Category: 5. Drugs acting on central nervous system

Due to decrease in excessive cholinergic activity (due to decreased dopamine) always given in combination with levo dopa.

Also given in drug induced Parkinsonism.

Never give dopamine agonist drugs as receptors are already occupied.

Adverse effects

1. Dryness in mouth
2. Decreased lacrimation
3. Blurred vision
4. Constipation
5. Difficulty in urination
6. Tachycardia

In Parkinson’s disease excessive salivation occurs, so these drugs have more effects on tremors and rigidity, but no effect on hypokinesia.

Always given in combination with dopamine agonists in Patients having parkinsonism. In drug induced, can be used alone.

Start at lower dose, which may be increased.

Antihistamines and anti-cholinergics

Due to anticholinergic effects, antihistamines are combined with anticholinergics.

Ergot Derivatives

Bromocriptine

Most important and commonly used derivative of ergot alkaloid.

Mechanism of Action

Same as that of levo dopa. Acts as an agonist on D2 receptors.

Pharmacological Actions

CNS

Same as those of levo dopa. As D2 agonist, improvement in symptoms, increased motility and improved posture.

Endocrines

1. Decrease release of prolactin, so used in hyperprolactenemia
2. Decrease in GH in acromegaly, increase in normal

Reticular formation

arousal of CNS, so used in hepatic encephalopathy.

Uses

1. Parkinsonism

Second line drug. Given to patients who cannot tolerate levo dopa or those suffering from response fluctuation (on off phenomenon). In such cases used with levo dopa, otherwise has no advantage over levo dopa.

2. Prevention/suppression of lactation

Especially after abortion, delivery. Since drug also has cardiovascular effects, it is given carefully in those suffering from cardiovascular diseases. Other drugs are preferred like Lisuride.
3. Hyperprolactinaemia
4. Acromegaly

As causes a decrease in release of GH.
5. Benign breast disease

Patients suffering from pain in breasts (myastalgia).
6. Hepatic encephalopathy

Reticular arousal, so given.

Adverse effects

Similar to levo dopa.

1. Vomiting due to effects on CTZ
2. Due to dopamine agonist effect on CNS –tachycardia, arrhythmias and hypertension
3. CNS effects –esp. when given in combination with levo dopa.
4. Can cause severe Postural hypotension. In some even on very first dose. Patient may faint. So first test dose is given, about 1 mg, to see whether hypotensive effects appear or not, given especially after food or when lying down to avoid 1^st dose hypotensive effects.

Drug interactions

Metoclopramide & Domperidone (anti-emetic) decrease gastric emptying, cause a decrease in hypoprolactemiac effect.
Dose: start at low dose of 1-1.25mg, which may be increased to 2-2.5mg ultimately upto 20-80mg, depending upon response of patient.

Lisuride

Although dopamine agonist, used in patients suffering from cardiovascular diseases, otherwise has no other advantage.

Pergolide

Persons who cannot tolerate bromocryptine or have excessive vomiting can be given. It acts both on D1 and D2 receptors.

The advantage is that adverse effects are less than levo dopa and bromocryptine. Half life is 2 hours. Also given orally.

Non-Ergot Derivatives

Pramipexole

Mainly act on D3 in addition to D1 and D2. Drug is given orally. Most is excreted unchanged in urine.

Half life is 8 hours. Bioavailability is 90%.

Important aspect is that it also has anti-oxidant effects. It increases the removal of hydrogen peroxide from brain, so has neuroprotective/neurotrophic effect.

Adverse effects

Same as those of levo dopa including vomiting, hypotension, insomnia, but less than bromocryptine and levo dopa.

Dose is started at 0.125 mg up to 0.5-1.5 mg.

Ropinirole

Mainly act at D1 and D2 receptors. Biavavailability is less than prmipexole when given orally (55%). Metabolized in liver. Half life is 6 hours.

Uses are similar to pramipexole. Given in combination with levo dopa or instead of bromocryptine.

Apomorphine

Oder drug, used as emetic drug. It is chemically a derivative of morphine. In actions resembles dopamine and has both D1 and D2 agonist effects.

Advantages

Given subcutaneously in patients suffering from on off phenomenon.

If drug is given orally, it takes 45-60 minutes, here subcutaneously used, so early recovery.

It is administered for at least 30 days.

Nausea is very troublesome, remedy is pre-treatment with Trimethobenzamide (300 mg T.D)

Selective COMT inhibitors

Catechol-o-methyl transferrase performs little methylation of levo dopa, when metabolized by it, 3-o-methyl dopa is formed.

