Toxicity of CNS Drugs: Anticholinergics, phenothiazine, TCA (CA) - PowerPoint Presentation

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Toxicity of CNS Drugs: Anticholinergics, phenothiazine, TCA (CA)

Anticholinergic:

Poisoning with these drugs is less common than it was in former years. Because these drugs are not used as frequently in drug therapy. Ex.

Belladonna alkaloids and related atropine- like drugs have been replaced with a different class of less toxic drugs H

2

antagonist, PPI. for treatment hyperacidity and

hyperspastic

disorders.

Atropine, hyoscyamine and similar drugs were formerly included in numerous cold & asthma remedies and antidiarrheal. Their use in a medicine have been shown to be dangerous, and they are no longer used for these purposes.

Still anticholinergic poisoning may come from other drugs having anticholinergic component. ex antihistamine, phenothiazines, TCAs.

Infants and children are essentially vulnerable to anticholinergic effects of these drugs even from ophthalmic preparations. 

II. TCA:

used in Neuropathic pain, migraine, enuresis, attention deficit hyperactivity disorder drug therapy since late 1950s. for treatment of depression. They are 3-ring structure substances or 4-ring referred to as tricyclic TCA., cyclic antidepressants CAD.

Amitriptyline:

To which most reported toxicities occur. In a study of 165 person wish TCA-poisoning admitted to one hospital in 2 years; 62% involved this drug, while 15% for doxepin, 10% imipramine, 8% desipramine and the rest represented other TCA.

Toxicities result from both accidental, deliberate overdoses.

Toxicities with TCA unlike that of antipsychotic in that they are life threatening.

Most poisonings involve multiple ingestions with one or more other drugs ethanol, diazepam, propoxyphene, codeine additional symptoms & problems encountered in treatment.

Many patients who take TCA or PTZ have a high risk for suicide.

Toxicity with TCA may be due to their low margin of safety over antipsychotics.

TCA are rapidly absorbed, tightly bound to plasma

ptns

(a

1

-acid

glycoprotein. & tissue, EHC, children are sensitive to CV-complication & seizure activities.

Large variations exist in adult toxic doses.

Deaths has occured in adults with 500 mg (imipramine).

Other survived doses >100 mg, this may be related to variable physiological conditions of the patients. ex heart diseases.

Mechanism of CA-toxicity:

CA- decrease the action of Ach centrally & peripherally.

Signs & symptoms:

Chorea: due to imbalance in Ach & dopamine levels at receptor site in basal ganglia.

Imipramine has a dual action depresses Ach & enhance dopamine levels.

Myoclonus: due to 5-HT uptake with its increase in the synapse.

Respiratory dysfunctions & disturbances in body temperature due to direct action on respiratory

centre

in the medulla and thermoregulatory site in hypothalamus and decreased sweating (due to anticholinergic effects).

Reticular activating system may be due to anticholinergic effects of TCA result in depression coma.

Characteristics of TCA- toxicity:

a. CNS:

Agitation, delirium, confusion, disorientation, ataxia, visual & auditory hallucinations, loss of short–term memory, seizure, respiratory difficulties & coma.

The onset may be rapid within an hour of ingestion.

Hyper or hypothermia: imipramine (hyperthermia), amitriptyline

(hyperthermia) due to CNS- depression.

Maprotiline – seizure, Desipramine has less effect on seizure threshold, amoxapine overdose less CV- toxicity while more incidence of seizure than other (CADs).

b. Anticholinergic effects:

Quantitative differences exist among anticholinergic actions of various TCAs:

Amitriptyline has more anticholinergic. whereas desipramine has the least amount.

Mydriasis, blurred vision, tachycardia, vasodilation, urinary retention, decrease GIT motility, decrease bronchial secretions, dry mucous membranes & skin.

c. CV- effects:

TCA- produce prominent pharmacologic action on CV-system even in therapeutic doses. In toxic doses the major symptoms are:

Tachycardia, arrhythmias, intraventricular conduction disturbances, hypo- or hypertension. (these effects may be due to:

Anticholinergic effects

Quinidine like effects

Inhibition of NE-uptake at adrenergic synapse.

