Narcotics And Non Narcotics

Front 1

What are analgesics

Back 1

Analgesics are drugs that relieve pain without significantly altering consciousness.

Divided into

1. narcotic and

2. non-narcotic analgesics:

Front 2

What are Narcotics

Back 2

Narcotic analgesics are analgesics that also have sedative or tranquilizing effects.

Front 3

The opioids are commonly refered to as

Back 3

narcotic analgesics

Front 4

The non-narcotic analgesics include :

Back 4

1. Acetaminophen

2. NSAIDs

3. Others ( Flupirtine, Ziconotide).

Front 5

Non-narcotic analgesics are particularly suitable for......... whereas narcotic analgesics are more suitable for...........

Back 5

musculoskeletal pain

moderate to severe visceral pain.

Front 6

How do opioids relieve pain

Back 6

Opioids relieve pain by binding to opioid receptors which are present in the central and peripheral nervous system (brain and spinal cord).

The opioid receptors include:

1. Mu (μ) receptors 2. Kappa (κ) receptors3. Delta (δ) receptors

Front 7

Endogenous opioids include-,-&- while the exogenous opioids are the

Back 7

1. Endorphins

2. Enkephalins

3. Dynorphins

Exogenous opioids are the narcotic analgesics

Front 8

Actions of the 3 classes of opiod receptors

Back 8

Receptor

Mu (μ) Analgesia ,

truncal rigidity,

miosis

Sedation and euphoria,

DependenceInhibition of respiration

Slowed gastrointestinal transit (receptors in the bowel)Modulation of hormone and neurotransmitter release

Kappa (κ) Dysphoria (through inhibition of dopamine release)Modulation of hormone and neurotransmitter release

Delta (δ) Psychotomimetic (hallucinogenic) effectsSlowed gastrointestinal transit

Front 9

Which receptors are thought to be responsible for most of the analgesic effects of opioids, and for some major unwanted effects.

Back 9

μ-Receptors

Front 10

Which receptor contributes to analgesia at the spinal level and may elicit sedation and dysphoria, but produce relatively few unwanted effects.

Back 10

κ-Receptors

Front 11

Classification of opioid analgesics

Back 11

1. NATURAL OPIOIDS (Agonist)Morphine, Codeine

2. SEMISYNTHETIC (Agonist) Oxycodone, hydrocodone, oxymorphone, Diacetylmorphine (heroin), hydromorphone,

3. SYNTHETIC

Agonist

Pethidine (Meperidine), Loperamide, Methadone, Fentanyl, sufentanil, remifentanil (last 2 are used as adjuncts in general anesthesia)

Partial agonists:

Pentazocine, Tramadol, Buprenorphine, Nalbuphine, butorphanol,

Antagonists:

Naloxone, Naltrexone, Methylnaltrexone , nalmefene

Front 12

Administered opioids localize in highest concentration in

Back 12

highly perfused organs such as liver, brain, lungs, kidney and spleen.

Front 13

.......and ........ are more potent than all other opioids. They are d/4 measured in micrograms. They are also very efficacious and are useful aesthetic adjuncts

Back 13

Fentanyl

sufentanil

Front 14

........... and....... Opiods have a lower first-pass metabolic effect and therefore are effective when given orally.

Back 14

Codeine

oxycodone

Front 15

route of administration of the opioids

Back 15

Most opioid analgesics are well absorbed after administration via the IM, Subcut, and oral routes.

They can also be given as lozenges and transdermal patches.

However, orally administered doses are less potent because they undergo first-pass metabolism.

Front 16

Most opioids are metabolized by ...... and eliminated......

Back 16

CYP3A4

Front 17

Morphine is metabolized by .....CYP enzyme by the Liver into ------- and ------

Back 17

the liver (CYP3A4) and excreted by the kidneys

morphine-3-glucuronide, M3G (90%) morphine-6-glucuronide, M6G (10%).

Front 18

The metabolic product of morphine that has 4-6 times more analgesic potency and longer action than the parent compound, morphine is

Back 18

Morphine-6-glucuronide.

Morphine-3-glucuronide is a neuroexcitant. It can cause seizures by inhibiting the GABA/glycine receptors.

However, these glucuronides (being water soluble) are eliminated by the kidneys and do not contribute to the CNS effects of morphine

Front 19

Codeine is metabolized to ,......... via ........enzyme

Back 19

morphine

CYP2D6

Hydroxylation of codeine to morphine is required for its efficacy , d/4 genetic variation in CYP2D6 (pharmacogenetics) causes varying efficacy of codeine in different patients.

