Drugs affecting CNS

and peripheral nervous systemand peripheral nervous system

Antiparkinsonian Drugs

• Parkinsonism is caused by an imbalance between excitatory action of acetylcholine (ACh) and inhibitory action of dopamine (DA), due to decreased production of dopamine.

• progressive degeneration of DA-producing neurons in substantia nigra reduced output of DA age-associated increase in MAO-B activity (metabolizes DA in the increase in MAO-B activity (metabolizes DA in the brain)

• Therapeutic goal: because it is not possible to reverse the degenerative process, drugs are used to: - increase DA activity

- reduce excitatory Ach activity in order to restore their balance

Antiparkinsonian Drugs

• Levodopa (L-Dopa)

� is an isomer of dopa which is decarboxylated in

the CNS to restore DA activity

� it reacts with DA receptors to activate inhibitory G � it reacts with DA receptors to activate inhibitory G

proteins

• Bromocriptine it is a DA receptor agonist

• Selegiline - MAO inhibitor that decreases DA

metabolism and prolongs its action

Opioids

• a group of substances that bind to opioid receptors in the nervous system and other tissues.

• They are mainly used for their analgesic activity

they have many other effects throughout the bodythey have many other effects throughout the body

• The body naturally creates its own opioid ligands:

• endorphins

• enkephalins

• there are four known receptor types:

μ, κ, δ and σ.

Opioids• Mechanism of Action

• Central and peripheral opioid receptors are coupled to inhibitory

G-proteins.

• The inhibition of adenylate cyclase activity

lowers Ca2+ and results in hyperpolarization.

• The effect on receptor types

– The effects μ receptors include– The effects μ receptors include

– supraspinal analgesia, respiratory

depression, miosis, and euphoria.

• The effects of κ receptors include

– spinal analgesia, sedation, and miosis.

• δ-receptors induce

– cardiovascular stimulation and can

cause dysphoria and hallucinations.

Classification of agonists and

antagonists• Depending on their interaction with the

receptors,

• opioids are classified as

– pure agonists,

– partial agonists, – partial agonists,

– mixed agonist-antagonist,

– pure antagonists

• Pure agonists bind to μ receptors and have maximum effect depending on

dosage.

– morphine, fentanyl and pethidine.

• Partial agonists,

• have a partially agonistic and antagonistic effect.

– buprenorphine

• Mixed agonists-antagonists like

• pentazocine are • pentazocine are

– antagonists at the μ receptor and

– agonists at the κ receptor with high intrinsic activity.

• Due to their antagonistic effect, they can block agonists from the receptor

and reverse their effects.

• Pure antagonists are competitive antagonists that bind to and block all

opioid receptors. naloxone and naltrexone.

Central and peripheral effects of opioids

Central effects include

• the reduction of pain transmission by stimulating opioid receptors.

– They activate the descending inhibitory system, spinal nociceptive impulses are

suppressed

– the pain sensation in the limbic system is modulated.

• opioids have a sedating effect on mental activity and a hypnotic effect.

• anxiolytic and euphoria-inducing resultanxiolytic and euphoria-inducing result

• respiratory depression and an antitussive effect.

Peripheral effects include

• analgesia,

• delayed gastric emptying due to contraction of the pylorus,

• reduced gastric motility,

• and increased tone of the smooth musculature of the gastrointestinal tract.

• the tone of the bladder muscle and bladder contractor muscle is increased.

• Histamine release is also common, causing intense itching

Indications for Opioids

• Indications for the use of opioids are

– severe and extreme pain

– (nociceptive type pain), i.e.

– in the context of surgeries and tumors.

– treating pain in cases of acute myocardial infarction and acutepulmonary edema

• because of their psycho-sedating effects.

Side effects:

• euphoria

• nausea and vomiting

• respiratory depression

• urinary retention

• pupil constriction

• constipation

High-potency opioidsMorphine

• is quickly absorbed after oral administration.

• if pain cannot be sufficiently relieved by administering oral morphine,

• continuous intrathecal or epidural morphine administration is suitable.

Indications :

• abdominal metastases and

• pain in the lower extremities with

– syringomyelia,

– spinal tumors,

– traumatic paraplegia– traumatic paraplegia

Buprenorphine

• is highly lipophilic, it is well absorbed and

is 40 times more potent than morphine.

