1.
DR.UMA KADAM M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC

2.
<ul><li> </li></ul>Opioids: Narcotic: imprecise term suggesting &quot;narcosis&quot;: indicated of a somnolent state Opioid analgesic: analgesia (pain absence) without resulting in loss of consciousness/sleep Opioids: Definition all natural/ semisynthetic opium alkaloid derivatives synthetic agents other drugs whose opioid-like effects are blocked by naloxone -nonselective opioid receptor antagonist Source: Opium from the opium poppy Constituents: morphine codeine Thebaine : nonanalgesic Papaverine -- nonanalgesic, vasodilator

3.
Opioids <ul><li>Prototype: morphine </li></ul><ul><ul><li>Morpheus: god of dreams </li></ul></ul><ul><li>Act on endorphin receptors: </li></ul><ul><ul><li>Mu (most important) </li></ul></ul><ul><ul><li>Kappa </li></ul></ul>

4.
History of Opioids <ul><li>Opium is extracted from poppy seeds (Paper somniforum) </li></ul><ul><li>Used for thousands of years to produce: </li></ul><ul><ul><li>Euphoria </li></ul></ul><ul><ul><li>Analgesia </li></ul></ul><ul><ul><li>Sedation </li></ul></ul><ul><ul><li>Relief from diarrhea </li></ul></ul><ul><ul><li>Cough suppression </li></ul></ul>

5.
Natural opioids occur in 2 places: <ul><li>1) In the juice of the opium poppy (morphine and codeine) </li></ul><ul><li>2) As endogenous endorphins </li></ul><ul><li>All other opioids are prepared from either morphine (semisynthetic opioids such as heroin) or they are synthesized from precursor compounds (synthetic opioids such as fentanyl) </li></ul>

6.
Three Opioid Receptors <ul><li>Mu  </li></ul><ul><li>Kappa (k1 & k3) </li></ul><ul><li>Delta </li></ul>

7.
Mu-Receptor: Two Types <ul><li> -1 </li></ul><ul><ul><li>Located outside spinal cord </li></ul></ul><ul><ul><li>Responsible for central interpretation of pain </li></ul></ul><ul><li> -2 </li></ul><ul><ul><li>Located throughout CNS </li></ul></ul><ul><ul><li>Responsible for respiratory depression, spinal analgesia, physical dependence, and euphoria </li></ul></ul>

8.
Kappa Receptor <ul><li>Only modest analgesia </li></ul><ul><li>Little or no respiratory depression </li></ul><ul><li>Little or no dependence </li></ul><ul><li>Dysphoric effects </li></ul>

9.
Delta Receptor <ul><li>It is unclear what delta’s responsible for. </li></ul><ul><li>Delta agonists show poor analgesia and little addictive potential </li></ul><ul><li>May regulate mu receptor activity </li></ul>

10.
No effect Decrease contraction δ Mouse vas deferens No effect Decrease contraction u Guinea pig ileum Isolated organ bioassays Inhibit u, δ Dopamine Inhibit u Acetylcholine Neurotransmitter release Decrease release Increase release u and/or δ Growth hormone Decrease release Increase release u Prolactin Hormone regulation Increase κ Diuresis No effect Increase u, κ Sedation Decrease feeding Increase feeding u, κ, δ Feeding No effect Increase κ Psychotomimesis No effect Decrease transit u, κ Gastrointestinal tract No effect Decrease u Respiratory function No effect Analgesic u, κ, δ Spinal No effect Analgesic u, κ, δ Supraspinal Analgesia Antagonist Agonist RECEPTOR SUBTYPE

11.
Mu and Kappa Receptor Activation Physical Dependence Decrease GI motility Dysphoria Euphoria Respiratory Depression Analgesia Kappa Mu-2 Mu-1 Response

12.
Terminology <ul><li>Pure Agonist: has affinity for binding plus efficacy </li></ul><ul><li>Pure Antagonist: has affinity for binding but no efficacy; blocks action of endogenous and exogenous ligands </li></ul><ul><li>Mixed Agonist-Antagonist: produces an agonist effect at one receptor and an antagonist effect at another </li></ul><ul><li>Partial Agonist: has affinity for binding but low efficacy </li></ul>