Front 20

Metabolism of pethidine (meperidine)

Back 20

Pethidine (Meperidine) is metabolized mainly to pethidinic acid by MAO and very little is demethylated to norpethidine (a neuroexcitant) by demethlase. In repeated doses of pethidine, renal failure, or those taking MAO inhibitors (inhibiting MAO-A) norpethidine can accumulate and cause seizures.

Front 21

Diacetylmorphine (heroin) is metabolized to

Back 21

morphine via an esterase reaction ( a fast reaction). Heroin therefore has a very fast onset. Heroin is hydrolyzed to monoacetylmorphine and finally to morphine which is then conjugated with glucoronic acid to M3G and M6G

Speed of onset is associated with the addictive profile of drugs. Faster onset drugs are more addictive.

Front 22

Mechanism of action of Opiods

Back 22

All opioid receptors are inhibitory G-protein coupled receptors and activation results in reduced release of excitatory neurotransmitter at nociceptive nerve terminals. This is achieved through the following processes:Inhibition of adenyl cyclase.Close voltage-gated Ca2+ channels on presynaptic nociceptive nerve terminals and d/b inhibits release of excitatory neurotransmitters e.g. glutamate, norepinephrine, serotonin. Hyperpolarize postsynaptic neurons by opening K+ channels

Front 23

Kappa receptor causes dysphoria while MU receptor causes

Back 23

Euphoria

Front 24

Which pharmacological CNS effect of opioids is used in diagnosis of opioid poisoning

Back 24

Pupillary constriction; pinpoint pupils

Front 25

Tolerance develops to all actions of opioids except the 3C which are

Back 25

Constipation,

Convulsions,

pupillary Constriction

Front 26

Pharmacologicak actions of opioids is divided into CNS and peripheral and they are

Back 26

CNS EFFECTS1. Analgesia: Opioids reduce sensory and emotional aspects of pain.2. Euphoria: Opioids induce feeling/sense of wellbeing.3. Sedation: Induce mental dullness, sleep.4. Pupillary constriction: Pinpoint pupils (used in diagnosis of opioid poisoning)5. Respiratory depression: By depression of brainstem respiratory centre.6. Cough suppression: This is also centrally mediated.7. Truncal rigidity: Opioids increase tone in the trunk muscles. Effect on respiratory muscles decreases ventilation.

PERIPHERAL EFFECTS

1. GIT: Opioids increase muscle tone in the GIT thereby reducing motility by inhibition of the enteric nervous system.2. CVS: The opioids may reduce heart rate and BP by inhibition of the vasomotor centre.3. Biliary Tract: Opioids contract the biliary smooth muscles resulting in biliary colic.4. Renal effects: renal function is reduced by opioids.5. Uterus: Opioids cause contraction of uterine smooth muscles. 6. Pruritus: Results from direct CNS effect as well as peripheral histamine release.

Front 27

Drug of choice in MI and Acute pulmonary edema is

Back 27

Morphine is drug of choice (Reduces shortness of breath by reduction of its perception, as well as decrease preload and afterload.

Front 28

Opioid of choice as cough suppressant and why

Back 28

. Dextromethorphan is devoid of constipating effect unlike other drugs in this group.

Front 29

Oxide of choice in non-infective diarrhea

Back 29

Loperamide and diphenoxylate are opioids of choice.

Front 30

Drug used to reduce shivering after anesthesia is

Back 30

Pethidine (meperidine)

Front 31

Clinical uses of opioids

Back 31

1. Analgesic agents: Visceral, dull and constant pain is relieved more effectively than inflammatory/musculoskeletal pain.

2.Myocardial infarction / acute pulmonary edema: Morphine is drug of choice (Reduces shortness of breath by reduction of its perception, as well as ↓ preload and afterload. 3. Cough suppressants. Codeine, pholcodeine, dextromethorphan and noscapine are effective cough suppressants. Dextromethorphan is devoid of constipating effect unlike other drugs in this group.4. Non-infective diarrhea: Loperamide and diphenoxylate are opioids of choice.

5. Pre-anaesthetic medication: Morphine, fentanyl, alfentanil, sufentanil are useful anaesthetic adjunts b/c of their analgesic, 6. Pethidine (meperidine) is used to reduce shivering after anaesthesia [by its action on a2 receptor]

Front 32

Opioid of choice for analgesia and mechanism of action

Back 32

Morphine

Pentazocine

Pethidine

Inhibition of pain impulses in spinal cord and brain through inhibition of μ-receptors

Front 33

Opioid of choice for cough suppression and mechanism of action

Back 33

Codeine

Dextromethophan (best choice bcoz it does not cause constipation)

Noscapine

Pholcodeine

Suppression of the cough centre

Front 34

Opioid of choice in Acute pulmonary edema or myocardial infarction and its mechanism of action

Back 34

Morphine

Reduces shortness of breath by reduction of its perception, as well as preload and afterload.

