Central nervous system

Central nervous system

General features of CNS drugs

v     General Features of CNS Drugs:

v     Most CNS drugs cause dependence; intake should be restricted to the shortest duration (anxiolytics, sedatives!)

v     Tolerance develops to the effect of CNS drugs (2 day following high dose of heroin intake is enough)

v     Drugs with short duration of action cause severe withdrawal effects (abstinence syndrome) drugs with long half life cause mild withdrawal effects (short: heroin; long: methadone)

v     Most of CNS diseases can be well treated with psychotherapy or placebo.

v     Insert images from class:

v     The limbic system:

v     Psyche: normal DA, 5-HT, NA

v     Psychosis:

v     High high (SCH) levels of NA

v     Low (D = depression), meaning low amounts of DA, 5-HT and NA.

v     α-methyl dopa inhibits LAA decaboxylase, which is the enzyme that catalyzes the conversion of dopa to dopamine and 5-OH-tryptophan to 5-OH-tryptamine.

v     ↑ levels of glutamate & GABA result in 3 types of convulsions:

v     Clonic (appears from the cortex)

v     Clonic-tonic (appears from the basal ganglia)

v     Tonic (skeletal muscle convulsions from spinal origin)

v     GAD enzyme inhibits glutamate (Glu) & GABA.

v     DA associated with the substantia nigra i.e. nigrostriatal system related to Parkinson disease.

v     5-HT raphe nuclei.

v     NA Locus coeruleus.

v     So, the lower basal ganglia of the brain are related to the psychosis.

v     Glycine is an inhibitory neurotransmitter only in the spinal cord.

v     Amphetamine releases dopamine and has an inhibitory effect on the reuptake of DA. It also stimulates the release of 5-HT, but does not act on its receptor. Amphetamines in the periphery have a stimulatory effect on the release of NA, and negative inhibitory effect on the reuptake of NA. So, can result in psychosis/euphoric state.

v     Table 1: CNS stimulants and psychotomimetic drugs

v     Nabilone, a synthetic cannabincid, is sometimes used as an antiemetic to reduce nausea during cancer chemotherapy.

v     MDMA, methylenedioxymethamohetamine; ADHD, attention deficit hyperactivity disorder; GABA, gamma-aminobutyric acid: NMDA, N-methyl-D aspartate; 5-HT, 5-hydroxytryptamine.

v     Fast and slow acting neurotransmitters:

v     Fast

v     Glutamate and GABA the distance the transmitter has to travel is across the synaptic cleft.

v     Ach-receptor can be muscarinic or nicotinic. Most are presynaptic in the brain and regulates other neuronal firing. The muscarinic receptors are responsible for the short term memory. Applying a parasympatholytic compound can induce an Alzheimer's disease.

v     Are responsible for the highest memory capacity!

v     Hioschine ?? turns short-term memory into that like of Alzheimer's disease in experimental animals.

v     Physostigmine Ach-esterase inhibitors ↑ Ach transmission (an indirect way of Tx for Alzheimer's disease)

v     Histamine receptors in the reticular activating system. Most important side effect of antihistamines is a sedative effect. Intact histamine receptors are needed for the 'arousal' (awakening) state EEG shows α, β waves + electromyographic (EMG) evidence is needed to prove skeletal muscle contractions are present. The EEG and EMG together prove this state.

v     Neuromodulators doesn't act by itself; only ↑/↓ the transmission of other neurotransmitters.

v     Neurotransmitters that can be regulated most easily by pharmacological means includes: DA > 5-HT > NA > Ach, glutamate, GABA (all fast neurotransmitters) > histamine

v     Most important neuromodulators: NO, endorphins, eicosanoids (e.g. anandamide activator of cannabinol, CB1, receptor; an endogenous receptor for marijuana), neuropeptides, melatonin

v     Slow

v     DA, 5-HT, NA (and phencyclidine).

