Pharmacology of CNS: introductionocw.usu.ac.id/course/download/1110000094-control-system/cst125_slide... · Central Analgesics– site of action is within the CNS NSSSAIDS – Non-steste

Pharmacology of CNS:gyintroduction

Aznan Lelo, Tri WidyawatiAznan Lelo, Tri Widyawati

Dep Farmakologi & TerapeutikDep. Farmakologi & Terapeutik,Fakultas Kedokteran

U i it S t UtUniversitas Sumatera Utara25 Januari 2008, KBK, FK USU

CNS drugsCNS drugs• act on

– brain and – spinal cord

i• in :– medical use

treatment of mental illness s ppression of• treatment of mental illness, suppression of seizures, relief of pain, and production of anesthesia) and

– non-medical uses • stimulants, depressants, euphoriants, and th i d lt i– other mind altering uses

T itt f th CNSTransmitters of the CNS

• Norepinephrine• Epinephrine p p• Dopamine• Acetylcholine• Acetylcholine• Serotonin• Gamma amino butyric acid (GABA)• Glutamate

Nervous system is chemical himachine

Chemical transmitter : chemical mediatorsNeurotransmitters :

l d b ti t i lreleased by presynaptic terminalproduced rapid excitatory or inhibitory responses in

post-synaptic neurons.post synaptic neurons.fast N.T : operated thru’ ligand-gated ion-channel:

glutamate, GABA.slow N.T : thru’G-protein-coupled receptors:

dopamine, neuropeptides.

Chemical ImbalancesNorepinephrine

Too much- anxiety, panic anorexia, excitability, insomniaToo little Depression ADD/ADHDToo little - Depression, ADD/ADHD

DopamineToo much- Psychoses, Tourettes/Tics, choreaToo little - Parkinson’s ADD/ADHD, depression, p

AcetylcholineToo much-delirium, confusion, psychosesToo little -Alzheimers

S t iSerotoninToo much- Sleep, Hallucinations,Decreased appetite, anxietyToo little - Depression, OCD, pain sensitivity

Gamma amino butyric acid (GABA)Gamma amino butyric acid (GABA)Too much- CNS depression, Resp. depression, SedationToo little - Seizures, Movement disorders

GlutamateToo much- Seizures, neuronal degenerationToo little - Schizophrenia, depression, cognitive impairment

Central Nervous System DrugsCentral Nervous System Drugs

• The brain’s ability to adapt to a drug canThe brain s ability to adapt to a drug can produce alterations in therapeutic effects and in side effects.

• The blood brain barrier- impedes entry of drugs into the brain, limited to lipid soluble agents or drugs by specific transport systems in an intact barrier, this is positive (protection from toxic substances) and negative (obstacle totoxic substances), and negative (obstacle to therapeutics) not fully developed at birth.

Topics to be discussedTopics to be discussed

• Analgesicsg• Anaesthetic agents• Anti-depressantsp• Anti-psychotics• Anti-Parkinson drugs• Anxiolytics /hypnotics• Anti-epileptic medicines• Muscle relaxants• Treatments for dementia

Pain ManagementPain Management

• PainPain– Unpleasant sensory and emotional

experience associated with tissue damageexperience associated with tissue damage– Patient’s pain description is the cornerstone of

pain assessmentpain assessment

Types of PainTypes of Pain

• Nociceptive painNociceptive pain– Results from injury to tissues

Called somatic or visceral pain– Called somatic or visceral pain• Neuropathic pain

f– Results from injury to peripheral nerves– Responds poorly to opioids

Centrally Mediated Pain InhibitionCentrally Mediated Pain Inhibition

• Many pathwaysMany pathways mediate pain-with many potential mechanisms for pain relief

• Targets descending inhibitory pain pathwayspathways

Targets descending inhibitory i hpain pathways

Analgesicsgdrugs with a predominant pain-relieving activityTwo classes:O i id ti l i i l dOpioids or narcotic analgesics – includes

alkaloids of opium poppies, semi-synthetic analogs of opium alkaloids and y gtotally synthetic agents that may or may not be related structurally

