Pharmacology Flashcards

1
Q

List the four types of intracellular receptors

A
  1. Ligand-gated ion channels
  2. G-protein coupled receptors
  3. Kinase-linked receptors
  4. Nuclear receptors
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2
Q

Discuss the ligand-gated ion channel receptors, making mention of clinical correlations.

A
  • ionotropic receptors
  • mainly involved in synaptic transmission
  • drugs that target ligand-gated ion channels can be agonists or antagonist
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3
Q

What are some examples of ligand-gated ion channel receptors?

A
  • nicotinic acetylcholine
  • glycine
  • glutamate and GABA
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4
Q

What is the process of g-protein coupled receptors signalling?

A
  1. resting state
  2. occupied receptor
  3. activation of downstream targets
  4. GTP hydrolysis
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5
Q

What is the process of a kinase-linked receptor?

A
  • a growth factor binds RTK, which results in dimerization with a neighbouring RTK
  • the dimerised RTKs auto phosphorylate one another
  • a SH2-domain protein binds to the intracellular active enzyme domain on the dimerised RTK resulting in phosphorylation of that SH2-domain protein.
  • the SH2-domain protein goes on to activate Ras, a g-protein anchored to the cell membrane
  • Ras is bound to GDP in its inactive state and GTP in its active state
  • when activated, Ras activates RAF kinase
  • RAF kinase goes on to phosphorylate and activate MEK kinase which then phosphorylates and activates MAP kinase
  • finally, MAP kinase phosphorylates various transcription factors ultimately altering gene transcription
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6
Q

What is the process of nuclear receptors?

A
  • hormones cross membranes and bind to receptors within the target cells
  • they migrate together to the DNA within the nucleus, binding to key sequences in the DNA to cause transcription of desired proteins
  • mRNA moves into cytoplasm for translation and biological action via newly made proteins
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7
Q

Why are their numerous time-frames for change in physiological processes?

A
  • due to the diversity of receptors present and their connection to intracellular signalling mechanisms
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8
Q

Beyond the receptor types, what are the other ways that drugs can work?

A
  • transporters
  • enzymes
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9
Q

How do transporters as drug tests?

A
  • by blocking the reuptake transporter on the presynaptic side of the synapse, the levels of serotonin stay increased for a longer period of time, increasing the chances that it may bind to receptors, thus improving signalling
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10
Q

True or false: all agonists are able to equally activate receptors?

A

False!
- an agonist may not fit as well into the receptor binding site so it comes off more quickly and does not activate the receptor to the same extent

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11
Q

What would it mean for low-affinity and high-affinity agonists in high concentrations?

A
  • the number of activated receptors for the low-affinity agonists is still much lower than for the high-affinity agonists
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12
Q

When considering a log-scale graph of drug concentration and response (x- and y-axis respectively), what do these axes tell us, and how is it clinically significant?

A
  • concentration (x-axis) tells us about potency: comparison of concentrations and effects of drugs
  • response (y-axis) tells us about efficacy: comparison of effectiveness of drugs, or ‘activation of receptors’
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12
Q

When considering a log-scale graph of drug concentration and response (x- and y-axis respectively), what do these axes tell us, and how is it clinically significant?

A
  • concentration (x-axis) tells us about potency: comparison of concentrations and effects of drugs
  • response (y-axis) tells us about efficacy: comparison of effectiveness of drugs, or ‘activation of receptors’
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13
Q

What would you expect a full agonist to be compared to a partial agonist?

A
  • full agonist is going to be very efficient
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14
Q

What would you expect a full agonist to be compared to a partial agonist?

A
  • full agonist is going to be very efficient, partial agonist is going to be less so
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15
Q

Define ‘antagonists’.

A
  • drugs that bind to receptors but do not activate them as they are unable to cause a shape change to enable signalling
  • they prevent the binding of agonists to the receptors and so work against the agonists’ effects
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16
Q

What are the four types of antagonists?

A
  1. competitive
  2. non-competitive (allosteric modulation)
  3. uncompetitive antagonism
  4. functional/physiological antagonism
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17
Q

Discuss how competitive agonists work

A
  • the high-affinity competitive agonist binds to the receptor, but does not activate its effectors
  • no response!
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18
Q

What happens when a competitive antagonist and an agonist are at receptor sites?

