Case 2 - Pharmacology

Question 1

how do opioids work

Answer 1

by combining with opioid receptors in the brain and spina cord. this blocks transmission of pain signals sent by the nerves to the brain. although the cause of the pain may still remain, but less pain is felt.

Question 2

what are the 4 types of opioid receptors

Answer 2

Mu1,2,3
Delta
Kappa
Nociception

Question 3

what are mu receptors

Answer 3

the receptors responsible for most of the analgesic effects of opioids and for some major unwanted effects

Question 4

where are mu receptors located

Answer 4

in the brain, spinal cord, peripheral sensory neurones and intestinal tract

Question 5

describe the Mu1 receptor

Answer 5

analgesia, physical dependence (this is the unwanted effect, where choleric use of opioid produces tolerance. the negative phyiscal withdrawal symptoms result from the abrupt discontinuation or dosage reduction)

Question 6

describe the Mu2 receptor

Answer 6

respiratory depression, mioisis (contraction of pupil), euphoria, reduced GI mobility, physical dependence - morphine

Question 7

describe the Mu3 receptor

Answer 7

possible vasodilation

Question 8

describe the delta receptor

Answer 8

they can result in analgesia but can also be a proconvulsant. these are located in the brain and the peripheral sensory neurones.

Question 9

what are the effects of the delta 1 and 2 receptors

Answer 9

analgesia, antidepressant effects, convulsant effects and physical dependence

Question 10

what do kappa receptors do

Answer 10

contribute to analgesia at the spinal level and produce relatively few unwanted effects

Question 11

do kappa receptors contribute to dependence

Answer 11

no

Question 12

where are kappa receptors located

Answer 12

in the brain, spinal cord, and the peripheral sensory neurones

Question 13

exact effects of the kappa1,2,3 receptors

Answer 13

analgesia, anticonvulsant effects, depression, hallucinogenic effects, diuresis, sedation and stress

Question 14

describe the nociception receptors

Answer 14

activation results in an anti opioid effect (supra spinal), analgesia, immobility and impairment of learning

Question 15

examples a nociception receptor

Answer 15

ORL1 = anxiety, depression, appetite, development of tolerance to mu-opioid agonists

Question 16

mechanism of action of opioid receptor activation

Answer 16

1. inhibition of adenylyl cyclaase - opioids reduce the intracellular cAMP content. this affects protein phosphorylation pathways and hence cell function
2. opiates promote the opening of potassium channels - this reduces synaptic transmission as it causes the axon membrane to be in a state of hyper polarisation
3. inhibit the opening of calcium channels - this reduces the amount of neurotransmitter released into the synaptic cleft, thus reducing synaptic transmission

Question 17

what is cocodamol

Answer 17

an opioid analgesic derived from morphine but less potent as a pain killer, less sedative and less toxic

Question 18

does co codamol cause euphoria

Answer 18

no - little to non

Question 19

what does cocodamol contain

Answer 19

codeine and paracetamol

Question 20

what is the side effect of co codamol

Answer 20

constipation

Question 21

is co codamol a prodrug

Answer 21

yes

Question 22

what is the mechanism of action of NSAIDs

Answer 22

• primary effect is inhibition of arachidonic acid oxidation by the fatty acid COX.
• this inhibits the production of prostaglandins and thromboxane.
• NSAIDs vary in the degree to which they inhibit each iso form of the COX enzyme.

Question 23

which COX are the anti-inflammatory effects related to

Answer 23

COX-2

Question 24

where do their unwanted affects happen

Answer 24

COX-1 inhibition

Question 25

what are the three main effects of NSAIDs

Answer 25

1. anti-inflammatory 2. analgesic effect 3. antipyretic effect

Question 26

Describe the anti inflammatory effect of NSAIDa

Answer 26

modulation of the inflammatory reaction. - this occurs as a result of a decrease on prostaglandin E2 and prostacyclin PG12

Question 27

describe the analgesic effect of NSIADs

Answer 27

it occurs as a result of a decrease in the production of prostaglandins that sensitise nociceptors

Question 28

describe the antipyretic effect of NSAIDs

Answer 28

lowering of body temperature when this is raised in disease. - IL1 releases prostaglandins in the CNS, where they elevate the hypothalamic set point for temperature control - NSAIDs prevent this completely

Question 29

what are some side effects of NSAIDs

Answer 29

- GI disturbance - skin rashes - prolonged bleeding - increase in the likelihood of thrombotic events such as myocardial infarction by inhibiting prostaglandin I2 synthesis

Question 30

mechanism of ibuprofen

Answer 30

weakly COX1 selective: mild short lived anti platelet activity. - stops production of prostaglandins therefore analgesic aswell