These sings &symptoms may be seen on ECG as prolongation of QT- intervals, widening of QRS,

Blood concentration ≥100 mg/dl fatal.

Tachyarrhythmia: due to their

vagolytic

effects.

specific effects: atrial tachycardia, fibrillation, flutter, AV-block, ventricular tachycardia.

Tachycardia: decrease C.O.P. & B.P.

Quinidine like action: decrease AV-conduction velocity, establish conditions favorable for re-entry ventricular arrhythmias.

Complete heart block may follow toxic doses of TCA.

Inhibition of NE or 5-HT reuptake into nerve terminal in the sympathetic –NS leading to accumulation within the synaptic area for long time & dominate sympathetic tone.

* Arrhythmias may occur secondarily to depressed respiration or metabolic acidosis.

B.P :

Hypertensions:

Due to decrease NT-reuptake into sympathetic neurons giving an effect on both alpha & beta-receptors.

* α1-↑ PVR & beta ↑ heart rate thus ↑ B.P.

The major termination of NE is by reuptake & less will be by COMT, MAO.

* peripheral α1- bk. leading hypotension (most common signs).

Management of TCA- poisoning:

TCA- poisoning is a serious medical emergency.

CV: patient must be monitored for CV& respiratory.

Cardiae resuscitation must be available especially within the 1-st 12 hour even if the signs appear normal the chance for delayed life- threatening CV-toxicity remains to be unexpected. Also, CV- complications may be delayed as long as 6-days even after clinical improvement was noted.

* Physostigmine:

Can produce signification bradycardia & asystole so it is no longer recommended for routine CA- poisoning management.

Also, it has many C/I: asthma, CV- diseases, gangrene, mechanical obstruction of GIT or urogenital tract.

* Phenytoin:

(NaHCO

3

, lidocaine)

For arrhythmias, enhance AV-conduction, reverses quinidine like effects of CA.

Note: class IA (quinidine, procainamide, disopyramide, moricizine) or class IC (flecainide, propafenone) are C/I similar pharmacological actions.

* Propranolol:

Slows heart rate & reduces myocardial susceptibility to ectopic foci. Also, C/I or used with caution in:

Asthma, CHF, heart block,

Quinidine, procainamide are C/I: ↓ AV- conduction.

* Dobutamine or dopamine

:( NE-preferred) or volume expansion with isotonic saline should be used cautiously to treat hypotension.

* Indirectly acting sympathomimetic

:

mephentermine

or metaraminol act by stimulating NE- release are not indicated because of inhibition of their uptake in adrenergic neurons by CA.

2. Once the patient has been stabilized, gastric decontamination should be undertaken using ipecac for recent ingestions. Gastric lavage is recommended even several hours after ingestion because of anticholinergic effects.

3. AC: MDAC: Effective for TAC & their metabolites (active), interrupt EHC.

4. Diuresis, hemodialysis, peritoneal dialysis not recommended become of high

Vd

, tight plasma protein binding, low H

2

O solubility.

5.

Haemoperfusion

: only in severe intoxication.

6. Hyperthermia & fever treated with ice- H

2

O sponging or immersion in cold water

7. Seizure: diazepam. If failed; barbiturate or propofol. Usually seizure with CA is brief and may stop before treatment can be initiated.

III. Antipsychotics,

antipsychotropic

, neuroleptics, major tranquilizer, psychotropic, ataractics:

Morbidity & mortality due to pure antipsychotic poisoning are low, but in many conditions, it represents mixed poisoning involving combination of different drugs.

There are many reasons for large numbers of poisoning:

Widely prescribed.

Mental patients institutionalized receive these drugs are outpatients.

All psychotic patients are at greater risk than general population for suicide attempts.

Many preparations resemble smooth candy confections & are attractive for children.

Their anticholinergic & sedative effects may be additive to other anticholinergic & sedative drugs taken concomitantly.

Mechanism of antipsychotic drug toxicity:

Blockade of dopamine-receptors D

2

in limbic system & bosal- ganglia result in decrease cell firing & decreased synthesis of catecholamine in CNS.

* CNS- effects:

Sedation, muscle relaxation, lowering of seizure threshold, anxiolytic activity, depression of vasomotor reflexes.