13.
Classification of Opioids: Agonist Partial Agonist/weak antagonist Partial Agonists Pentazocine Antagonist Antagonist Pure Antagonists Naloxone, Naltrexone Agonist Antagonist Agonist-Antagonist Nalbuphine, butorphanol, Buprenorphine Agonist Agonist Pure Agonists Morphine, codeine, meperidine, fentanyl , remifentanil, propoxyphene , hydrocodone , oxycodone KAPPA MU DRUGS

14.
Chemical substitutions: <ul><li>Partial agonist/antagonist characteristics: replacement of methyl moiety on the nitrogen atom with larger substituents </li></ul><ul><li>Allyl substitution: nalorphine and naloxone </li></ul><ul><li>Substitutions at the C3 and C6 morphine hydroxyl groups </li></ul><ul><li>Pharmacokinetic properties altered </li></ul><ul><li>Methyl substitution at C3 reduces first-pass hepatic metabolism by glucuronide conjugation: as a consequence codeine and oxycodone have a higher oral: parenteral potency </li></ul>

15.
Methylated at C3 Codeine Oxycodone Morphine OH OH

16.
Pharmacokinetics: <ul><li>Absorption: </li></ul><ul><li>Opioid analgesics: generally well absorbed from cutaneous / intramuscular/mucosal surfaces </li></ul><ul><li>Fentanyl transdermal: important Route of Administration </li></ul><ul><li>Gastrointestinal absorption: </li></ul><ul><li>some opioids subject to first-pass effects: codeine; oxycodone have high oral: parenteral potency (protected from conjugation by substitution on C3 aromatic hydroxyl) </li></ul><ul><li>Distribution: </li></ul><ul><li>Various extent of plasma protein binding </li></ul><ul><li>Highest concentrations in tissues </li></ul><ul><li>Skeletal muscle: largest reservoir </li></ul><ul><li>For highly lipophilic Opioids (e.g. fentanyl): concentration in adipose tissue </li></ul><ul><li>Blood Brain Barrier: </li></ul><ul><li>Amphoteric agents (possessing both an acidic and basic group, e.g. morphine {phenolic hydroxyl at C3}: greatest difficulty for brain entry) </li></ul><ul><li>other substitutions that C3 improve blood-brain barrier penetration: e.g., </li></ul><ul><li>heroin, codeine </li></ul><ul><li>Neonatal considerations: neonates lack the blood-brain barrier: </li></ul><ul><li>placental opioid transfer (uses in obstetric analgesia) can result in depressed respiration in the newborn. </li></ul>

17.
Pharmacokinetics: <ul><li>Metabolism: </li></ul><ul><li>Opioids with hydroxyl groups: conjugated with glucuronic acid into morphine-6-glucuronide: analgesic potency Examples: morphine , levorphanol; in patients with compromised renal function: accumulation of metabolites cause prolonged analgesia </li></ul><ul><li>Esters: hydrolyzed by tissue esterases: </li></ul><ul><li>Examples: heroin, remifentanil (short duration of action) </li></ul><ul><li>N-demethylation : (minor pathway) accumulation of demethylated meperidine metabolite, normeperidine in patients with decreased renal function or on high dosages cause seizures (more likely in children) </li></ul><ul><li>Oxidative metabolism (hepatic) primary route of phenylpiperidine opioid metabolism: e.g. Fentanyl, alfentanil, sufentanil </li></ul><ul><li>Excretion: </li></ul><ul><li>polar metabolites -- renal; small amounts excreted unchanged </li></ul><ul><li>glucuronide conjugates -- bile (enterohepatic circulation minor) </li></ul>

18.
Mechanism of action <ul><li>Reduce neurotransmitter release; by closing a voltage-gated ca2+ channel on presynaptic neuronal terminals or </li></ul><ul><li>Inhibit postsynaptic neurons (hyperpolarization) by increasing and K+ channel conductance </li></ul>Spinal Cord Sites of Opioid Action K+ Ca++