Front 35

Opioid of choice in non infective diarrhea and mechanism of action

Back 35

Loperamide

Diphenoxylate

Reduction of gastric and intestinal motility

Front 36

Opioid of choice as pre anesthetic medication and mechanism of action

Back 36

Morphine

Fentanyl

Sufentanyl

Alfentanyl

Analgesic, sedative and anxiolytic effects

Front 37

Opioid of choice for shivering and mechanism of action

Back 37

Pethidine( meperidine)

Inhibitory effect on alpha-2 receptor

Front 38

4 Contraindications and precautions in the use of opioid

Back 38

1. Head injury: Morphine is absolutely contraindicated in head injury because it increases intracranial tension by causing retention of CO2 (due to respiratory depression). It also interferes with the assessment of neurological function by masking the important pupillary signs (causes miosis).

2. Pulmonary, hepatic or renal dysfunction: These drugs should be used cautiously in patients with pulmonary, hepatic or renal dysfunction.3. Infants and elderly: Use of opioids in infants and elderly also require caution.4. Pregnancy: Prolonged use of opioids in pregnancy may lead to in-utero physical dependence of fetus and severe withdrawal symptoms may be precipitated after birth.

Front 39

Opioid antagonist and actions

Back 39

Naloxone, naltrexone, methylnaltrexone, alvimopan and nalmefene are potent μ receptor antagonists with significant blocking action at k and d receptors also.

ActionsThese have no action in the absence of agonists but promptly reverses the opioid effects when administered i.v. They can precipitate withdrawal symptoms in opioid dependent subjects.

Front 40

What is the drug of choice for acute opioid poisoning. It is also used in neonatal resuscitation to reverse the effects of opioids (if used during labour).

Back 40

Naloxone

Front 41

Drug used as a maintenance drug for opioid poisoning. It is also used to prevent relapse after opioid de-addiction as well as to decrease craving in chronic alcoholics.

Back 41

Naltrexone

Front 42

........and ........are peripheral opioid antagonists indicated for opioid-induced constipation

Back 42

Methylnaltrexone

alvimopan

Front 43

The commonest analgesic with the least incidence of adverse effect is

Back 43

Acetaminophen(paracetamol)

It can be given as

Tablets

Injections

Syrup

Suppositories

NB it has a narrow therapeutic index

Front 44

3 Clinical uses of opioid antagonists

Back 44

1.Naloxone is the drug of choice for acute opioid poisoning. It is also used in neonatal resuscitation to reverse the effects of opioids (if used during labour).2. Naltrexone is used as a maintenance drug for opioid poisoning. It is also used to prevent relapse after opioid de-addiction as well as to decrease craving in chronic alcoholics.

3. Methylnaltrexone and alvimopan are peripheral opioid antagonists indicated for opioid-induced constipation.

Front 45

2 pathway for metabolism of acetaminophen

Back 45

1. Minor pathway of metabolism via conjugation with glucoronide or sulfate.

2. Major pathway of metabolism via N-hydroxylation by CYP2E1 (P450 enzyme) to N-acetyl-para-benzoquinone imine (NAPQI), a reactive metabolite.NB

In normal doses, N-acetyl-para-benzoquinone imine is conjugated with GSH (glutathione) to form mercapturic acid and excreted in urine.

Front 46

What happens in paracetamol poisoning

Back 46

In paracetamol overdose, GSH (Glutathione and antioxidant) is exhausted so that:

1. Hepatocytes become susceptible to oxidation injury since GSH are antioxidants.2. Increased N-acetyl-para-benzoquinone imine binds to cell membranes leading to cell death.

Front 47

Discuss paracetamol toxicity and treatment

Back 47

Centrilobular hepatic necrosis can occur a result of accumulation of N-acetyl-para-benzoquinone imine (centrilobular b/c it is where where CYP2E1 activity is highest).

This results in increase in transaminases (AST, ALT) and abnormalities in coagulation because of decrease production of hepatic coagulation proteins. Renal tubular necrosis can also occur

Treatment of paracetamol toxicityThe aim of treatment is to replenish GSH (glutathione) stores. This is accomplished through the administration of N-acetylcysteine (a GSH precursor). NAC functions as antidote to acetaminophen toxicity via three mechanisms:A. Replenishment of GSHB. NAC directly reduces NAPQI (to mercapturic acid) b/c like GSH it has antioxidant properties.C. NAC provides sulfur to enhance the nontoxic conjugation pathway of acetaminophen metabolism.