When drug is given with dopa decarboxylase, more levo dopa is methylated into 3-o-methyl dopa, which can interfere with entry of levo dopa in brain, as competes.

Patients taking dopa decarboxylase inhibitors, decreased response is observed. It can be given to decrease levels of 3-o-methyl dopa. Half life is 2 hours. Usually given in combination with levo dopa when decreased response occurs, so person is taking dopa decarboxylase inhibitors.

Tolcapone	Entacapone
More potent	Less potent
Hepatotoxic	Not so
Both central and peripheral actions	Only peripheral action
Less dose required	More dose required
Less preferred	More preferred

MAO-B Inhibitors

Deprenil acts on MAO-B, causing decrease in metabolism of dopamine, increasing the levels of levo dopa. Always given in combination with levo dopa.

Given especially to patients suffering from fluctuations in response, esp. end of dose akinesia, treatment is facilitated when drug is combined. Dose is 5-10 mg.

L-dopa when given with non selective MAO inhibitors, may cause hypertension crisis (due to peripheral action of norepinephrine) so are not used together.

Peripheral DOPA decarboxylase inhibitors

Most of the DOPA is decarboxylated peripherally, only 1-5% enters the brain. To counter peripheral decarboxylation, inhibitors are given.

They inhibit peripheral decarboxylation, thus more enters brain.

When given with levo dopa, more of it enters brain.

Dose can be reduced 25-75% when given in combination.

Adverse effects include dyskinesias.

Dopamine Releasing Drugs

Amantadine

Also an anti-viral drug, used for prevention of H2 influenza. Also has dopamine agonist effects.

Mechanism of Action

1. Increases synthesis and release of dopamine from dopamine nerve endings.
2. Also inhibit reuptake of dopamine by dopaminergic fibers. So increase the bioavailability of dopamine at nerve endings
3. Also has anticholinergic effect, which contributes to Parkinson’s disease.
4. Also has NMDA receptor blocking effect.

Due to anticholinergic effect, used for treatment of drug induced Parkinsonism. Usually used in combination with levo dopa.

In very old patients there is decrease in effects of amantadine. As mainly acts by release of dopamine, in old age fibers degenerate. In long standing disease, effects are low, as fibers are already degenerating.

Pharmacokinetics

Well absorbed from oral route. Mostly excreted unchanged in urine. Half life is 2-4 hours.

Adverse effects

1. Anxiety
2. Insomnia
3. Cardiac effects
4. Ankle edema
5. Hallucinations
6. Difficulty in concentration
7. Tachyphylaxis due to depletion of neurotransmitter stores.

Dose

Started at low dose of 100 mg. increased to 100 mg twice or thrice daily.

Parkinson’s disease is chronic progressive disease, only symptoms can be treated. As time passes, since it is progressive, ultimately complete degeneration of dopaminergic fibers occurs. Drugs then become less effective.

Main drug used is levo dopa. It is chemically precursor of dopamine and is a derivative of amino acid L-tyrosine. Chemically it is dihydroxy phenyl alanine.

Mechanism of Action

Since it acts mainly by increasing the stores of dopamine in the brain, as the drug is converted into dopamine by dopa decarboxylase, which is responsible for the effects.

There are five types of dopamine receptors: D1, D2, D3, D4, and D5.

Mainly D2 receptors are involved. To some extent D1 act as well.

D1 are linked with adenyl cyclase and act by increasing cAMP levels.

D2 rather inhibit adenylate enzyme. They decrease the cAMP and inhibit the activation of indirect pathways, which may cause decrease in dopaminergic activity.

Increased cAMP leads to activation of direct pathways. When direct pathways are stimulated, increase in dopaminergic activity occurs.

Both are beneficial.

Pharmacological  Actions of Levodopa

1. CNS

Main effect. When converted into dopamine, increase in dopaminergic activity occurs, leading to improvement of symptoms of Parkinsonism. It:

1. Decreases tremors
2. Decreases rigidity
3. Improves hypokinesia/akinesia
4. Improves posture
5. Improve facial expression (mask like in parkinsonism)
6. Dopamine receptors are also present in CTZ, when they are stimulated vomiting occurs. This is the main adverse effect. To avoid this, anti-emetic is used. After prolonged use, tolerance to this effect develops.

