—Narcotics that can cause analgesia. They are opioids (naturally comes from Poppy plant).
Opioids—agents which pharmacologically behave like Opium. (May not be natural)
—any substances which occupy the opioid receptors. (New definition)
*** Pharmacological effects of opioid are antagonized by Naloxone.
CLASSIFICATION—
· Natural opium alkaloids (2 types according to the chemical structure)—
1. Phenanthrene group—Morphine (10%), Codein (0.5%), Thebatin (0.2%)
{Analgesic and smooth muscle constrictor}
2. Benzyl Isoquinoline group—Papaverine, Noscapine, Narcotine, Narceine
{Not analgesic and smooth muscle relaxants}
· Semisynthetic opioids—Heroin (Di-acetyl Morphine), Dihydromorphine, Oxymorphine
Dihydrocodeine, Oxycodeine, Ethorphine
· Synthetic Opioids—
1. Phenyl Piperedine derivatives—Pethidine (meperidine), Fentanyl (anesthetics)
Diphenoxylate, Luperamide (control diarrhoea)
Alfentyl, Sufentyl (anesthetics)
2. Methadone series—Methadone (given to addicts), Dextropropoxyphene
Levomethadyl Acetate (new, long duration)
3. Benzomorphoxo series—Pentazocin, Cyclazocin, Phenazocin
4. Morphinans—Levorphanol
· Mixed agonist and antagonists—Nalbuphine, Butorphenol
(Both agonist and antagonist are alkaloids)
· Antagonists—Naltrexone, Nalmefen, Naloxone (full antagonists)
Nalorphine, Levallorphan (partial antagonists)
· Endogenous opioid peptides (opiopeptines)—β Edorphine, Dynorphine, Encephalin
Pain carrying pathway—when there is tissue damage in the periphery, afferent fibers from the damaged site carry the pain impulses via dorsal root ganglion and terminate in the Substancia Gelatinosa Rolandi (SGR) situated at the tip of the dorsal horn. The first neuron ends here.
The second neuron arises from the SGR, crosses to the opposite side and constitutes anterior and lateral spinothalamic tract (STT).
There are 2 groups of fibers in the STT—
- Direct spinothalamic system—these fibers terminates in the ventral posterolateral nucleus of the thalamus. Next order neuron arises from there and terminates in the post-central gyrus of the cerebral cortex.
- Spino-reticular thalamic system—these fibers arising from SGR terminate in the intermediate relaying center of the brain stem. Next order neuron arises from here and to terminate in the thalamus, then to the cortex.
Endogenous pain inhibiting system—our body contains a pain inhibiting system, which when stimulated can partly or sometimes wholly reduce the perception of the pain.
Pathway—PAG (peri aqueductal grey) is a grey matter situated in the upper part of the brain stem close to the aqueduct of Sylvius. Fibers arise from the PAG and terminate in the Magnus Raphe Nucleus (MRN) situated in the junction of the pons and medulla. Next order neuron arises from here and terminates in the SGR of dorsal horn.
So, SGR has 3 fibers.
When SGR is stimulated by Ascending pain carrying fiber (APCF), there is release of substance P (chemical mediator). Substance P will travel along the STT. Substance P have their own receptors in the STT.
DPIF (descending pain inhibiting fiber) secret endogenous opioid –encephalin that have receptors (mu, kappa, delta etc) on the APCF terminal end.
When endogenous opioids are released from the terminal end of DPIF they get attached to the receptors of the terminal end of the APCF and prevents the release of substance P.
Exogenous opioids like Morphine—
- Combines with the opioid receptors and inhibit the release of the substance P.
- They also oppose the effect of already released substance P.
- Exogenous opioid combines with the mu receptors of PAG and MRN and stimulate DPI system resulting in more release of endogenous opioid, causing inhibition of pain.
Mechanism of Action of Narcotic Analgesics—all the opioid analgesics bind with selective endogenous opioid receptors and produces action. They are all G-protein linked (2nd messenger system). They produce action by 2 well known mechanisms.
