barbiturates can also block glutamate receptors and sodium channels.
• The multiplicity of sites of action of barbiturates may explain their ability to induce full surgical anesthesia and their more pronounced central depressant effects.
Actions of barbituates
Depression of CNS
• At low doses, the barbiturates produce sedation.
• At higher doses hypnosis, followed by anesthesia, and finally coma and death.
• Thus, any degree of CNS depression is possible, depending on the dose.
• Barbiturates suppress the hypoxic and chemoreceptor response to CO2. Overdosage causes respiratory depression and death.
• Barbiturates induce liver cytochrome P450 enzymes.
• Ultra short acting barbiturates, such as thiopental are used IV to induce anesthesia.
• Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus and eclampsia.
• Replaced by benzodiazepines.
Hepatic Metabolic Uses
• Phenobarbital has been used to treat hyperbilirubinemia and kernicterus in the neonate.
• The nondepressant barbiturate N-phenylbarbital works equally well.
AE of Barbiturates
• CNS: drowsiness, impaired concentration,mental and physical sluggishness.
• Paradoxical excitement
• Barbiturates increase porphyrin synthesis: contraindicated in patients with porphyria.
• In the presence of pulmonary insufficiency they may cause serious respiratory depression.
• Rapid IV injection of a barbiturate may cause cardiovascular collapse.
• Pain: May worsen perception of pain.
• Addiction: severe withdrawal syndrome.
• Poisoning: severe respiratory depression and central CV depression.
Non-Benzodiazepine benzodiazepine receptor agonists
These drugs act only on the BZ1 subtype of benzodiazepine receptors
• Antihistamine with antiemetic activity.
• Approved for symptomatic relief of anxiety.
• Widely used to control performance anxiety.
• Clonidine may also modify autonomic expression of anxiety.
• Nonprescription antihistamines with sedating properties, such as diphenhydramine and doxylamine, are effective in treating mild types of insomnia.
• However, these drugs are usually ineffective for all but the milder forms of situational insomnia.
• Hypnotic. Short duration of action.
• Short half life = 1.5 - 3.5 h.
• Indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.
• Minimal muscle relaxing and anticonvulsant effects.
• Little or no tolerance.
• Low incidence of adverse effects.
• Rapid onset and very short duration of action.
• Elimination half life = 1 h.
• Indicated for the short-term treatment of insomnia.
• (S)-Entantiomer of zopiclone.
• Pharmacologically active enantiomer of zopiclone.
• FDA-approved for treatment of insomnia.
• Decreases sleep latency and improves sleep maintenance.
• Half-life = 6 hours.
5-HT1A partial agonists
• No hypnotic, anticonvulsant or muscle relaxant properties.
• Only anxiolytic.
• Indicated for management of anxiety
• Onset: 2 - 3 weeks.
• Mechanism of action may be analogous to antidepressants.
• Less psychomotor impairment than BZ.
• No drug interactions with EtOH
• No drug interactions with benzodiazepines and other sedative-hypnotics
• No rebound anxiety or withdrawal signs on abrupt discontinuance
• No dependence
Melatonin receptor agonists
• Agonist at MT1 & MT2 melatonin receptors.
• Indicated for the treatment of insomnia characterized by difficulty with sleep onset.
• Anxiety is a normal response to stressful or fearful circumstances.
• Anxiety allows an individual to adapt to or manage the stressful/threatening situation.
• Anxiety that becomes excessive, causes irrational thinking or behavior, and impairs a person's functioning is considered an anxiety disorder.
• Anxiety disorders are among the most frequent mental disorders encountered by clinicians.
• Untreated anxiety disorders may result in increased healthcare utilization, morbidity and mortality, and poorer quality of life.
• First-line agents in management of chronic GAD.
• They have replaced benzodiazepines as the drugs of choice for chronic GAD due to:
• side effect profile
• no risk for dependency
• efficacy in common comorbid conditions including depression, PD, OCD and SAD
• Antidepressants reduce the psychic symptoms of anxiety with a modest effect on autonomic or somatic symptoms.