Domperidone or Cyclizine as antiemetic can be given 30 minutes before L-dopa if required

2. CVS

Most DOPA is decarboxylated in periphery before entry into brain. When dopamine levels are increased in periphery, alpha and beta receptors are stimulated leading to:

1. Increase in heart rate
2. Tachycardia
3. Increased blood pressure
4. Sometimes postural hypotension occurs as well.
5. Dopamine also causes vasodilatation in splanchnic blood vessels
6. Also cause a decrease in central sympathetic outflow due to alpha 2 receptors negative feedback, decreasing norepinephrine.
7. Endocrine

Dopamine causes decrease in release of prolactin, also used in hyperprolactemia.

Also decrease secretion of GH in acromegaly

GH increases in normal persons.

Pharmacokinetics

a. Absorption

Well absorbed after oral administration from proximal part of small intestine by active transport mechanism. Absorption decreases

1.  In hyperacidity
2. Protein rich food, because of amino acids competes with L-dopa for absorption
3. Drugs which decrease gastric emptying (domperidone)

Drug is metabolized in liver. Homovalenic acid is the ultimate metabolite of enzymes COMT and MAO.

b. Peripheral metabolism

Since most of drug is decarboxylated peripherally, only 1-5% levo dopa enters brain.

To avoid this effect, dopa decarboxylase inhibitors are used to prevent peripheral conversion into DOPA.

Excretion occurs mainly in bile

c. Half life

Half life is only 1-3 hours, it is shorter after oral absorption

Peak plasma concentration occurs after about 1 hour.

d. Interaction with pyridoxine

Therapeutic uses

1. Parkinsonism

Drug of choice. start with low dose, gradually increased after 2-4 days. Dose is limited when:

1. Symptom alleviate, increase in activity is observed
2. Adverse effects are seen

Once improvement occurs, patient is maintained on drug for 4-5 years. After this decline in response occurs due to:

1. Development of tolerance
2. Disease is progressive –degeneration of dopaminergic fibers occurs

Then other agonists are used, or drug is combined with them.

2. Hyperprolactinaemia

Hyperprolactinemia leads to glactorrhoea and infertility due to decrease in gonadotrophic hormones. Can be used in such patients, drug of choice is bromocryptine.

3. Hepatic encephalopathy

In coma due to hepatic encephalopathy, as increased stimulation of CNS arouses. Thus it is useful in patient of hepatic failure and encephalopathy.

Adverse effects of levodopa

These are the exaggeration of pharmacological actions.

1. GIT

• Due to effect on CTZ severe vomiting occurs, anti-emetic drug is given 30 minutes before.

Peripheral D2 antagonist is used. Central D2 antagonists (Metoclopramide) is never used as will further aggravate the situation.

• Anorexia
• May also cause increase in symptoms of peptic ulcer.

2. CVS

Due to peripheral conversion into dopamine:

1. Heart-beta 1 effect, increased heart rate, tachycardia, palpitations, cardiac arrhythmias
2. Postural hypotension

3. Dyskinesias

Very important adverse effect, related to dose. As drug has to be given for prolonged period, an increase in dose leads to development of dyskinesia or involuntary movements. These include:

1. Chorea
2. Ballismus
3. Athetosis
4. Dystonia
5. Myoclonus
6. Faciolingual tics
7. Grimacing
8. Head bobbing
9. Oscillatory and rocking movements of arms, legs or trunk

Treatment

1. lowering dose of levodopa
2. using levodopa alone not in combination
3. drug holiday, 3-21 days until symptoms disappear
4. D₂ receptor antagonists (oxiperomide and tiapride)

4. Behavioral effects

Due to effects on CNS. These are opposite to Parkinson’s disease and include:

1. Hallucinations
2. Psychosis
3. Mania
4. Anxiety

To control these effects, dopamine antagonists are not given, as relapse of disease might occur.

2^nd generation antipsychotics are used including Clozapine and Olanzapine, which have less extrapyramidal effects.

5. Ocular effects

Because of conversion into dopamine, sympathomimetic effects-mydriasis

6. Blood

1. Dyscrasias
2. Positive Coomb’s test

7. Fluctuation in response

Important, as improvement in symptoms occur with a dose on which the patient is stabilized, after 4-5 years, conditions begin to decline again, which are manifested in various forms:

a. Early morning akinesia

Before intake of drug in morning symptoms of Parkinson’s disease appear.

b. Peak dose dyskinesia

When drug levels reach maximum value, dyskinesias and involuntary movements might occur.

c. End of dose deterioration

d. On-off phenomenon

Most important and troublesome for the patient, as fluctuation in the response occurs. During on period, no symptoms are present, while during off period, they reappear.