1. they either close voltage gated Ca+2 channel presynaptically and decreases the release of excitatory neurotransmitters, such as substance –P, Ach, Glutamate etc.
2. They may hyperpolarize or inhibit post-synaptic membrane by opening of K+ channel.
RECEPTORS—
Mu receptor (μ)—when occupied by its agonist like morphine produces the following pharmacological effects—
a. Analgesia | b. Myosis |
c. Euphoria | d. Constipation |
e. Respiratory depression | f. Physical dependence |
Kappa receptors (κ)—when occupied by its agonist like Pentazosine, following pharmacological effects are seen—
a. Analgesia | b. Dysphoria |
c. Minor respiratory depression | d. Sedation |
e. Minor myosis |
*** There are also delta (δ) and sigma (σ) receptors.
Receptor distribution—
a. Dorsal horn of the spinal cord
b. Substancia granulosa
c. Nucleus tractus solitarius
d. Limbic system
e. Medial and lateral thalamus, area prostrema (vomiting center)
f. Periaqueductal grey matter
g. Rostral ventral medulla
h. Locus cerulous of brain stem
Note:-
1. Morphine acts as a pure agonist for every type of opioid receptors, Fenatyle also.
2. Naloxone is the pure antagonist of all types of opioid receptors.
3. Some drugs like Nalorphine and Pentazosine act as agonist to some receptors and antagonist to other receptors.
v Morphine contains Phenanthrene ring (3 rings)
Carbon 3 position—phenolic group, carbon 6 position—alcoholic group.
So –OH group is present in both the positions.
It is less absorbed and more first pass metabolism.
v Codein has –CH3 group in carbon 3 position instead of –OH group.
Therefore lipid solubility increases, there is more absorption and less first pass metabolism.
v Heroin (di acetyl morphine) has acetyl group in both carbon 3 and 6 positions.
More lipid soluble, more decrease in the first pass metabolism.
Remains in the blood for prolonged time and crosses the BBB more easily.
*** When carbon 3 and 6 position –OH group free then liver glucoronidation is quick, but if occupied then not easily conjugated. So escapes first pass metabolism. In Heroin both are occupied.
MORPHINE
Chemistry—it is a natural opium alkaloid.
Source—Poppy plant (Papaver somniferum)
Extraction—from the seed capsule of the Poppy plant. Usually spiral/transverse incision is given to the seed capsule in the afternoon. White oozes come out and solidify with a brown colour. This is called opium. About 20 alkaloids are extracted among them Morphine is the principal alkaloid.
Structure—A, B ring is perpendicular to each other.
C, D —aliphatic ring.
A, B —planner ring.
Analgesic property is due to presence of N-methyl Piperedine.
Pharmacokinetic profile—Morphine is completely and rapidly absorbed from the IM, sub-cutaneous, mucosal surface of the nose and other orifices. It is also completely and rapidly absorbed from the GIT when given orally. But it is not given orally as there is extensive first pass metabolism.
This drug and others are bound to the plasma protein with varying degree. It rapidly leaves the blood and concentrates in the tissues like liver, kidney, spleen, lung and skeletal muscle. It poorly concentrates in the brain and poor penetration of the BBB but brain is the main site of action. It can cross the placental barrier and cause fetal respiratory depression.
Metabolized by glucoronide conjugation (mainly). After conjugation it produces active polar metabolite –Morphine-6-glucoronide that is more active than Morphine. It is excreted by kidney.
*** We don’t use M-6-glucoronide as it is excreted (polar).
Pharmacological effects of Morphine / Opioids—
On CNSà
Inhibitory effects— § Analgesia § Cough suppression § Respiratory center depression | Excitatory effects— § Myosis § Vomiting § Euphoria |
*** It produces tolerance against analgesia and respiratory depression.
Tolerance—a condition where with chronic usage the same drug fails to produce effects of same intensity by the same dose. To produce the effect of same intensity, now increasingly greater dose will have to be used. (Iqbal Sir)
A. Analgesia—analgesic action is central (recently peripheral also), ↓ pain perception as well as,
↓ Reflex responses to pain stimuli –so ↑ Pain threshold.
