Flashcards in Pharm - Antipsychotics! Deck (24):
Constellation of disorders with disturbances in PERCEPTION, AFFECT, BEHAVIOR and COMMUNICATION
Positive Symptoms --> Hallucinations, Delusions
Negative Symptoms --> Diminished speech (alogia), affective flattening/blunting, Anhedonia (no pleasure), social isolation, avolition (decreased goal directed behavior)
What do the drugs do?
The drugs we have are generally for the treatment of POSITIVE SYMPTOMS
Side effects could actually mimic/worsen the negative symptoms
How did the dopamine theory of schizophrenia come into play?
Reserpine --> first drug for schizophrenia --> blocks VMAT --> more NE, 5HT and DA in the cytoplasm --> more breakdown (exposure to MAO) = Less NT overall
Antihypertensive and Antipsychotic effects
This led to the NORADRENERGIC THEORY --> found that it also affected 5HT, so serotonergic theory also possible
Chlorpromazine --> doesn't affect 5HT --> DA theory comes into play (blocks DA and NE)
Halperidol --> Doesn't affect NE whatsoever, blocks DA synaptic transmission selectively
What is the most effective drug for Schizophrenia?
Dirtiest drug in psychiatry!!! Don't know why it is the most effective drug -- does more than just DA blockade
Basal Ganglia Review
Cortex wants us to MOVE!
Cortex sends inputs to the STRIATUM (C + P) --> this sends INHIBITORY signals to the GPi (normally GPi inhibits thalamus, inhibiting movement) --> THUS, when excited, the Striatum INHIBITS the INHIBITOR --> no inhibition on the thalamus --> excitatory to cortex = MOVEMENT!
There is an indirect pathway too --> inhbitory input to the GPe, which DISinhibits the subthalamic nucleus --> STN activates GPi --> GPi sends inhibitory signals to thalamus --> NO MOVEMENT
SUBSTANTIA NIGRA PARS COMPACTA --> promotes movement --> sends excitatory input into the striatum via DOPAMINE
Outputs promote the DIRECT PATHWAY --> increased DA will send EXCITATORY SIGNALS TO THE STRIATUM --> this will INHIBIT GPi via the direct (MOVEMENT!)
DA also BLOCKS THE INDIRECT PATHWAY --> thus this ALSO promotes movement (separate DA receptor than the direct pathway ones)
DOPAMINE PROMOTES MOVEMENT!!!!
What do typical antipsychotics do?
These drugs BLOCK D2!!!
D1 is excitatory to the striatum/DIRECT pathway
D2 is inhibitory to the INDIRECT pathway
If we BLOCK D2 --> there is no blockage of the indirect pathway --> thus, there is MORE INHIBITION OF MOVEMENT --> this is why we get the EXTRAPYRAMIDAL SYMPTOMS (Parkinsonian)
Dopamine Receptor BLOCKAGE means in increase in the production of dopamine, but it doesn't matter since the receptors are blocked!!!
D2 receptor blockage = NO INDIRECT PATHWAY BLOCKAGE = More indirect firing = MORE INHIBITION OF MOVEMENT = AKINESIA
Typical Drugs and D2 Receptor Affinity
The more potent a drug is for increasing DA neuron firing rate, the more potent it is for treating schizophrenic symptoms
This holds true for TYPICAL drugs and their affinity for the D2 receptor --> Linear relationship between therapeutic potency and D2 receptor affinity (higher affinity = higher potency!!!)
D2 receptor blockage is responsible for the EPS/Parkinsonian symptoms
Dopamine also INHIBITS PROLACTIN RELEASE (these drugs cause a lot of prolactin release!!!)
Atypical Drugs and D2 receptors
Don't fit the linear relationship between DA blockade and clinical potency
Thus, their potency is much greater than what would be predicted by their affinity for the DA receptors (don't have much affinity, but their therapeutic potency is acting like drugs that have very high affinity -- doing less, producing same effect -- why? who knows)
Have weaker affinity for D2 Receptors
Truly atypical drugs!!!!
