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Drugs - Coggle Diagram
Drugs
epilepsy
CARBAMAZEPINE
Mechanism: Sodium channel blocker
Use: focal seizures (not primary generalized)
Half-life: 8-12 hours (auto-induction)
Metabolism: Hepatic (CYP3A4)
Adverse effects: hyponatraemia, rash, pruritus, fluid retention, aplastic anaemia, hepatotoxicity, GI effects, sedation, ataxia, nystagmus, depression, dizziness, diplopia, lethargy, headache, idiosyncratic
Comments: May make primary generalised epilepsy worse. May reduce effectiveness of hormonal contraception.
OXCARBAZEPINE
Mechanism: Sodium channel blocker
Use: Focal seizures (not primary generalized)
Half-life: 8-10 hours
Metabolism: Hepatic
Adverse effects: hyponatremia, rash, GI effects, nystagmus, vertigo, ataxia, idiosyncratic, sedation, headache, dizziness, and diplopia
Comments: May be better tolerated than CBZ
Related: Esclicarbazepine – once daily long-acting carbamazepine agent
VALPROATE
Mechanism: multiple - blocks voltage-dependent sodium channels, increases GABA concentrations
Use: generalized and focal seizures (better for generalized)
Half-life: 6-14 hours
Metabolism: Hepatic. P450 inhibitor
Adverse effects: GI upset, tremor, weight gain, hair loss, hepatotoxicity, thrombocytopaenia, insulin resistance, subclinical hypothyroidism
Comments: Neural tube defects – avoid in pregnancy, lower IQ in exposed babies, association with polycystic ovaries
LEVETIRACETAM
Mechanism: Binds to a synaptic vesicle protein, may modulate synaptic transmission through alteration of vesicle fusion, may indirectly modulate GABA
Use: Broad spectrum - adjunctive therapy for focal-onset seizures, juvenile myoclonic epilepsy, primary generalized tonic-clonic seizures in idiopathic generalized epilepsy
Half-life: 6-10 hrs
Metabolism: Renal
Adverse effects: Mood disturbance, behavioural disturbance, fatigue, somnolence, dizziness
Comments: Generally well tolerated, caution with pre-existing mood disorder
No drug-drug interaction
Related: Briviracetam, similar mechanism
ETHOSUXAMIDE
Mechanism: Blocks T-type calcium channels in thalamic neurons
Use: Absence seizures
Half-life: 30-60 hours
Metabolism: Hepatic - 80%
Adverse effects: nausea, vomiting, sleep disturbance, drowsiness, and hyperactivity
Comments: Rarely lupus-like reactions, SLE
LAMOTRIGINE
Mechanism: Effects on Na+ channel, may diminish the release of excitatory neurotransmitters
Use: Adjunctive or monotherapy for focal and generalised seizures, Lennox-Gastaut syndrome. Half-life: 12-60 hours
Metabolism: Hepatic
Adverse effects: Rash (Stevens-Johnson), tremor, headache, GI, insomnia, somnolence
Comments: Levels may be increased/decreased by other AEDs. Slow titration due to risk SJS, increased levels with Valproate, Clearance increased by hormonal contraception, pregnancy
TOPIRAMATE
Mechanism: Multiple mechanisms - blocks voltage-dependent sodium channels, enhances GABA activity, antagonizes NMDA–glutamate receptor, weakly inhibits carbonic anhydrase
Use: Adjunctive therapy for focal seizures, may have efficacy for other seizure types
Half-life: ~ 24 hours
Metabolism: Hepatic
Adverse effects: Sedation, cognitive slowing, renal stones, weight loss, glaucoma, paresthesias, headache, fatigue, dizziness, depression, mood problems, metabolic acidosis
Comments: Many side effects dose related
GABAPENTIN
Mechanism: Increases brain GABA levels - binds to voltage-dependent calcium channel, inhibits inward calcium currents and attenuates release
Use: Add-on therapy for refractory focal seizures
Half-life: 5-9 hrs
Metabolism: Renal
Adverse effects: sedation, dizziness, ataxia, GI upset, weight gain.