Reasons

1. After prolonged administration, decrease in absorption of DOPA occurs.
2. Decreased entry of levo dopa in brain occurs
3. Less conversion of levo dopa to dopamine due to decreased activity of dopa decarboxylase in brain

This can be treated by various means:

1. As decreased absorption occurs, levo dopa is not given with food. Timing of giving drug is adjusted esp. with protein rich food.
2. Decrease interval between doses, hourly or two hourly basis.
3. Add other dopamine agonists drugs with DOPA like bromocryptine, apomorphine.

8. Endocrine System

1. Decreased prolactin secretion
2. Increased growth hormone secretion in normal
3. Decreased growth hormone secretion in acromegaly.

This is due to over activity of tuberoinfundibular pathway, leading to increased dopamine.

9. Reproductive System

1. Priapism (painful erection and tenderness). It is one of the most common symptom of sickle cell anemia. Treatment is intra-cavernous injection of beta blockers.
2. Brown discoloration of vaginal discharge.

10. Metabolic

1. Increased blood urea and nitrogen
2. Increased ALT and AST
3. Increased ALP
4. Increased bilirubin

11. Miscellaneous

1. Darkening of urine with secretions
2. Darkening of skin due to increase in melanin and increased oxidation of catecholamines to melanin
3. May be abnormality of taste and smell
4. Increase in incidence/precipitation of gout in certain patients
5. In those prone to psychiatric illness, increased incidence of schizophrenia

12. Fenton’s Reaction

When L-dopa is given, it is converted into dopamine, which reacts with oxygen in presence of:

12. MAO b
13. Aldehyde dehydrogenase

The product of this reaction is DOPAC and hydrogen peroxide. Hydrogen peroxide reacts with iron (abundant is substantia nigra) producing oxidative stress, leading to rapid degeneration of dopaminergic neurons producing ‘end of dose phenomenon’.

Central adverse effects include dyskinesias and behavioral effects.

Contraindications

1. Given carefully to patients suffering from psychosis or psychiatric illnesses
2. Glaucoma
3. Cardiovascular diseases
4. Renal impairment

Dose

Start at low dose 250 mg/day in divided doses. It may be increased to 2-8 grams.

Drug Interactions of levodopa

1. Pyridoxine (vit b6)

Decrease in activity of levo dopa in these patients (patients suffering from T.B, taking isoniazid and bit B6)

Those taking vitamin B complex

As dopa decarboxylase is pyridoxine dependent, increased conversion to dopamine in periphery leads to decrease in response.

2. Antipsychotics

Levo dopa antagonizes the effect of antipsychotics

3. Nonspecific MAO inhibitors

Acts on both MAO  A and B.

Decreases metabolism of catecholamines and dopamine, leading to hypertension, cardiac arrhythmias

4. Anticholinergics

Although given but in high doses or for prolonged periods, can decrease gastric emptying, decreasing motility and absorption of levo dopa.

5. Sympathomimetics

Effect is potentiated. Sometimes patient does not know, because over the counter preparations like nasal decongestants (ephedrine, adrenaline) can aggravate the effects.

Parkinson’s disease/Parkinsonism

Disease of old people after about 60 years of age. 1 in 200 elderly are affected. Mainly due to decrease in dopamine in dopaminergic pathways:

1. Nigrostriatal
2. Mesocortical
3. Mesolimbic
4. Tuberoinfundibular

Also present in the chemoreceptor trigger zone.

Two neurotransmitters are involved:

1. Dopamine -inhibitory
2. Acetyl choline –excitatory

Decrease in dopamine and increase in cholinergic activity leads to various symptoms.

Features

1. Tumors at rest
2. Rigidity
3. Hypokinesia/bradykinesia (difficulty in initiating movement) /akinesia
4. Flexed posture
5. Short steps
6. Excessive salivation due to cholinergic fibers

Etiology

• Idiopathic nigrostriatal degeneration most common
• Infections e.g. encephalitis
• Atherosclerosis (CVA)
• Drugs

1. Antipsychotics –block dopamine receptors
2. Reserpine
3. Alpha methyl dopa

• Poisoning (Wilson’s disease) –deposition of copper in basal ganglia

Classification

Drugs that increase dopaminergic activity

Dopamine precursor

Levo dopa

Peripheral dopa – decarboxylase inhibitors

Sinemet: levodopa+carbidopa (10:1)

(100 -250mg)          (10 -25 mg)