• It has poor bioavailability due to its high first-pass effect

• the usual administration is

– parenteral

– transdermal

– sublingual

Oxycodone

• has a similarly good analgesic effect compared to morphine and is especially used

in orthopedics

Fentanyl, alfentanil, sufentanil,remifentanil

• Fentanyl, alfentanil, sufentanil, remifentanil

• are pure and selective μ agonists

• used for intravenous administration

Their benefits include

– good analgesic efficacy,

– low hemodynamic influence and

– no liver or kidney toxicity

– they do not trigger malignant hyperthermia. – they do not trigger malignant hyperthermia.

Antagonizing Opioids

The receptor-specific opioid effects

may be competitively canceled out either completely via

pure antagonists such as naloxone

partially via mixed agonists-antagonists

such as nalbuphine.

Antagonists are used in order to eliminate opioid-induced respiratory depression

Antidepressants

• are a heterogeneous group of chemically different drugs usedfor the treatment of major depression

• They are also used for other conditions such as :

– anxiety disorders,

– obsessive-compulsive disorders,

– chronic pain.

• Tricyclic antidepressants (TCAs)

• Selective serotonin reuptake inhibitors (SSRIs)

• Norepinephrine reuptake inhibitors (NRIs)

• Serotonin-norepinephrine reuptake inhibitors(SNRIs)

• Monoamine oxidase inhibitors (MAOIs)

Tricyclic antidepressantshydrophobic, three-membered ring system.

• TCAs also bind to peripheral

• acetylcholine, histamine, and adrenergic receptors

• that explain many of their adverse effects.

TCAs have two distinctive effects.

• the immediate sedative effect

– characterized by sedation, sleepiness, and reduction of mental and physical activity. This

effect is also observed in the healthy individuals.effect is also observed in the healthy individuals.

• the antidepressant effect

– that solely occurs after long-time use, is only detected in patients with depression and

mood disorders.

• Drugs:

• Amitriptyline,

• Doxepin,

• Imipramine,

• Nortriptyline,

• Desipramine,

• Trazodone

Selective serotonin reuptake inhibitors (SSRIs)

• inhibit the reuptake of serotonin into the presynaptic neurons from the

synaptic gap by blocking the serotonin transporters.

• these drugs do not block histamine, muscarinic or adrenergic receptors,

• they have less adverse effects and are often the first line drugs in the

treatment of major depression.

• Drugs: Fluoxetine (prototype), Paroxetine, Sertraline, Citalopram,

Escitalopram

Norepinephrine reuptake inhibitors (NRIs)Norepinephrine reuptake inhibitors (NRIs)

• Similar to the mechanism in SSRIs,

• the norepinephrine reuptake inhibitors (NRIs) prevent the reuptake of

norepinephrine into the presynaptic neuron.

• They are suitable for treatment of

• mild depression.

• Drugs: Reboxetine

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

• In this class, both serotonin and norepinephrine

• reuptake is inhibited into the presynaptic neurons.

• Drugs: Venlafaxine, Duloxetine, Mianserin, Mirtazapine, Levomilnacipran

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase enzyme catalyzes the breakdown of neuro-active and vaso-active amines.

� MAO-A (monoamine oxidase type A) metabolizes norepinephrine, serotonin, dopamine, and tyramineserotonin, dopamine, and tyramine

� MAO-B (monoamine oxidase type B), metabolizes dopamine.

The monoamine oxidase inhibitors (MAOIs) block these enzymes and henceincrease the levels of these neurotransmitters in the synaptic cleft.

Drugs: Moclobemide.

Selegiline, the MAO type B inhibitor, is used in the treatment of parkinsonism.

Class Adverse effects

TCAs Voiding disorders, accommodation

disorders, tremor, xerostomia, dizziness,

cardiac conduction disorders, unrest,

weight gain, loss of libido, erectile

dysfunction, edemas, exanthema

Nausea, unrest, sexual dysfunction, SSRIs Nausea, unrest, sexual dysfunction,

headache, tremor

NRIs Unrest, urinary retention, tachycardia

MAOIs Unrest, sleep disturbance; Serotonin

syndrome

Antipsychotics

• Effects of Increasing Dopamine

• Dopamine is a monoamine neurotransmitter

• that is synthesized by the conversion of tyrosine

• The functions of dopamine depend on the pathway

involved.

• They include:• They include:

– motor control in the nigrostriatal pathway;

– behavioral effects in the mesolimbic and

mesocortical pathways;

– endocrine control in the tuberoinfundibular

pathway.

• Amphetamines

• cause increased levels of dopamine in the brain

• can result in acute psychotic episodes

• similar to what is seen in schizophrenia.

• drugs used in Parkinson’s disease,

– levodopa and dopamine agonists,

– can cause hallucinations as a side effect.– can cause hallucinations as a side effect.