v     DA, NA, 5-HT act on their neighboring neuron and distant neurons 'aerosol effect'

v     Long-lasting agonists will ultimately result in down-regulation of receptors and vice versa. E.g. in heart failure, using β-blockers in low doses will ultimately help because β-receptors will be upregulated ↑ inotropic effect on the heart slows down the progress of heart failure and ↑ the lifespan of the patient.

v     The long term response of the brain to drugs is ultimately what is important i.e. whether there will be up regulation or down regulation of receptors to a stimulus.

v     Unfortunately, a tolerance can develop to the therapy and an opposite effect may result from what we want to achieve.

v     Mescal peyotl from a Mexican cactus called Lophophora Williams psychotomimetic drug. ???

III/1. Uptake, distribution and potency of inhalation anesthetics.

General anesthesia:

• essential for surgical practice provides analgesia, unconsciousness, muscle relaxation and suppression of undesirable reflexes.
• Reversible inhibition of:

pain (analgesia)

consciousness (hypnosis)

muscle tone

Autonomic reflexes

Sleep ↔ Narcosis (loss of consciousness due to drugs)

uptake and distribution of inhalation anesthetics:

- driving force patial pressure difference

Uptake Is influenced by:

1. solubility
2. cardiac output and its organ distribution
3. concentration effect
4. second gas effect
5. ventilation

Pharmacological effects:

• CNS
• ANS
• Respiration
• circulation
• Uterus
• Liver

Mechanism of general anesthesia:

III/2. Characteristics of different stages of anesthesia.

Pharmacological effects of anesthetics.

Stages of anesthesia:

	WHO classification: 1. loss of consciousness 2. loss of hyperactivity 3. weak surgical anesthesia 4. moderate surgical anesthesia 5. deep surgical anesthesia 6. Circulatory/respiratory disturbance 7. reversible clinical death 8. partially reversible clinical death 9. irreversible clinical death

Ether:

1. stadium analgeticum
2. Stadium exitationis
3. stadium tolerantae

a)      sleep & analgesia

b)      loss of reflexes

c)      loss of muscle tone

d)      intercostal paralysis

4. Stadium Paralyticum

Characteristics of the signs  

III/3. Inhalation anesthetics.

Diethyl-ether

Morton 1846

MAC = 2%

Good: Muscle relaxation, no circulation

bad: Tracheal irritation, slow induction (increase blood, decrease gas), nausea, explodable

Chloralom, Chlorethyl

Halothane

MAC = 0.75%

Good: Muscle relaxation, No irritation, explosive

Bad: Circulation, arrhythmias, hepatotoxicity (adults), malignant hyperthermia (+Dantrolene)

Mothoxyflurane

Isoflurane

MAC = 1,2%

Good:

muscle relaxation

irritation

circulation

Bad:

respiration

Enflurane, sevoflurane, Desflurane

Dinitrogen oxide (N2O) Nitrogenium Oxydulatum

wells, 1844

MAC = 105%

Good:

Safe

anagesia

'incomplete'

Bad: diffusion hypoxia

III/4. Intravenous anesthetics.

Barbiturates (USA)

Distribution to the brain is very large. Has an hypnotic effect (10-15 min)

There is a redistribution after the administration due to blood flow → it is rapidly washed out and redistributed according to the lipid solubility.

After administration → rapid decline effect. The concentration in the brain is rapidly increasing and then washed out from it rapidly again.

Stays in the fat tissue for a long time and deposits there in an increasing amount.

Deep anesthesia can be maintained with inhalation anesthesia.

These drugs are good for rapid anesthesia.

Rapid administration is a problem: is you administrate too slowly → fast distribution throughout the body → no effect. Too quietly → very high plasma concentration → high amount presented to the brain → depression of the vital sign → death.

No antidote available.

• Examples:
• hexobarbital BRIETAL
• Thiobarbiturates (Thio derivatives are the most common)

Ethyl-butil INNCTIN

ethyl-metpropil - VENOBARBITAL

Ethyl-metbutil TRAPANAL

Non barbiturates derivatives:

• Ketamine different mechanism of action CALYPSOL

'dissociative anesthesia

NMDA decrease

• Propanidide SOMBREVIN

popular, but expensive

margin of safety is better, elimination is quick. No hang over effect, no sedative effect.