19.
Mechanism of action:

20.
Mechanism of action: <ul><li>Enhance activity in descending aminergic bulbospinal pathways (antinociceptive pathway) that exert inhibitory effects on the processing of nociceptive information in the spinal cord. </li></ul>

21.
Pharmacological actions: <ul><li>CNS effects: (  and  receptor-mediated) </li></ul><ul><li>Analgesia, sedation, euphoria, respiratory depression. </li></ul><ul><li>Analgesia: Pain Components </li></ul><ul><li>Affective (emotional): Opioids have greater effect on this element </li></ul><ul><li>Sensory </li></ul><ul><li>Analgesia results from complex interactions involving: sites in the brain, spinal cord, peripheral tissue (selective action on neuronal modulators and transmitters of pain ;other sensory modality/motor functions: remain intact) </li></ul>

22.
Pharmacological actions: <ul><ul><li>Euphoria: </li></ul></ul><ul><ul><ul><li>Anxiolytic; pleasant; &quot;floating sensation&quot;; </li></ul></ul></ul><ul><ul><ul><li>Individuals not in pain may experience dysphoria </li></ul></ul></ul><ul><ul><li>Sedation: </li></ul></ul><ul><ul><ul><li>Common consequence of opioid administration </li></ul></ul></ul><ul><ul><ul><li>Limited amnesia </li></ul></ul></ul><ul><ul><ul><li>Given as monotherapy, Opioids produce sleep from which individual can be easily awakened </li></ul></ul></ul><ul><ul><ul><li> Opioids in combination with sedative-hypnotics induce very deep sleep </li></ul></ul></ul><ul><ul><ul><li>Significant Sedation: more likely with phenanthrene derivatives (e.g., morphine, oxycodone etc. less likely with synthetic agents e.g. fentanyl, meperidine) </li></ul></ul></ul>

23.
Pharmacological actions: <ul><ul><li>Respiratory Depression: </li></ul></ul><ul><ul><ul><li>Significant respiratory depression (inhibiting brain stem respiratory centers) </li></ul></ul></ul><ul><ul><ul><li>Respiratory depression is dose-related influenced by extent to sensory input </li></ul></ul></ul><ul><ul><ul><li>opioid induced --slight respiratory depression: tolerated in patients with no prior respiratory difficulty </li></ul></ul></ul><ul><ul><ul><li> opioid induced -- slight respiratory depression: poorly or not tolerated in patients with: </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Asthma </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Chronic obstructive pulmonary disease (COPD) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Cor pulmonale </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Increased intracranial pressure </li></ul></ul></ul></ul></ul>

24.
<ul><li>Cough Suppression </li></ul><ul><li>Opioids suppress the “cough center” in the brain </li></ul><ul><li>Especially effective: codeine </li></ul><ul><ul><ul><li>management of pathologic cough </li></ul></ul></ul><ul><ul><ul><li>management of patients with endotracheal tubes </li></ul></ul></ul><ul><ul><ul><li>Associated with: secretion accumulation-- leading to atelectasis, airway obstruction </li></ul></ul></ul><ul><li> Miosis </li></ul><ul><ul><li>Pupillary constriction: commonly seen with opioid agonists </li></ul></ul><ul><ul><li>Blocked by opioid antagonists </li></ul></ul><ul><ul><li>No development of tolerance </li></ul></ul><ul><ul><li>Mechanism: </li></ul></ul><ul><ul><ul><li>Edinger-Westphal nucleus of the oculomotor nerve </li></ul></ul></ul><ul><ul><ul><li>Parasympathetic system -- may be blocked by atropine </li></ul></ul></ul>Pharmacological actions:

25.
Pharmacological actions: <ul><li>Truncal Rigidity: </li></ul><ul><ul><li>Increased large trunk muscle tone: Supraspinal action </li></ul></ul><ul><ul><li>Most often seen with highly lipophilic Opioids, upon rapid IV administration e.g. Fentanyl, sufentanil, alfentanil </li></ul></ul><ul><ul><li>Reversal of Truncal rigidity done by opioid antagonists </li></ul></ul><ul><ul><li>Maintenance of analgesia with reduced Truncal rigidity needs concurrent neuromuscular blocking drug use. </li></ul></ul><ul><li>Nausea and Vomiting: </li></ul><ul><ul><li>Opioid analgesics: stimulate brain stem chemoreceptor trigger zone (CTZ) </li></ul></ul><ul><ul><li>Vestibular component may also be present </li></ul></ul>