A
  • the competitive antagonist physically blocks the sites the agonist’s would be received by, so it reduces ability of the agonist to bin and cause a response
  • the effect of this is a reduction in the effect of the agonist at each concentration
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19
Q

How do non-competitive antagonists work?

A
  • the antagonist binds somewhere other than the active site on the receptor, which changes the shape of the binding site so it can no longer bind agonists
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20
Q

How does uncompetitive antagonism work?

A
  • some of the receptors become permanently bound to antagonist, at the site as where the agonist binds
  • when the agonist is applied, the maximum number of receptors available is less than 100% as some of them are permanently occupied by the antagonist
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21
Q

How does functional/physiological antagonism work?

A
  • two drugs act on two different types of receptors and antagonise the action of each other
  • may involve second messenger pathways
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22
Q

Provide a concise summary of what the effect of a drug is characterised by

A
  • maximum effect (Emax) and the concentration that produces half-maximal effect (EC50)
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23
Q

How does drug tolerance develop?

A
  • because of prolonged exposure of receptors to an agonist drug leading to a decrease in effect or receptor response because receptor numbers and signalling can change
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24
Q

What are the two mechanisms through which drug tolerance is developed?

A
  • receptor uncoupling (desensitisation)
  • receptor loss (down-regulation)
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25
Q

What does ADME mean?

A
  • absorption
  • distribution
  • metabolism
  • excretion
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26
Q

List the parental routes of drug administration, as well as some advantages and disadvantages of each.

A

Intravenous:
+ rapid action, complete dosing
- risk of toxicity, must be sterile, risk of sepsis
Intramuscular:
+ rapid absorption
- painful, possible tissue damage
Subcutaneous:
+ good for slower absorption
- variable dosage
Inhalation:
+ good for local application
- variable dosage

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27
Q

List the enteral routes, as well as some advantages and disadvantages of each

A

Oral:
+ convenient, non-sterile, self administration
- GIT irritation, inactivation, variable absorption
Sublingual:
+ avoids inactivation in GIT
- applicable to very few drugs
Rectal:
+ avoids inactivation in GIT
- inconvenient for patient

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27
Q

List the enteral routes, as well as some advantages and disadvantages of each

A

Oral:
+ convenient, non-sterile, self administration
- GIT irritation, inactivation, variable absorption
Sublingual:
+ avoids inactivation in GIT
- applicable to very few drugs
Rectal:
+ avoids inactivation in GIT
- inconvenient for patient

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28
Q

How do drugs get into the blood stream?

A
  • GI tract
  • skin
  • blood brain barrier
  • placenta
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29
Q

What does absorption depend upon?

A
  1. concentration gradient
  2. lipophilicity of drug
  3. blood flow at site
  4. surface area
  5. gut motility
  6. formulation - rate of drug releasing
  7. GI tract content
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30
Q

What is the impact on the liver in drug absorption?

A
  • ‘first pass’ through hepatic vein: effect is that orally taken drugs (or entering through bloodstream) will pass through liver, where it metabolises the drug and reduces the concentration of the drug available to work on the rest of the body
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31
Q

Define bioavailability, and list what it is regulated by

A
  • the fraction absorbed into the systemic circulation
    Regulated by:
    (Absorption) - GI tract contents, gut motility, gut blood flow
    (Degradation) - gut microflora, acid stability, liver metabolism
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32
Q

How can the first-pass effect on absorption be avoided?

A
  • administering drugs rectally, subcutaneously, intravenously, intramuscularly
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33
Q

What is the volume of distribution?

A
  • the amount in body/plasma concentration
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34
Q

Once a drug is in the blood, what affects it’s ability to work on receptors? And how? Provide some examples.

A

Proteins! (i.e. human serum albumin, lipoproteins, etc.)
- the less a drug binds to the proteins in the blood, the more available it is to work on receptors
- thus, high protein binding will lead to a decrease in free drug, and low protein binding will mean that drug can more easily traverse cell membranes or diffuse to tissue receptors

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35
Q

What is the purpose of metabolism of drugs?

A
  1. increase the rate of elimination
  2. decrease likelihood of toxicity
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36
Q

What are the two major types of enzymatic reactions?

