Antipsychotic Drugs and Side Effects

Antipsychotic Drugs and Side Effects

Side Effects of antipsychotic drugs

D– Acute dystonia=usually appears first (hours to days), most often unilateral, neck and above

Treatment= Anticholinergic Drug (Benztropine (Cogentin), trihexyphenidyl (Artane), procyclidine (Kemadrin), Benadryl
Do not use antipsychotic drugs in elderly, glaucoma, BPH = use VALIUM for first choice (muscle relaxer)

A- Akathisias= motor internal restlessness; will commit suicide from Akathisias

Pay close attention to patient; some doctors up the dose and patient will get worse
Treatment=Antianxiety

T– Tardive Dyskinesia= Can be irreversible

With long-term potent drug therapy, dopaminergic receptors in the brain become sensitive and they lose control of motor movement
Higher in females; patient usually unaware
Can mask TD with increasing dose of medication but when TD comes back..it’s worse
Treatment is prevention…NO CURE

E- Extrapyramidal side effects Think pseudo-Parkinson’s (drug-induced Parkinson’s disease)

Bradykinesia is from drug-induced Parkinson’s because biochemical reason for Parkinson’s is an imbalance between dopamine and acetylcholine
We supply dopamine to adjust the balance of underlining pathophysiology of schizophrenia. As a result, if there is too much dopamine we bring down dopamine; but if we bring it down too far or fast you will see manifestations of Parkinson’s (PSEUDO PARKINSON’S)
See shuffling gait, mask-like appearance, cognitive rigidity, tremors
Treatment= make adjustment on dose or change to less potent agent

Neuroleptic Malignant Syndrome (NMS)

Pt has been on a drug that blocks dopamine (antipsychotic, Reglan/metoclopramide, Compazine/prochlorperazine, Phenergan/promethazine, and Inapsine/ droperidol) causing decreased dopamine receptor activation.
The dopamine has been blocked and results in a LOSS of CONTROL in the CNS and patient will manifest some of the s/s as in serotonergic syndrome
MUST DO A GOOD HISTORY TO SEE IF PATIENT IS ON ANTIPSYCHOTIC THERAPY
Hyperthermia is a big component of neuroleptic malignant syndrome, the main thing that needs to be treated during the neuroleptic malignant syndrome flare up is the body temperature with drugs like Dantrium/dantrolene.
Aggressive hydration of the body may be required to help prevent kidney damage due to the high CPK levels in the blood stream by increasing the ratio of water to CPK proteins.

Biochemical basis of Schizophrenia

Seems to involve excessive levels, activity or effect of dopamine (DA) in certain parts of the brain that control emotions, thoughts, and behavior because:
- Drugs that block DA receptors or ↓ DA levels there ↓ S/S of schizophrenia
- Drugs that stimulate DA receptors or ↑DA levels in the dopaminergic synapses there cause or worsen S/S of schizophrenia
Put a patient on levodopa or Carbidopa if they have mental changes and start hallucinating (↑ DA levels)
In Schizophrenia there is cognitive impairment with positive/negative symptoms
New drugs (2nd generation) antipsychotic are better for treating the negative symptoms (the most debilitating part of schizophrenia)
No cure: relapse is common because compliance is very hard
Very important that you make the proper diagnosis, pick the right drug, and monitor therapy

POSITIVE SIGN/SYMPTOMS SCHIZO	NEGATIVE SIGN/SYMPTOM SCHIZO
Hallucination	APATHY
Paranoia	ABULIA (lack of motivation)
Hyperactivity	ALGEDONIC (lack of pleasure)
Hearing voices	ALOGIA (short of speech)
	AUTISIUM (don’t have a good thought process)
	ASSOCIATION LOOSE (DEC FRIENDS)
	ABSENT SPEECH

Antipsychotic Drugs

Used mainly for schizophrenia, acute or long-term
Are sometimes called “neuroleptic drugs”
Are adjuncts to, not substitutes for, psychotherapy and other treatment modalities
Critical elements of treatment
- proper diagnosis
- picking the right drug out of many
- monitoring therapy
- proper, effective, support interventions
- patients must be motivated to follow-through with tx

Class of Antipsychotic

According to potency*:potency refers to size of dose, not to efficacy
- low potency (e.g., chlorpromazine)
- high potency (e.g., haloperidol)
According to chemical class
- Phenothiazine (e.g. Chlorpromazine)
- Butyrophenones (e.g. Haloperidol)

Major actions of Antipsychotic

Block dopamine, Ach (muscarinic), histamine (H1) and adrenergic (alpha) receptors in CNS and in periphery
Antipsychotic effects
- Are primarily from central dopamine receptor blockade
- Initial symptoms control may occur after a few days of therapy, but “good” control (normalization of thought processes, mood behavior) may take a month or so of continued therapy.
- These drugs aren’t permanent “cures”