All are Schedule II, III, IV agents due to high addictive , , g gpotential

Prototypical agent is morphine - all agents are compared to this standard agent that is a natural p gopium alkaloid

Central Analgesics – site of action is within the CNSNSAIDS – Non-steroidal anti-inflammatory drugsS S o ste o da a t a ato y d ugs

they are NOT narcotics and have no addiction potentialalso have useful antipyretic activity and/or anti-inflammatory actions

WHO Analgesic LadderWHO Analgesic Ladder

• Step 1- Mild to moderate painStep 1 Mild to moderate pain– Nonopiod analgesic

Step 2 More severe pain• Step 2- More severe pain– Add opioid analgesic

• Step 3- Severe pain– Substitute opioid-morphine

OPIOIDS

NMDAµ1 POST-SYNAPPRE-SYNAP

Glu

NMDAB

ITIO

N

ACTIVATIONACTIVATIONf PAIN

Subs.P

M1 NK-1INH

IB

ACTIVATIONof PAIN

Adr α2

α2

Adr

ACh

α2

INHIBITION

CLONIDINEINHIBITION

f PAINACh

GABAGABA

of PAIN

MIDAZOLAME

Opioid (Narcotic) AnalgesicsOpioid (Narcotic) Analgesics

• AnalgesicAnalgesic– Relieves pain without loss of consciousness

Opiod• Opiod– Drug similar to morphine

f– Derived from opium

Non-drug Therapy for Pain Management

• Application of heat and coldApplication of heat and cold• Massage

E i• Exercise• Acupuncture• Relaxation• ImageryImagery• Peer group support

Drugs for HeadacheDrugs for Headache

• Migraine HeadachesMigraine Headaches– Inflammation and dilation of intracranial blood

vesselsvessels• Head Pain

T• Types– With aura (classic migraine)– Without aura (common migraine)

Local anestheticsLocal anesthetics

• Reversible blockade of neural conduction by ytheir action on the sodium channels of neuron

• MOA: prevents generation and conduction of i i l d d i bnerve action potentials and conduction by

inhibiting ion fluxes increasing the electrical excitation threshold slowing the impulseexcitation threshold, slowing the impulse generation and rise of the action potential

• Two Classes of local anesthetics based on chemical structure: – Esters and

Amides– Amides

General AnestheticsGeneral AnestheticsMechanism of Action: the goal is to produce a certain partial pressure of the

gas in brain tissueDecreased ne ronal acti it b increasing the electrical threshold needed to• Decreased neuronal activity by increasing the electrical threshold needed to induce an action potential

• The different stages and planes of anesthesia are a result of differential selectivity and sensitivity of neurons to increasing concentrations of an anesthetic agentanesthetic agent

– Sensory pathways are very sensitive to low levels of the agents leading first to analgesia (Stage I)

– Next inhibitory neurons are effected leading to delirium, excitation and vomiting (Stage II)( g )

– Further depression of reticular activation system neurons leads to Stage III– Stage IV occurs due to CV and respiratory control neurons inhibition (relatively

resistant to anesthetics but a small portion of the population are very sensitive leading to death

M l l h i f l th i i l t l l d fi dMolecular mechanisms of general anesthesia are simply not clearly defined– Lipid solubility theory-activity increases with lipid solubility– Miller-Pauling theory-increased potency associated with ability to induce

ordered, crystal-like structure to water in neuron membranesPotency related to the ability of the agent to reduce surface tension– Potency related to the ability of the agent to reduce surface tension

Anti-DepressantspPRINCIPLES• theory (probably wrong) supposes central• theory (probably wrong) supposes central

monoamine deficiency (5HT/NAd). Explains efficacy of drugs that:– increase monoamine synthesis (tryptophan)– prevent reuptake of monoamines (TCAs/SSRIs)– prevent monoamine breakdown (MAOIs)p ( )

• generally takes 3-4 weeks for effect to be evident (elderly longer).