Comments: Easy to use. Also used to treat neuropathic pain. No significant drug interactions. Can make generalized seizures worse.
PHENOBARBITAL
Mechanism: Acts at GABA receptor (Cl-)
Use: generalised and focal seizures
Half-life: ~ 72 hours
Metabolism: Hepatic
Adverse effects: Sedation, respiratory depression, low vit D, Dupuytren’s
Comments: Hyperactivity in children; cheap; beware of withdrawal convulsions. May reduce effectiveness of hormonal contraception
PHENYTOIN
Mechanism: Sodium channel blocker
Use: acute focal and generalised seizures, status epilepticus
Half-life: 24 hours
Metabolism: Hepatic (CYP2C9, CYP2C19)
Adverse effects: Drowsiness, nystagmus, ataxia, rash gingival hypertrophy, increased body hair, folic acid depletion, decreased bone density, idiosyncratic, skin necrosis/pruritus with IV infusion
Comments: reduces effectiveness of most hormonal contraception
Fosphenytoin – other IV form, more rapid infusion, no skin necrosis
BENZODIAZEPINES
Examples: Midazolam, lorazepam, clobazam, diazepam, clonazepam
Mechanism: Binds to site at GABA receptor
Use: Broad spectrum. Acute seizures, Status Epilepticus
Half-life: Varies
Metabolism: Mainly hepatic
Adverse effects: Sedation, respiratory depression, irritability, ataxia.
Sudden discontinuation may lead to withdrawal seizures
Comments: Tolerance may develop, limited usefulness in chronic treatment of epilepsy
Anti- epileptic agents in women of childbearing age
Reported adverse effects: congenital malformations, intrauterine growth retardation, adverse neurodevelopmental effects
Risk affected by the type of AED and dose at conception
High risk: Sodium valproate
Moderate risk: Phenytoin, Phenobarbital, Carbamazepine
Low risk: Levetiracetam, Lamotrigine
Women of childbearing age on AEDs must be informed of:
the risk of exposure to antiepileptic agents during pregnancy
the need to use effective contraception
the need for regular review of medication and immediate consultation with a doctor if family planning wishes change
Antipsychotics
The theory is that psychotic symptoms result from an imbalance in the neurotransmitter dopamine in the brain
Some antipsychotics block D2 dopamine receptors in the brain and reduce psychotic symptoms, especially hallucinations
d2 antagonists
Adverse effects of d2 antagonists:
FIRST GENERATION ANTIPSYCHOTICS ARE ABLE TO BLOCK DOPAMINERGIC FUNCTION IN ALL PARTS OF THE BRAIN
Where schizophrenia is probably a problem in the mesolimbic and mesocortical pathways which control emotion and cognition . D2 antagonists block all pathways
Dopaminergic pathways
Tuberoinfundibular inhibits prolactin secretion (in males and females)
hyperprolactinemia
Dopamine (DA) holds a role in the regulation of prolactin secretion
Dopamine binding to D2 receptors blocks prolactin secretion
Antipsychotic drugs binding to D2 receptors can increase prolactin secretion
Caused by blocking the tuberoinfundibular pathway that inhibits prolactin secretion (in males and females)
IN MALES :
DECREASED LIBIDO AND IMPOTENCE
GYNECOMASTIA
IN FEMALES:
AMENORRHEA (STOPPING MENSTRUATION)
INFERTILITY
Mesolimbic pathway controls motivation and arousal
Nigrostriatal pathway controls motor function
However antipsychotic drugs are generally unable to treat cognitive deficits
PSYCHOSIS IS CAUSED PARTIALLY BY OVERACTIVITY OF THE DOPAMINERGIC SYSTEM. DOPAMINE AGONISTS AND DRUGS THAT INCREASE DA ACTIVITY CAN CAUSE SYMPTOMS OF PSYCHOSIS WHILE UNDER THEIR INFLUENCE (PSYCHOTOMIMETIC) IE. AMPHETAMINES & COCAINE.