Madopar: levodopa+benserazide (4:1)

(50 -200mg)     (12.5 -50 mg)

Dopamine releasing drugs

Amantadine (100mg)

Dopamine receptor agonists

Ergot derivatives

Bromocriptine

Lisuride

Pergolide (0.5mg – 3mg/day)

Non ergot derivatives

Pramipexole (d3 agonist) (0.125mg – 0.5 -1.5mg)

Ropinirole (0.25mg – 2 – 8mg)

Apomorphine (2 – 8mg)

Selective COMT inhibitors

Tolcapone (100mg tds) nitrocatechol derivative

Entacapone (200mg tds)

MAO-b inhibitors

L-deprenil (selegiline) (5 – 10mg)

Rasagaline

Drugs that decrease cholinergic activity

Central anticholinergics

Benzhexol (2-20mg)

Benztropine (0.5 mg – 6mg)

Procyclidine, (7.5 – 30 mg)

Biperiden (1mg – 20 mg)

Antihistamines with anticholinergic activity

Orphenadrine (200 – 400 mg)

Diphenhydramine (25 – 100 mg)

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Levo Dopa

Peripheral DOPA decarboxylase inhibitors and Dopamine Releasing Drugs

Dopamine Receptor Antagonists

Drugs Decreasing Cholinergic Activity

The clinical uses of antidepressants include the following:

1. Depression

Mild to moderate. Normally advised psychotherapy, cognitive, behavior therapy. If depression is more, advised antidepressants.

If acute therapy is required, effects of antidepressants are not seen for 1-2 months. A trial of 2-3 months has to be given. If no effects appear after 3 months, doctor may switch to another one or a combination. After patient is stabilized, treatment is given for at least 6-12 months. If not given for long period, there are higher chances especially of relapse. At times recurrences of attacks are seen in sensitive patients.

Maintenance therapy is prescribed for longer duration. Studies have not been done for more than 5 years.

In some forms of bipolar disorders, antidepressant use is controversial. In this type, if antidepressant is taken, patient may go into mania. Its better to give mood stabilizing agent.

Choice of antidepressant depends on severity of disease and patient’s profile.

2. Anxiety disorders

Most commonly clinically significant are:

1. traumatic stress,
2. OCD –strong urge to do something repeatedly
3. generalized anxiety disorders –chronic state anxiety, even without existing cause
4. panic disorder -patient avoids situations he may feel might go into panic
5. social anxiety disorder –patient avoids social interaction

most commonly SSRI or SNRI and benzodiazepines are given. Benzodiazepines are usually the first line of treatment, as acute relief of symptoms occurs, but for longer term treatment tolerance and dependence occurs so SSRI and SNRI are drugs of choice.

In OCD along with these Chlorpromazine is prescribed

In social anxiety Venlafaxine is found to be effective.

3. Pain disorders

Ascending cortical pathways involving monoamines, responsible for some role in analgesia. Antidepressants have analgesic property in addition. Given in chronic pain associated with depression.

Antidepressants are not given in normal routine as painful, non-responding debilitating pain known as neuropathic pain of DM, post hepatic neuralgic pain, trigeminal neuralgia, chronic backache. Most commonly TCAs and SNRI are used.

Duloxetine is well known for this condition.

4. For premenstrual dysphoric disorders

Becomes irritable and change in mood occurs, which is usually mild. In some, troublesome signs, symptoms appear like fatigue, irritability, depression, seen in 2^nd half of menstrual cycle (luteal phase), related somewhat to increased levels of progesterone.

SSRI – Fluoxetine has been used successfully, used either continuously or for these two weeks of luteal phase. Both ways equally effective.

5. Smoking cessation

Bupropion, has different mechanisms:

1. Nicotine like action, norepinephrine, dopamine
2. Antagonistic effect on nicotinic receptors.

Nicotine has antidepressant property, substitute for nicotine. As effective as transdermal nicotine patch. Other drug is nortiptyaline.

6. Eating disorder

Antidepressants are also used. In Bulimia nervosa, patient takes food in large quantity followed by voluntary purging of food either by emesis or laxatives or others. most common complication is hypokalemia. Patient loses weight.

Drug used is Fluoxetine.

In obesity, patient has habit of taking lot of food, in these Bupropion has been tried to decrease urge of feeding.

Anorexia nervosa –patient does not eat, feeling being fat having distorted image of own self. Antidepressants are of no use, only psychotherapy, refeeding and behavior therapy is required.