Sedation from Antipsychotic

Depends on which drug is selected and dose
May/may not be desirable (depends on the Pt’s needs)
↑ potency of other drugs with CNS depressant activity

Old Drugs

Special Properties/Uses of Some Phenothiazine’s

Mostly used for nausea vomiting; because stimulation of N/V center is precipitated by DA—block DA block N/V
Low potent and weak in controlling schizophrenic
They block DA, ACE, and Alpha-adrenergic blocker capability
Cause sedation
Compazine, Thorazine, promethazine,
Phenergan (promethazine)
- useful antihistaminic (H-1 blocking),antipruritic, and antitussive (cough suppressant) effects
- used for allergy s/s, esp. when sedation is desirable
Compazine(prochlorperazine)
- useful antiemetic effects, e.g., in the setting of chemotherapy, surgery, other cases of uncontrollable vomiting
- cough suppressing effects

Other Effects of Phenothiazine’s

Shared by all drugs in class, but…
Some of the phenothiazine…
- have a greater ability than others to → certain rather unique effects
- Have special uses in nonpsychotic pts. because of these special properties/effects: antihistamine (H-1 blocking) activity; antitussive effects; antiemetic effects

Side-effects, Contraindications, Adverse Reactions of Most Antipsychotics

Incidence, severity, vary from drug to drug and are usually dose-dependent
Autonomic
- atropine-like→ “anti-SLUDGE”
- alpha-adrenergic blockade→hypotension
Other
- gynecomastia, altered menses , increase fertility, galactorrhea (secretion of milk), weakness of bone (interferes with the regulation of prolactin release=block DA and DA is the prolactin inhibitory factor)
- ↓temperature perception,→ ↑susceptibility to hyperthermia (heat stroke) or hypothermia (body cannot adapt to temperature changes…like a reptile)
- ↓seizure threshold→↑risk of seizures (esp. a problem for, but not limited to, people with epilepsy)
- allergic or hypersensitivity rxn (esp. blood ,skin ;sometimes severe)
- EKG changes, risk of potentially serious/life-threatening ventricular arrhythmias(some phenothiazine’s, not all)

Adverse Effects of Antipsychotics-I Extrapyramidal Reactions (EPS)

Brain’s extrapyramidal system is responsible for maintaining normal voluntary control of skeletal muscle activity
Extrapyramidal side effects(EPS) of antipsychotics probably due to creating excessive imbalance between DA and Ach in brain as a result of blocking DA receptors

Early-Developing EPS
(days, weeks, months)

Acute dystonia can occur within hours or a few days after starting therapy
- severe spasmodic movements of tongue, neck, back, extremities
- oculogyric crisis, opisthotonus
- may be a medical emergency
- Managed with centrally-acting antimuscarinics (e.g., diphenhydramine)
Parkinsonism tends to develop within a month or so
- including skeletal muscle tremor, rigidity, and consequences thereof
- managed with central-acting antimuscarinics
Akathisias usually develop by about a month
- Often intense subjective feeling of jitteriness, restlessness, leading to pacing about, squirming
- signs/symptoms can be confused with worsening schizophrenia

Extrapyramidal Side Effects(EPS) of Phenothiazine’s

Resemble Parkinson’s Disease s/s
- bradykinesia
- akinesias
- dyskinesia
- Akathisias
Caused by excessive↓ of DA effects in brain areas (extrapyramidal system) that regulate voluntary/involuntary control of skeletal muscle
severity, vary among the individual drugs
S/S tend to develop gradually (month, years) with the “ low potency” antipsychotics, can occur in days with “high potency” agents
May disappear w/continued tx., usually tend to worsen
May progress to→ tardive dyskinesia (irreversible)

Tardive Dyskinesia’s: Late-Developing EPS

Affects 15-20% of all patients on long-term treatment
Risks: high potency antipsychotics>low potency>>> atypical agents (lowest potential)
Typically occurs after many months, to several years, after the start of therapy
Initial s/s include choreoathetotic movements (mainly tongue and face, eventually progresses to involve extremities, trunk)
S/S probably involve central DA receptor supersensitivity
S/S irreversible, so best approach is prevention (e.g., limit antipsychotic tx. duration and dose to a minimum that is feasible)

EPS: What to Do When We Start Seeing S/S of It?