26.
Pharmacological actions: <ul><li>Cardiovascular Effects: Usually minimal effects (some bradycardia) </li></ul><ul><li>BP : in the absence of stress, well maintained; With stress cause hypotension due to Peripheral arterial dilation, venous dilation & may be due to central vasomotor effects and histamine release </li></ul><ul><li>Effects on the myocardium are not significant in normal individuals. However in patients with coronary artery disease & AMI, 8 to 15 mg of morphine administered intravenously produces a decrease in oxygen consumption, left ventricular end-diastolic pressure, and cardiac work at the same time relieves emotional apprehension. </li></ul><ul><li>Reduced blood volume: increased susceptibility to opioid hypotensive effects can aggravate hypovolumic shock. </li></ul><ul><li>With respiratory depression (secondary to opioid administration), PCO2 increases and causes: </li></ul><ul><ul><ul><li>Cerebral vasodilation </li></ul></ul></ul><ul><ul><ul><li>An increase in cerebral blood flow </li></ul></ul></ul><ul><ul><ul><li>An increase in intracranial pressure </li></ul></ul></ul>

27.
Pharmacological actions: <ul><li>Gastrointestinal Opioid Effects: </li></ul><ul><ul><li>Constipation: Local enteric & CNS mechanisms involved </li></ul></ul><ul><ul><li>Stomach: motility decreases, tone increases & gastric acid decreases </li></ul></ul><ul><ul><li>Small Intestinal Effects: tone: increases; with spasm </li></ul></ul><ul><ul><li>Large Intestinal Effects : propulsive peristaltic waves diminished,tone </li></ul></ul><ul><ul><li>increased, These effects delay fecal passage (constipating), promote water </li></ul></ul><ul><ul><li>reabsorption (constipating) Opioid pharmacological actions in the large </li></ul></ul><ul><ul><li>intestine are the basis for opioid use in management of diarrhea </li></ul></ul><ul><ul><li>Biliary tract: </li></ul></ul><ul><ul><li>Opioids: promote biliary smooth muscle constriction: biliary colic </li></ul></ul><ul><ul><ul><li>Sphincter of Oddi may constrict: </li></ul></ul></ul><ul><ul><ul><li>biliary and pancreatic secretion reflux </li></ul></ul></ul><ul><ul><ul><li>elevated plasma lipase/amylase </li></ul></ul></ul>

28.
<ul><li>Effects on the Hypothalamic thermoregulatory centers : Opioids alter the equilibrium point of the hypothalamic heat-regulatory mechanisms, such that body temperature usually falls slightly. However, chronic high dosage may increase body temperature </li></ul><ul><li>Neuroendocrine: </li></ul><ul><ul><li>Opioid analgesics promote release of: </li></ul></ul><ul><ul><ul><li>Antidiuretic hormone* </li></ul></ul></ul><ul><ul><ul><li>Prolactin </li></ul></ul></ul><ul><ul><ul><li>Somatotropin </li></ul></ul></ul><ul><ul><li>Opioid analgesics inhibit released of: (GnRH) and (CRF), from hypothalamus thus decrease circulating concentrations of (LH) & (FSH), ACTH, and  - endorphin decreased . As a result of the decreased concentrations of pituitary trophic hormones , the concentrations of testosterone and cortisol also decreased </li></ul></ul>Pharmacological actions:

29.
Pharmacological actions: <ul><li>Genitourinary tract: </li></ul><ul><ul><li>Renal Function: depressed </li></ul></ul><ul><ul><li>decreased renal plasma flow </li></ul></ul><ul><ul><li>Bladder and ureteral tone: increased </li></ul></ul><ul><ul><ul><li>urinary retention (particularly in postoperative patients) </li></ul></ul></ul><ul><ul><ul><li>increased opioid-induced ureteral tone may worsen ureteral colic due to renal calculus </li></ul></ul></ul><ul><ul><li>Uterus: </li></ul></ul><ul><ul><ul><li>Prolong labor </li></ul></ul></ul><ul><li>Other Effects: </li></ul><ul><ul><li>Flushing, sweating, itching: central effects & histamine early </li></ul></ul><ul><ul><li>Opioid affecting the immune system by influencing: </li></ul></ul><ul><ul><ul><li>chemotaxis </li></ul></ul></ul><ul><ul><ul><li>antibody production </li></ul></ul></ul><ul><ul><ul><li>the disciple effort of responses </li></ul></ul></ul>

30.
Adverse effects: <ul><li>Dysphoria : behavioral restlessness; hyperactivity </li></ul><ul><li>Respiratory depression: slight respiratory depression not tolerated in patients with: </li></ul><ul><ul><ul><li>Asthma </li></ul></ul></ul><ul><ul><ul><li>Chronic obstructive pulmonary disease (COPD) </li></ul></ul></ul><ul><ul><ul><li>Cor pulmonale </li></ul></ul></ul><ul><ul><ul><li>increased intracranial pressure </li></ul></ul></ul><ul><li>Nausea and vomiting </li></ul><ul><li>Increased intracranial pressure </li></ul><ul><li>Hypotension: worsened by preexisting hypovolumia or by other medications given concurrently (e.g. nitroglycerin in acute management of myocardial infarction) </li></ul><ul><li>Constipation </li></ul><ul><li>Urinary retention </li></ul><ul><li>Urticaria , itching </li></ul><ul><li>Tolerance and physical dependence: clinical appearance on two-three weeks of frequent administration of therapeutic doses </li></ul><ul><li>Cross-tolerance: individuals tolerant to morphine effects are also tolerant to other opioid agonists </li></ul><ul><li>Antagonist-precipitated withdrawal: rapidly developing, powerful abstinence syndrome cause by administration of naloxone or another antagonist </li></ul><ul><li> Psychological Dependence </li></ul>

31.
Opioid Effects: Degree of Tolerance Developed Convulsions Mental clouding Constipation Euphoria, dysphoria Miosis Bradycardia Analgesia Limited/None Intermediate High Cough suppression Nausea / vomiting Antidiuresis Respiratory depression Antagonist actions Sedation

32.
Some Symptoms of Opioid Withdrawal Hyper ventilation Yawning Piloerection Hostility Diarrhea Anxiety Vomiting Muscular aches Hyper ventilation Chills Lacrimation Rhinorrhea

33.
<ul><li>Acute opioid toxicity: </li></ul><ul><li>May result from clinical overdosage, accidental overdosage in addicts, or attempts at suicide. </li></ul><ul><li>Occasionally, a delayed type of toxicity may occur from the injection of an opioid into chilled skin areas or in patients with low blood pressure and shock. </li></ul><ul><li>Symptoms and Diagnosis: The triad of coma , pinpoint pupils , and depressed respiration strongly suggests opioid poisoning. </li></ul>Adverse effects:

34.
Treatment: <ul><li>The first step is to establish a patent airway and ventilate the patient. </li></ul><ul><li>Opioid antagonists can produce dramatic reversal of the severe respiratory </li></ul><ul><li>depression and the antagonist naloxone is the treatment of choice. </li></ul><ul><li>However, care should be taken to avoid precipitating withdrawal in dependent patients, who may be extremely sensitive to antagonists. </li></ul><ul><li>The safest approach is to dilute the standard naloxone dose (0.4 mg) and slowly administer it intravenously, monitoring arousal and respiratory function. </li></ul><ul><li>Patients should be observed for rebound increases in sympathetic nervous system activity , which may result in cardiac arrhythmias and pulmonary edema </li></ul><ul><li>For reversing opioid poisoning in children , the initial dose of naloxone is 0.01 mg/kg. If no effect is seen after a total dose of 10 mg, one can reasonably question the accuracy of the diagnosis. </li></ul><ul><li>Pulmonary edema sometimes associated with opioid overdosage may be countered by positive-pressure respiration. </li></ul><ul><li>Tonic-clonic seizures, occasionally seen as part of the toxic syndrome with meperidine and propoxyphene, are ameliorated by treatment with naloxone. </li></ul>