7. Miscellaneous

a. Enuresis –children night bed wetting

TCA are given, Impaprazine, advantage is that also has anticholinergic property. Bladder control is improved. It has less sedating effects, child wakes up easily.

b. For urinary stress and incontinence duloxetine is prescribed

c. Vasomotor symptoms –premenopausal, menopausal if troublesome, antidepressants can be given SNRI Venlafaxine, nefazadone. As SSRI delay sexual functions, they are given in certain sexual dysfunctions like premature ejaculation. Chronic use depends on patient’s profile, age, gender, and existing diseases. Also on drug tolerability and toxicity profile.

Economical factors –cost effective, given as have to take for longer period of time

Specific Clinical Uses

SSRI

1. Depression
2. Anxiety disorder
3. Bulimia nervosa

5HT2 antagonists

1. Depression
2. Anxiety disorder
3. Insomnia

Tetracyclic and unicyclic antidepressants

1. Depression unresponsive
2. Bupropion –obesity

SNRI

1. Depression
2. Pain disorder
3. Anxiety disorder
4. Stress
5. Urinary incontinence
6. Vasomotor symptoms of menopause

TCAs

1. Depression unresponsive
2. Pain disorders
3. Enuresis
4. Insomnia

MAOIs

1. Anxiety disorder
2. Selegiline –Parkinson’s disorder

Chemistry

Hydrazine derivative –Phenelzine/Isocarboxazid

Non-hydrazine derivatives –rest all

Tranylcypromine also has amphetamine like activity

Pharmacokinetics

Monoamine oxidase is present in many areas of the body, in vast numbers in gut wall, when given orally extensive blocking of enzymes in gut wall takes place. Other routes of administration are also tried e.g. Selegiline is prepared as transdermal patch as well as sublingual preparation. These drugs undergo metabolism via different pathways e.g. hydroxylation, acetylation, N and D methylation.

Mechanism of action

MAO exists in two isoforms:

1. A –present in noradrenergic, dopaminergic neurons mainly responsible for degradation of norepinephrine, epinephrine, serotonin, dopamine and tryptamine. This enzyme is mainly found in gut, liver, placenta and brain.
2. B –mainly responsible for degradation of monoamines. Mainly present in serotonergic, histaminergic neurons, responsible for degradation of phenyl ethyl amine, tyrramine, benzylamine, dopamine, tryptamine.

This enzyme is present mainly in brain, in platelets and in liver.

These drugs also cause CNS stimulation, responsible for adverse effects, like agitation, insomnia, irritability, etc.

Adverse effects

1. Orthostatic hypotension –seen because MAO inhibitors change amines in food or other into octopamine, replacing norepinephrine acting as false neurotransmitter, leading to decreased levels of released norepinephrine.
2. Weight gain
3. Sedation
4. Also amphetamine like effects –CNS stimulation, insomnia, irritability
5. Cause diminished sexual functions, like other antidepressants when discontinued abruptly
6. Discontinuation syndrome
7. Excitement, confusion, delirium

Drug interactions

1. Cheese reaction

Food –containing tyramine or other amines when given in large quantity to patient on MAO inhibitors, normally tyramine is taken from food and metabolized by MAO in gut, so less reaches circulation. If MAO is blocked, amines are not metabolized and pass from gut to circulation, to sympathetic nerve endings. Acting indirectly, displace norepinephrine from nerve endings, leading to episodes of malignant hypertension, which may lead to stroke, cerebral hemorrhage, MI.

Foods like cheese, sugar products, beer, and dried sausages are avoided.

2. Same is true for sympathomimetic drugs which increase sympathetic activity, leading to hypertension.

At times patient is ignorant of taking drugs like over the counter medications have pseudoephedrine. This has some effects.

3. Selective serotonin reuptake inhibitors may lead to serotonin syndrome.

Over dosage

Also have over dosage. Patient shows:

1. Signs of CNS excitement
2. CVS hyper excitability

Treated conservatively by gastric lavage, vitals, airway, etc.

5-HT₂ antagonists

Chemically triazole moiety, having antidepressant effect.

Pharmacokinetics

Well absorbed after oral administration.

Extensive plasma protein binding

Extensively metabolized in liver

Both drugs are converted into active metabolites, having potent antidepressant activity.

Trazodone is converted to MCPP (m-chloro phenyl piperazine)

Nefazodone is converted into hydroxyl nefazodone and MCPP.

Mechanism of action

Antagonist at 5HT_2A  receptors so have antianxiety, antipsychotic and antidepressant effects.