Usually accompanied with well being and sense of relief.
Mechanism of action of opioid analgesia—pain consists of both sensory and affective (emotional) components. Opioid can change both components by,
i. Opioid agonists inhibit the release of excitatory neurotransmitter from the primary afferents of the spinal cord and directly inhibit dorsal horn pain transmission neuron of the spinal cord.
ii. It also directly inhibits the sites concerned with pain modulation. Ex-clostrum.
iii. ↑ Pain threshold.
iv. It also releases endogenous opioid peptide.
B. Sedation—it also produces sedation but less than sedatives and hypnotics. Can produce amnesia and can also disrupt REM and non-REM sleep.
C. Euphoria—causes powerful sense of well being by relieving anxiety, worry and tension.
D. Respiratory depression—all opioid analgesics can produce significant respiratory depression by inhibiting the respiratory center (pons and medulla). This depression is dose dependant.
Mechanism of action of respiratory depression—↓ sensitivity of the respiratory center to CO2 tension in the blood.
So, ↑ CO2 causes cerebral vasodilatation and thereby,
§ ↓ cerebral vascular resistance.
§ ↑cerebral blood flow
§ ↑ intracranial pressure
Also decreases respiratory rate, minute volume, tidal volume. Drug should be given continuously.
E. Cough suppression—well recognized action of opioids—Codein, Folcodein, Dextromethorphen. It suppresses the medullary integration of cough reflex. Due to cough suppression there is accumulation of secretion which causes airway obstruction Atelectasis.
F. An emetic effect—stimulates the chemoreceptor trigger zone and causes emesis.
*** It reduces the sensitiveness of the medullary respiratory center to CO2. However the sensitivity to O2 lack remains intact.
On CVSà
1. Cerebral vasodilatation—leads to increase intracranial pressure. So in head injury we avoid Morphine because the pressure is already increased. Due to respiratory depression there is increased PCO2 in the cerebral blood vessels (hypoxia) causing vasodilatation.
2. Slight peripheral vasodilatation—Morphine releases histamine (also penicillin), they inhibit sino-aortic baroreceptor reflexes (leading to postural hypotension). So ↓ peripheral resistance, ↓BP.
On GITà
1. Morphine causes constipation (local effect), by ↑ the tone of the smooth muscle in the large gut, ↓ amplitude of peristaltic wave and also ↓ the motility. So there is more transit time for the contents in the GIT. It also ↑ absorption of water.
2. May be nausea, vomiting (central effect).
On Biliary tractà
Morphine causes ↑ in the tone of the biliary smooth muscle and spasm of the sphincter of Oddi and thus increases the intra-biliary pressure. Pressure in the pancreatic duct also increases. May cause reflux of biliary and pancreatic secretions.
It also ↑ plasma amylase and lipase
On Respiratory tractà
Causes broncho-constriction by releasing histamine from the mast cell. This effect though not very much remarkable in normal person, but dangerous in bronchial asthma.
On GUTà
Kidney—↓ renal blood flow, ↑ ADH.
Ureter and Bladder—↑ tone of the smooth muscle and sphincter, ↑ ADH secretion. May precipitate urinary retention.
On Eyeà
Morphine combines with the μ receptor of the Edenger Westphal nucleus in the mid brain and causes myosis. With large dose Morphine causes pinpoint pupil.
On Uterusà
Causes prolongation of the labour.
Effect on Trunkà
It increases the tone of the large trunk muscle and the effect is at the supra-spinal level. There is decreased thoracic compliance.
On Skinà
Flushing due to release of histamine.
Endocrine effectsà
↓ LH, FSH, ACTH, Cortisol, Testosterone.
↑ ADH, GH.