• No antidepressant is clearly more effective than• No antidepressant is clearly more effective than another

• Most patients with major depression respond to p j p pinitial medication regardless of the type of antidepressant

Anti-PsychoticsAnti Psychoticschlorpromazine thioridazine olanzepine/flupentixol/haloperidol

Sedation +++ ++ +

Anti-cholinergic ++ +++ +Anti cholinergic

EPS ++ ++ +++

• Dopamine theory: blockade helps• Dopamine agonists worsen schizophrenia• ? Lots of other neurotransmitters involved• Rise in prolactin levels can cause gynaecomastia or galactorrhoea

Characteristics of Antipsychotic drugsCharacteristics of Antipsychotic drugs

Antipsychotic Receptor affinityAntipsychotic drugs

Receptor affinityD1 D2 α-Adr 5-HT2 Musc H1

Chlorpromazine ++ +++ +++ ++ ++ ++

Thioridazine + ++ +++ ++ ++ -

Clozapine ++ ++ ++ - ++ ++

Haloperidol + +++ ± + ± +

Risperidone ++ +++ ++ + - -p

Drugs for Parkinson’s DiseaseDrugs for Parkinson s Disease

• Treatment strategyTreatment strategy– Restore balance between DA and ACH by

• activating DA receptors or• activating DA receptors or • blocking ACH receptors.

• Drug selection and dosages are• Drug selection and dosages are determined by activities of daily living performanceperformance

Epilepsyp p yGroup of disorders characterized by

excessive neuron stimulation within the CNS

Antiepilectic Drugsp g• Suppress neuronal discharge at the

i ’ f d b iseizure’s focus and brain• Mechanism of action

S i f di i fl– Suppression of sodium influx– Suppression of calcium influx

prevent depolarisation of neurones:prevent depolarisation of neurones:inhibition of excitatory neurotransmittersdirect membrane stabilisationstimulation of inhibitory neurotransmitters

Drugs of Choice in Treatment of Specific S i TSeizure Types

S i di d Drugs of choiceSeizure disorder g(1st choice in bold)

Primary generalised tonic clonic Valproate(grand mal) Carbamazepine

PhenytoinPartial including secondary CarbamazepinePartial, including secondary generalised

Carbamazepine PhenytoinValproatep

Absence (petit mal) Ethosuxamide Valproate

Atypical absence, myoclonic, atonic Valproate

NEWER ANTIEPILEPTIC AGENTSNEWER ANTIEPILEPTIC AGENTS• add on therapy in patients who are not adequately controlled with current medication

• A licence for monotrherapy is usually obtained later when evidence of safety and efficacy obtained• A licence for monotrherapy is usually obtained later when evidence of safety and efficacy obtained

Agent mechanism comments

Vigabatrin structural analogue of GABA CNS effectsirreversible inhibition of causes weight gaing gGABA-transaminase ` combination only

Lamotrigine membrane stabiliser by blocking voltage less CNS effects than older agentsdependent sodium channels maculopapular skin rash / SJ syndsecondary impaired release of excitatory mono or combination

i idaminoacids

Gabapentin GABA analogue but mechanism of action combination onlyobscure

Topiramate blockade of voltage sensitive sodium adjunct in partial seizuresTopiramate blockade of voltage sensitive sodium adjunct in partial seizureschannels, enhanced GABA, glutamate inhibition

Oxcarbazepine similar to carbamazepine

Levetiracetam adjunct treat for partial seizuresj p

Drugs for Alzheimer’sDrugs for Alzheimer s

• Cholinergic transmission decreased in Alzheimer’sg• Drugs that enhance ACh activity by acetylcholinesterase

inhibition theoretically should work• Eg donepezil rivastigmine galantamine• Eg. donepezil, rivastigmine, galantamine

• ? Do they work

• Adverse effects : – nausea, – diarrhoeadiarrhoea, – abdominal cramps, – bradycardia, – urine incontinence– urine incontinence

AnalepticsAnaleptics

• A drug used to stimulate the CNS that canA drug used to stimulate the CNS that can induce convulsions in a dose-dependent mannermanner

• CaffeineMOA l ti t i t f– MOA: non-selective antagonist of adenosine receptors, increased cAMP i h h di t i hibitivia phosphodiesterase inhibition