• amphetamine, as well as other

• Dopamine antagonists

– including antipsychotic agents,

– are effective in treating

– the positive symptoms of schizophrenia.

.

• Schizophrenia pathogenesis

• In schizophrenia, there is an

• overactivity of D2 receptors in the mesolimbic dopaminergic pathway, which causes positive symptoms.

• Aside from the role of dopamine,

• glutamate underactivity may play an important part in this condition.

Psychotic Disorder Medication

Antipsychotic drugs work chiefly byAntipsychotic drugs work chiefly by

blocking of post synaptic dopamine D2 receptors.

Therapeutic effects are achieved when there is blockade of

at least 80% of the D2 receptors.

the blockade of dopamine receptors is an immediate effect of drug administration,

the therapeutic effect may be delayed for up to several weeks,

• Antipsychotics are broadly divided into two categories:

• first-generation antipsychotics, (typical antipsychotics)

• and second-generation antipsychotics, (atypical antipsychotics)

Typical and atypical antipsychotics differ in relation to their mechanism of action, side effect profile and clinical effect.

Typical antipsychotics primarily bind and inhibit dopaminergic D2 receptors and treat positive symptoms.

Atypical antipsychotics bind to D2 receptors as well as serotonergic 5-HT2a receptors.

Atypical agents

treat positive symptoms,

induce an effect in improving :• negative symptoms and

• cognitive impairment

because of 5-HT2a receptor antagonism.

Examples of typical and atypical

antipsychotics

Typical (first generation)Atypical (second

generation)

Chlorpromazine

Amisulpride

AripiprazoleChlorpromazine

Clopentixol

Flupentixol

Fluphenazine

Haloperidol

Aripiprazole

Clozapine

Quetiapine

Risperidone

Sertindole

Ziprasidone

Zotepine

Side effects of antipsychoticsExtrapyramidal motor side effects:

• Motor disturbances are the result of direct or indirect

• blockade of D2 receptors in the nigostriatal dopaminergic pathway.

Cardiac effects:

• ventricular arrhythmias and sudden cardiac death.

Endocrine effects:

• Blockade of dopamine receptors in the tuberoinfundibular pathway results

in increased prolactin secretion

Anti-muscarinic effects:

• Blockade of muscarinic cholinergic receptors may cause effects such as• Blockade of muscarinic cholinergic receptors may cause effects such as

• dry mouth and eyes, blurred vision, increased intraocular pressure, urinary

retention, constipation and confusion.

Anti-adrenergic effects:

• Blockade of adrenergic receptors can result in orthostatic hypotension and reflex

tachycardia.

Anti-histamine effects:

• Blockade of histamine receptors can result in sedation.

Metabolic and cardiovascular side effects:

weight gain, diabetes mellitus and cardiovascular disease.

Bipolar Disorder Medication

• Drugs used in the treatment of bipolar disorder include:

– Lithium

– Anti-epileptic drugs

– Atypical antipsychotic drugs

– Antidepressants (for bipolar depression)

– Other drugs, including benzodiazepine, memantine, amantadine and ketamine.

Mood stabilizersLithium Lithium

– is typically used as a mood stabilizer for the long-term

– treatment of bipolar disorder

– treatment of acute mania

Lithium

• Lithium has a narrow therapeutic range,

• between 0.5-1 mmol/L.

• At levels above 1.5 mmol/L, it becomes toxic.

Toxic effects of lithium include

– gastrointestinal disturbances such as nausea and vomiting,

– tremor, nephrogenic diabetes insipidus, renal failure, thyroid enlargement, hypothyroidism, weight gain, hair loss and mild cognitive impairment.

– Acute toxicity can cause significant neurological effects

• confusion, motor impairment, seizures, coma and death.

Epilepsy

• Epilepsy is a group of neurological disorders

characterized by the recurrence of seizures.

– A seizure is a brief surge of uncontrolled, abnormal

electrical activity in the brain which may produce a

physical convulsion in some individuals or minor physicalphysical convulsion in some individuals or minor physical

signs in others.

• Many structures and processes are involved in the

development of a seizure,

• including neurons,

• ion channels, receptors, glia,

• inhibitory and excitatory synapses.

Epilepsy

• Anti-seizure or antiepileptic drugs

• are targeted to inhibit neurotransmission.

