Opioids PRESENTATION

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OPIOID ANALGESICS

by MANKARAN SINGH


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History contd

Used medicinally and recreationally fromearly Greek and Roman times

Opium and laudanum (opium combined

with alcohol) were used to treat almost allknown diseases

Morphine was isolated from opium in the

early 1800s and since then has been themost effective treatment for severe pain


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Terminology

opium is a Greek word meaning juice,

or the exudate from the poppy

opiate is a drug extracted from theexudate of the poppy

opioid is a natural or synthetic drug that

binds to opioid receptors producing

agonist effects


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Natural opioids occur in 2 places:

1) In the juice of the opium poppy (morphine

and codeine)

2) As endogenous endorphins

All other opioids are prepared from either

morphine (semisynthetic opioids such as

heroin) or they are synthesized from

precursor compounds (synthetic opioids suchas fentanyl)


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Pharmacological Effects

Sedation and anxiolysis Drowsiness and lethargy

Apathy

Cognitive impairment

Sense of tranquility

Depression of respiration Main cause of death from opioid overdose

Combination of opioids and alcohol is especially dangerous

Cough suppression Opioids suppress the cough center in the brain

Pupillary constriction pupillary constriction in the presence of analgesics is characteristic of opioid use


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Pharmacological effects contd.

Nausea and vomiting Stimulation of receptors in an area of the medulla called the

chemoreceptor trigger zone causes nausea and vomiting

Unpleasant side effect, but not life threatening

Gastrointestinal symptoms Opioids relieve diarrhea as a result of their direct actions on the

intestines

Other effects Opioids can release histamines causing itching or more severe

allergic reactions including bronchoconstriction Opioids can affect white blood cell function and immune function


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Mechanism of action

Activation of peripheral nociceptive fiberscauses release of substance P and other pain-signaling neurotransmitters from nerve terminalsin the dorsal horn of the spinal cord

Release of pain-signaling neurotransmitters isregulated by endogenous endorphins or byexogenous opioid agonists by acting

presynaptically to inhibit substance P release,causing analgesia


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Mu-Receptor: Two Types

Mu-1

Located outside spinal

cord

Responsible forcentral interpretation

of pain

Mu-2

Located throughout

CNS

Responsible forrespiratory depression,

spinal analgesia,

physical dependence,

and euphoria


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AGONISTS

*Morphine

*Heroin

*Hydromorphone

*Fentanyl*Codeine


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General Pharmacokinetics

LATENCY TO ONSET

*oral (15-30 minutes)

*intranasal (2-3 minutes)

*intravenous (15 30 seconds)

*pulmonary-inhalation (6-12 seconds)

DURATION OF ACTION anywhere between 4 and 72hours depending on the substance in question.

Metabolism hepatic via phase 1 and phase 2

biotransformations to form a diverse array of metabolites( eg., morphine to morphine-6-glucuronide).


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O

HO

H

NH

CH3

HO1

2

3

4

5

6

7

8

9

10

11

12

1314

15 16

N-CH2CH2Ph increases

N-CH2CH=CH2 creates antagonist

Reduction increases activity

Oxidation, coupled with reduction of 7,8 C=C, increases activityAcetylation increases activity

Removal increases activity

Removal of OH reduces activity

Introduction of OH increases activity

Summary of structure-activity relationships (SARs)


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What structural elements are

necessary for activity?

O

HO

H

NH

CH3

HO1

23

4

5

67

8

9

10

11

12

1314

15 16

R3R1

N

CH3

Basic NitrogenQuaternary Carbon Center

Spacer

R2

Aromatic Ring


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Removing the oxide bridge (and hydrogenating double bond,

removing one alcohol) produces levorphanol, which hasenhanced analgesic properties over morphine.

O

HO

H

NH

CH3

HO1

23

4

5

6

7

8

9

1011

12

1314

15 16

H

NH

CH3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

Levorphanol

Levorphanol is used to treat severe pain and has several brand names.


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Surprisingly, its mirror image still has antitussive

properties, but no analgesic properties

H

NH

CH3

HO1

2

3

4

5

6

7

8

9

10

11

12

1314

15 16

Levorphanol

H

NH

H3C

OH1

23

4

5

6

7

8

9

10

11

12

1314

1516

dextrorphan

Mirror

analgesic + antitussiveAntitussive only


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Methylating the phenolic hydroxyl group improves

this antitussive activity

H

NH

H3C

OCH31

2

3

4

5

6

7

8

9

10

11

12

1314

1516

Dextromethorphan (DM)

