Lecture 22, 23, 24

Front 1

How is pain defined? Including if it is part of normal life, uncontrolled consequences, possible associated effects and profounder of other changed

Back 1

unpleasant sensory & emotional experience associated with actual or potential tissue damage

normal part of everyday life - serves vital defensive function 􏰀

If uncontrolled: dramatically diminish quality of life 􏰀

often associated with range of psychological & central disturbances 􏰀 anxiety, depression, insomnia, anorexia 􏰀

profound changes in autonomic function: HR, BP, urination

Front 2

What are the 2 types of pain?

Back 2

Acute and chronic

Front 3

How is acute pain different from chronic pain?

Back 3

1. Recent onset & limited duration. note that chronic pain is usually greater than 3 months

2. usually has identifiable cause relating to injury ordisease

Front 4

What are the 2 types of acute pain? How are they different from each other?

Back 4

1. Somatic: sharp, well localised

2. Visceral: dull, poorly localised

Front 5

What are the 3 boarders of chronic pain, including their characteristics.

Back 5

1. Defined Nociceptive Basis

arises from stimulation of nerves by damage or disease

2.Well-Defined Neuropathological Basis

arises from damage to nerves

3.Idiopathic

arises spontaneously with unknown pathogenesis

Front 6

What are the stages of pain perception?

Back 6

1.Noxious(有害的 stimulus (noxious intensity ≈ degree of tissue damage)

2.→activation of pain sensors (nociceptors, high threshold) at peripheral terminal

3.→ Genenrate AP (Pain “appreciation” in peripheral tissues)

4.→ Transmission of pain info. to dorsal horn, dorsal horn relays the signal: inhibited or amplified by local spinal circuits & descending tracts fromhigher brain centres

5.→ Signal passage (through brainstem areas & thalamus) to the cortex of the brain

6,→Appropriate action.→ Descending modulatory control pathway.

Front 7

What receptors does opium act on, and what does it induce?

Back 7

Acts mostly through μ- opioid receptor (GPCR)􏰀

Can induce analgesia止痛, euphoria幸福感, dependence, constipation

Front 8

What are opiate substances?

Back 8

derived from opium poppy

Front 9

What are two types of opioid compounds?

Give 2 examples for each.

Back 9

1.naturally occurring: morphine & codeine

2.Synthetic: e.g. methadone & fentanyl

Front 10

What are the endorphins?

Back 10

Endogenous opioidpeptides

neurotransmitter & hormone: peptides made in the brain that have activity similar to morphine

Front 11

What are the 3 main families of endorphins?

Back 11

1.β-endorphin

2.met- & leu-enkephalin

3.dynorphin

Front 12

Where ar endorphins synthesised and released?

Back 12

Synthesised & released from nerves: Brain & spinal cord, GIT

Front 13

What are the 2 physiological roles of endorphins?

Back 13

1. Analgesia: inhibit pain neurotransmission & perception of pain

2.Regulation of intestinal motility

Front 14

What are the 2 pharmacological significances of endorphins?

Back 14

1. Act at opioid receptors (several GPCRs)

2. Since they are Peptides - not absorbed from gut, are rapidly metabolised, do not pass through Blood-brain barrier→ not useful as therapeutics

Front 15

Where can μ- opioid Gi receptors be found?

Back 15

Dense in brain & spinal cord

Front 16

What are the 3 ways μ- opioid agonists(opiod) can act in thenociceptive circuit?

Back 16

1. Inhibit Peripheral nerve stimulation

- Presynaptic: inhibition of Ca2+ influx of action potential

2. Inhibit activity of relay neurons in dorsal horn.

- Postsynaptic: μ-opioid receptor activation

→↑ K+ conductance (hyperpolarizing)

→↓postsynaptic response to excitatory neurotransmission

3. Acting directly on descending modulatory (inhibitory) control pathway

- enhance inhibition of the dorsal horn

Front 17

What are the effects of morhpine on CNS?

Back 17

1.analgesia 􏰀

2.euphoria 􏰀

3.respiratory depression, due to ↓ sensitivity of medullary respiratory centre to CO2􏰀

4. nausea & vomiting

5.pupillary constriction (miosis), diagnostic feature of overdose

6.antitussive (cough suppression)

Front 18

What are the effects of morphine on periphery?

Back 18

• Constipation results from μ-receptors on myenteric neurons decreasing AChrelease, lessening motility

• Histamine release from mast cells (not mediated by opioid receptors) leads tobronchoconstriction and vasodilation

Front 19

Pharmacokinetics of morphine, including administration, metabolism and half-life

Back 19

Administration: usually given i.v. or i.m.

oral absorption variable (bioavailability ≈25%)slow-release oral preparations for chronic pain

Metabolism: significant hepatic metabolism to morphine 6-glucuronide (more potent analgesic 4-6 fold, butpoor CNS entry)

Half life: 3-6 hours

Front 20

Explain what it means by the tolerance of morphine?

