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Phase 2A > Pharmacology and prescribing 2 > Flashcards

Pharmacology and prescribing 2 Flashcards

1
Q

what toxicities are tested for in animals during drug development?

A

carcinogenicity, teratogenicity and organ-specific toxicities

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2
Q

what are adverse drug reactions?

A
  • injuries following administration of a drug or combination of drugs under normal conditions of use
  • unwanted or harmful effects that occur in humans after it has been marketed, due to adverse effects not being seen in animals
  • suspected to be related to the drug
  • has to be noxious and unintended
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3
Q

what are examples of adverse drug reactions that occur during prolonged use of a drug?

A
  • osteoporosis during continued high-dose glucocorticoid therapy
  • tardive dyskinesia during continuous use of antipsychotics
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4
Q

what are examples of adverse drug reactions occurring on ending treatment?

A
  • within a few days: tachycardia on abrupt discontinuation of beta-adrenoceptor blockade
  • months/years after discontinuation: second malignancies following successful chemotherapy
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5
Q

who suggested classifying ADRs according to DoTS? what is DoTS?

A
  • Aronson and Ferner (2003)

- dose, time course and susceptibility

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6
Q

who suggested the ABCDE approach to classifying ADRs?

A

Rawlins and Thomson (1985)

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7
Q

what are type A ADRs?

A
  • adverse effects related to the known pharmacological actions of the drug are predictable
  • augmented
  • related to dose and individual susceptibility
  • common
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8
Q

what are examples of type A ADRs?

A
  • postural hypotension with alpha1-adrenoceptor antagonists
  • bleeding with anticoagulants
  • sedation with anxiolytics
  • morphine and constipation
  • hypotension and antihypertensive
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9
Q

how serious are type A ADRs?

A
  • often is reversible, and the problem can be dealt with by reducing the dose
  • can be serious (e.g. intracerebral bleeding caused by anticoagulants, hypoglycaemic coma from insulin)
  • may not be easily reversible (e.g. drug dependence from opiod analgesics)
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10
Q

what is an example of type A ADRs leading to discrete events rather than graded symptoms?

A
  • makes them difficult to detect
  • drugs that block COX-2 (coxibs, e.g. rofecoxib, celecoxib, valdecoxib and NSAIDs) increase risk of MI in a dose-dependent manner
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11
Q

when can type B ADRs be predictable?

A
  • if taken in excessive dose (e.g. paracetamol hepatotoxicity or aspirin-induced tinnitus)
  • increased susceptibility (e.g. pregnancy)
  • predisposing disorder
  • mutation in mitochondrial DNA
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12
Q

what are type B ADRs?

A
  • adverse effects unrelated to the known pharmacological action of the drug
  • unpredictable
  • idiosyncratic
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13
Q

what are type B ADRs often initiated by? what are examples of this?

A
  • chemically reactive metabolite rather than the parent drug
  • often immunological in nature
  • drug-induced hepatic/renal necrosis, bone marrow suppression, carcinogenesis and disordered fetal development
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14
Q

what are examples of severe type B ADRs?

A
  • aplastic anaemia from chloramphenicol

- anaphylaxis due to penicillin

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15
Q

what is involved in toxicity testing in animals?

A
  • wide range of tests in different species
  • long-term administration of the drug
  • regular monitoring for abnormalities
  • detailed postmortem examination to detect gross or histological abnormalities
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16
Q

what doses are used in toxicity testing?

A

doses well above the expected therapeutic range

- establishes which tissues or organs are likely targets of toxic effects of the drug

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17
Q

why are recovery studies in toxicity testing done?

A

to assess whether toxic effects are reversible, and looking for irreversible changes e.g. carcinogenesis or neurodegeneration

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18
Q

what are the ranges of toxic effects caused by a drug?

A
  • can range from negligible to so severe that development of the compound is stopped
  • intermediate levels of toxicity are more acceptable in drugs for severe illnesses
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19
Q

when can safety of a drug be determined?

A

only during use in humans; toxicity can be detected in animals too

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20
Q

what are some tests of hepatic damage and renal function?

A

hepatic: levels of transaminase enzymes measured in blood plasma or serum
renal function: usually creatinine concentration

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21
Q

how does toxin-induced cell damage/death occur?