• Onset of antianxiety effect takes 2 - 4 weeks.
• Venlafaxine and SSRIs are usually preferred over TCAs due to improved safety and tolerability.
• Recommended for acute treatment of GAD when short-term relief is needed, as an adjunct during initiation of antidepressant therapy, or to improve sleep.
• Buspirone does not have abuse potential, does not cause withdrawal reactions, and does not potentiate alcohol and sedative-hypnotic effects.
• Has a gradual onset of action (i.e., 2 weeks).
• Does not provide immediate anxiety relief.
• Second-line agent for GAD due to inconsistent data regarding its efficacy.
• Hydroxyzine and pregabalin.
• SSRIs are the drugs of choice.
• A TCA or MAOI may be effective when an SSRI is not.
• Not preferred for long-term treatment.
• May be used when patients fail several antidepressant trials.
• Alprazolam, although widely used, may cause rebound anxiety between doses and has been associated with a withdrawal syndrome, including seizures.
Social Anxiety disorder
• SSRIs are the drugs of choice due to their tolerability and efficacy.
• The onset of response may be as long as 8 to 12 weeks.
• Clomipramine, fluoxetine, fluvoxamine, paroxetine, and sertraline are all FDA- approved for OCD.
• Comparisons show no difference in efficacy between clomipramine and the SSRIs.
• The SSRIs have a better adverse effect profile.
• For highly anxious OCD patients, adding a benzodiazepine or an antipsychotic drug may be beneficial.
• SSRIs are the first-line drugs.
• Other antidepressants (e.g., venlafaxine, TCAs and MAOIs) can also be effective, but they have less favorable side-effect profiles.
• Sertraline and paroxetine are both approved for the acute treatment of PTSD.
• Sertraline is approved for the long-term management of PTSD.
• Propranolol and other β-blockers are the preferred treatments.
• Parkinsonism is a neurologic syndrome characterized by 4 features:
• Resting tremor
• Muscular rigidity
• Impairment of postural balance
• The most common cause of parkinsonism is idiopathic Parkinson's disease.
• The cause is unknown.
• There is a loss of the neurons in the substantia nigra which provide dopaminergic innervation to the striatum.
• Dopamine synthesis originates from the amino acid precursor tyrosine.
• Tyrosine must be transported across the blood-brain barrier into the dopamine neuron.
• Tyrosine is transported by system L across the blood brain barrier in a Na+- independent manner.
Tyrosine Hydroxylase is the rate limiting step
DOPA is converted to dopamine by aromatic L-amino acid decarboxylase (DOPA decarboxylase).
DOPA decarboxylase turns over so rapidly that DOPA levels in the brain are negligible under normal
• It is therefore possible to enhance the formation of dopamine by providing this enzyme with increased amounts of substrate.
• The benefits of dopaminergic antiparkinsonism drugs appear to depend mostly on stimulation of the D2 receptors.
• But D1 stimulation may also be required for maximal benefit.
Pathophysiology of Parkinson's disease
• In Parkinson's disease, there is destruction of the neurons of the nigrostriatal pathway responsible for secreting dopamine in the striatum.
• This results in loss of the control of muscle movement.
Loss of neurons in the substantia nigra
• At least 70% of the neurons are destroyed at the time symptoms first appear.
• Often, 95% of the neurons are missing at autopsy.
Strategy of treatment for PD
Drugs used in Parkinson's disease
• Levorotatory stereoisomer of dopa.
• Metabolic precursor of dopamine (and norepinephrine).
• Restores dopamine levels in the extrapyramidal centers.
• In patients with early disease, the number of residual dopaminergic neurons in the substantia nigra is enough for conversion of levodopa to dopamine.
• With time, the number of neuronsand there are fewer cells capable of taking up levodopa and converting it to dopamine.
• Consequently, motor control fluctuation develops.
• Relief provided by levodopa is only symptomatic and lasts only while the drug is present in the body.
• Much of the drug is decarboxylated to dopamine in the periphery.
• This results in peripheral side effects (nausea, vomiting, cardiac arrhythmias, hypotension).