• This can be achieved via blocking sodium or

calcium excitatory channels/currents, calcium excitatory channels/currents,

• enhancing the inhibitory activity of

– gamma-aminobutyric acid (GABA),

• or by blocking glutamate receptors

Pathophysiology of Seizure Types

• Focal

– Decreased inhibition—defective activation of GABA neurons, defective GABA-A/ -B inhibition, a defect in intracellular calcium regulation

– Increased excitation—increased activation of glutamate N-methyl-D-aspartate (NDMA) receptors, increased synchrony or activation of receptors, increased synchrony or activation of neurons

• Generalized

– Altered thalamocortical rhythms (regulated by the T-type calcium channels/currents)

Sodium channel blockade:

phenytoin and phenobarbital and valproic acid at high doses.

Block of voltage-gated sodium channels in neuronal membranes

prevents Na+ influx, which results in decreased axonal conductance by

increasing the refractory period of the neuron.

the main effect of antiseizure drugs is to suppress

the abnormal electrical activity at the epileptic foci in the brain.

Antiseizure Drugs (Anticonvulsants)

Promotion of GABA-related inhibition:

Increase the frequency of chloride ion channel opening—benzodiazepinesIncrease the frequency of chloride ion channel opening—benzodiazepines

Increase the duration of chloride ion channel opening—barbiturates, such as

phenobarbital

Glutamate NMDA receptor blockade: decreased glutamic acid excitability—

felbamate

Phenytoin

Most widely used antiepileptic drug

Fosphenytoin

Mechanism of action:

sodium channel blockade

Use: Status epilepticus , GTC seizures (primary or secondary), Focal seizures

Selection of antiseizure drugs

GTC SeizuresFocal (Partial)

Seizures

Typical Absence

Seizures

Atypical

Absence

Seizures,

Myoclonic

Seizures

Valproic acid Lamotrigine

First

line

Valproic acid

TopiramateCarbamazepine

Phenytoin

Phenobarbital(infants)

Lamotrigine

Carbamazepine(oroxcarbazepine)

Phenytoin

Ethosuximide

Valproic acid

Valproic Acid

Lamotrigine

Selection of antiseizure drugs

GTC SeizuresFocal (Partial)

Seizures

Typical Absence

Seizures

Atypical

Absence

Seizures,

Myoclonic

Seizures

Second

Line

Phenytoin

Phenobarbital(adults)

Phenobarbital

Topiramate

Valproic Acid

Lamotrigine

Clonazepamd

Levetiracetam

Zonisamide

Clonazepam

Levetiracetam

Zonisamide

Intravenous Anesthetics• Barbiturates

• Barbiturates such

as thiopental and methohexital induce anesthesia by

acting on GABAAreceptors.

• Thiopental is also recommended in traumatic brain injury

patientspatients

• to induce coma or for urgent surgical interventions such as

– epidural hematoma because

• it decreases the intracranial pressure

– by decreasing the cerebral blood flow without inducing

vasodilation.

Benzodiazepines act on GABA receptors

• Diazepam can be used– for seizure abortion

– it does not have an anesthetic or an analgesic effect.

– It can decrease anxiety before surgery.

• Midazolam is used to induce anesthesia.

KetamineKetamine

is a analgesic causes analgesia and amnesia

Ketamine acts by inhibiting

• the NMDA glutamate receptors.– it can increase the intracranial pressure.

• ketamine should be used with caution in patientswith cardiovascular disease– it can elevate the blood pressure

Sedative and Hypnotic Drugs

• Sedation:

• state of decreased responsiveness to any level of

stimulation

• associated with some decrease in motor activity and

ideation.

• Sedatives:

• drugs which subdue excitement (anxiolytic)

• calm the subject without inducing sleep,

• though drowsiness may be produced.

• Hypnotic:

• the drugs which induce and/or maintain sleep, similar

to normal arousable sleep.

Classification of Sedative and Hypnotic Drugs

• Barbiturates

– Long Acting: Phenobarbital

– Short Acting: Secobarbital

– Ultra Short (immediate) Acting: Thiopentone

• Benzodiazepines• Benzodiazepines

– Long Acting: Flurazepam

– Short Acting: Alprazolam

– Ultra Short (immediate)

actingcting: Triazolam, Lorazepam, Diazepam

– Atypical: Zopiclone, Eszopiclone, Zaleplon, Zolpidem,

Barbiturates

Act at GABAA:

→Keep the GABA induced opening of Cl– channel

for longer duration

→ Increase the ionic flow across the membrane

→ produce inhibitory effect

Important: As compared to benzodiazepines, Important: As compared to benzodiazepines,

barbiturates increase the duration of opening instead

of frequency of opening.

• depress

– the glutamate induced neural depolarization

through AMPA receptors.

• at high concentrations inhibit

– sodium and potassium channels.