A
  1. Phase 1 reactions (oxidations, reduction, hydrolysis)
  2. Phase 2 reactions (add water-soluble moiety to drug: glucuronide, glutathione, sulphate, acetate)
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37
Q

What is the result of all phase 1 reactions (reduction, oxidation and hydrolytic reactions)?

A
  • increases the water solubility of the resulting metabolite
38
Q

Provide some generalisations about phase 2 metabolites

A
  • more highly ionised
  • more water soluble
  • more likely to be excreted by the liver and kidneys
  • less pharmacologically active
  • less toxic
39
Q

What are some factors that affect drug metabolism?

A
  • genetics
  • age
  • gender
  • food or grapefruit juice
  • other drugs being taken
40
Q

Most lipophilic drugs and environmental chemicals are substrates of what haemoprotein?

A
  • cytochrome P450
41
Q

State what CYP enzymes are inducible by, and then the result of this induction.

A
  • drugs/other compounds
  • results in more rapid metabolism, increased elimination, and decreased pharmacological effect
42
Q

When does inhibition of CYP enzymes usually occur, and what is the result of this? Also mention the clinical significance

A
  • when 2 drugs are metabolised by the same enzyme
  • can result in increased plasma levels and drug toxicity
  • clinically significant for drugs with small therapeutic windows
43
Q

What is a ‘pro-drug’? Provide an example

A
  • therapeutics that require metabolism to an active metabolite for activity
  • usually used to increase absorption and distribution in the body

Codeine!

44
Q

Provide 4 key points of metabolism covering what purpose it serves, where it occurs, its rate, and its inhibition

A
  1. drug metabolism serves to eliminate drugs from the body
  2. metabolism occurs primarily in the liver
  3. the rate of metabolism can by induced by other drugs, diet, herbs, environmental agents
  4. metabolism can be inhibited by other drugs or xenobiotics that share the same metabolising agents
44
Q

Provide 4 key points of metabolism covering what purpose it serves, where it occurs, its rate, and its inhibition

A
  1. drug metabolism serves to eliminate drugs from the body
  2. metabolism occurs primarily in the liver
  3. the rate of metabolism can by induced by other drugs, diet, herbs, environmental agents
  4. metabolism can be inhibited by other drugs or xenobiotics that share the same metabolising agents
45
Q

What is a clinical correlate of renal excretion of drugs?

A
  • for drugs primarily excreted by the kidneys, renal disease can lead to increased plasma concentrations
46
Q

Where are drug metabolites more likely to be excreted, and why??

A
  • the urine - as they are more water soluble and not as likely to be reabsorbed back into the blood stream
47
Q

What are some complications of renal function that impact drug excretion?

A
  • poorly developed in neonates and the elderly -> may prolong the time course and efficacy of excretion
  • a patient with chronic renal failure will have almost non-existent drug excretion
  • a patient with cardiac failure will have reduced blood flow to the kidneys, which may decrease renal excretion of unchanged drugs and metabolites
48
Q

What are some key points about the renal system in drug excretion?

A
  1. drug excretion occurs primarily in the kidneys
  2. only free (unbound) drug can be filtered at the glomerulus
  3. drugs can be actively secreted in the proximal tubules - involves transporters
  4. drugs can be reabsorbed in the distal tubules - involves passive diffusion
49
Q

List the major event in the local inflammatory response

A
  1. chemical signals released by activated macrophages and mast cells at the injury site cause nearby capillaries to widen and become more permeable
  2. fluid, antimicrobial proteins, and clotting elements move from blood to the site - clotting begins
  3. chemokines released by various kinds of cells attract more phagocytic cells from the blood to the injury site
  4. neutrophils and macrophages phagocytose pathogens and cell debris at the site, and the tissue heals
50
Q

What controls inflammation, and what are the major mediators?

A
  • inflammatory mediators are intercellular chemical messengers released by numerous inflammatory cells
    Mediators include:
  • eicosanoids (derived of arachidonic acid, including prostaglandins and leukotrienes)
  • histamine (store in mast cells, mediates allergic reactions)
51
Q

How do prostaglandins bring about their (inflammatory) effects?