A
  • necrosis
  • apoptosis is increasingly recognised to be of equal or greater importance than necrosis, especially in chronic toxicity
  • covalent or non-covalent mechanisms
  • caused by reactive metabolites of the drug
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22
Q

what are potentially cytotoxic, non-covalent processes of drug-induced cell damage/death?

A
  • lipid peroxidation
  • generation of toxic ROS
  • depletion of reduced glutathione (GSH)
  • modification of sulfhydryl groups
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23
Q

what is the process of lipid peroxidation? what is it initiated by?

A
  1. initiated either by reactive metabolites or by ROS
  2. lipid peroxyradicals (ROO•) can produce lipid hydroperoxides (ROOH)
  3. ROOH produce further lipid peroxyradicals (ROO•)
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24
Q

what are defence mechanisms against lipid peroxidation?

A

GSH peroxidase and vitamin E

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25
Q

how does lipid peroxidation cause cell damage?

A

from alteration of membrane permeability or from reactions of the products of lipid peroxidation with proteins

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26
Q

what is the process of ROS production?

A

reduction of molecular oxygen to superoxide anion may be followed by enzymatic conversion to hydrogen peroxide, hydroperoxy and hydroxyl radicals or singlet oxygen

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27
Q

how does ROS production cause cell damage?

A
  • ROS are cytotoxic, both directly and through lipid peroxidation
  • important in excitotoxicity and neurodegeneration
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28
Q

what can protect cells from oxidative stress?

A

GSH redox cycle

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29
Q

how is GSH depleted? how is it usually maintained and regenerated?

A
  • GSH can be depleted by accumulation of normal oxidative products of cell metabolism or by the action of toxic chemicals
  • usually maintained in a redox couple with its disulfide, GSSG
  • oxidising species convert GSH to GSSG
  • GSH is regenerated by NADPH-dependent GSSG reductase
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30
Q

how can depletion of reduced glutathione damage cells?

A
  • GSH redox cycle protects cells from oxidative stress
  • when cellular GSH falls to about 20-30% of normal, cellular defence against toxic compounds is impaired and cell death can result
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31
Q

how can modification of sulfhydryl groups be produced?

A
  • by oxidising species that alter sulfhydryl groups reversibly
  • by covalent interaction
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32
Q

what is the role of free sulfhydryl groups?

A

catalytic activity of many enzymes

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33
Q

what are important targets for sulfhydryl modification by reactive metabolites?

A
  • cytoskeletal protein actin GSH reductase

- Ca2+ transporting ATPases in the plasma membrane and ER

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34
Q

what is the action of the targets of sulfhydryl modification?

A

maintain cytoplasmic Ca2+ concentrations at about 0.1 mewmol/l in the face of an extracellular Ca2+ concentration of more than 1 mmol/l

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35
Q

what does inactivation of protein actin GSH reductase and Ca2+ transporting ATPases by sulfhydryl modification lead to?

A
  • sustained rise in cell Ca2+

- this compromises cell viability

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36
Q

what are lethal processes that lead to cell death after acute Ca2+ overload caused by modification of sulfhydryl groups?

A
  • activation of degradative enzymes (neutral proteases, phospholipases, endonucleases) and protein kinases
  • mitochondrial damage
  • cytoskeletal alterations (e.g. modification of association between actin and actin-binding proteins)
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37
Q

what are targets for covalent interactions?

A

DNA, proteins/peptides, lipids and carbohydrates

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38
Q

what are the roles of mutagenic/non-mutagenic chemicals?

A
  • mutagenic chemicals covalently bond to DNA

- non-mutagenic chemicals form covalent bonds with macromolecules

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39
Q

what are examples of covalent interactions? what can they lead to?

A
  • cholinesterase inhibitor paraoxon binds acetylcholinesterase at the NMJ and causes necrosis of skeletal muscle
  • Amanita phalloides (from poisonous toadstool binds actin, and another binds RNA polymerase, interfering with actin depolymerisation and protein synthesis, respectively
  • adduct formation between a metabolite of paracetamol and cellular macromolecules
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40
Q

what can covalent binding to proteins and DNA lead to?

A
  • binding to protein can produce an immunogen

- binding to DNA can cause carcinogenesis and teratogenesis

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41
Q

what is liver damage manifested as?

A

manifested clinically as hepatitis or in laboratory abnormalities (e.g. increased activity of plasma aspartate transaminase, an enzyme released from damaged liver cells)

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42
Q

what is an enzyme that’s released by damaged liver cells?