Back 20

Increased dose required for equivalent effect

This indicates that there is a Gradual loss of effectiveness of analgesia, euphoria and sedative properties

However Does not affect constipation and miosis

Depends on potency of agonist and frequency/route of administration

Front 21

Explain the dependence of morphine?

Back 21

physical “withdrawal” or “abstinence” syndrome when usage ceases

Physical reaction is proportional to level of tolerance and lasts for days

Psychological craving渴望 for morphine lasts for months or years!

Front 22

What are some characteristics of heroin? Including effects and addictiveness

Back 22

Effects:Analgesic, pneumonia, tuberculosis, sedative for cough 􏰀

Addictiveness:

- highly lipid soluble prodrug

- more rapid entry to CNS than morphine

- metabolized rapidly in brain to produce 3- & 6- acetylmorphine & then morphine

- results in fast, strong activation of pleasure centre & euphoria

Front 23

What are some characteristics of methadone?

Back 23

1.orally active􏰀

2.slow onset􏰀 long half-life >24 h􏰀

3.withdrawal reaction less intense but prolonged􏰀

4.accumulation may occur due to long half life􏰀 used for treatment of opioid dependence

Front 24

What are some characteristics of naloxone?

Back 24

1.opioid receptor antagonist- affinity for all opioid receptors 􏰀

2. rapid hepatic metabolism, so usually given i.v. (half-life ≈1 h) 􏰀

3.normally no effect, but will induce withdrawal in an opioid- tolerant patient 􏰀

4.treat opioid overdose: to reverse sedation & respiratory depression

Front 25

What are some characteristics of codeine?

Back 25

Methylmorphine􏰀

less potent than morphine􏰀

orally active

- ≈10% metabolised to morphine in liver

- 10% Caucasians lack enzyme

→no analgesia􏰀 little or no euphoria􏰀 little respiratory depression

Constipation􏰀

antitussive at sub-analgesic doses

Front 26

What are some characteristics of Fentanyl?

Back 26

1.potent (100 x morphine) 􏰀

2.short half-life 1-2 h (i.m.): suitable for incident or procedure-related pain (analgesic therapy) 􏰀

3.no active metabolites & less CNS adverse effects than morphine 􏰀

4,least constipating opioid 􏰀

5.acute strong pain ,ongoing severe pain

- transdermal patch (great for anaesthesia)

- changed every 3 days

- after removal, half-life in blood 15-20 h

Front 27

How is Opioids used in analgesic therapy

Back 27

Front 28

How is Opioids used in anaesthesia

Back 28

Front 29

How is obesity defined, and what are the consequences?

Back 29

BMI > 30kg/m^2

Excess Body Fat: diabetes, sleep apnoea, osteroathritis, cancer, asthma, coronary heart diseaseand hypertention

Front 30

What are the 2 kinds of peptides that regulate food intake?

Back 30

1. Orexigenic peptides, increase feeding

2.Anorexigenic, decrease feeding

Front 31

What is the mechanism of adipose control of appetite?

Back 31

Directly received by hypothalamus

Front 32

What are the 2 examples of adipose control of appetite?

Back 32

Insulin & Leptin

Front 33

Where is insulin released from?

Back 33

Pancreas

Front 34

What are some characteristics of leptin?

Back 34

1.release from adipose tissue

2.Plasma levels proportional to BMI and fat

3.Crosses blood-brain barrie as receptors located in the hypothalamus

4.Inhibits food intake via the alteration of neuropeptides

5.Saturable Process: excessive leptin levels lead to deficient signalling

Front 35

What is the mechanism of satiation control of appetite?

Back 35

Using nervous input to the medulla stimulates hypothalamus

Front 36

What are the 2 kinds of drugs that have been banded? Why are they banded?

Back 36

Sibutramine & Rimonabant

Reason: Risk associated

Front 37

What are the 2 kinds of drugs that are currently used?

Back 37

Phentermine & Orlistat

Front 38

What are some characteristics of phentermine, including its mechanism, duration, if required combination with other drug and adverse effects.

Back 38

Sympathomimetic amine : BMI>30

MechanismL ↑ NA available to bind to receptors → suppress appetides(↓neuronal reuptake or ↑indirect release of NA via transporters )

DurationL - only useful short term,(i.e.12 weeks)

no combination with other weight loss drug

Adverse effects: ↑BP, HR,

insomnia,

nervousness,

headache

Front 39

What are some characteristics of orlistat? Including associated change of diet, mechanism, duration and adverse effects.

Back 39

MUST combinewith a low fatdiet & vitamin supplementation (D& E lipidsoluble)

Inhibits gastric and pancreatic lipases→↓Dietary fat absorption􏰀

↓body weight, waist circumference􏰀

↓blood glucose, insulin (Type 2 diabetes)􏰀

↓Dyslipdaemia􏰀

↓BP

Duration: BMI>30, long term anti-obesity drug

Adverse Effects:

If adhere to low fat diet the adverse effects can be controlled.

