dr. laila m. matalqah ph.d. pharmacology pharmacology of cns part 2 general pharmacology m212
DESCRIPTION
Opioid receptors All 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 dynorphinsTRANSCRIPT
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