ANTIPSYCHOTIC MEDICATIONS: HISTORY: In France, anti-histamines were intensively investigated since 1930s In 1951, Paul Charpentier with Rhone-Poulenc had synthesized a new phenothiazine which he later called chlorpromazine Gave it to Henri Laborit, an MD who had been experimenting with the use of anti-histamines to reduce pre-surgical stress. Now at the Val-de- Grace military hospital in Paris, Laborit gives the drug to a schizophrenic patient, with good results Two leading Parisian psychiatrists, Jean Delay and Pierre Deniker begin giving chlorpromazine to schizophrenics in early 1952, publish the results in June 1952 + And proceed to pretty much clear out the back wards of the Parisian mental hospitals! + Dubbed this family of drugs "neuroleptics" The scene shifts: In the US, a patent-medicine firm, Smith Kline & French, signs a licensing agreement for chlorpromazine as an antiemetic + Calls it Thorazine + Gets a big-name psychiatrist to publish results from his clinic + Aggressively markets Thorazine throughout the USA + Where such compounds are called antipsychotics THE CONVENTIONAL NEUROLEPTICS: Like the TCAs, to which they were closely related, these compounds were antagonists at: + Histaminergic H1 receptors + Muscarinic M1 receptors + Adrenergic alpha1 receptors UNLIKE TCAs, these compounds were also D2 antagonists THERAPEUTIC EFFICACY: Highly correlated to affinity for the D2 receptor + This was only discovered in the 1960s, with animals THE TRICYCLICS: In addition to chlorpromazine/thorazine, these include many neuroleptics: your book lists 12 + All have multiple side-effects, and LOW D2 affinity BUTYROPHENONES: These compounds are potent D2 antagonists, with fewer sedative and autonomic effects. Haloperidol is the most common butyrophenone, and until recently the most common neuroleptic in the US + Pimozide is another example + This category of compounds is still considered a "typical" neuroleptic, although they were developed somewhat later than chlorpromazine LIKE THE TCAs, THERAPEUTIC EFFICACY OF NEUROLEPTICS ONLY KICKS IN AFTER SEVERAL WEEKS OF ADMINISTRATION PHARMACOKINETICS: METABOLISM: By P450 in liver HALF-LIVES: Can vary from hours to months, depending on the compound, dose, etc DOSE: Usually possible to give a single oral dose daily SIDE EFFECTS: MOST SIDE-EFFECTS ARE EXTRAPYRAMIDAL MOVEMENT DISORDERS Thought to result from blockade of D2 receptors in the nigrostriatal system Hence closely linked to clinical efficacy These side effects are typically severe, creating real problems in maintenance and management THE EXTRAPYRAMIDAL SIDE-EFFECTS, IN ORDER OF APPEARANCE: ACUTE DYSTONIC REACTIONS: Dystonia: abnormal TONE (hypo or hyper) in any muscle Description: sustained, involuntary muscular spasms, usually of face, head, eye or neck muscles - these spasms are painful and distressing Onset: within the first 4 days of treatment Risk: Young males receiving potent D2 blockers Incidence: as high as 20% of males under 30 AKATHISIA: Meaning: an inability to sit still Description: Motor restlessness - patients experience inner restlessness, inability to stand still, constant pacing, often accompanied by anxiety Onset: within weeks of beginning treatment Incidence: from 1/5th to 1/3rd of patients PARKINSONISM: Meaning: Symptoms often indistinguishable from the movement disorders of Parkinson's disease Description: rigidity, tremor, shuffling gait, akinesia, masked facies Onset: within months of beginning treatment Incidence: over half of longer-term patients experience one or more symptoms TARDIVE DYSKINESIA: Meaning: Tardive (late) dyskinesia (movement disorder) Description: A disfiguring, sometimes permanent, motor disorder involving: + Mouth, face and tongue movements such as lip- smacking, sucking, facial grimacing + Irregular, slow, writhing, involuntary movements of fingers, arms, legs or trunk Onset: 5% of patients by the end of the first year of treatment, increasing to 20% by the end of the fourth year of treatment Risk Factors: Females, the elderly are more at risk OTHER SIDE EFFECTS: THE NEUROLEPTIC MALIGNANT SYNDROME: A potentially-fatal side effect - mortality around 20% Characterized by high fever, muscular rigidity, autonomic instability (increased blood pressure and heart beat rate), semi-consciousness and elevated WBC count Incidence: as high as 1% Risk factors include: + Young males + Rapid increase in dose of potent neuroleptics HYPERPROLACTINEMIA: D2 antagonism releases the pituitary from inhibition, causing a pronounced rise in prolactin secretion + Can cause amenorrhea, milk secretion and breast abcess in women + Testosterone often declines in response, accounting in part for sexual dysfunction in both sexes EFFECTS SHARED WITH TCAs: Sedation: Seen in over 70% of patients; tolerance does occur over time Weight gain: seen in 15 - 20% of patients Orthostatic hypotension: An antiadrenergic effect seen in 10% to 30% of patients Anticholinergic effects: cognitive impairment, dry mouth, constipation - some 60% experience SEIZURES: Seizure thresholds are reduced, resulting in seizures in a small percentage of patients (0.1%) FIGHTING DRUGS WITH DRUGS: TREATMENT OF SIDE EFFECTS: EXTRAPYRAMIDAL SIDE EFFECTS: Adjust medication: Reducing dose or changing to a second-generation "atypical" neuroleptic are indicated + There is a maximum-effective dose for antipsychotic efficacy beyond which dose increase simply increases side-effects Acute Dystonia: Injectable anticholinergics will resolve symptoms within half an hour! Neuroleptic-Induced Parkinsonism: Anticholinergics, including benztropine and trihexyphenidyl, are helpful here, and in true Parkinson's + Some clinicians routinely prescribe such compounds to prevent occurrence of Parkinsonian side-effects + But these drugs have the predictable anticholinergic side effects! + Antihistamines can also help, but ONLY traditional antihistamines with anticholinergic side effects! + Finally, an odd dopamine agonist, amantadine, has short-term benefit Akathesia: + -blockers such as propanolol are helpful, no one knows why + Benzodiazepines can also help Tardive Dyskinesia: few treatment modalities exist + Stop neuroleptics + Switch to the atypical neuroleptic clozapine DRUG-DRUG INTERACTIONS: Interactions with P450 metabolism: + TCAs, SSRIs, -blockers and anticonvulsants all compete effectively for P450 enzymes, resulting in higher blood levels and greater side effects of neuroleptics + Conversely, neuroleptics compete more effectively against the benzodiazepines Functional interactions: Generally, neuroleptics increase the effects of general CNS depressants, including analgesics, anesthetics and hypnotics ATYPICAL ANTIPSYCHOTICS: SECOND-GENERATION ANTIPSYCHOTICS Fewer extrapyramidal side effects At least as effective against psychoses But with sometimes-severe side effects of their own! Will consider clozapine, risperidone CLOZAPINE: History: + Discovered in Austria in the mid-1960s + Lack of extrapyramidal side effects made many clinicians doubt its efficacy! + 1974 - eight deaths in Finland from side-effects + Drug only slowly overcame this disaster, still is used primarily when other drugs fail Those side effects: + Agranulocytosis: sometimes-fatal reduction in the ability of bone marrow to produce leukocytes + seen in 1-2% of patients + Requires weekly monitoring of blood + This, plus high cost of clozapine, makes the drug very expensive + Other side effects include profound sedation, hypersalivation, enuresis and anticholinergic side effects, and orthostatic hypertension Indications: + treatment-refractory schizophrenia + extrapyramidal side effects + seems more effective than traditional neuroleptics in reducing NEGATIVE symptoms RISPERIDONE: Has replaced haloperidol as the most-prescribed neuroleptic in the USA Like Clozapine, has good effects on treatment- resistant schizophrenia as well as fewer extrapyramidal side effects, and greater impact on negative symptoms This compound is a potent D2, 5-HT2A and à- adrenergic receptor antagonist, without anticholinergic or antihistaminergic properties side-effects are predictable, including orthostatic hypotension, tachycardia, sexual dysfunction and sedation