• Benzodiazepines

short acting BZ are frequently used.

Used as sedative (sleeping pills help only falling asleep, effect doesn't last for the whole night), prevention of anxiety etc.

have an antidote may antagonist the effect

the only compound used as IV anesthesia

Diazepam (medium acting) DIAZEPAM

Midazolam (short acting) DORMICUM

III/5. Premedication of general anesthesia.

Nacrosis premedication

• anxiolytics (benzodiazepines) - Diazepam
• Sedatohypnotics (Barbiturates) -USA
• Parasympatholytics atropine

may be administrated before the surgery → depression of the sympathetic system to overcome the imbalance between the sympathetic and the parasympathetic

• Antihistamines

useful due to the synergic effect of the CNS and because of the surgery itself → inhibition of the histamine release → prevents histamine effects (etc elevated BP)

Induction of Narcosis

• anxiolytics (benzodiazepines) Midazolam
• Sedatohypnotics (barbiturates) USA
• Peripheral muscle relaxants - succinylcholine
• narcotic analgesics - morphine, Fentanyl

'Neurolept-analgesia' 'neurolept-anesthesia' for minor surgical intervention

has an antidote against Fentanyl → control

Droperidol + Fentanyl = INNOVAR

• TIVA ↔ VIMA (TIVA- Total Intravenous Anesthesia, Volatile Maintained Anesthesia)

may be used for minor intervention, burn dressing. Lasts for a couple of minutes

Maintenance of narcosis

- may be administrated with muscle relaxants

• combination of inhalation anesthesia
• peripheral muscle relaxants - Curare, Pancuronium

Promotion of the recovery

the quicker the recovery the better for the patient

normal circulation is needed for helping the elimination of the gases and normal trasportation of the drugs in the body.

Combination anesthesia may eliminate the effect of the drugs by using some antagonist

antagonist of muscle relaxants. Rapid recovery of spontaneous respiration

Neostigmine

Opiate antagonists

pain killers

Opioids:

Overview:

Opioids are use for management of severe or chronic malignant pain

May be natural or synthetic compound that produce morphine-like effect

Opiate, such as morphine or codeine, are produced from the juice of the opium poppy

Acting by binding to the opioids receptors in the CNS → mimicking the action of endogenous peptide neurotransmitters (e.g. endorphins, enkephalins and dynorphins)

Wide use may lead to abuse with euphoric effect

threshold for pain

produce euphoria, high potential for abuse

other sensory pathways (smell, hearing, vision)

hypnosis or general anesthesia

antiinflammatory

Opioids Analgesics and Antagonists:

Strong antagonists:

Alfentanil

Fentanyl

Heroin

Meperidine

Methadone

Morphine

Oxycodone

Remifentanil

Sufentanil

Moderate/Low Agonist

Codeine

Propoxyphene

Mixed Agonists-Antagonists and Partial Agonists

Buprenorphine

Butorphanol

Nalbuphine

Pentazocine

Opioids receptors:

interact stero-specifically with protein receptors on:

a.       membranes of certain cells in the CNS

b.      nerve terminals in the periphery

c.       cells on the gastrointestinal tract

d.      other anatomic regions

There are three major receptor families: m (mu), k (kappa) and d (delta).

G protein-coupled receptor family

Inhibit adenyl cyclase

Associated with icon channels

increasing postsynaptic K+ efflux or reducing presynaptic Ca+ influx → impending neuronal firing and transmitter release

Distribution of receptors:

1. Brain stem
2. Medial thalamus
3. spinal cord
4. Hypothalamus
5. Limbic system
6. Periphery
7. Immune cells

III/6. Drugs acting on opioid receptors: strong agonists.