• Levodopa is absorbed rapidly from the small intestine.
• Food delays the appearance of levodopa in the plasma.
• Certain amino acids can compete with the drug for absorption from the gut and for transport from the blood to the brain.
• Carbidopa is a dopa decarboxylase inhibitor that does not cross the blood-brain barrier.
• Levodopa is given in combination with carbidopa.
• Carbidopa decreases the metabolism of levodopa in the GI tract and peripheral tissues, thus increasing the availability of levodopa to the CNS.
• Sinemet is a dopa preparation containing carbidopa and levodopa in fixed proportion (1:10 or 1:4).
Peripheral metabolism of levodopa + Carbidopa
Metabolism of Levodopa
Clinical uses of Levodopa/Carbidopa
Wearing-Off Reactions (End-Of-Dose Akinesia)
• Fluctuations related to the timing of levodopa intake.
The On-Off Phenomenon
• Fluctuations in response unrelated to the timing of doses.
• The exact mechanism is unknown.
• For patients with severe off-periods who are unresponsive to other measures, apomorphine SC may provide benefit.
Levodopa: Interactions and contraindications
• Vitamin B6 is a cofactor for Dopa decarboxylase: it increases peripheral metabolism of levodopa
• Concomitant administration of nonspecific MAO inhibitors, may precipitate hypertensive crisis.
• Levodopa should not be given to psychotic patients, as it may exacerbate the mental disturbance.
• Levodopa is contraindicated in angle-closure glaucoma.
• Cardiac patients should be carefully monitored because of possible arrhythmias.
• Antipsychotic drugs are contraindicated in PD: they may produce a parkinsonian syndrome.
Dopamine Receptor Agonists
• The enzymes responsible for synthesizing dopamine are depleted in the brains of PD patients.
• Dopamine receptor agonists may have a beneficial effect additional to that of levodopa.
• ERGOT DOPAMINE AGONISTS
• NONERGOT DOPAMINE AGONISTS
Ergot Dopamine Agonists
• D2 agonist.
• Little response in patients who do not respond to levodopa.
• Often used with levodopa in patients responding to drug therapy.
• GI Effects
• Cardiovascular Effects
• Mental Disturbances
• Miscellaneous Adverse Effects:
• Pulmonary infiltrates
• Pleural and retroperitoneal fibrosis • Erythromelalgia
NonErgot dopamine agonists
Pramipexole & ropinirole
• Better adverse effect profile.
• Well tolerated.
• They are used increasingly as initial treatment for PD rather than as adjuncts to levodopa.
• Particularly for younger patients.
• Older patients are more vulnerable to the adverse cognitive effects of the dopamine agonists.
• Available in a transdermal formulation. • Once-daily use.
• Rescue therapy for treatment of "off" episodes of akinesia in patients on dopaminergic therapy.
• Emetogenic; pretreatment with the antiemetic trimethobenzamide is recommended.
• Other adverse effects: QT prolongation, dyskinesias, drowsiness, sweating, hypotension and bruising at the injection site.
MAOI and Parkinson's
• Selectively and irreversibly inhibits MAO-B (which selectively metabolizes dopamine),
• Retards breakdown of dopamine in the brain.
• Enhances the effect of levodopa.
• Allows dose of levodopa to be reduced.
• Little potential for causing hypertensive crises.
• Mainly used as adjunct to levodopa.
• Second MAO-B inhibitor approved for treatment of PD.
• Modestly helpful when taken alone for early disease or in addition to levodopa/carbidopa in advanced disease.
COMT and Parkinson's
• Both MAO and COMT are responsible for the catabolism of levodopa as well as dopamine.
This increases plasma levels of 3-O-methyldopa
3-o-methyl dopa copetes with levodopa for an active carrier that transports levodopa across the intestinal mucosa and the blood-brain barrier.
• Inhibition of COMT by tolcapone & entacapone leads to:
• Decreased metabolism of levodopa
• Decreased plasma levels of 3-O-methyldopa • Increased uptake of levodopa
• Higher dopamine levels in the brain.