↓dose (or stop) current drugs (which will likely restore s/s of schizophrenia),or
Switch to another antipsychotic with less risk of EPS, or
“Treat” with Antiparkinson drugs, which will…
- mask/obscure mild EPS S/S but…
- won’t prevent underlying brain biochemical changes that ultimately develops to tardive dyskinesia if administration of the offending antipsychotic continues

Other Adverse Reactions

Reduction of brain’s “seizure threshold”→↑risk of seizures, esp. in patients with history of epilepsy
Neuroleptic malignant syndrome
Hyperprolactinemia: DA receptor blockade prevents normal inhibition of hypothalamic-pituitary prolactin release. Main consequences are; gynecomastia, galactorrhea, irregular menses
Avoid in women with prolactin-dependent breast cancer

What is the seizure threshold

Think of it as the amount of extra or abnormal brain electrical activity needed to “destabilize” normal neurons to start a seizure/convulsion. Exceed that “threshold”→ a seizure will develop
Phenothiazine, most other antipsychotics, and several other drugs (quite different drug classes)↓the threshold (the amount of extra or abnormal electrical activity) necessary to→ seizures, making it easier for seizures to develop
The seizure risk applies to all patients receiving phenothiazine’s, but obviously, it is of greater concern for patients who already have a seizure disorder (i.e., epilepsy)

Neuroleptic Malignant Syndrome:
A Serious and Rather Common Adverse Response

Sudden, unpredictable, rapidly worsening onset of…
- Fever
- muscle tremor→→severe muscle rigidity
- autonomic hyperactivity
- catatonia(a detached, trance-like state)
May occur after 1^st few doses or after months of tx..it’s unpredictable
Overall incidence about 1 in 5 patients, fatal about 5% of the time overall
Close assessment, early and correct intervention essential to↓ chance of serious outcomes

Neuroleptic Malignant Syndrome
(NMS) Treatment

↓Body temperature promptly with physical means and cautious use of antipyretics(ASA,APAP)
Ensure adequate hydration
Normalize BP and cardiac responses(HTN, tachycardia often occur)
Control anxiety {(e.g., IV benzodiazepines(BZDS)}
Muscle-relaxants (BZDs, dantrolene)
Block central DA receptors (with Bromocriptine)…will discuss further in Parkinson’s disease lecture

Adverse Effects of Most Antipsychotics in the Periphery

Anticholinergic side effects (muscarinic receptor blockade) may be significant
Orthostatic hypotension (alpha- adrenergic blockade)
Dermatitis, abnormal skin pigmentation, photosensitivity (skin sensitized to UV light→↑risk of sunburn)
Agranulocytosis
Severe cardiac arrhythmias (with some, not all phenothiazines)

Nonphenothiazine Antipsychotics

Older Antipsychotics

Major example is Haldol (haloperidol)– butyrophenone class, a “high potency” antipsychotic
Fast onset (< 30 min with parenteral administration),short acting
Main antipsychotic for acute S/Sx (given parenterally): it’s what you’re most likely to give in the ER for acute psychosis
Other psychiatric uses besides schizophrenia (e.g., Tourette syndrome)
Compared w/chlorpromazine (Thorazine)
- Greater risk and faster onset of EPS
- Fewer/milder autonomic SEs
- Lowers seizure threshold
Thorazine, Compazine, Haldol and Irretractable hiccups

Newer Agents of Antipsychotics

Aripiprazole (Abilify)

Olanzapine (Zyprexa)

Clozapine (Clozaril)

Ziprasidone (Geodon)

Quetiapine (Seroquel)

These agents block dopamine and serotonin; and greater chance to block serotonin than they do DA= they tend less DATE and NMS side effects
Older drugs have greater chance to have DATE
Now see metabolic syndrome X = DKA (will present in ER)

Most common in the following drugs (Don’t have a COW)
Clozapine (Clozaril)
Olanzapine (Zyprexa)
Weight coming up as a result of = Quetiapine (Seroquel)
Monitor blood sugar, blood pressure,daily weight, triglycerides and lipids on regular basis

Clozaril (clozapine)

ONLY USED FOR VERY RESISTANT SCHIZO B/C one of most dangerous SE is agranulocytosis
Antipsychotic action mainly from CNS blockade of 5-HT (serotonin) receptors
Very weak DA receptor blockade accounts for very low incidence of EPS (DATE)
Few significant peripheral autonomic side effects
May also cause:
- Very high Anticholinergic profile (Increase spit and bedwetting)
- hyperglycemia (→prediabetic or true diabetic state)
- high incident to increase seizures threshold more than other antipsychotics
- myocarditis
- significant weight gain (appetite stimulation) (esp.; Clozaril, Zyprexa)
Main and most serious adverse response (Clozaril):↓↓WBC count, risk of serious infection, and potential agranulocytosis(fatal)-requires normal WBC counts (blood test )before each prescription can be refilled
PAY CLOSE ATTENTION TO WBC AND ANC absolute neutrophil count
The ANC refers to the total number of neutrophil granulocytes present in the blood.
- Normal value: 1500 cells/mm3.
- Mild neutropenia: 1000 – <1500/mm3.
- Moderate neutropenia: 500 – <1000/mm3.
- Severe neutropenia: < 500/mm3.
Neutrophils= major WBC that play resistance to disease state
Make sure someone can bring pt to get lab work