Dr. Laila M. MatalqahPh.D. Pharmacology

PHARMACOLOGY OF CNS part 2

General PharmacologyM212

Opioids analgesics

Opioid receptorsAll opioids act by binding to specific opioid receptors

Location: CNS, periphery, GIT and other organs

Receptor families: μ (mu), κ (kappa) and δ (delta)

Endogenous peptide neurotransmitters (endogenous

opioids): endorphins, enkephalins and dynorphins

Opioid receptorsReceptor subtype

Functions

μ (mu)AnalgesiaSedationInhibition of respirationSlowed gastrointestinal transitModulation of hormone and neurotransmitter release

δ (delta)AnalgesiaModulation of hormone and neurotransmitter release

Κ (kappa)AnalgesiaPsychotomimetic effectSlowed gastrointestinal transit

Opioid analgesics A. STRONG AGONISTS Morphine: Main receptor: μ (mu) agonist Side effects: 1. Euphoria: General feel of well being ??2. Respiratory depression: Due to ↓ sensitivity of respiratory centre

neurons to CO2 level3. Miosis: Pinpoint pupil 4. Emesis: CTZ 5. Constipation: Decrease GIT motility6. Depression of cough reflex 7. Histamine release --- bronchospasm , hypotension 8. Increase ADH- less urine output 9. Tolerance and dependence

MorphinePh/K: 1. Oral, IV, S.C, and IM2. Duration of action is 4 – 6 hours for morphine naïve patients Metabolism: glucoronidation in the liver to

Morphine-6-glucoronide (very potent analgesic)Morphine-3-glucuronide (no analgesic activity – believed to

cause neuroexcitatory @ high doses)Avoid in neonates no enough glucoronidation

Opioid analgesics

1. Morphine Therapeutic uses:1. Analgesics: Analgesia: loss of pain without loss of

consciousness2. Treatment of diarrhea3. Relief of cough Pulmonary edema associated with left

ventricular failure, possibly by its vasodilatory effect.

Antidote: (Opioids anatgonists) 1. Naloxones2. Naltrexones

Opioid analgesics

2. Heroin Same action like morphine Heroin is converted to morphine in the body threefold more potency than morphine More euphoria and marked dependence and tolerance

3. Methadone MOA: μ receptors agonist and antagonist of the N-methyl- D-

aspartate (NMDA) receptor Orally Action similar to morphine (equianalgesic) less Euophoria than morphine Less withdrawal syndrome Use in treatment of morphine and heroin dependence,

neuropathic pain

Opioid analgesics

2. Opioids analgesics B. Moderate Agonists:1. Codeine Is a much less potent analgesic than morphine. Codeine’s analgesic potency is approximately 30

percent that of morphine. Good antitussive activity at doses that do not

cause analgesia. Has a lower potential for abuse than morphine. Codeine is often used in combination with aspirin

or acetaminophen

2. Opioids analgesics C. Mixed agonist-antagonists and partial

Agonists :1. Pentazocine acts as an agonist on κ receptors and weak

antagonist at μ and δ receptors. used to relieve moderate pain. orally or parenterally Tolerance and dependence

3. Other analgesics 4. μ-Opioid receptor weak agonistTramadol is a centrally acting analgesic that binds to the

-μ opioid receptor. It is used to manage moderate to moderately

severe pain. Its respiratory-depressant activity is less than

that of morphine.

Meperidine / PethidineSynthetic opioid - lower potency – structurally not

related to morphine

κ agonist with some μ agonist

The active metabolite is normeperidine is very neurotoxic Analgesic for acute pain only (short term less than 48 hours)

Shorter duration of action than morphine (2 – 4 hours)

Oral, but parenteral is more often used

Opioid antagonistsDrugs that bind to opioid receptors block the full

agonist at μ-receptor won’t be able to exert it’s effect, they reverse its effect and precipitate symptoms of opioids withdrawal.

Alone no effect, no activation receptor-mediated response

Uses: opioid toxicity antidote, and aid for opioid dependence withdrawal

They antagonise I.V opioids and not oral

Naloxone and naltrexone

4. Anticonvulsant (Drugs for Epilepsy)

Epilepsy is a sudden, excessive, and synchronous discharge of cerebral neurons.