Question 31

mechanism of paracetamol

Answer 31

selective through weak COX2 inhibitor. paracetamol does not have any gastric or platelet side effects

Question 32

TCA mechanism in more detail

Answer 32

the main effect of TCAs is to block the re uptake of airiness by nerve terminals, by competition for the binding site of the amine transporter. - most TCAs inhibit noradrenaline and 5-HT reuptake but have much less effect on dopamine re uptake

Question 33

what does inhibiting re uptake mean in simple terms

Answer 33

its in the synapse for longer so has a greater effect

Question 34

which receptors do TCAs also effect

Answer 34

mostly muscarinic acetylcholine receptors (antagonist). they do not contribute to the antidepressant effects

Question 35

what can TCAs cause when in overdose

Answer 35

may cause ventricular dysrhythmias associated with prolongation of the QT interval

Question 36

what is gabapentin

Answer 36

an anticonvulsant drug used to treat partial epilepsy and neuropathic pain, including peripheral neuropathy

Question 37

mechanism of action of Gabapentin

Answer 37

- GABA is a neurotransmitter in the CNS, involved with neuronal excitability - GABApentin interacts with cortical neurones at auxiliary subunits of voltage sensitive calcium channels - action potentials - gabapentin increases the synaptic concentration of GABA, enhances GABA response at non-synaptic sites in neuronal tissues, and reduces the release of mono-amine neurotransmitters

Question 38

what are the three steps of the WHO analgesic ladder

Answer 38

mild pain: non-opioid e.g paracetamol moderate pain: simple analgesic e.g paracetamol + weak opioid like coding severe pain: strong opioids e.g morphine

Question 39

what is the origin of drug liking in opioid addiction

Answer 39

- when heroin, oxycodone or any other opiate travels through the bloodstream to the brain, the chemicals attach to specialised proteins, called mu opioid receptors, on the surface of opiate sensitive neurones - the linkage of these chemicals with receptors triggers the same biochemical brain processes that reward people with feelings of pleasure when they engage in activities that promote basic life functions - opioids are prescribed theraputically to relieve pain, but when opioids activate these reward processes in the absence of significant pain, they can motivate repeated use of the drug simply for pleasure

Question 40

what is the main brain circuit activated by opioids

Answer 40

the mesolimbic (midbrain) pathway

Question 41

describe the mesolimbic pathway

Answer 41

this system generates signals in a part of the brain called the ventral tegmental area, VTA, that results in the release of the chemical dopamine in the nucleus accumbens. this release of dopamine into the nucleus accumbens causes feelings of pleasure. other areas of the brain create a lasting record to memory that associates these good feelings with the circumstances and environment in which they occur. they are called conditioned associations, often leading to the craving for drugs when the abuser reencounters those persons, places, or things and they drive abusers to seek out more drugs in spite of many obstacles

Question 42

describe opioid withdrawal

Answer 42

from a clinical standpoint, withdrawal is one of the most powerful factors in driving opioid dependence and addictive behaviours. treatment of the patients withdrawal systems is based on understanding how withdrawal is related to the brain's adjustment to opioids. repeated exposure to escalating dosages of opioids alters the brain so that it functions more or less normally when the drugs are present and abnormally when they are not. two important clinical results of this alteration are opioid tolerance and drug dependence. withdrawal symptoms occur only in patients who have developed tolerance.

Question 43

describe opioid tolerance

Answer 43

occurs because the brain cells that have opioid receptors on them gradually become less responsive to the opioid stimulation. for example, more opioid is needed to stimulate the VTA brain cells of the mesolimbic reward stream to release the same amount of dopamine in the NAc. therefore, more opioid is needed to produce pleasure comparable to that provided in previous drug episodes.

Question 44

what does opioid dependence involve

Answer 44

the locus ceruleus

Question 45

describe opioid dependence in terms of effects in the locus ceruleus

Answer 45

neurones in the LC produce noradrenaline and distribute it to other parts of the brain where it stimulates wakefulness, breathing, BP and general alter ness. when opioid molecules link to the mu receptors on the brain cells in the LC, they suppress the neurones release of NA, resulting in drowsiness, slow respiration, low BP. with repeated exposure to opioids, however the LC neurones adjust by increasing their level of activity. now, when opioids are present, their suppressive impact is offset by this heightened activity, with the result that roughly normal amounts of noradrenaline are released and the patient feels more or less normal. when opioids are not present to suppress the LC brain cells' enhanced activity, however, the neurones release excessive amounts of noradrenaline

Question 46

what do these excessive amounts of noradrenaline trigger

Answer 46

jitters, anxiety and muscle cramps

Question 47

next...

Answer 47

go onto pharmacology notes and study the screenshots I have put in for more detailed learning