35.
Contraindications/Therapeutic Cautions: <ul><li>For patients receiving the opioid agonists: </li></ul><ul><ul><li>Do not administer a mixed agonist-antagonist (e.g. Pentazocine): withdrawal may be precipitated. </li></ul></ul><ul><ul><li>Diminishment of analgesia may occur in patients with head injuries: opioids may induce a further increase in intracranial pressure </li></ul></ul><ul><li>Pregnancy: chronic use </li></ul><ul><ul><li>Fetus may become physiological independent in utero </li></ul></ul><ul><ul><ul><li>withdrawal symptoms may appear in the early postpartum time frame </li></ul></ul></ul><ul><ul><ul><li>management of fetal withdrawal symptoms: </li></ul></ul></ul><ul><ul><ul><ul><li>mild: management with diazepam </li></ul></ul></ul></ul><ul><ul><ul><ul><li>more severe: oral methadone; tincture of opium (paregoric) </li></ul></ul></ul></ul><ul><li>Patients with impaired lung function: </li></ul><ul><ul><li>Acute respiratory failure may be precipitated by opioid-mediated respiratory depression </li></ul></ul><ul><li>Patients with impaired hepatic or renal function: </li></ul><ul><ul><li>Half-life may be prolonged in patients with impaired renal function; e.g. morphine and its active metabolite morphine-6-glucuronide may accumulate (reduction in dosage) </li></ul></ul><ul><ul><li>Since the liver is the primary metabolic site for morphine and related compounds, very use in patients with pre-hepatic coma may be inappropriate </li></ul></ul><ul><li>Patients with endocrine disorders: </li></ul><ul><ul><li>Adrenal-insufficiency (Addison's disease) or hypothyroidism (myxedema): prolonged, exaggerated opioid responses </li></ul></ul>

36.
Therapeutic uses: <ul><li>Analgesia: </li></ul><ul><ul><li>Opioids most effective in severe, constant pain & less effective in sharp, intermittent pain </li></ul></ul><ul><ul><li>Management of cancer pain; pain associate with other terminal illnesses </li></ul></ul><ul><ul><li>Obstetrical labor: cause fetal/neonatal opioid depression reversible by naloxone </li></ul></ul><ul><ul><li>Renal / Biliary Colic: </li></ul></ul><ul><li>Acute Pulmonary Edema: </li></ul><ul><ul><li>IV morphine: relieves dyspnea secondary to pulmonary edema </li></ul></ul><ul><ul><li>Possible mechanism of action: </li></ul></ul><ul><ul><ul><ul><ul><li>Reduced awareness of shortness of breath </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Reduced patient anxiety </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Reduced preload (decreased vascular venous tone) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Reduced afterload (decreased peripheral resistance) </li></ul></ul></ul></ul></ul><ul><li>Cough: </li></ul><ul><ul><li>Cough suppression: occurs at lower doses than for opioid analgesia </li></ul></ul><ul><ul><li>Reduced usage of opioids for cough suppression: due to newer non-analgesic, nonaddictive synthetic agents </li></ul></ul>

37.
Therapeutic uses: <ul><li>Diarrhea: </li></ul><ul><ul><li>All diarrhea controllable with opioids </li></ul></ul><ul><ul><li>Diarrhea secondary to infection, treat the infection with appropriate chemotherapy </li></ul></ul><ul><ul><li>Current antidiarrheals utilize agents selected for the gastrointestinal tract with limited CNS actions </li></ul></ul><ul><li> Opioids and Anesthesia: </li></ul><ul><ul><li>Anesthetic Premedication advantageous because of Sedative-Anxiolytic-Analgesic properties </li></ul></ul><ul><li>Intraoperative Use: ( general ) </li></ul><ul><ul><li>Adjuncts to other anesthetics </li></ul></ul><ul><ul><li>At high doses: primary anesthetic component </li></ul></ul><ul><ul><ul><li>Cardiovascular surgery &Other high-risk surgery (desire to minimize cardiovascular depression) </li></ul></ul></ul><ul><li>( regional ) </li></ul><ul><ul><li>Epidural </li></ul></ul><ul><ul><li>Subarachnoid spaces </li></ul></ul><ul><ul><li>Rectal suppositories & Transdermal patch </li></ul></ul><ul><ul><li>Patient controlled analgesia (PCA): common use </li></ul></ul>