AnorexiantsAnorexiants

Indications: short-term adjunct used in conjunctionIndications: short term adjunct used in conjunction with caloric restriction for exogenous obesity (no more than 8-12 weeks recommended)

MOA: direct stimulate effect on the satiety center in the hypothalamic and limbic regions of the brain producing a loss of appetite

Two classes:• Amphetamine like analogs – phenethylamines • Non-phenethylamines

KEBANGGAAN INDONESIA UNTUK DUNIAKEBANGGAAN INDONESIA UNTUK DUNIA

Analeptics – A drug used to stimulate the CNS that can induce convulsions in a dose-dependent manner

NN

O CH3CH3

NoDoz® - 100-200 mg tablets, chewable tablets and injectable

Indications: fatigue, drowsiness, adjunctive in analgesic preparations, respiratory depression (injection), actopic

NNOCH3

C ff i

dermatitis, obesity in combo with ephedrine, headache, treatment of excited or comatose alcoholic patients, postprandial hypotension

Caffeine MOA: non-selective antagonist of adenosine receptors, increased cAMP via phosphodiesterase inhibition

NO

Indications: postanesthesia drug induced respiratory depression or apnea due to drugs other than muscle relaxants, stimulation of drug induced CNS depression,

NO

CH3

HCl COPD associated with acute hypercapnia, apnea of prematurity

MOA: stimulates peripheral carotid chemoreceptors—i tid l l d i ti t d i

Doxapram HCl - Dopram®increases tidal volume and respiration rate, as dose is increased medullary respiratory centers are stimulated

Anorexiants

Indications: short-term adjunct used in conjunction with caloric restriction for exogenous obesity (no more than 8-12 weeks recommended)

MOA: direct stimulate effect on the satiety center in the hypothalamic and limbic regions of the brain producing a loss of appetite

Two classes:

1. Amphetamine like analogs – phenethylamines

2. Non-phenethylamines

Patient information: Best if taken on an empty stomach (except mazindol which can be taken with food to prevent GI upset), avoid taking medication late in the day to avoid insomnia, do not crush or chew SR products tolerance will occur if taken more frequently thanproducts, tolerance will occur if taken more frequently than prescribed

Can produce psychological disturbances due to caloric restrictions---can lead to psychosis indistinguishable from schizophrenia can lowerlead to psychosis indistinguishable from schizophrenia, can lower seizure thresholds, NOT recommended if CV disease present---monitor BP in hypertensive patients continually

Analgesics – drugs with a predominant pain-relieving activity

Two classes:

1. Opioids or narcotic analgesics – includes alkaloids of opium poppies, semi-synthetic analogs of opium alkaloids and totally synthetic agents that may or may not be related structurally

• All are Schedule II, III, IV agents due to high addictive potential

• Prototypical agent is morphine---all agents are compared to thisPrototypical agent is morphine all agents are compared to this standard agent that is a natural opium alkaloid

2. Central Analgesics – site of action is within the CNS

3 NSAIDS N id l i i fl d h NOT i3. NSAIDS – Non-steroidal anti-inflammatory drugs---they are NOT narcotics and have no addiction potential

• Many also have useful antipyretic activity and/or anti-inflammatory tiactions

• When compared to the narcotic agents their analgesic activity is: relatively weak involving primarily peripheral actions with minor centrall mediated actionscentrally mediated actions

Central Analgesic agentsAgents that produce analgesia not mediated by opiate receptorsAgents that produce analgesia not mediated by opiate receptors but via other neuronal mechanisms

Orally used as an anti-hypertensive agent

NH N

HCl

For analgesic activity it is given via the epidural route. Used in combination with opiates when opiates alone are ineffective

N Cl

Clonidine - Duraclon®

NOT recommended for ostetrical, post-partum or peri-operative pain management

MOA: produces analgesia at both presynaptic and postjunctional α2-adrenoceptors in the spinal cord that are responsible for pain transmission to the brain