Histamine Release—Morphine releases histamine from the mast cells causing—urticaria, sweating, veno-dilatation and broncho-constriction.
Clinical use of Morphine—
1. As Analgesic—it relieves moderate to severe pain. Usually relieves dull-ache not sharp or intermittent pain. It usually relieves—
§ Deep sited visceral pain | § Post operative pain |
§ Cardiac pain | § Fracture pain |
§ Cancer pain | § Severe pain of dying patient |
2. As Anti-Anxiety—in shock, hematuria, heart failure etc. in serious patients mainly.
3. In Acute pulmonary oedema—to relief nocturnal dyspnoea associated with left ventricular failure.
Mechanism of action—Morphine releases histamine causing vasodilatation. So, causes shunting of blood from heart to the peripheral organs. So, ↓ preload and after load and thus ↓ pulmonary oedema and ↓ nocturnal dyspnoea. Thus relieves anxiety, induce sedation, hypotension.
4. To control Cough—Codein and dexomethorphin are used in non-productive cough.
5. To control Diarrhoea—controlled almost any causes but not infectious diarrhoea—Loperamide and Diphenoxylate.
6. As pre-anaesthetic medication—frequently used because of sedative, anxielytic and analgesic properties.
7. As regional analgesic—epidural.
8. Relief restlessness in patient with liver failure.
9. Produce euphoria in dying patients.
Contraindication of Morphine—
Absolute— | § Respiratory insufficiency—bronchial asthma, COPD, emphysema. § Patient with liver disease § Patient with renal failure § Along with MAO inhibitor it can produce hyperpyrexia or hyperpyrexic coma |
Relative— | § Patient with head injury § Pancreatitis § Cholecystitis § Diverticulitis § During pregnancy § Patients with endocrine disorders—Addison’s disease, myxoedema |
Adverse effects of Morphine—most of the effects are due to extension of its pharmacological effects—
· Nausea | · Vomiting |
· Respiratory depression | · Pin point pupil |
· Behavioural restlessness | · Hyperactivity |
· ↑ intracranial pressure | · Postural hypotension |
· Urinary retention | · Itching around the nose |
· Urticaria | · Constipation |
· Bronchospasm | · Tolerance dependence—addiction |
· Opioid poisoning |
Opioid poisoning—
Acute—
i. Attempt to suicide
ii. Accidental overdose
Chronic—
i. Patient with shock
ii. Hypotensive patient
iii. Injection in the cold area (cannot circulate, so toxicity)
iv. Death due to respiratory failure
Sign-Symptoms of Morphine poisoning—
1. Patient in the stupor condition or may be in coma | |
2. Cyanosis | 3. ↓ body temperature |
4. Respiratory depression | 5. Skin may be cold and clammy |
6. ↓ BP | 7. Jaw relaxed |
8. Pin point pupil | 9. Urinary retention |
How we can diagnose acute poisoning / addiction?—
Acute—coma, respiratory depression, pinpoint pupil.
Addiction—these 3 + many needle marks in the arm.
Treatment of poisoning—
1. Establish patent airway
2. Artificial respiration with ventilation
3. Antidotes are Naloxone and Naltrexone {competitive reversible antagonist of Morphine}
Treatment of addiction—
1. Give the same group of drugs (opioid analgesics) for long duration.
2. Methadione is the drug of choice for the treatment of acute withdrawal symptom of Morphine after stopping of any chronically administered opioid such as Morphine, Pethidine, Heroin etc.
Methadione is used because—
o Slower onset of action
o Longer duration of action
o Tolerance and physical dependence develop more slowly than Morphine
o Withdrawal symptoms are less than Morphine
PETHIDINE
o Also known as Meperidine
o Synthetic derivatives of Piperedine
o 10 times less potent than Morphine
o Half life is 5 hours
O Readily absorbed from the GIT
o Rapidly inactivated from the liver but active metabolite remains. (nor-Pethidine)
o Excreted by the kidney—90% metabolized and 10% unchanged
· Mechanism of action—binds with the mu and kappa receptors. Same as Morphine.