Agonists to %HT_2A receptors produce hallucinations and psychotic behavior.

Weak inhibitor of serotonin and norepinephrine transporter raising amine levels.

Trazodone effects alpha adrenergic receptors inhibiting antihistamines in addition.

Adverse effects

Sedation –Trazodone antihistamine

GIT upset

Nefazodone is known for hepatotoxicity

Orthostatic hypotension

Drug interactions

  Trazodone cyp 3 A4 substrate

  Nefazodone cyp 3 A4 inhibitor

Tetracyclic Unicyclic Antidepressants

Chemically versatile group.

Bupropion is unicyclic aminoketone

Chemically resemble amphetamines

Rest of the drugs are tetracyclic in structure

Amoxapine is a metabolite of old antipsychotic loxapine.

Pharmacokinetics

Well absorbed after oral administration.

Extensive PPB.

Extensively metabolized in liver

Bupropion has three active metabolites:

Hydroxyl bupropion-typical biphasic elimination

1^st phase 1 hour, 2^nd phase 14 hours

Amoxapine forms active metabolite hydroxyl amoxapine, which is well known for D2 receptor blocking activity.

Mirtazapine undergoes metabolism. Various P450 enzymes and pathways are involved.

Mechanism of action

Slightly variable among drugs.

Bupropion inhibits reuptake of norepinephrine and dopamine but has prominent effect on presynaptic release, which is enhanced. Has both effects.

Mirtazapine mainly acts on

1. norepinephrine and serotonin levels and increase their release and inhibitory receptors alpha 2, 5HT₂ and 5HT₃ leading to increased presynaptic release of these amines.
2. Anti-histaminic effect

Amoxapine and Maprotiline block NET and SERT, increasing levels of norepinephrine and serotonin, also has anticholinergic effect.

Amoxapine has D2 blocking effect.

Adverse effects

Sedation –Bupropion –antihistaminic effect

Parkinsonism –Amoxapine –D2 antagonist

Maprotiline –tricyclic antidepressant like effects

Bupropion –causes stimulation, leading to agitation, insomnia, anorexia.

Drug interactions

Hydroxy bupropion is 2D6 inhibitor, if combined with drugs acting here, have to monitor, like TCAs

Avoided in patients taking monoamine inhibitors.

Mirtazapine as metabolized by several cyp, is affected by inducers and inhibitors

Has sedating, CNS depressing effect, caution needs to be taken when given with other sedatives, benzodiazepines, alcohols

Amoxapine and maprotiline, as anticholinergic and histaminergic, caution needs to be taken when taking with anticholinergics and antihistaminics.

Selective SNRIs

Chemistry

  Venlafaxine / Desvenlafaxine – bicyclic

  Duloxetine – 3-ring

  Milnacipran – cyclopropane ring

Pharmacokinetics

Well absorbed after oral administration.

Desvenlafaxine (cyt P450 2D6)– lowest PPB (27-30%)

Excreted unchanged in urine, rest is directly conjugated and excreted urine

Duloxetine – extensive PPB / extensive oxidative metabolism

Mechanism of Action

SERT / NET

Same as SSRI, not only inhibit serotonin but also norepinephrine transporters. Both serotonin and norepinephrine levels increase. Increased transcription of neurotrophic growth factors occurs.

Difference – TCAs

Tricyclic antidepressants acting along these transporters, also act on alpha, muscarinic and histamine receptors.

Tricyclic anti-depressants (TCAs)

Chemistry

Iminodibenzyl (tricyclic) ring

Pharmacokinetics

  Absorption– well absorbed after oral administration

  PPB –have extensive protein binding

  Undergo extensive metabolism Demethylation / hydroxylation / glucuronide conjugation

 Metabolized by CYP2D6, if polymorphism occurs, either slow or rapid metabolism

Mechanism of Action

SERT – clomipramine / imipramine

NET – desipramine / nortriptyline

As SNRI, act both at serotonin and norepinephrine transporter, inhibit uptake of monoamine, increasing levels at neuronal junctions. Some drugs have more affinity for serotonin, others for norepinephrine.

Apart also affect also receptors:

  Antimuscrinic, anticholinergic effect

  Antihistamine – Doxepin, block H1 effect, used in pruritis

  α – Adrenergic blockade –orthostatic hypotension is adverse effect

Adverse effects

More than others because of action on multiple receptors.