Morphine and Codeine are the major drugs of this

Morphine:

Mechanism of Action:

interactions with opioids receptors in the CNS, GI, Urinary bladder etc.

Actions:

1. hypopolarization of nerve cells

2. inhibition of nerve cells firing

3. presynaptic inhibition of transmitter release

act on k receptors

inhibits the release of excitatory transmitters from nerve terminals carrying nociceptive stimuli

Actions:

a. Analgesia:

relief of pain without the loss of consciousness

rise the pain threshold at the spnial cord level and alters the brain's preception of pain

b. Euphoria

produces a powerful sense of contentment and well-being

may be caused by disinhibition of the ventral tegmentum

c. respiration

reduced the respiratory center sensitivity to Carbon dioxide → respiration depression

with high doses may cause respiratory arrest

d. depression of cough reflex

antitussive properties

e. Miosis

stimulation of the parasympathetic system → pinpoint pupil characteristic to the use of
Morphine

f. Emesis

stimulation of the area pstrema → chemoreceptors stimulation → vomitting

g. Gastrointestinal tract:

decrease motility and increasing the tone of the intestinal circular smooth muscles → relieves
diarrhea and sysentery

increase anal sphincter tone

causes constipation

(from the lecture)

Pharmacological effects of Morphine:

CNS -

o       Depression

Analgesia (m, k kappa)

Anxiolytic, sedative (m

Euphoria, dependence dose dependent

Respiratory depression (m) dose dependent, higher doses produce depression of the respiratory center the threshold for excitation with carbon dioxide is decreased → amplitude of respiration deceases gradually

Suppression of cough never to be used with daily problems (cold etc)

stereo-selectivity,

o       Dextromethorphan (Romilar)

analgesia, ↓ in respiration, euphoria

? NMDA ↓

o       Stimulation

Bradycardia central vagal stim dose dependent effect

Miosis oculomotor center (can be differential diagnosis of some compounds opioids produce pin-point pupil)

Nausea, vomiting chemosensitive trigger zone

Endocrine effects - ↑ ADH, prolactin especially important in long term use

CNS - Peripheral effects:

o       Smooth muscles

Intestine constipation (the activity of the long. Muscle are inhibited, and the sphincters are closed. Dangerous when there is a stone!) - ↓ propulsive, ↑ sphincter must not administrated alone! Always with a muscle relexant

Bile duct - ↑ tone (! Stone)

Ureter - ↑ tone (!stone)

Urinary retention sphincter ↑ & ADH ↑

Bronchoconstriction

o       Circulation no real effect, only in large/toxic doses:

↓ vasomotor center → ↓ BP, heart stops

↓ baroreceptor → hypotonia

Therapeutic indications:

analgesia

o       strong agonists (morphine)

severe acute and chronic pain

surgical intervention, postoperative, tumor, burning

colic (biliary, renal) + spasmolytic

o       weak agonists (codeine)

Weak pain (+ASA, acetaminophen)

Antitussive less common these days (even prohibited)

o       Mixed agonists/antagonist

Severe pain, smaller respiratory depression

o       Short acting (Fentanyl)

Neuroleptanalgesia (+droperidol) used in

Neuroleptanesthesia may reach a phase where the patient does not feel pain, but continuous, answers your questions but does not care what happens

o       Acute pulmonary edema → depression of the gas exchange → within minutes the patient can die. Treatment: support the heart, mobilization of the fluid from the lungs, or, depression the fighting need for oxygen.

o       Relieving opioid withdrawal symptoms

Adverse effects:

CNS

o       dysphoria, nausea, vomiting (40%)

o       euphoria, dependence

o       sedation

o       miosis

o       respiratory depression

GIT  - constipation, spasm, Oddi-sphincter

UT urinary retention

Histamine release :

o       Bronchoconstriction, itching, hypotension

CVS

o       Orthostatic hypotonia

o       Increase intra cranial pressure

Acute intoxication

severe respiratory depression

coma, cyanosis

pinpoint pupil

Treatment of acute intoxication:

Naloxone iv

artificial respiration

vasoconstrictors

Contraindication:

undiagnosed acute abdominal pain

respiratory insufficiency (asthma)

brain injury

pregnancy, infancy

insomnia, cough

euthanasia

Administration:

past ' pro re nata' dose as needed, every 6 h iv

present small doses every 4 h, per os, for prevention

III/7. Drugs acting on opioid receptors: intermediate agonists

III/8. Drugs acting on opioid receptors: antagonists.