Methotrimeprazine - Levoprome® - Structure ??? – a phenothiazineIndications: relief of moderate to marked pain in non-ambulatory patients, obstetrical analgesia and sedation in order to avoid respiratory depression in the infants and mother pre anesthetic anti anxiety agentinfants and mother, pre-anesthetic anti-anxiety agent

MOA: increases pain threshold and produces amnesia, possesses antihistaminic, anticholinergic and antiadrenergic effects

NORMAL TRANSMISSIONMODEL 1 - NORMAL TRANSMISSION

INNOCOUS OR NOXIOUS STIMULATIONINNOCOUS OR NOXIOUS STIMULATION

Afferent Input

SP GluTAMATE

Ca2+

AMPA NK1

P t ti ti it

Normal SensibilityDoubell et al., 1999Modifikasi Meliala, 2003

Postsyneptic activity

SUPRESSED TRANSMISSIONMODEL 2 – Supressed Transmission

Activation of segmental and descending inhibitory systemsActivation of segmental and descending inhibitory systems

Afferent Input

Presynaptic

SP GluTAMATE

GABAMORSHT Adenocine

Gly

Ca2+

Postsynaptic

AMPANK1P t ti ti it

MCR SHT GLYCINEGABA

Reduced Sensibility

Postsyneptic activity

Doubell et al., 1999Modifikasi Meliala, 2003

FASCILITATED TRANSMISSIONMODEL 3 – Fascilitated Transmission

Increased excitation/reduced inhibitionIncreased excitation/reduced inhibition

Afferent Input

Ca2+ ATP Ca2+

SP SDNF GLUTAMATE

ReducedPresynaptic

inhibition

GABA

MOR

SHT

AdenocineVSCCP2X3NMDA

mGluR

Mg2+

Ca2+

PresynapticAugmentation

Ca2+

AMPA MORReduced

GABAT kBVSCC NMDACa2+Ca2+Ca2+

Retrogrtade signale e.g.NOIncreased transmitter release

AMPANK1

MOR

GLYCINE

Postsynapticinhibition

GABA

mGluR

Mg2+

TrkB SHTVSCC NMDA

Ca2+ PKC

S/TTyr

Brc

Postsynapticfacilitation

Reduced Sensibility

Postsyneptic activity

Doubell et al., 1999Modifikasi Meliala, 2003

CaPLC

Terapi Nyeri Neuropatik Berdasarkan Mekanisme

OtakInhibisidesendenNE/5HTLesi Tx

TCATramadolOpioid

M d ll

Reseptoropioid

Lesi Opioiddll

Sensitisasi

GBPOXCLTGMedulla

SpinalisSensitisasi perifer/ ion Na

Sensitisasisentral(NMDA,Calcium)

TxLTGKetaminDextrome-thorphan

CBZOXCPHTTxMexiletineLidocain, etc

Beydoun, 2002

• Aktivitas ektopik• Sensitisasi nosiseptor

MekanismePerifer

p• Interaksi abnormalantar serabut saraf

• Sensitisasi terhadapkatekolamin

NYERI NEUROPATIK

MekanismeS t l

• Sensitisasi sentral

NEUROPATIK

Sentral • Disinhibisi

Evoked spontaneousMekanisme Perifer

Calcium channels

NMDAetc

Hyperexcitability

GABA Ad i

Alteration and redistributionof channels, etc

Adenosine?Peripheral nerve

Spinal cord

Damaged zoneEctopic/ephaptic

impulses Spinal cordimpulses

Dickenson, 2000

Mekanisme Perifer

NON EPHAPTIC CROSS EXCITATION

neurotransmitter

NON-EPHAPTIC CROSS-EXCITATION

K+

StimCNS K+

Devor & Seltzer, 1999

Pharmacology of CNS: introductionPharmacology of CNS: introduction

• Division of the CNSDivision of the CNS• Types of central excitation and inhibition

N h l h i f CNS• Neuro-hormonal mechanism of CNS• Classification of CNS drugs• Characteristics of general CNS depression

and stimulations• Factors that effect intensity and duration of

CNS drug effectCNS drug effect