• Fulminating hepatic necrosis is associated
with the use of tolcapone
• Entacapone is not hepatotoxic and is therefore preferred.
Where Tolcapone, Entacapone, and Carbidopa act
• Antiviral drug with antiparkinsonian actions.
• Increases synthesis, release or re-uptake of dopamine from the surviving neurons.
• Less efficacious than levodopa and tolerance develops more readily, but it has fewer side effects.
• May cause restlesness, agitation, confusion, hallucinations.
• At high doses: acute toxic psychosis.
• Peripheral edema: not accompanied by signs of cardiac, hepatic or renal disease; responds to diuretics.
• Amantadine should be used with caution in patients with a history of seizures or heart failure.
• Livedo reticularis sometimes occurs in patients taking amantadine. Usually clears within a month of withdrawing the drug.
Antimuscarinics and Parkinson's
• Adjuvant therapy.
• May improve tremor and rigidity but have little effect on bradykinesia.
• Can produce mood changes, xerostomia, pupillary dilation, confusion, hallucinations, urinary retention and dry mouth.
• Cannot be used in patients with glaucoma, prostatic hypertrophy or pyloric stenosis.
Choice of treatment for Parkinson's
• Epilepsyisachronicdisordercharacterizedby recurrent seizures.
• Seizuresarefiniteepisodesofbraindysfunction resulting from abnormal discharge of cerebral neurons.
• The pathophysiologic mechanisms underlying seizure disorders are unknown.
• Seizures are still classified according to their clinical manifestations rather than their biological basis.
1. PARTIAL SEIZURES
• SIMPLE PARTIAL SEIZURES
• COMPLEX PARTIAL SEIZURES
• PARTIAL WITH SECONDARILY GENERALIZED TONIC-CLONIC SEIZURES
2. GENERALIZED SEIZURES
• TONIC-CLONIC SEIZURES
• ABSENCE SEIZURES
• SIMPLE PARTIAL SEIZURES
• COMPLEX PARTIAL SEIZURES
• PARTIAL WITH SECONDARILY GENERALIZED TONIC-CLONIC SEIZURES
• TONIC-CLONIC SEIZURES
• ABSENCE SEIZURES
There is no loss of consciousness
Often there is abnormal activity of a single limb or muscle group
Complex partial seizure
• There is loss of consciousness.
• Motor dysfunction may involve chewing movements, diarrhea, urination.
Partial seizure with secondarily generalized tonic-clonic seizure
Grand Mal Seizure
Petit Mal Seizure
• Brief, abrupt and self-limiting loss of consciousness.
• The patient stares and exhibits rapid eye-blinking.
Other generalized Seizures
• ATONIC SEIZURES
• TONIC SEIZURES
• CLONIC SEIZURES
• MYOCLONIC SEIZURES • INFANTILE SPASMS
• FEBRILE SEIZURES
• STATUS EPILEPTICUS
Nature and mechanisms of seizures
• A decrease in inhibitory synaptic activity or an increase in excitatory activity might trigger a seizure.
• GABA and glutamate are the main inhibitory and excitatory neurotransmitters, respectively.
Experimental data shows that:
• Antagonists of the GABAA receptor trigger seizures.
• Agonists of glutamate receptors trigger seizures.
• Drugs that enhance GABAergic transmission inhibit seizures.
• Glutamate receptor antagonists inhibit seizures.
Therefore, pharmacological regulation of synaptic function can regulate the propensity for seizures.
Mechanism of antiepileptic drugs
• The principal mechanisms of action of antiseizure drugs involve:
• Blockade of Voltage-Gated Ion Channels
• Modulation of Synaptic Transmission
Drugs that block VgIon Channels
1. Drugs that block Voltage-Gated Na+ channels
2. Drugs that block T-type Ca2+ channels
• Principal mechanism of action of
• It may contribute to the effects of
Drugs that block T-type Ca2+ Channels
• Absence seizures involve oscillatory neuronal activity between thalamus and cortex.
• The T-type Ca2+ current governs oscillatory responses in thalamic neurons.