III/9. Nonsteroid antiinflammatory, antipyretic analgesics: mechanism of action,

indications, side effects.

III/10. Nonsteroid antiinflammatory, antipyretic analgesics: salicylates, salicylate-like

analgesics.

III/11. Nonsteroid antiinflammatory, antipyretic analgesics: non-salicylate derivatives.

Hypnotic Drugs

III/12. Hypnotic drugs: barbiturates.

Anxiolytic Drugs & sedatives, Hypnotics

Anxiety: an abnormal and overwhelming sense of fear often marked by physiological signs similar to fear (as Sweating tension, tachycardia, trembling, and palpitation)

Antianxiety drugs = anxiolytic or minor tranquillizers.

• Sedation: a relaxed state with decrease mental and physical performance
• Hypnosis : a state resembles physiological sleep

The same molecule:  

low dose - anxiolytic/sedative (cc. mg)

Medium dose - hypnotic

Large dose - anesthetic

Toxic dose - coma, respiratory depression and death

Anxiolytic and Hypnotic Drugs:

• Benzodiazepines

Alprazolam

chlordiazepoxide

clonazepam

Diazepam

Estazolam

Flurazepam

Lorazepam

Quazepam

Oxazepam

Temazepam

Triazolam

• Benzodiazepine Antagonists

Flumazenil

• Other Anxiolytic Drugs

Buspirone

Hydroxyzine

Antidepressants

Benzodiazepines

the most widely used anxiolytic drugs

mechanism of Action:

Act on specific GABAa receptors to enhance the effect of GABA (γ-aminobutyric acid)

acting on α1 and α2 subunit of the receptors opens the chloride channels → increase of Chloride Cl- influx → hyperpolarization and neuronal inhibition.

Benzodiazepines receptors are allosteric modulators and involve a and g subunits

Actions:

have neither anti psychotic activity nor analgesic action anxiolytics

reduction of anxiety (alpha-2) - at low doses

sedative and hypnotic actions (alpha-1)

anterograde amnesia (alpha-1) impairment of memory and learning ability

anticonvulsant (alpha-1) may be used to treat epilepsy, seizures

muscle relaxants (alpha-2) at high doses.

Zolpidem and Zaleplon are not Benzodiazepine structures but act on the BZ receptors and they have minimal muscle relaxants and anticonvulsant effect

Picture: GABAa receptor

v     6 different a subunits

v     4 different b subunits

v     3 different g subunits

- most common mammalian structure (a1)2-(b2)2-(g1)

GABAa subunit

• a1 and/or a5 = sedative effect, muscle relaxant, amnesia
• a1 and/or a3 = anxiolytic effect, anticonvulsive
• a4 and/or a6 = BZ insensitive, neurosteroids, alcohol)

Therapeutic uses:

a. Anxiety disorders:

• All BZ have similar action, they differ in their duration of action
• Treatment of Anxiety symptoms
• should not be used for everyday life stress but for continued severe anxiety disorders only due to their addiction potential
• Long acting: clonazepam, lorazepam, diazepam.
• Panic disorders: Alprazolam

b. muscle disorders:

• diazepam treatment for muscle spasm (e.g. from degenerative diseases MS, Cerebral palsy)

c. Amnesia

• short acting agents often employes as premedication for anxiety provoking and unpleasant procedures
• E.g.: Endoscopic, bronchoscopy, dental procedures, angioplasty
• they cause conscious sedation, allowing the person to follow instructions during the procedure.
• Midazolam injectable-only benzodiazepine

d. Seizures

• clonazepam epilepsy treatment
• Diazepam and lorazepam- grand mal epileptic seizures, status epilepticus
• due to cross tolerance, they are useful in treating alcohol withdrawal-related seizures

e. Sleep disorders:

• all BZ have sedative and calming effects, but not all are useful for hypnotic purposes
• ↓ latency of sleep onset, ↑ stage II of non REM sleep.