RESPERIDONE --> pretty typical in terms of actual action --> this drug is basically a typical drug based on its affinity for blocking DA receptors --> marketed as a new generation Atypical
These drugs have effects on SEROTONIN, HISTAMINE, MUSCARINIC, and ADRENERGIC receptors, without an obvious pattern!
Dopaminergic Side Effect of TYPICAL Antipsychotics (what does D2 inhibition actually do?)
D2 are found in the BG, nucleus accumbens, pituitary, frontal lobes, and the limbic cortex
BG blockade = Parkinsonian Symptoms - Akinesia
Nucleus accumbens/Limbic system D2 blockade = Anhedonia (lack of pleasure), and Akathesia (inability to sit still - could lead to extreme anxiety and agitation if forced to sit still!!!)
Frontal Lobe D2 block = Impaired cognitive function
Pituitary Gland D2 block = Increased prolactin release
Tolerance to DA side effects
Extrapyramidal symptoms DECREASE OVER WEEKS TO MONTHS and one can develop complete tolerance to them!! Good!
Akathesia and Anhedonia vary from patient to patient (could be due to side effects or the underlying schizophrenia) -- hard to tell if tolerance develops
Cognitive and attentional dysfunction also hard to tell if they develop tolerance (could be the side effect not going away or just exacerbation of the Schizo symptoms)
There is definitely NOT TOLERANCE to the increase in prolactin release!
Other Side Effects
Remember that these drugs also block ANTICHOLINERGIC and ANTI-ADRENERGIC Receptors!
Blocking Anticholinergic = Dry mouth, constipation, urinary retention --> ALL CAN DEVELOP TOLERANCE!!! yay
Blocking Adrenergic = Sedation, hypotension, decreased SEIZURE THRESHOLD
Sedation and hypotension can develop tolerance
DECREASE IN SEIZURE THRESHOLD DOES NOT DEVELOP TOLERANCE --> so this is why patients are also put on anti-epileptics!
Therapeutic BENEFIT of DA blockage
Effect at the same brain areas that cause the side effects obviously cause the beneficial effects!
It is probably the entire network of DA neurons (blocking them) that causes the reduction in HALLUCINATIONS and DELUSIONS!
These drugs also don't work right away --> days or weeks --> same when stopping (don't go back to hallucinating right away)
Side effects like prolactin release and EPS OCCUR IMMEDIATELY
While these drugs obviously have wide ranges of potency, there is VERY LITTLE DIFFERENCE IN EFFICACY
Not that CLOZAPINE is the BEST drug for refractory/relapsed patients
Unfortunately, these do NOT treat the cognitive deficits inherent to Schizophrenia --> still feel lazy, uninterested, unmotivated --> these drugs actually POTENTIATE these effects!
Dissociation --> tasks like describing the color of the word rather than the word itself --> Schizos have a tough time with this stuff --> BUT if you take one of us who is not schizo, put them on these drugs and that task will also be hard!!!!!!
Why do we prescripe antimuscarinic drugs in Schizophrenia?
They can REVERSE/PREVENT parkinsonian symptoms!
Dopamine comes into the striatum, GABA goes to the GPi
Cholinergic neurons (excitatory) in the striatum synapse onto a GABAergic interneuron (inhibitory)
BLOCKING DA which is normally inhibitory at the cholinergic will gives LOTS of cholinergic activity --> EXCITES the GABA interneuron --> shuts down the GABA outflow from the SN --> No GABA outflow --> no inhibition of GPi = blockade of thalamus = Parkinsonian symptoms
Thus if we give an antimuscarinic, we would REDUCE the Parkinsonian symptoms!
DA is still BLOCKED, but then so is the cholinergic interneuron --> thus, the GABAergic interneuron is NOT excited and does NOT shut down the GABA outflow from the SN --> GABA inhibition is fine, inhibits the GPi --> thalamus can fire excitatory pro-movement signals to the cortex
SO, muscarinic blockade is good and bad (blocks the EPS, but also causes dry mouth, constipation, and urinary retention
Doses needed to block DA, NE, and ACh?