• Ethosuximide and valproate inhibit this current and are effective in absence seizures.
Drugs that affect synaptic transmission
1. Drugs that enhance GABAergic neurotransmission
• Postsynaptically • Presynaptically
2. Drugs that reduce glutamatergic neurotransmission
Drugs that enhance GABAergic neurotransmission postsynaptically
• Direct action on the GABA receptor
• Benzodiazepines • Barbiturates
Drugs that enhance GABAergic neurotransmission presynaptically
• Inhibition of the reuptake of GABA:
• Inhibition of degradation of GABA: Vigabatrin inhibits GABA aminotransferase.
• Increase of GABA release: Gabapentin & pregabalin.
Drugs that reduce glutamatergic neurotransmission
• Phenobarbital & topiramate block glutamate receptors.
• Gabapentin and pregabalin decrease glutamate release by blocking presynaptic voltage-gated Ca2+ channels.
Drug treatment for: Simple and complex partial and secondarily generalized tonic-clonic seizures
Drugs of choice are carbamazepine, oxcarbazepine, lamotrigine or phenytoin.
Valproate and topiramate are alternatives
New drugs (eg gabapentin, pregabalin, zonisamide) can be used as adjuncts
Phenobarb is used for generalized tonic-clonic and complex or simple partial seizures
It may also be used for myoclonic seizures
It used to be a first-line drug, but now is second-line because of its adverse effects: sedation, depression and agitation.
Drug treatment for generalized seizures
• Valproate, carbamazepine and phenytoin are the drugs of choice.
• Drugs of choice: ethosuximide and valproate.
• If tonic-clonic seizures are present valproate is the drug of choice.
• Valproate is also preferred for atypical absence seizures.
• Clonazepam is effective, but sedation is prominent and tolerance may develop.
• Acetazolamide may be effective but tolerance develops.
• Valproate is the drug of choice.
Atonic seizures are often refractory to all drugs.
Valproate and lamotrigine may be beneficial
Benzodiazepines may improve seizure control in some patients but may worsen attacks in others.
Felbamate is effective in some patients, but the drug's toxicity limits its use
Corticotropin or glucocorticoids are commonly used. Their mechanisms of action is unknown
Vigabatrin is also effective
Other drugs that have been used include valproate, clonazepam, pyridoxine, felbamate and lamotrigine
Other convulsive Emergencies
Drug-induced seizures in nonepileptic patients may be controlled with diazepam, lorazepam or phenobarbital
Adverse effects of seizure treatments
Carbamazepine, Phenobarbital and Phenytoin induce CYP450
Discontinuing Antiepileptic Therapy
Antiepileptic Overdose Toxicity
Teratogenicity of antiepileptic drugs
There is an increased risk of congenital malformations in infants born of women taking antiseizure drugs
Valproate appears to cause a significantly higher rate of fetal malformations compared to other antiepileptic drugs
Prophylactic use of folic acid is recommended for all women of childbearing age because it decreases incidence of neural tube defects
Newborn hemorrhagic disease in antiepileptic drugs
Other uses of Antiseizure drugs
Nonpharmacologic approaches to epilepsy
about 1/3 of pts with epilepsy continue to have seizures on meds
The Ketogenic Diet
• Four parts fat to one part protein and carbohydrate.
• The high fat content and extremely low carbohydrate content produce ketosis, which appears to have a direct antiseizure effect.
• How the ketogenic diet suppresses seizures remains unclear.
Vagal nerve stimulation
-intermittent electrical stimulation of the left vagus nerve with an implanted pacemaker-like device
The patient can activate the device when they sense a seizure is imminent
• Abuse is the excessive self-administration of any substance for nonmedical purposes.
• Some drugs of abuse do not lead to addiction.
• This is the case of substances that alter perception without causing sensations of reward and euphoria, such as the hallucinogens.