Long acting: flurazepam reduce sleep-induction time, and number of awakenings.

Intermediate acting: temazepam peak sedative effect occurs 1-3 hours after oral dose, used in individuals who have problems to stay asleep  

Short acting: triazolam used for individuals who have problems falling asleep

Pharmacokinetics:

• Absorption and distribution:

lipophilic → rapidly absorbed orally (slow for oxazepam), rapid for Diazepam, triazolam.
Clorazepate is a prodrug (decarboxylated in gut into nordazepam)

• Duration of actions:

divided into short, intermediate and long duration

• Fate:

Bound to plasma proteins 85-95%

metabolized by liver microsomal enzymes into active metabolites

Oxazepam, Lorazepam and temazepam are converted into inactive metabolite.

Excreted conjugated with glucuronic acid by the kidney or Oxidized metabolites

Drug's effect is terminated not only by excretion but also by distribution

BZ cross the placenta and may depress the CNS of the fetus. May also pass by breast feeding

Classification according to a pharmacokinetic property:

• Long acting drugs are mainly anxiolytic/sedative: Awake (approx. 18 hours)

Short acting drugs are mainly hypnotic: Sleep (appr. 8 hours)

• Long acting (t1/2 > 24 hours):

Diazepam, nordazepam, clonazepam, flurazepam and clorazepate.

• Intermediate acting (t1/2 6-24 hours):

Temazepam, oxazepam, lorazepam, halazepam, Alprazolam and Chlordiazepoxide

• Short acting (T1/2 < 6 hour): triazolam, midazolam

Dependence

• high dose over a prolonged time → psychological and physical dependence
• discontinuation → withdrawal symptoms:

Actions on the CNS:

v     anti-anxiety and relieve neurosis:

v     sedative and hypnotic effect by flurazepam, temazepam, and triazolam

v     central muscle relaxant action especially diazepam

v     anticonvulsant and antiepileptic action especially diazepam, Lorazepam and clorazepate

v     anaesthesia: they produce drowsiness, amnesia and finally unconsciousness especially diazepam and midazolam i.v.

Actions on the CVS: (cardio-vascular system)

v     slight effect on heart (negativeand blood vessels (vasodilation)

v     strong effect in intoxication (syncope or CVS collapse)

The sleep cycle;

Altering state and stages of sleep that occur over an 8 hour time period

v     NREM: non rapid eye movement: stages 1-4; 75% of the night

v     REM: rapid eye movement : dreams occurs, 25% of the night

Insomnia:

v     over 30% of American adults experience occasional insomnia; 10% on a chronic basis

v     those most at risk:

v     women

v     older adults

v     pts with psychiatric disorders

v     pts with medical disorders (pain syndrome, asthma, CV)

v     2^nd / 3^rd shift workers

Treatment of insomnia:

v     GABAa receptor allosteric modulators

v     Benzodiazepines (e.g. midazolam)

v     Non-Benzodiazepines (e.g. zolpidem)

v     barbiturates (rarely because of low theruaputic index)

v     chloral hydrate

v     melatonin receptor agonist (against jet leg)

v     OTCs (over-the-counter) acts on serotonin

v     Antihistamines (diphenhydramine)

v     L-tryptophane no side effects

v     Alcohol

v     Herbals (Valeriana, Chamomile, Passion flower etc)