Remember that therapeutic dose = DA dose!!!!
Haloperidol --> DA = 1 mg, NE = 10 mg, ACh = no effect
SO, at therapeutic doses (1 mg) there is NO SEDATION (b/c it is NE mediated and 10x less than the dose needed)
BUT since there is no activity at ACh receptors, HALOPERIDOL ALSO CAUSES THE MOST PARKINSONIAN SYNDROMES (EPS)!!!! Remember antimuscarinic activity helps to reverse it, and Halo has none.
Doses needed to block DA, NE and ACh?
THIORIDAZINE and CHLORPROMAZINE
THIORIDAZINE --> DA = 50 mg, NE = 10 mg, ACh = 20 mg
Chlorpromazise --> DA = 50 mg, NE = 10 mg, ACh = 60 mg
Thioridazine is the MOST POTENT MUSCARINIC ANTAGONIST!!! At therapeutic doses (50), it is 2.5 x higher than needed for ACh effects (20). This means that at therapeutic doses, this causes the LEAST PARKINSONIAN SYMPTOMS!!!!! Muscarinic blockade is strong, so there's better reversal of symptoms.
For Chlorpromazine, at 50 mg, it is still not enough to cause ACh effect (60 mg needed) --> so it causes Parkinsonian symptoms!!
BOTH OF THESE DRUGS CAUSE SIGNIFICANT SEDATION --> remember it is NE mediated, and these drugs at therapeutic doses are 5x as high as the dose needed to sedate! Lots of sedation!!!
This is a LATE ONSET side effect
After prolonged use, 5-10% of patients will see this effect after a year (involuntary, repetitive movements) --> 30% see it after chronic use (several years)
This is actually an OVER-COMPENSATION of the BASAL GANGLIA
Remember that the Parkinsonian symptoms develop tolerance --> 30% of the time when patients get over their akinesia, the basal ganglia will OVER-COMPENSATE (upregulation of receptors in the striatum) -> thus, DYSKINESIA DEVELOPS (lots of DA receptors in striatum, and GABA receptors in the SNpr -- so the GABAergic striatum projections will inhibit the shit out of the GPe and cause LOTS of movement!!!)
Elderly are susceptible ot this problem
1/3 of patients who stop the drug STILL see this effect!!!
LITTLE OR NO EXTRAPYRAMIDAL SIDE EFFECTS!!!!!
Since there is little affinity for the D2 receptors (except in Respiridone and Olanzapine- some)
As a result, these drugs show INCREASED COMPLIANCE
Also there should be an ABSENCE of prolactin release!!!
Truly atypical!! NO D2 effects
Recommended for REFRACTORY (resistant) patients
Has anti-adrenergic action, so it is SEDATING
*****This drug is NOT FIRST LINE because of the risk of AGRANULOCYTOSIS***** (severely lowered WBCs)
Also TRULY atypical
****FIRST LINE DRUG****
Sedation via anti-adrenergic actions
Somewhat atypical (some D2)
So it has SOME extra-pyramidal side effects and also has dose-dependent prolactin release
20% have EPS at low doses
Only atypical to have prolactin release at therapeutic doses
*****FIRST LINE DRUG*******
Some weight gain
Somewhat Atypical (some D2)
Prolactin release ONLY AT VERY HIGH DOSES (above therapeutic)
****FIRST LINE DRUG*****
High incidence of weight gain!!!
Biggest issue with the atypicals?
Mechanisms may be mediated by the 5HT receptors on pancreatic beta cells (5HT regulates insulin secretion it promotes release of insulin when sugar is high -- blocking it results in diabetes/uncontrolled blood sugar!)
Results in diabetes, hyperglycemia, hypertension, dyslipidemia, abdominal obesity
VERY DIFFICULT TO REVERSE