* peripheral actions:

Blockade of α1- receptors, anticholinergic, antihistaminic, adrenergic action secondary to inhibition of neurotransmitter reuptake.

Life threatening neurological emergency with D

2

-antgonist, or within withdrawal of D-agonist like L-Dopa.

Risk- Factors:

Young, male, ECF- contractions, potent antipsychotic, depot preparations, cotreatment with Li+, combination with other agent rapid increase in dose.

Characteristics of poisoning with antipsychotic drugs:

CNS:

All levels of the CNS are affected, particularly limbic system, hypothalamus, basal ganglia.

Amygdala (part of limbic system) stimulated by large doses result in lowering of seizure threshold EEG resemble epilepsy.

Mostly with aliphatic PTZ than piperazine or

thioxanthenes

.

* Reticular activating system (RAS): control overall activity of CNS & control wakefulness. Antipsychotic overdoes depress RAS result in sedation, an hour after ingestion.

* Coma: especially in children, restlessness, tremors, spasms dystonic reaction.

* RAS- also modulate respiration, higher dose of antipsychotics may cause depression of respiration.

* Vasomotor & temperature regulation by hypothalamus may be affected at higher doses due to vasodilation & hypotension.

* Hypo or hyperthermia, haloperidol cause hypothermia, other may cause increase in body temp. 41°C

* neuroleptic malignant syndrome.

2. Extrapyramidal system (EPS)

Antipsychotics block dopamine receptors in the striatum within basal ganglia leading to EPS- at therapeutic doses which may became prominent in overdoses. (10% of patient).

Atypical antipsychotics: are less prone to produce EPSs, because they are inhibitors of 5-HT

2A

receptors.

Involuntary movement: (tremor, tics, athetosis), voluntary movement akinesia, change in muscle tone: rigidity, dystonia.

3. Autonomic NS.

Potent anticholinergic and α1-blocking activity.

Anticholinergic potency is variable: thioridazine has greatest activity, chlorpromazine intermediate, piperazine & haloperidol have the least.

α1-blocking: also, different: hypotension with reflex tachycardia. Trifluoperazine > chlorpromazine >thioridazine> fluphenazine > haloperidol.

4. Cardiovascular system:

Due to central & peripheral effects:

Orthostatic hypotension may be due to blockade of vasomotor Centre & α1-blocking in peripherally.

Quinidine like effects on heart result in decreased AV- conduction, heart block, ventricular arrhythmias.

ECG: prolonged PR, QT – intervals, blunted T-wave depressed ST- segment.

Thioridazine produces greater T- wave abnormalities.

Children are more susceptible to antipsychotic cardiotoxicity.

Greater risk are patients with hypokalemia, and/or preexisting cardiovascular disease.

Deaths may be due to vent. fibrillation or cardiac arrest that may be as rapid as 3-5 hrs. of ingestion.

Management of poisoning with antipsychotic drugs:

antipsychotic drugs have a relatively wide therapeutic margin ex. Adult therapeutic dose range 25mg -5000mg chlorpromazine, 0.5-30 mg haloperidol.

Chlorpromazine minimum serve toxicity 1.4g. Serve intoxication 6.2g. Survival was reported after 10-30 g.

Clinical assessment, stabilization of vital signs, severe hypotension may produce shock → elevation of B.P, maintenance of normal blood flow must be done immediately. Fluids, NE, dopamine (preferred over NE because of selective cardiac action).

Phenothiazines are radiopaque, tablets can be visualized in GIT.

Phenytoin, lidocaine: control arrhythmias decreases automaticity and conduction velocity

Quinidine & procainamides are C/I.

4.

Phenytoin for (moderate) seizure, if not controlled diazepam should be added. Barbiturates are not recommended due to respiratory suppression.

5. Physostigmine: is the drug of choice for treating anticholinergic toxicity. Used only for:

Unstable supraventricular tachycardia.

Ventricular arrhythmias unresponsive to phenytoin, lidocaine.

Atropine: for the control of physostigmine overdose.

6. Decrease absorption: emesis or large + saline cathartics.

AC: MDTC

Forced diuresis, dialysis,

haemoperfusion

are not effective.