A
  • g-protein coupled receptors
  • great diversity in receptor structures and G-protein interactions
  • the effects may differ by tissue (e.g. contraction of GI and uterine smooth muscle, increased gastric secretions)
52
Q

List the different types of corticosteroids and features of their production and their functions

A

Endogenous corticosteroids:
- made in adrenal cortex
- mineralocorticoids are involved in water and electrolyte balance (aldosterone)
- glucocorticoids have widespread effects on metabolism, as well as mechanisms of defence (hydrocortisone)
Exogenous glucocorticoids:
- most commonly used for anti-inflammatory effects

53
Q

What is the main anti-inflammatory mechanism of action of SAIDs

A
  • overall result is the reduced production of prostaglandins
54
Q

What are the anti-inflammatory indications of corticosteroids?

A
  • transplant rejection
  • rheumatoid arthritis
  • inflammatory bowel diseases (Crohn’s, UC)
  • psoriasis and systemic lupus erythematosus
  • asthma/allergies
  • septic shock
55
Q

What are some potential side effects of corticosteroids?

A
  • immunosuppressive activity increases risk of microbial infections
  • worse diabetes (by promoting hyperglycaemia by lowering glucose uptake and promoting gluconeogenesis)
  • hypertension and heart failure
  • may increase the risk of peptic ulcers (greater gastric acid, less gut protection)
  • may increase osteoporosis
56
Q

What are NSAIDs used for?

A

(Non-steroidal anti-inflammatory drugs) - used extensively to control mild pain and inflammation

57
Q

How do NSAIDs work?

A
  • inhibit prostaglandin synthesis
58
Q

What effects do all anti-inflammatory NSAIDs have, and are these effects always of the same magnitude?

A
  • anti-pyretic (lower body temp)
  • analgesic (reduce pain)
  • NO! magnitude of the effects vary for each drug and pain indication
59
Q

What are some examples of what NSAIDs provide relief from?

A
  • swelling in arthritis
  • bone fractures
  • soft tissue injury
  • postoperative and dental pain
  • menstrual pain
  • headaches and migraines
60
Q

What does COX-1 produce, which then has what functions?

A

Produces protective prostaglandins that:
- coat the stomach lining with mucus (= protection)
- aid in platelet aggregation (prevent excessive bleeding)
- regulate renal blood flow
- induce parturition

61
Q

What does COX-2 produce, which then has what functions?

A

Inflammatory prostaglandins that:
- sensitise skin nociceptors
- increase body temperature by acting on the hypothalamus
- recruit inflammatory cells towards injured parts of the body

62
Q

What are the anti-pyretic effects of NSAIDs?

A
  • body temp is controlled by hypothalamus, ensures homeostatic ‘thermostat’
  • fever occurs when hypothalamic interleukin-1 (inflammatory mediator), generates E-type prostaglandins that elevate the set point
  • NSAIDs act by interrupting this synthesis of PGE and resetting the set-point to normal temperature
  • the body then adjusts dilation of blood vessels, sweating, etc. to restore normal body temp
63
Q

What are the side effects common to most NSAIDs (mainly due to inhibition of COX1)?

A
  • gastrointestinal disturbances
  • renal effects
  • cardiovascular effects
  • skin reactions (idiosyncratic rashes, erythematosus and photosensitivity)
64
Q

How does aspirin work? Mention its effects on pain and fever, and blood clotting

A

(salicylates class)
- irreversibly inhibits COX 1 and 2 though COX acetylation
Pain and fever:
- decreases hyperalgesia after tissue injury (analgesic!)
- anti-inflammatory in arthritis
- prostaglandins in the hypothalamus change the ‘set point’ for body temp - aspirin resets the body’s internal thermostat to normal -> decreases fever
Blood clotting:
- antiplatelet activity

65
Q

List the major side effects of aspirin

A
  • blood clotting (risk of internal/excessive bleeding)
  • nephrotoxicity
  • CNS effects (tinnitus, confusion, delirium, convulsions, coma)
  • gastric irritation (can cause gastric ulceration)
  • pregnancy (can delay labour)
  • Reye’s syndrome (fatty degeneration of liver and kidneys, swelling of the brain, can be fatal)
66
Q

What age groups are contraindicated for the prescription of aspirin?

A

<12
<20 with viral fever

67
Q

What is indomethacin, and how does it work? Mention its effects on pain and fever, as well as adverse effects.