Dopamine antagonists tend to relieve positive symptoms of psychosis. This is based upon the observation that the ability for a drug to act as an effective antipsychotic is directly proportional to its ability to block dopamine D2 receptors,
Adverse effects of d2 antagonists :THE PROBLEM WITH FIRST GENERATION ANTIPSYCHOTICS IS THEIR NON-SPECIFICITY. FIRST GENERATION ANTIPSYCHOTICS ARE ABLE TO BLOCK DOPAMINERGIC FUNCTION IN ALL PARTS OF THE BRAIN. Where schizophrenia is probably a problem in the mesolimbic and mesocortical pathways which control emotion and cognition
D2 antagonists block all pathways
Dopaminergic pathways
Nigrostriatal pathway controls motor function
Mesolimbic pathway controls motivation and arousal
Tuberoinfundibular inhibits prolactin secretion (in males and females)
Antipsychotics are divided into two major categories:
Typical : First-generation antipsychotics
USEFUL FOR MANAGING ONLY : POSITIVE SYMPTOMS OF SCHIZOPHRENIA
There are five subtypes of dopamine receptors numbered D1 through D5
Typical antipsychotics block the D2 (dopaminergic) receptor
Extrapyramidal Syndrome (EPS)
Pseudoparkinsonism, which resembles symptoms of parkinsonism, is a major side effect of typical antipsychotic drugs ACTING AT D2 RECEPTORS.
When patients take high-potency typical antipsychotic drugs for extended periods, EPS is more pronounced.
TIME COURSE FOR EXTRAPYRAMIDAL EFFECTS
DURING EARLY TREATMENT:
ACUTE DYSTONIA
AKATHISIA
DURING LATER TREATMENT:TARDIVE DYSKINESIA
Protrusion and rolling of the tongue
Sucking and smacking movements of the lips
Chewing motion
Facial dyskinesia
Involuntary movements of the body and extremities
Tardive dyskinesia is a serious adverse reaction that occurs in approximately 20% to 30% of patients who have taken a typical antipsychotic drug for more than 1 year.
A higher dose and longer duration of treatment increases the likelihood of developing tardive dyskinesia
The prevalence is higher in cigarette smokers.
The antipsychotic drug should be stopped in all who experience tardive dyskinesia, and another antipsychotic agent should be used.
Tardive dyskinesia can also be caused by extended use of D2 antagonists used as antiemetic drugs such as metoclopramide
Tetrabenazine (which decreases dopamine reuptake) can help in reducing some movement associated with tardive dyskinesia.
Procyclidine (a cholinergic antagonist) can help reduce EPS (especially dystonia) but is NOT effective in tardive dyskinesia
Pseudoparkinsonism
Stooped posture
Shuffling gait
Rigidity
Bradykinesia
Tremors at rest
Pill-rolling motion of the hand
Caused by blocking the Nigrostriatal pathway which controls motor function
Acute dystonia
Facial grimacing
Involuntary upward eye movement Muscle spasms of the tongue, face, neck,
and back (back muscle spasms cause trunk to arch forward)
Laryngeal spasms
The symptoms of acute dystonia usually occur in 5% of patients within days of taking typical antipsychotics.
This condition is treated with an anticholinergic drug such as benztropine.
The benzodiazepine lorazepam may also be prescribed.
Akathisia
Restless
Trouble standing still Paces the floor
Feet in constant motion, rocking back and forth
Akathisia occurs in approximately 20% of patients who take a typical antipsychotic drug.
With this reaction, the patient has trouble standing still, is restless, paces the floor, and is in constant motion rocking back and forth).
Akathisia is best treated with a benzodiazepine such as lorazepam or a beta blocker such as propranolol.
Atypical: Second-generation antipsychotics
effective treatment for both: POSITIVE SYMPTOMS OF SCHIZOPHRENIA and NEGATIVE SYMPTOMS OF SCHIZOPHRENIA.
Atypical antipsychotics are also known as Second Generation antipsychotic drugs
Atypical antipsychotics are also called Serotonin/Dopamine Antagonists
These agents are D2 and D4-dopamine and 5-HT2A receptor antagonists
ATYPICAL DRUGS AVAILABLE INCLUDE
RISPERIDONE
Disadvantages of the atypical antipsychotics: Risperidone has a tendency to increase prolactin levels and has the highest EPS risk among atypical drugs. RISPERIDONE BINDS STRONGLY TO D2 RECEPTORS AS WELL.