A

plasma aspartate transaminase

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43
Q

in which cases of hepatotoxicity have genetic differences in drug metabolism been implicated?

A

isoniazid, phenytoin

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44
Q

what causes reversible obstructive jaundice?

A

chlorpromazine and androgens

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45
Q

what is the effect of a toxic dose of paracetamol?

A

enzymes catalysing the normal conjugation reactions are saturated, and P450 mixed-function oxidases convert the drug to the reactive metabolite N-acetyl-p-benzoquinone imine

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46
Q

what is the reactive metabolite of paracetamol?

A

N-acetyl-p-benzoquinone imine (NAPBQI)

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47
Q

what are the effects of NAPBQI?

A
  • oxidation of SH groups on cellular Ca2+ ATPases
  • lipid peroxidation
  • NAPBQI-protein adducts
  • GSH depletion -> oxidative stress
  • NAPBQI-GSH adduct formation -> GSH depletion -> oxidative stress

all of these processes lead to cell death

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48
Q

what does regeneration of GSH depend on?

A
  • regeneration of GSH from GSSG depends on the availability of cysteine
  • intracellular availability of cysteine can be limiting
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49
Q

what can be substitute for cysteine?

A

acetylcysteine or methionine

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50
Q

what can be used to treat patients with paracetamol poisoning?

A

acetylcysteine or methionine (substitutes for cysteine which enables regeneration of GSH from GSSG)

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51
Q

what is an example of liver damage being caused by immunological mechanisms?

A

halothane hepatitis

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52
Q

what are types of causes of adverse effects by NSAIDs on the kidney? give examples

A
  • principal pharmacological action (e.g. inhibition of prostaglandin biosynthesis)
  • unrelated to principal pharmacological action (e.g. allergic-type interstitial nephritis)
  • unknown whether or not related to principal pharmacological action (e.g. analgesic nephropathy)
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53
Q

what are the adverse effects of NSAIDs on the kidney by principal pharmacological action?

A
  • acute ischaemic renal failure
  • sodium retention (leading to or exacerbating hypertension and/or heart failure)
  • water retention
  • hyporeninaemic hypoaldosteronism (leading to hyperkalaemia)
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54
Q

what are the adverse effects of NSAIDs on the kidney by causes unrelated to principal pharmacological action?

A
  • renal failure

- proteinuria

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55
Q

what are the adverse effects of NSAIDs on the kidney by causes unknown whether or not related to principal pharmacological action?

A
  • papillary necrosis

- chronic renal failure

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56
Q

what are some of the commonest precipitants of acute renal failure?

A

NSAIDs and ACE inhibitors

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57
Q

what can renal damage cause?

A
  • renal tubular cells are exposed to high concentrations of drugs and metabolites as urine is concentrated
  • renal damage can cause papillary and/or tubular necrosis
  • inhibition of prostaglandin synthesis by NSAIDs causes vasoconstriction and lowers GFR
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58
Q

how can a drug’s genotoxic potential be assessed?

A
  • carry out a battery of in vitro and in vivo tests for genotoxicity
  • usually comprise tests for gene mutation in bacteria, in vitro and in vivo tests for chromosome damage and in vivo tests for reproductive toxicity and carcinogenicity
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59
Q

how can drugs lead to carcinogenesis/mutation?

A
  • chemical agents cause mutation by covalent modification of DNA
  • certain mutations result in carcinogenesis, because the affected DNA sequence codes for a protein regulating cell growth
  • mutations in proto-oncogenes (regulate cell growth) and tumour suppressor genes (code for products that inhibit transcription of oncogenes) are common
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60
Q

how do most chemical carcinogens act on DNA? what does this lead to?

A
  • most act by modifying bases in DNA, particularly guanine
  • O6 and N7 positions of guanine readily combine covalently with reactive metabolites of chemical carcinogens
  • substitution at the O6 position is more likely to produce a permanent mutagenic effect
  • N7 substitutions are quickly repaired
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61
Q

when is the accessibility of bases in DNA to chemical attack the greatest?

A

when DNA is in the process of replication (i.e. during cell division)

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62
Q

what are genotoxic carcinogens?

A

carcinogenic compounds that interact directly with DNA

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63
Q

what are epigenetic carcinogens?

A

carcinogenic compounds that act at a later stage to increase the likelihood that mutation will result in a tumour

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64
Q

what is the sequence of events in muatgenesis and carcinogenesis?