A

(indolacetic acid)
- competitive, reversible inhibitor of COX1 and 2
Effects on pain and fever:
- most potent (anti-inflammatory) of all NSAIDs
- 10-fold more effect analgesic effect than aspirin
- better anti-pyretic effect than aspirin
- generally only administered for gout and arthritis
ADVERSE EFFECTS:
- cause more significant GI toxicity than any other NSAID
- causes more significant cardiovascular side effects than any other NSAID

68
Q

What groups are contraindicated for the use of indomethacin?

A
  • <14 years
  • pregnant women
69
Q

What is naproxen, and how does it work? Mention its effects on pain and fever and adverse effects

A

(propionic acids) competitive, reversible inhibitor of COX 1 and 2
Effects on pain and fever:
- more anti-inflammatory effect than aspirin
- same thermoregulatory effect as aspirin
- longer lasting relief against menstrual pain than ibuprofen
- can be sued to treat headaches, arthritis, etc.
ADVERSE EFFECTS:
- does not have the same effects on blood clotting as aspirin, can INCREASE risk of thrombosis
- some gastric irritation can occur
- better tolerated than other NSAIDs (but more adverse effects on the liver than ibuprofen)

70
Q

What is diclofenac, and how does it work? Mention its effects on pain and fever, as well as its adverse effects.

A

(fenamate) - competitive, reversible inhibitor of COX 1 and 2
Effects on pain and fever:
- one of MOST potent NSAIDs
- significantly more potent analgesic effects than aspirin and indomethacin
- longer lasting analgesic effect of any NSAID (6-8hr)
- generally only used to treat chronic inflammatory conditions
- can be applied topically (e.g. Voltaren)
ADVERSE EFFECTS:
- increased risk of cardiovascular disease over other NSAIDs
- risk of GI disturbances
- risk of acute liver damage
- hypersensitivity reactions from topical application

71
Q

What are cox-2 specific inhibitors, and how does it work? Mention its uses, as well as its adverse effects.

A

(Celecoxib)
Uses:
- treatment of rheumatoid and osteo-arthritis
- patients where traditional NSAIDs are contraindicated due to GI disturbances
ADVERSE EFFECTS:
- cardiovascular problems (increased risk of heart attack and stroke)
- increased risk of gastrointestinal bleeding

72
Q

How does COX-2 inhibition have these adverse effects?

A
  • inhibition of COX-2 in vasculature reduces prostacyclin which is antithrombotic and antiatherogenic
  • inhibition of COX-2 in the kidneys reduces PGI2 and PGE2 which results in hypertension and oedema as arterial pressure homeostasis is disrupted
73
Q

What is the maximum time period for celecoxib to be used in Australia?

A
  • 3 weeks
74
Q

What is paracetamol, and how does it work? Mention its effects on pain and fever, as well as its adverse effects.

A

(acetaminophen) not a traditional NSAID: COX-3 selective in the CNS
Effects on pain and fever:
- weak anti-inflammatory effect (thought to be because the mechanism is not necessarily associated with the prostaglandins)
- good analgesic effect
- most well tolerated analgesic drug
- suitable substitute for aspirin for antipyretic and analgesic effects
ADVERSE effects:
- no adverse gastric effects
- no effect on bleeding time and no cardiovascular toxicity
- major toxic effects are in the liver - highly hepatotoxic when overdoes due to metabolism in the liver

75
Q

Discuss the toxic and hepatotoxic effects of paracetamol.

A

Toxic:
- dose-dependent, hepatic necrosis which can be fatal, as well as renal necrosis
- chronic use can lead to irreversible nephrotoxicity in some people
- fatal dose around 20-30 gms
Hepatoxicity:
- due to formation of toxic reactive intermediary
- hepatic damage signs appear in 2-4 days
- liver enzymes and bilirubin levels in plasma rise
- 1-2% of untreated patients will die of liver failure

76
Q

Discuss how nociceptive input is received by the spinal cord

A
  • via spinothalamic pathway
  • this pathway is modulated by descending inhibitory pathways from the brain to the dorsal horn of the spinal cord; these pathways are rich with opioid receptors that we make use of medicinally
77
Q

Detail the descending inhibitory pathways

A
  • cortical brain regions project downwards to the PAG region of the midbrain
  • PAG neurons project to the rostral ventromedial medulla and then onwards to the dorsolateral funiculus in the spinal cord
  • this pathway is key to the body’s endogenous pain management system, which utilises serotonin and enkephalins, the latter of which blocks spinothalamic transmission of pain
78
Q

Discuss nociception at the synaptic level

A
  • opioid activity reduces afferent signalling pathway activity and promotes activity of the descending inhibitory pathways, leading to an overall reduction of nociception and pain
79
Q

Define ‘opioids’ and ‘opiates’

A

Opioids: all opiates + manmade compounds (oxycodone) + synthetics (fentanyl, methadone)
Opiates: include morphine and codeine

80
Q

What happens pre- and post-synaptically in the activation of opioid receptors?