If not, will lead to GI problems, Include explosivediarrhoea, faecal fat

Front 40

What is glucagon-like Peptide 1?

Back 40

released in stomach in response to meals rich in carbohydrates

Front 41

What is an example of synthetic glucagon-like peptide-1?

Back 41

Liraglutide

Front 42

What are some characteristics of Liraglutide? Including what it can be used to treat for, administration, effects and adverse effects.

Back 42

Can be used to treat type 2 diabetes

Administration: injection 2/day

Effects:

1. Brain: ↑neuroproduction and ↓appetite

2. Stomach: ↓gastric emptying

3. Pancreas: ↑insulin secretion & ↓Glucagon secretion

4. ↑insulin sensitivity

5. Adipose tissue and muscle: ↑Glucose uptake and storage

6. Liver: ↓glucose production in liver

Adverse Effects: 􏰀

1. Nausea, vomiting, diarrhoea 􏰀

2. Mild-to-moderate hypoglycaemia 􏰀

4. Antibody formation, immune reactions, pancreatitis

Front 43

What rules must be followed to design drugs for obesity?

Back 43

1. Known mechanism

2. Reduce body weight and medical complications

3. benefits outweigh side-effects

4. No addictive properties

5. Long-term use

Front 44

What are the 3 reasons why drugs are used in sport?

Back 44

1. to treat injury (legal)

2. to enhance performance (prohibited)

3. Recreationally

Front 45

What are the 3 kinds of drugs being used to treat injury in sports?

Back 45

1. Local anaesthetic drugs, to reduce sensation

2. Analgesic drugs, to reduce pain

3. Anti-inflammatory drugs, to reduce inflammation

Front 46

What are the 2 drugs used for anti-inflammation?

Back 46

Non-steroidal anti-inflammatory drugs(NSAIDs)

Glucocorticoids

Front 47

What is the mechanism of glucocorticoids?

Back 47

Glucocorticoids inhibit the production of phospholipase.

Front 48

What are the side effects of glucocorticoids?

Back 48

Immunosuppression

Skin thinning

Muscle wasting

Central adiposity

Front 49

How is glucocorticoids usually used?

Back 49

Due to the side effects, only apply locally at the site of injury. No systemic use.

Front 50

What is the mechanism of NSAIDs?

Back 50

Inhibit cyclo-oxygenase, therefore much faster onset compared to glucocorticoids

Front 51

What are some other effects of NSAIDs beside anti-inflammation?

Back 51

1. Analgesic

2. Antipyretic

3. Gastric ulceration( This is due to under normal circumstances Prostaglandins are responsible for production of mucus layer to protect stomach wall from acid. When NSAID block PG production, mucus layer is lost as well, acid will damage gastric cells on stomach wall)

Front 52

What are some responsibilities of WADA?( World Anti-Doping Agency)

Back 52

1. Oversees drugs use in sports

2. Publish list of prohibited substances

3.

Front 53

What are the 2 types of prohibited substances, give examples.

Back 53

1.Prohibited at all time, i.e anabolic agents, growth factors and non-approved substances

2. Prohibited in-competition only, i.e stimulants

Front 54

What is an example of anabolic agent?

Back 54

Anabolic-androgenic steroids(androgen)

Front 55

What is the clinical use of androgen?

Back 55

male hypogonadism, delayed puberty

Front 56

What are the advantages of androgen in sport?

Back 56

1.↑muscle strength by encouraging new growth 􏰀

2.allow the athlete to train harder and longer

Front 57

What are some disadvantages of androgen?

Back 57

1.high blood pressure 􏰀

2. Become more male like(virilization)

Front 58

What is EPO, and where is it produced?

Back 58

It is a protein growth factor, and is produced by kidneys

Front 59

What is the mechanism of EPO?

Back 59

It can bind on EPO receptors in cells in bone marrow, to stimulates growth of red blood cells.

As a consequence, it can increase oxygen carrying capacity of blood. Widely used in endurance耐久 sports.

Front 60

How is EPO administrated?

Back 60

Intravenously, can't taken orally as it is a protein, it will be metabolised

Front 61

What is the side effect of EPO?

Back 61

May lead to clotting of blood( blood thickened)

Front 62

How is stimulant administrated?

Back 62

Orally

Front 63

Give 2 examples of stimulant.

Back 63

Amphetamine

Methamphetamine

Front 64

What are some advantages of taking stimulants?

Back 64

Front 65

What are some side effects of stimulants?

Back 65

Front 66

How is drug testing usually conducted in athletes

Back 66

Urine samples, and use chromatographic methods

Front 67

What are the 2 challengers in drug testing?

Back 67

Masking agent and proteins

Front 68

How does masking agent challenge drug testing in athletes?

Back 68

Front 69

How does protein challenge drug testing in athletes?

Back 69