THIS IS THOUGHT TO BE THE CAUSE OF ITS EXTRAPYRAMIDAL SIDE-EFFECTS
CLOZAPINE: •IF ATYPICAL DRUGS DON’T WORK FOR NEGATIVE SYMPTOMS. NUMEROUS SIDE EFFECTS, SOME POTENTIALLY SERIOUS
OLANZAPINE
cariprazine
The most effective second-generation antipsychotic for treating negative symptoms is the relatively new drug Cariprazine (2015)
Cariprazine has partial agonist activity at D2 and D3
Partial agonists are useful because they can inhibit overactive systems and at the same time weakly activate underactive systems
Common adverse effects
WEIGHT GAIN
DROWSINESS
UNSTEADY GAIT
HEADACHE
INSOMNIA
DEPRESSION
DIABETES MELLITUS
Second-generation drugs were thought to have less tendency to produce extrapyramidal side effects.
However, a long-term study of olanzapine, risperidone, quetiapine and ziprasidone concluded that they too can induce extrapyramidal side effects
SECOND-GENERATION DRUGS ALSO ACT AS ANTAGONISTS AT 5HT2A RECEPTORS
THIS IS BELIEVED TO CAUSE INCREASED DOPAMINE ACTIVITY IN THE NIGROSTRIATAL SYSTEM
THIS MAY BE WHY SOME ATYPICAL ANTIPSYCHOTICS SHOW LESS EXTRAPYRAMIDAL SIDE EFFECTS
5-HT2A receptor antagonism
5-HT2A receptor antagonism may improve the negative symptoms of schizophrenia
Primavanserin, a drug recently introduced for the treatment of psychosis associated with Parkinson's disease which may be beneficial as an adjunct to other antipsychotic drugs in the treatment of schizophrenia
Primavanserin is an inverse agonist at the 5-HT2A receptor and has no activity at dopaminergic receptors.
Distinction between first- and second-generation drugs is not clearly defined but rests on:
receptor profile
incidence of extrapyramidal side effects (less in second-generation group)
efficacy (specifically of clozapine) in ‘treatment-resistant’ group of patients
efficacy against negative symptoms
Current use of antipsychotics
Atypical Antipsychotics: first line agents of choice in the treatment of schizophrenia due to better efficacy in also controlling negative symptoms and Slightly more favourable side effect profile (less EPS)
Typical Antipsychotics are less prescribed Due to being ineffective in controlling negative symptoms of schizophrenia and because of marked EPS and tardive dyskinesia
Antipsychotic drugs have severe drawbacks
•Not all schizophrenic patients respond to drug therapy.
•The 30% of patients who do not respond are classed as ‘treatment resistant’ and present a major therapeutic problem
•It is recommended to try clozapine in patients who are resistant to other antipsychotic drugs
noncompliance: Noncompliance with antipsychotics is common. This is due to numerous side effects for typical antipsychotics Even atypical antipsychotic drugs, olanzapine and clozapine cause significant weight gain and sedationThis also affects compliance
EVIDENCE AGAINST THE DOPAMINERGIC HYPOTHESIS OF SCHIZOPHRENIA
•Dopamine antagonists often relieve positive symptoms of psychosis.
•The ability for a drug to act as an effective antipsychotic is directly proportional to its ability to block dopamine D2 receptors
•But it isn’t really this simple
PCP and ketamine are NMDA antagonists and induce both positive and negative symptoms of schizophrenia
They have no activity at dopamine receptors
they produce pharmacological “models” of schizophrenia.
These agents are known as psychotomimetics.