· Degree of analgesia—equivalent to Morphine but short duration (2-4 hrs).
So, can’t relieve severe pain (myocardial ischaemia).
· Spasmogenic effect—lesser than Morphine.
· Tolerance and dependence—like Morphine.
· No anti lussive/anti cough effects—because very low effect on cough center.
· Psychic effect—less than Morphine
· Significant anti-muscarinic effect. (Morphine has no anti-muscarinic effects)
· Low therapeutic efficacy. (so cannot give in severe pain)
· Less urinary retention.
· With excess dose CNS stimulation—seizure, myoclonus, convulsion (due to nor-Pethidine)
· Widely used in obstetrics as analgesia—does not delay labour like Morphine.
· Increases force of contraction in oxytocin induced uterus.
· Less respiratory depression of foetus like Morphine.
· Less pupillary constriction.
Antidote of overdose—Naloxone, Naltrexone.
Difference between Morphine and Pethidine—
Pethidine | Morphine |
Synthetically produced | Naturally produced |
It does not suppress cough successfully | Suppress cough usefully |
Does not produce constipation but its effects on upper small intestine is similar to Morphine. There is spasm of sphincter of Oddi | Morphine causes constipation |
Less likely to produce urinary retention | May cause urinary retention |
Less likely to prolong labour | Prolongs labour |
Has little hypnotic effect than Morphine | More hypnotic effect |
Has shorter duration of analgesia (2-3hrs) | Has longer duration of analgesia (4-6hrs) |
Pethidine has some Aspirin like action including dry mouth and blurred vision | Not so |
Drug abuse—use of inappropriate and usually self administration of drugs for non-medical purpose. Like steroid by the body-builders.
Drug misuse—use of a drug for a wrong indication, wrong dose and wrong duration of action.
Tolerance—gradual diminished responsiveness due to frequent, repeated administration of drug. A usually large dose is needed to achieve the same effect. Usually tolerance develops at frequent and large dose. (Shakila Madam)
Mechanism of action—unknown but there may be cellular adaptive response. They—
1. Changes the 2nd messenger system related to Ca++ influx, Adenyl Cyclase inhibition or phosphorylation.
2. Decrease the number of receptors.
3. Down regulation of the receptors.
Types of Tolerance—
1. Pharmacokinetic or metabolic tolerance.
2. Pharmacodynamic tolerance—changes either in receptors or effector system. It is also called cellular tolerance.
3. Behavioural tolerance.
Dependence—it develops due to—
1. Psychological or awarded dependence—caffeine, tea, cigarettes.
2. To avoid punishing effect / compulsive urge / physiological effect.
So, dependence can be defined as repeated compulsive use / urge of a drug in order to receive its chemical rewarding effect or to avoid its punishing effect. It is characterized by—
1. Psychological dependence or Habituation.
2. Physiological dependence or Addiction.
Psychological dependence—compulsive drug using behaviour in which the individual uses the drug for personal satisfaction often in the phase of known risk to health. Usually larger dose is not needed. Ex—anti fatigue effect of caffeine, pure pleasure by Amphetamine, euphoria by narcotic analgesics.
Physiological dependence—it is a state where the drug is used to avoid the punishing effect / withdrawal symptoms. Also called addiction – it is a state of chronic intoxication due to repeated administration of a drug and is characterized by—
1. overpowering desire to procure the drug
2. tendency to increase the dose
3. psychological as well as physical dependence
4. harmful effect to the individual and to the society
5. Withdrawal symptom—if the drug is not given to the individual.
1 comment:
Analgesics are medicines that are used to relieve pain and are also known as painkillers or pain relievers. Analgesics drugs exporter in India should manufacture and supply products which are of good quality.It is taken to relieve pain that arises from conditions like gastrointestinal disorders, migraines, nervedamage, multiplesclerosis etc.
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