A

Pre:
- inhibition of presynaptic Ca2+ ion channels in the synaptic bouton, which reduces neurotransmitter release
Post:
- opening of postsynaptic K+ ion channels, causing hyperpolarisation, making the receiving neuron less responsive

81
Q

What does the activation of opioid receptors lead to, and to what effect?

A
  • either inactivation of adenylyl cyclase enzyme function (reduces intracellular calcium), or increase potassium ion flow out of the neurons, making it more hyperpolarised

Inhibit pain transmission and provide pain relief

82
Q

What are the major effects of opioids, broadly and then specifically ?

A
  • on the heart
  • on the GIT
  • analgesia
  • dysphoria/euphoria
  • inhibition of cough reflex
  • myosis (pin-point pupils)
  • elements of possible physical dependence
  • respiratory depression
  • sedation
83
Q

Why does miosis occur, and why is it a good clinical tool in diagnosis of drug overdose?

A
  • due to direct stimulation of Edinger-Westphal nucleus of CN3 (activates sympathetic component of the sphincter muscle of iris)
  • little to no tolerance to this effect, so is a good marker of drug overdose
84
Q

What are the opioid effects on the gastrointestinal system?

A

Nausea and vomiting:
- tolerance develops with repeated use
Constipation:
- increase in tone and decrease in motility
- delay of passage of gastric contents, may lead to increased retention of water
- tolerance does not develop

85
Q

What is the ADME of codeine and morphine?

A
  • codeine undergoes less first-pass metabolism in the hepatocyte than morphine, so has greater bioavailability
  • morphine is well-absorbed in the gut and undergoes extensive first-pass metabolism in the liver
  • hepatic disease may impact of metabolism
  • codeine is converted to morphine (‘pro-drug’)
86
Q

Knowing that 10% of codeine metabolises into morphine, why is it used instead of morphine?

A
  • because it is a pro-drug, it reduces side effects but continues to have beneficial effects
  • codeine: moderately severe pain
  • much less commonly abused than morphine (less addictive and dangerous in overdose)
  • also no effect from taking more, whereas morphine is far more potent, and even slight increase in dosage can be dangerous
87
Q

Why are lower concentrations of moderate agonists often coupled with NSAIDs for pain treatment?

A
  • because moderate agonists cause intolerable side effects when given in doses sufficient to relieve severe pain
88
Q

What opioid antagonists are used to treat overdose?

A
  • naloxone
  • naltrexone
89
Q

What is fentanyl, and what are its uses?

A

(synthetic strong opioid agonist)
- formulated into a patch to provide continuous pain relief: this delivery is possible due to its high potency and lipid solubility
- often used in general anaesthetic conditions
- fast onset
- 50-100 times more potent than morphine

90
Q

What is methadone, and what are its uses?

A

(strong long-acting synthetic agonist)
- used to treat opioid/heroin addiction or chronic pain
- does not cause euphoric behaviour
- postpones experience of withdrawal
- can be lethal in overdose, injected or when combined with drugs such as alcohol

91
Q

What is pethidine, and what are its uses?

A

(synthetic moderate)
- tends to cause restlessness, euphoria, and has antimuscarinic effects as well (no myosis)
- preferred to morphine during labour as it does not affect uterine smooth muscle function
- may cause issues with respiratory depression in the neonate

92
Q

How do the antagonists naloxone and naltrexone work?

A
  • prevent or abolish excessive respiratory depression caused by morphine
  • pharmacologically competitive antagonists, competing with opioid for opioid receptor binding sites
  • blocks the euphoric effect of heroin when given before heroin
93
Q

What are the two major requirements that all drugs must satisfy before human use?

A
  • efficacy
  • safety
94
Q

What is an ADR?

A
  • adverse drug reaction: any response to a drug that is noxious, unintended and which occurs at doses normally used for therapy of disease