Behaviors that include one or more of the following:
-impaired control over drug use
-continued use despite harm
State of adaptation manifested by drug class specific withdrawal syndrome
The withdrawal syndrome can be produced by:
-rapid dose reduction
-administration of an antagonist
Physiological and behavioral changes directly related to sudden cessation or reduction in use of a psychoactive drug to which the body has become adapted
Mechanisms of Addiction
The Mesolimbic dopamine system is the prime target of addictive drugs
As a general rule, all addictive drugs activate the mesolimbic dopamine system
DSM-IV and dependence:
The DSM IV uses the term dependence to describe what is usually understood as addiction*
Drugs of abuse
• CNS DEPRESSANTS- ethanol, benzodiazepines, barbiturates
• PSYCHOSTIMULANTS- methylxanthines, cocaine, amphetamines
• PSYCHEDELIC AGENTS- LSD, Mescaline, Psilocibin, Phenciclidine, MDMA
• INHALANTS- NO, Volatile organic solvents, organic nitrates
• ANABOLIC STEROIDS
Ethanol and abuse
• Ethanol is classed as a depressant because it produces sedation and sleep.
• The initial effects of ethanol are often perceived as stimulation due to suppression of inhibitory systems.
• Ethanol influences several cellular functions:
• GABAA receptors
• Kir3/GIRK channels
• Adenosine reuptake
• Glycine receptors
• NMDA receptors • 5-HT3 receptors.
Ethanol withdrawal syndrome- heavy consumption of EtOH leads to acquired tolerance and physical dependence
Withdrawal syndrome may include tremor, nausea, vomiting, sweating, agitation, and anxiety.
This may be followed by hallucinations
Generalized seizures may appear after 24-48 hours.
After 48-72 hours, DT may appear
DT is associated with 5-15% mortality
Tx of alcohol addiction
Facilitates GABA function, antagonizes glutamate receptors.
May reduce cravings.
Benzodiazepines and abuse
Can cause physical dependence and addiction.
Addiction is rare.
High dose or normal dose dependencies
Low dose-withdrawal: nausea, vomiting, tremor, incoordination, restlessness, blurred vision, sweating and anorexia
High dose withdrawal: seizures, psychosis, and depression
Barbiturates and abuse
• The use of barbiturates has declined greatly in recent years due to the increased safety and efficacy of newer medications.
• Abuse problems with barbiturates resemble those seen with benzodiazepines.
Methylxanthines and abuse
Caffeine, theophylline, and theobromine
Caffeine is the most widely consumed stimulant
100-200 mg caffeine (1-2 cups of coffee) causes decrease in fatigue and increased mental alertness.
1.5g caffeine (12-15 cups of coffee) produces anxiety and tremors
The spinal cord is stimulated only by very high doses (2-5g) of caffeine
Tolerance and withdrawal:
-Tolerance can rapidly develop to the stimulating properties of caffeine.
-Withdrawal consists of feelings of fatigue and sedation.
-Addiction is rare
-Caffeine is not listed in the category of addicting stimulants
Cocaine and abuse
Due to its abuse potential, cocaine is classified as a schedule II drug by the DEA
• Cocaine inhibits dopamine, norepinephrine and serotonin reuptake.
• The prolongation of dopaminergic effects in the brain's limbic system produces the intense euphoria that cocaine initially causes.
• Stimulation of cortex and brainstem.
• Increases mental awareness and produces a feeling of well-being and euphoria.
• Paranoia may occur after repeated doses.
• At high doses: tremors and convulsions, followed by respiratory and vasomotor depression.
SYMPATHETIC NERVOUS SYSTEM
• Peripherally, cocaine potentiates the action of norepinephrine: fight or flight syndrome.
• Tachycardia, hypertension, pupillary dilation and peripheral vasoconstriction.
Cocaine increases heat production through a direct effect on thermoregulatory centers in the hypothalamus and increased psychomotor activity
Cocaine also impairs sweating and cutaneous vasodilation and heat perception.