Antitussive only

Dextromethorphan (DM or DXM) is

an antitussive drug that is found inmany over-the-countercold and

cough preparations, usually in the

form of dextromethorphanhydrobromide. It is also commonly

taken above the recommendeddosage by users seeking itsdissociative effect.
http://en.wikipedia.org/wiki/Antitussivehttp://en.wikipedia.org/wiki/Over-the-counter_substancehttp://en.wikipedia.org/wiki/Common_coldhttp://en.wikipedia.org/wiki/Cough_syruphttp://en.wikipedia.org/wiki/Hydrobromidehttp://en.wikipedia.org/wiki/Hydrobromidehttp://en.wikipedia.org/wiki/Cough_syruphttp://en.wikipedia.org/wiki/Common_coldhttp://en.wikipedia.org/wiki/Over-the-counter_substancehttp://en.wikipedia.org/wiki/Antitussive


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O

HO

H

NH

CH3

HO

1

23

4

5

6

7

8

9

10

11

12

1314

15 16

R3R1

N

CH3


Spacer

R2

Aromatic Ring

N

CH3

O

O

Et

Meperidine(DemerolTM)(PethidineTM)


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Meperidine

Pethidine or meperidine is a fast-acting opioidanalgesicdrug.

In the United States, it is more commonly known asmeperidine or by its brand name Demerol.

Pethidine is indicated for the treatment of moderate tosevere pain, and is delivered as its hydrochloride salt in

tablets, as a syrup, or by intramuscular or

intravenous injection.
http://en.wikipedia.org/wiki/Opioidhttp://en.wikipedia.org/wiki/Analgesichttp://en.wikipedia.org/wiki/Pain_and_nociceptionhttp://en.wikipedia.org/wiki/Hydrochloridehttp://en.wikipedia.org/wiki/Intramuscularhttp://en.wikipedia.org/wiki/Intravenous_injectionhttp://en.wikipedia.org/wiki/Intravenous_injectionhttp://en.wikipedia.org/wiki/Intramuscularhttp://en.wikipedia.org/wiki/Hydrochloridehttp://en.wikipedia.org/wiki/Pain_and_nociceptionhttp://en.wikipedia.org/wiki/Analgesichttp://en.wikipedia.org/wiki/Opioid


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Opioids to treat diarrhea?

O

HO

H

NH

CH 3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

R3R 1

N

CH 3


Spacer

R 2

Aromatic Ring

N

CH3

O

O

Et

Meperidine(DemerolTM )(PethidineTM )

NO

O

Et

Diphenoxylate(active ingredient of Lom otil)

(mixture w ith atropine, to prevent abuse)

CN

HON

Loperamide(active ingredient of Imodium )

Does not cross BB B, thus no analgesic effect

O

N

CH 3

CH3

Cl


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Fentanyl

O

HO

H

NH

CH3

HO1

2

3

4

5

6

7

8

9

10

11

12

1314

15 16

R3R1

N

CH3


Spacer

R2

Aromatic Ring

N

CH3

O

O

Et

Meperidine(DemerolTM)

(PethidineTM

)

N

CH2CH2Ph

O

Et

Fentanyl(80X more potent than morphine!)

N


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Fentanyl

Fentanyl is an opioidanalgesic, with ananalgesic potency of about 80 times that ofmorphine. Fentanyl was introduced into

medical practice in the 1960s as anintravenous anesthetic under the trade name

of Sublimaze.

N

CH2CH2Ph

O

Et

N
http://en.wikipedia.org/wiki/Opioidhttp://en.wikipedia.org/wiki/Analgesichttp://en.wikipedia.org/wiki/Morphinehttp://en.wikipedia.org/wiki/1960shttp://en.wikipedia.org/wiki/Anesthetichttp://en.wikipedia.org/wiki/Anesthetichttp://en.wikipedia.org/wiki/1960shttp://en.wikipedia.org/wiki/Morphinehttp://en.wikipedia.org/wiki/Analgesichttp://en.wikipedia.org/wiki/Opioid


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Fentanyl analogs

N

CH2CH2Ph

O

Et

Fentanyl(80X more potent than morphine!)

NNO

Et

Alfentanil(Alfenta)

N

OCH3

N

N N

N

ONO

Et

Remifentanil

N

OCH3

OCH3

O

O

NO

Et

Sufentanil(Sufenta)

5X more potent than Fentanil

N

OCH3

SNO

Et

Carfentanil(100X more potent than Fentanil!)

N

OCH3O


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Methadone

O

HO

H

NH

CH3

HO1

23

4

5

6

7

8

9

10

11

12

1314

15 16

R3R1

N

CH3


Spacer

R2

Aromatic Ring

NCH3

O

CH3

CH3

Methadone


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Methadone

Methadone was best known for its use in treatingnarcotic addiction.

N

CH3O

CH3

CH3
http://en.wikipedia.org/wiki/Narcotichttp://en.wikipedia.org/wiki/Narcotic

Opioids PRESENTATION

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