CVS

a. hypertension due to norepinephrine release, due to alpha blockage, may cause postural hypotension

b. increased BP in dose dependent manner – venlafaxine

c. Cardiac rhythm, TCAs have antiarrhythmic effect, quinidine like property at higher doses may cause arrhythmias.

Venlafaxine is also cardio toxic.

CNS activation, stimulation, irritability, insomnia, agitation

Hepatic toxicity– duloxetine, not seen with other members of group

Anticholinergic effects – amitriptyline / imipramine –dry mouth, constipation, urinary retention, blurred vision

α – Adrenergic blockade 

Antihistamine – weight gain / sedation

Sexual function diminished, both genders

Discontinuation syndrome, when discontinued abruptly- dizziness, parasthesias

Cholinergic rebound / flu like symptoms

Drug interactions

Pharmacokinetic

  Duloxetine – CYP2D6 inhibitor

  TCAs – CYP2D6 substrate so increased levels are seen

  CYP2D6 polymorphism – additive effects may be seen

Pharmacodynamic

Not combined with monoamine oxidase inhibitors , as increase levels

As have anticholinergic, antihistamine and alpha blocking effect so care is taken when given with anticholinergics / antihistamines /  antihypertensives

Over dosage

  Venlafaxine – cardiac toxicity

  TCAs are well known for toxic effects– CVS effects include hypertension, tachycardia, arrhythmias / CNS effects include irritation, irritability, seizures

Management

Managed conservatively. Gastric lavage, vital signs, airways.

Chemistry

Different chemical structure.

Fluoxetine / sertraline / citalopram have enantiomers R and S, formulated as racemic products

Escitalopram S enantiomer is available as separate formulation.

Pharmacokinetics

Absorption

Well absorbed after oral administration

PPB –in between 80-90%

Undergo hepatic metabolism, some form active metabolites

Notably fluoxetine forms Norfluoxetine which is an active metabolite

T_1/2 7 days, once weekly dose

  Potent enzyme inhibitor –especially inhibits CYP 2D6 / 3A4, drug interaction occurs with the drugs metabolized here as given for longer duration

Mechanism of Action

SERT – 80%

In serotonergic neuronal endings there are serotonergic transporters labeled as SERT, which are glycoprotein in nature. They are responsible for reuptake of serotonin from synaptic cleft. Normally when binds this SERT, brings about conformational change in transporter protein. Due to this serotonin and sodium and chloride are passed inside and from inside potassium ions bind and bring back transporter to original shape leading to release of serotonin inside.

In this way, serotonin is taken up by synaptic cleft and brought inside.

SSRI bind transporter SERT, site is different from where serotonin binds. They inhibit uptake of serotonin by these transporters, leading to increased levels of serotonin in synaptic cleft. Activity of transporter is inhibited up to 80% to bring about clinical effectiveness.

This serotonin is in turn responsible for enhanced transcription of genes for neurotrophic factors, which are responsible for antidepressant effect.

Polymorphism

Polymorphism exists is these genes responsible for variability in mood, some are more vulnerable and some resistant.

Other sites

SSRI do not effect other receptors, as seen with other groups.

Adverse effects

As serotonergic neurons are not only present in CNS, but also on many other body parts, responsible for adverse effects.

GIT

Most abundant in GIT.

a. nausea

b. gastrointestinal upset

c. diarrhea

settles down in about a week or so.

Sexual function

Decreased sexual functions

Decreased libido, both males and females

Changes in pattern of sleep

Either loss of sleep, insomnia or leads to increased sleep or hypersomnia

Headache

Weight gain esp. with Paroxetine when discontinued abruptly

Discontinuation syndrome

Dizziness, paresthesias

Suicidal tendency

Not used in patients less than 25 years of age as noted that patients have increased suicidal tendency.

Drug interactions

Pharmacokinetic – CYP 2D6 / 3A4 inhibitor

When given with drugs metabolized by these enzymes, toxicity of those drugs is enhanced.

Pharmacodynamic

When monoamine oxidase inhibitors inhibit monoamine enzyme responsible for degradation, increased serotonin occurs at neuronal endings occurs, which  is not degraded, and levels reach toxic levels.

Serotonin syndrome

Esp. in central grey nuclei and medulla

Cognitive effect, delirium, coma

Autonomic, hypertension and tachycardia

Somatic effects myoclonus, hyperreflexia, tremors

To avoid this interaction, gap of 2 weeks between administration of these drugs either SSRI or MAO inhibitors, for fluoxetine it is 4-5 weeks as active metabolites with longer half life are formed.