Cocaine-related drugs are more common in hot weather
Cocaine Withdrawal syndrome
Dysphoria, depression, sleepiness, fatigue, cocaine craving and bradycardia
Cocaine withdrawal is generally mild
Treatment of withdrawal symptoms is usually not required
Treatment of cocaine addiction
Many agents, mainly antidepressants and dopamine agonists have been tested as treatments for cocaine abuse
None have demonstrated clear efficacy
Amphetamines and abuse
Increase release of catecholamines
Weak inhibitors of MAO
Possible direct catecholaminergic agonists in the brain
• Behavioral effects similar to those of cocaine.
• Due to release of dopamine.
• Increased alertness, decreased fatigue, depressed appetite and insomnia.
• At high doses, psychosis and convulsions.
SYMPATHETIC NERVOUS SYSTEM
• Activate receptors through norepinephrine release.
ADHD- amphetamine and methylphenidate
Narcolepsy- amphetamine and methylphenidate
Tolerance can be marked.
An abstinence syndrome can occur upon withdrawal
Symptoms include increased appetite, sleepiness, exhaustion, and mental depression
Antidepressants may be indicated
Nicotine and abuse
Second only to caffeine as the most widely used CNS stimulant. Second only to alcohol as the most abused drug
In low doses: ganglionic stimulation by depolarization
At high doses: ganglionic blockade
• Cigarette smoking or administration of low doses of nicotine produces some degree of euphoria and relaxation.
• Improves attention, learning, problem solving, and reaction time.
• High doses of nicotine result in central respiratory paralysis and severe hypotension caused by medullary paralysis.
• Nicotine is an appetite suppressant.
Nicotine withdrawal is mild
Involves irritability and sleeplessness
However, nicotine is among the most addictive drugs
Relapse is very common
Treatment for nicotine addiction
Nicotine replacement therapy
Sustained-release bupropion (mechanism unclear)
Varenicline- partial agonist at nicotinic receptors in the CNS
Opioids and abuse
The most commonly abused opioids are heroin, morphine, codeine and oxycodone, and - among health professionals- meperidine and fentanyl.
Detoxification using opioid agonists
The illicit agent is replaced by a long-acting opioid
The dose is slowly reduced
Drugs used: Methadone or buprenorphine
Detoxification using adrenergic agonists
-chronic opioid intake leads to tolerance to the effects of opioids on the ANS, mediated by noradrenergic pathways.
Withdrawal leads to a rebound firing of the neurons.
A noradrenergic storm results and is responsible for many of the withdrawal symptoms
Drugs used: Clonidine and lofexidine. They are presynaptic alpha2 agonists
Marijuana and abuse
Two cannabinoid receptor subtypes: CB1 and CB2
Both are G protein-linked receptors
Both couple to Gi
CB1 receptors are found primarily in the brain and mediate the psychological effects of THC.
CB2 receptors are present mainly on immune cells.
Actions: TCH can produce euphoria, followed by drowsiness and relaxation.
Affects short-term memory and mental activity.
Impairs highly skilled motor activity.
Other effects: appetite stimulation, xerostomia, visual hallucinations, delusions, enhancement of sensory activity.
At high doses: toxic psychosis
Tolerance and mild physical dependence occur with continued, frequent use of the drug.
Therapeutic THC is called dronabinol
Dronabinol is FDA approved for:
-anorexia associated with weight loss in patients with AIDS
-nausea and vomiting associated with cancer chemotherapy (second line)
Psychedelic agents and abuse
LSD, Mescaline, Psilocibin, Phenciclidine, MDMA
Affect thought, perception adn mood. Don't cause marked psychomotor stimulation or depression
LSD and abuse
LSD-like group of drugs include
The hallucinogenic actions of LSD appear to be mediated by agonist effects at 5-HT2 receptors in the CNS
LSD does not cause addiction
There is no withdrawal syndrome
Users may require med attention because of "bad trips"
severe agitation may require medication: diazepam is effective
Phencyclidine (PCP/angeldust) and abuse
Withdrawn in humans due to AE but retained in veterinary practice.
Ketamine, an analog, replaced phencyclidine as an anesthetic for use in humans.
MDMA and abuse
Nitrous oxide and abuse
Volatile organic solvents and abuse
Organic nitrits and abuse
Anabolic steroids and abuse
Used to increase muscle size by body-building competitors