This abnormal electrical activity may result in a variety of events: loss of consciousness, abnormal movements, atypical behavior, abnormal movements distorted perceptions

4. Anticonvulsant (Drugs for Epilepsy) Classification of seizures

4. Anticonvulsant (Drugs for Epilepsy)Mechanism of action of antiepileptic

drugs1.Blocking voltage-gated channels (Na+ or

Ca2+),2.Enhancing inhibitory γ-aminobutyric acid

(GABA)-ergic impulses, 3.Inhibit the excitatory glutamate

transmission.

4. Anticonvulsant (Drugs for Epilepsy)

1. Benzodiazepines: MOA: bind to GABA inhibitory receptors Diazepam and lorazepam for:

Status epilepticusProlonged generalised tonic-clonic seizures

2. Carbamazepine: reduces the propagation of abnormal impulses

in the brain by blocking sodium channels

4. Anticonvulsant (Drugs for Epilepsy)

3. Ethosuximide: MOA: inhibiting calcium channels Only for absence generalised seizures

4. Felbamate: broad spectrum 1) blocking sodium channels, 2) competing with glutamate receptor, 3) blocking calcium channels, and 4) potentiating the action of GABA.

5. Gabapentin: is an analog of GABA, Well tolerated by elderly patients

6. Lamotrigine: blocks sodium channels as well as high voltage–dependent calcium channels

For broad variety of seizures

4. Anticonvulsant (Drugs for Epilepsy)

7. Phenobarbital: enhancing the inhibitory effects of GABA-mediated neurons

For status epilepticus when other agents fail 8. Phenytoin and fosphenytoin: blocks voltage-gated

sodium channels9. Pregabalin: Binds to Ca+2 voltage-gated channels in CNS10. Topiramate: blocks voltage-dependent sodium channels, 11. Valproic acid (Divalproex): sodium channel blockade

and calcium channels, blockade of GABA transaminase12. Primidone:

Prodrug Phenobarbital Longer t1/2 than phenobarbital Only for refractory epilepsy

4. Anticonvulsant (Drugs for Epilepsy)Drugs of choice:1.Partial epilepsy: lamotrigine and Topiramate 2.Primary generalized

a) Absense : Ethosuximide b) Tonic clonic / Myoclonic : Benzodiazepines, Carbamazipines, Lamotrigine and valproic acid c) Status epilipticus: Phenobarbital, Phenytoin, Benzodiazepines, and Barbiturate

Epilepsy in pregnancy: Divalproex and barbiturates should be avoided.Elderly: Gabapentin and lamotrigine

epilepsy

Phenytoinblocks voltage-gated sodium channels can also

block voltage-dependent calcium channels

Phenytoin is effective for treatment of partial seizures and generalized tonic-clonic seizures and in the treatment of status epilepticus

The drug is 90 percent bound to plasma albumin.

Phenytoin induces drugs metabolized by the CYP2C and CYP3A families

PhenytoinPhenytoin exhibits saturable enzyme metabolism

at a low serum concentration (zero-order kinetics)Small increases in a daily dose can produce large

increases in the plasma concentration, resulting in drug-induced toxicity

Side effect / toxicity:Depression of the CNSAtaxia and Nystagmus Gingival hyperplasiaperipheral neuropathies and osteoporosis

Orally, can not be given I.M?? Tissue necrosis and damage

FosphenytoinProdrug of phenytoinConverted to phenytoinGiven : I.M and I.V Rapid onset of action

Valproic acid and divalproexDivalproex Na = Na valproate + valproic acidSodium valproate was developed to improve gastrointestinal

tolerance of valproic acidMOA

sodium channel blockadeblockade of GABA transaminaseaction at the calcium channels

broad spectrum of activity against seizures. It is effective for the treatment of focal and primary generalized epilepsies

Drug-drug interactions :1.Valproate is bound to albumin (greater than 90

percent), which can cause significant interactions with other highly protein-bound drugs

2.inhibits metabolism of the CYP2C9Teratogenic

CarbamazepineCarbamazepine is effective for treatment of

partial seizures and, secondarily, generalized tonic-clonic seizures.

C/I: absence seizuresIt induces its own drug metabolism and has an

active metabolite. Carbamazepine is an inducer of the isozyme

families CYP1A2, CYP2C, and CYP3AS/E:

Hyponatremia (Elderly)Rash