Therefore, Drug-induced psychosis can occur without activation of brain dopamine receptors
Not all clinically effective antipsychotic drugs have high affinity for dopamine D2 receptors
Although clozapine still binds with low affinity to dopamine receptors, its clinical potency correlates with its 5HT2 receptor-blocking activity
While the D2 receptors are blocked immediately when antipsychotic drugs are first administered, the therapeutic effects of the drugs usually require several weeks to develop
ATYPICAL ANTIPSYCHOTIC DRUGS for bipolar disorder
Atypical antipsychotic drugs (e.g. olanzapine, risperidone) are second-generation drugs developed for the treatment of schizophrenia
These agents are D2-dopamine and 5-HT2A receptor antagonists
They are effective for treatment of mania NOT CYCLING
The exact mechanism of action is unknown
SELECTIVE SEROTONIN (5-HT) REUPTAKE INHIBITORS (SSRIS) e.g. ESCITALOPRAM, SERTRALINE AND PAROXETINE
SEROTONIN/NORADREN-ALINE REUPTAKE INHIBITORS (SNRIS) e.g. VENLAFAXINE AND DULOXETINE
OLDER ANTIDEPRESSANTS TCAS & MAOIS -EFFECTIVE BUT WITH SIGNIFICANT SIDE-EFFECT PROFILE > SSRIS
BENZODIAZE-PINES CO-ADMINISTERED DURING SSRI USE
Treatment of bipolar
Mood stabilizers
Lithium was the first drug used to manage this disorder. Lithium can help to stop the cycling between manic and depressed states. It controls the flight of ideas and hyperactivity. Lithium is often administered as Lithium Carbonate
Lithium has a calming effect but may cause some memory loss and confusion.
Patient compliance is often an issue
However, if the person stops taking lithium, manic behaviour may return
adverse effects and toxicity
Normal dose: nausea, vomiting and diarrhoea | weight gain | hair loss | tremor
Toxic Dose: Acute lithium toxicity results in various neurological effects, progressing from confusion and motor impairment to coma, convulsions and death
Serious renal tubular damage may occur, making it essential to monitor renal function regularly in lithium-treated patients
Thyroid enlargement, sometimes associated with hypothyroidism
Mood stabilizers are used prophylactically over long periods
Beneficial effects take 3–4 weeks to develop. Mood stabilizers prevent the swings of mood and can stop initiation of manic and depressed phases. Given in an acute attack, they are effective only in reducing mania, but not the depressive phase
Other mood stabilizers are also currently first-line drugs of choice for bipolar disorder, such as
CARBAMAZEPINE: STABILIZES THE INACTIVATED STATE OF VOLTAGE-GATED SODIUM CHANNELS
Valproic acid
Lamotrigine
Carbamazepine, valproate and lamotrogine (sodium-channel blockers with antiepileptic actions) have fewer side effects than lithium and have proved efficacious in the treatment of bipolar disorder.
They are effective in preventing the cycling between manic and depressed states
These drugs are also used in treating epilepsy
MANY ANTIEPILEPTIC DRUGS BIND TO CHANNELS IN THE DEACTIVATED STATE, PREVENTING THEM FROM RETURNING TO THE RESTING STATE. THUS REDUCING THE NUMBER OF FUNCTIONAL CHANNELS AVAILABLE TO GENERATE ACTION POTENTIALS.
SSRIs in bipolar depression
•THE USE OF ANTIDEPRESSANT DRUGS IN BIPOLAR DISORDER IS SOMEWHAT CONTROVERSIAL.
•IT IS RECOMMENDED THAT THEY ARE GIVEN IN COMBINATION WITH AN ANTIMANIC AGENT BECAUSE, IN SOME PATIENTS, THEY MAY INDUCE OR ENHANCE MANIA.
•BECAUSE OF THIS OLANZAPINE IS GIVEN IN COMBINATION WITH THE ANTIDEPRESSANT FLUOXETINE
SSRIS AND SNRIS CAN PRECIPITATE MANIA
THIS CAN OCCUR IN PATIENTS WITH UNIPOLAR (MAJOR) DEPRESSION
THIS CAN LEAD TO A MISDIAGNOSIS OF BIPOLAR DISORDER
A range of drugs are now used to control the mood swings characteristic of manic-depressive (bipolar) illness.
Mood stabilizers are used to treat bipolar affective disorder.