Barbiturates

• Adverse effects

– Hangover

– Tolerance

– Dependence– Dependence

– Mental confusion

– Porphyria

– Hypersensitivity

Benzodiazepines (BZD)

• They increase the frequency of opening of GABAA:

receptor-Cl– Channels.

• They enhance the binding of GABA with

GABAA receptor.

• They don’t have the GABA mimetic action.

• Even after 20 times higher hypnotic doses

– respiration will not be depressed

• They decrease BP

• Diazepam and Lorazepan decreases cardiac output

• Midazolam decreases peripheral resistance.

Benzodiazepines (BZD)• Selective anxiolytic,

• sedative,

• muscle relaxant

• anticonvulsant action.

• All BZD reduce duration of REM except Clonazepam• All BZD reduce duration of REM except Clonazepam

• diazepam have higher muscle relaxant activity

• Hepatic metabolism is the main pathway of disposal.

• They are metabolized into more active metabolites.

Classification of Local Anesthetics

• Structurally, local anesthetics have

– a lipophilic aromatic ring

– which is connected to a hydrophilic group

– by an intermediate chain,

– which can be an amide or an ester.which can be an amide or an ester.

• Amides

• Lidocaine (or lignocaine), prilocaine, mepivacaine,

etidocaine, bupivacaine, ropivacaine and

levobupivacaine

• Esters

• Cocaine, procaine, chloroprocaine, tetracaine and

benzocaine

Drug Onset Duration

Bupivacaine Slow Long

Chloroprocaine Fast Short

Etidocaine Rapid Long

Lidocaine Fast Intermediate

Pharmacological Properties of Some Local Anesthetics

Lidocaine Fast Intermediate

Mepivacaine Moderate Intermediate

Prilocaine Fast Short

Procaine Fast Short

Ropivacaine Moderate Long

Tetracaine Slow Long

Bupivacaine

Properties

The duration of effect is 6-–18 hours.

– Causes more sensory than motor block.

– One of the longest acting local anesthetics

(half-life, 3.5 h).(half-life, 3.5 h).

Use

– Agent of choice for postoperative/labor epidural analgesia

(liposome injectable suspension can provide postoperative

analgesia lasting ≥ 24 h).

Toxicity

– Considerable risk of cardiotoxicity;

Cocaine

It has significant surface local anesthetic activity.

– It is the only local anesthetic with intrinsic

vasoconstrictor activity;

this helps reduce intraoperative bleeding

– Preferred in head, neck and pharyngeal

surgerysurgeryEtidocaine

More motor blockade.

– Motor block makes it unsuitable for use during labor.

– Less toxic than bupivacaine and more toxic than

lidocaine.

Mepivacaine– Not metabolized by neonates.

– Anti-arrhythmic properties

– Not recommended in obstetric anesthesia.

– Rapid placental transfer.

PrilocainePrilocaine

Most useful for high-dose blocks (pudendal and head–neck–face blocks).

– Can cause methemoglobinemia when doses

> 600 mg (because of the metabolite ortho-toluidine).

Procaine

It is metabolized very rapidly by pseudocholinesterase (half-life, 1–2 min).

– Agent of choice when there is a history of malignant hyperpyrexia.

– Used in patients with an allergy to amides.

– Relatively nontoxic.

Ropivacaine

– One of the longest acting local anesthetics (half-life, 4.2 h).

– Causes more sensory than motor block.– Causes more sensory than motor block.

– High-dose peripheral blocks.

– Postoperative/labor epidural analgesia.

– Less toxic than bupivacaine.

Tetracaine

Has some surface activity.

– Intradural blocks.

– Can cause cardiac asystole or ventricular fibrillation.

Lidocaine

– Has some surface activity.

– Metabolized by the liver;

plasma clearance is dependent on hepatic blood flow

– Onset of action: 2–5 min.

– Duration: 30 min to 2 hours without epinephrine

and up to 3 hours with epinephrine.

LidocaineRoutes of administration:

intravenous or intramuscular;

it is never given orally because

– of high first-pass effect

– the metabolites are more cardiotoxic

Use:

− Local anesthetic

− Type 1B antiarrhythmic—useful in acute ischemic ventricular arrhythmias (by

reducing abnormal automaticity)reducing abnormal automaticity)

− Useful in digoxin-induced arrhythmias

Cardiovascular and neurotoxic effects

(usually CNS stimulation, including seizures)

– Cardiotoxicity can be enhanced in the presence of hyperkalemia

– Rashes

– High incidence of transient neurologic symptoms