BZ are preferred than Barbiturates due to:

high therapeutic index

minimal effect on sleep rhythm (less REM supreesion)

mild psychic and physical dependence

little respiratory depression and little cardiovascular effects

little or no hangover

not significantly enzyme inducers (so little interactions)

slow development of tolerance

side effects:

v     amnesia

v     impaired mental and motor function

v     dependence upon prolonged use (psychic and physical)

Toxicity;

v     dose dependence

v     loss of consciousness

v     paralysis of respiratory center

v     death

v     dose independent allergy

Therapy of overdose:

v     symptomatic arterial respiration, warming of patients

v     flumazenil is and antagonist of BZ

Other anxiolytic drugs:

Buspirone (5HT1a partial agonist advantage over others:

v     no anticonvulsant effect

v     no muscle relaxation

v     less dependence

v     less interaction with alcohol

v     disadvantages over others:

v     slow onset of action

Features:

v     eszopiclone (S-zopiclone) minimal effect on sleep pattern

v     ramelteon synthetic melatonin receptors agonist

v     histamine 3 receptor agonist

III/13. Hypnotic drugs: alcohol, benzodiazepines, and other agents.

III/14. Antiepileptic drugs.

III/15. Antipsychotic drugs: Pharmacologic effects and adverse effects.

Pharmacology Neuroleptic Drugs

Neuroleptic drugs = antipsychotic = antischizophrenic (major tranquillants treat psychosis; minor tranquillants e.g. benzodiazepines)

Psychosis

Schizophrenia

Affective disorders (maniaco-depressiva)

Organic psychosis

Symptoms of schizophrenia:

Positive Symptoms:

Delusion

Paranoia

Hallucination

Negative Symptoms (more neurons are lost → unresponsiveness; loss of interaction with the environment):

Loss of social interactions

Apathy

Dementia

Theories of schizophrenia:

Idiopathic we don't know exactly the cause

Genetic polygenic, multi-factorial

Total population (1%)

Non-identical twins (8%)

Identical twins   (22%)

Non-genetic

Slow viruses? Autoimmune? Head injury?

Abnormal neuronal circuits?

Dopamine theory (biochemical alterations take place in this disease):

Amphetamine (drug abuse) ↑ '+' Symptoms

Apomorphine, bromocriptine, L-DOPA (ppt. '+'-sings) ↑ '+' Symptoms

Reserpine ↓ '+' Symptoms

Correlation: D2 receptors ↓ therapeutic effect

(Graph of effectiveness of drug and antidopaminergic potential of the compounds. When increasing the dose of the neuroleptic drug ↑ anti-dopaminergic effect.)

Serotonigerg ↓, Glutamaterg ↓

But, the therapeutic effect develops slowly; only after several weeks of Tx dose the antidopaminergic effect occur.

Inhibition of the receptor ↑ liberation of DA (chronically) stimulation of postsynaptic DA-membrane??

Haloperidol rat- DA neuron activity. Initial Dose ↑ DA activity chronically, inhibition occurs of the presynaptic??? membrane due to downregulation of the DA-receptors Parkinson-like symptoms.

Pharmacologic effects of neuroleptic drugs (chlorpromazine):

Antidopaminergic

v      Antipsychotic

↓ motor behavior, spontaneous activity

↓ arousal reaction (example: a can gets excited when a mouse is present)

↓ aggression

↓ Paranoid ideation after weeks

v      Anti-emetic activity

v      ↓Temperature regulation → hibernation

v      Extrapyramidal motor disturbances (disturbances in the DA and cholingergic neurotransmitters one cannot create small coordinated movements)

v      Acute dystonia to Tx either ↓ dose of the antipsychotic drug or also give antiparkinsonian drugs

v      Akathisia (body movements are not coordinated e.g. restless leg) ↓ dose, propranolol, anxiolytic

Motor restlessness, anxiety

v      Parkinson-like symptoms e.g. muscle rigidity, bradykinesia, base-line tremor dose dependent & reversible.

v      Tardive dyskinesia

May ↑ when the dose ↓ - not reversible

v      Endocrine effects

Inhibition of cholinergic receptors ↑ serum prolactin gynecomastia, galactorrhea.