38.
Methadone (Phenylheptylamines) <ul><li>Pharmacodynamics : </li></ul><ul><ul><li>Similar to morphine, longer acting </li></ul></ul><ul><ul><li>Reliable following oral administration </li></ul></ul><ul><ul><li>Compared to morphine, methadone tolerance and physical dependence develops more slowly </li></ul></ul><ul><ul><li>Following abrupt methadone discontinuation withdrawal symptoms less severe than with morphine </li></ul></ul><ul><ul><ul><li>Useful drug for detoxification in maintenance of chronic, heroin addict </li></ul></ul></ul><ul><ul><ul><li>Cross-tolerance with heroin (methadone prevents addiction-reinforcing heroin actions) </li></ul></ul></ul>

39.
Phenylpiperidines (e.g. Meperidine, fentanyl, Diphenoxylate, Loperamide) <ul><li>Meperidine: </li></ul><ul><ul><li>Significant anticholinergic (antimuscarinic) effects </li></ul></ul><ul><ul><li>Contraindicated in the presence of underlying tachycardia </li></ul></ul><ul><ul><li>May have a negative ionotropic cardiac effect </li></ul></ul><ul><ul><li>Risk of seizures: due to accumulation of CNS active metabolite, normeperidine </li></ul></ul><ul><li>Fentanyl group: (fentanyl, sufentanil, alfentanil, remifentanil) differences in biodisposition & potency </li></ul><ul><ul><li>Sufentanil : 5-7 times more potent than fentanyl </li></ul></ul><ul><ul><li>Alfentanil less potent than fentanyl ,more rapid acting & shorter duration of action </li></ul></ul><ul><ul><li>Remifentanil: Rapidly metabolized: tissue cholinesterases resulting in: Extremely short half-life </li></ul></ul><ul><li> Diphenoxylate: metabolite (difenoxin) </li></ul><ul><ul><li>In management of diarrhea used in combination with atropine </li></ul></ul><ul><ul><li>limited abuse potential </li></ul></ul><ul><li>Loperamide: </li></ul><ul><ul><li>management of diarrhea </li></ul></ul><ul><ul><li>limited abuse potential </li></ul></ul>

40.
Opioid agonist-antagonists: <ul><li>Pentazocine: </li></ul><ul><ul><li>Common: sedation + analgesia in therapeutic doses </li></ul></ul><ul><ul><li>Sweating, Dizziness, Nausea: common at higher doses </li></ul></ul><ul><ul><li>Respiratory Depression: significant respiratory depression less likely than with pure opioid agonists; reversible by naloxone; agonist antagonists (nalorphine) less likely to be effective in reversing respiratory depression </li></ul></ul><ul><ul><li>Psychotomimetic effects: agonist-antagonists </li></ul></ul><ul><ul><ul><li>Nightmares, Anxiety, Hallucinations </li></ul></ul></ul><ul><li>Nalbuphine: </li></ul><ul><ul><li>Kappa (k) agonist;  antagonist </li></ul></ul><ul><ul><li>Parenteral administration </li></ul></ul><ul><ul><li>Possibly less respiratory depression than with morphine </li></ul></ul><ul><ul><li>When respiratory depression occurs: may be more difficult to reverse with naloxone </li></ul></ul><ul><li>Buprenorphine: </li></ul><ul><ul><li>Long acting, potent, Partial  agonist </li></ul></ul><ul><ul><li>Slowed dissociation form receptor hence relative naloxone-reversal resistant </li></ul></ul><ul><li>Butorphanol: </li></ul><ul><ul><li>Analgesic equivalent to Buprenorphine and Nalbuphine, more sedation </li></ul></ul><ul><ul><li>Kappa (k) agonist </li></ul></ul>

41.
THANK YOU