Other effects:

Antimuscarinic the same compound may produce a simultaneously effect.

Antihistamine (H₁) -

Antiadrenergic (α₁)

Antiserotoninergic sedative effect.

Adverse effects (AE):

Does not cause acute toxicity - successful suicide attempts with the drug are very rare

Postural hypotension (α) significant

Sedation

Mydriasis, dry mouth, constipation (all are antimuscarinic effects)

Extrapyramidal effects - related to the antidopaminergic effect

Gynecomastia, galactorrhea

Idiosyncrasy, hypersensitivity

Neuroleptic malignant syndrome may be one of the most severe adverse outcomes excess release of Ca²⁺ from the sarcoplasmic reticulum muscle contraction excessive heat production by the body.

Cholestatic jaundice

Leukopenia, agranulocytosis

Convulsions in epileptic patients

Drug interactions (DI):

sedatohypnotics and alcohol

Opioid analgesics (barbiturates, benzodiazepines)

Anesthetics

Antihypertensive agents

Anticholinergic drugs

Pharmacokinetics:

Per os = absorbed ((however, varies widely amongst individuals during absorption and biotransformation of the drug. Differences of 20 to 30 times may be seen in the plasma concentration of the drug between patients. So, a patient with a high plasma concentration of the drug may have a higher likelihood of having adverse effects so, the dose should be monitored and corrected as indicated.))

Give single dose at bedtime

Slow release preparations

Therapeutic use:

Psychiatry

motoric-psychotic restlessness, paranoia, psychosis, mania

drugs may be used to stop Nausea, Vomiting

Huntington's chorea (Haloperidol)

Depression (Sulpiride)

Surgical anesthesia premedication

'Phantom-limb' pain -

Typical drugs: (DONT LEARN THIS LIST!)

Phenothiazine derivatives (tricyclic structure similar to tricyclic antidepressants similar effects) Sed Extrap Hypot

Dimethylamine derivatives: +++ ++ +++

chlorpromazine (HIBERNAL) inj, tbl, drops,   supp

Levomepromazine (TISERCIN) inj, tbl.

Piperidine derivatives +++ + +++

Pipotiazine (PIPORTIL oil inj) 1 x month

Piperazine derivatives + +++ +

Fluphenazine (MODITEN DEPO) inj

[Thiethylperazine (TORECAN) inj, tbl, supp emesis]

Butyrophenon derivatives + +++ +

Haloperidol (HALOPERIDOL) inj, tbl

[Droperidol (DROPERIDOL) inj + FENTANYL]

Thioxanthene derivatives +++ ++ ++

Chlorprothixen (TRUXAL) inj, tbl

Flupentixol (FLUANXOL) inj

Zuclopenthixol (CISORDINOL) tbl, DEPOT inj, -ACUTARD inj

Dipenylbutyl-piperidine derivatives

Fluspirilen (IMAP) inj 1 x week

Pimozid (ORAP) tbl 1 x day

Atypical agents: ++ none ++

Clozapine (LEPNEX) inj, tbl; 5-HT₂ ↓

olanzapine

quetiapine

Tiaprid (TIAPRIDAL) inj, tbl

Sulpirid (DEPRAL) tbl D₂, D₄ ↓

Risperidon (RISPERDAL) 5-HT₂ ↓, α₁ ↓

III/16. Antipsychotic drugs: Groups of agents.

III/17. Antianxiety drugs.

III/18. Skeletal muscle depressants that act on the spinal cord. (Centrally acting muscle

relaxants).

III/19. Antiparkinsonic drugs.

III/20. Central nervous system stimulants of the convulsant type. Xanthine derivatives.

III/21. Psychomotor stimulants and anorectics.

III/22. Hallucinogens.

III/23. Antidepresant drugs: MAO inhibitors.

III/24. Antidepresant drugs: non-MAO inhibitors.

III/25. Antihistaminic drugs : H and H receptor antagonists.