A
  • primary carcinogen -> alteration of DNA (mutation)
  • secondary carcinogen -> reactive metabolite via metabolising enzymes -> mutation
  • co-carcinogen: amplifies mutations
  • promotor: amplifies mutations leading to oncogene expression
  • oncogene expression -> malignant transformation
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65
Q

what is the Ames test?

A
  • test for mutagenicity
  • widely used
  • measures the effect of substances on the rate of back-mutation (reversion from mutant to wild-type form) in Salmonella typhimurium
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66
Q

what is back-mutation?

A

reversion from mutant to wild-type form

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67
Q

what does the Ames test involve?

A
  • growing the mutant form on a medium containing a small amount of histidine, plus the drug to be tested
  • after several divisions, the histidine becomes depleted
  • only cells that continue dividing are those that have back-mutated to the wild type
  • count of colonies following subculture on plates deficient in histidine gives a measure of the mutation rate
  • a liver microsomal enzyme preparation for generating reactive metabolites is present
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68
Q

what are some short-term in vitro tests for genotoxic chemicals?

A
  • measurements of mutagenesis in mouse lymphoma cells

- assays for chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells

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69
Q

what are the most important groups of therapeutic drugs that increase the risk of cancer?

A
  • drugs that act on DNA (i.e. cytotoxic and immunosuppressant drugs)
  • sex hormones
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70
Q

what is teratogenesis?

A

the production of gross structural malformations during fetal development, in distinction from other kinds of drug-induced fetal damage e.g. growth retardation, dysplasia or asymmetrical limb reduction from vasoconstriction caused by cocaine

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71
Q

what are examples of known teratogens?

A 
thalidomide
penicillamine
warfarin
phenytoin
valproate
cytotoxic drugs
ethanol
retinoids
ACE inhibitors
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72
Q

what are examples of suspected teratogens?

A

carbamazepine

tetracycline

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73
Q

what are examples of micellaneous teratogens?

A 
corticosteroids
androgens
oestrogens
stilbestrol
aminoglycosides
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74
Q

what is the effect of thalidomide on fetal development?

A

phocomelia, heart defects, gut atresia

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75
Q

what is the effect of penicillamine on fetal development?

A

loose skin etc

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76
Q

what is the effect of warfarin on fetal development?

A

saddle nose, retarded growth, defects of limbs, eyes and CNS

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77
Q

what is the effect of corticosteroids on fetal development?

A

cleft palate and congenital cataract - rare

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78
Q

what is the effect of androgens and oestrogens on fetal development

A

masculinsation in female and testicular atrophy in male, respectively

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79
Q

what is the effect of stilbestrol on fetal development?

A

vaginal adenosis in female fetus and vaginal or cervical cancer

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80
Q

what is the effect of phenytoin on fetal development?

A

cleft lip/palate, microcephaly, mental retardation

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81
Q

what is the effect of valproate on fetal development?

A

neural tube defects

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82
Q

what is the effect of carbamazepine on fetal development?

A

retardation of fetal head growth

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83
Q

what is the effect of cytotoxic drugs on fetal development?

A

hydrocephalus, cleft palate, neural tube defects etc

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84
Q

what is the effect of aminoglycosides on fetal development?

A

deafness

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85
Q

what is the effect of tetracycline on fetal development?

A

staining of bones and teeth, thin tooth enamel, impaired bone growth

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86
Q

what is the effect of ethanol on fetal development?

A

fetal alcohol syndrome

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87
Q

what is the effect of retinoids on fetal development?

A

hydrocephalus etc

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88
Q

what is the effect of ACE inhibitors on fetal development?

A

oligohydramnios, renal failure

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89
Q

what is a key characteristic of a mutant Salmonella typhimurium?

A

unlike the wild type, it cannot grow without histidine

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90
Q

what are disadvantages of carcinogenicity testing?

A
  • involves chronic dosing of groups of animals
  • is expensive and time-consuming
  • doesn’t readily detect epigenetic carcinogens
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91
Q

what are the three phases of mammalian fetal development?

A
  1. blastocyst formation
  2. organogenesis
  3. histogenesis and maturation of function
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92
Q

what are the drug effects on blastocyst formation?

A

gestation period: 0-16 days
main cellular processes: cell division
affected by: cytotoxic drugs, alcohol

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93
Q

what are the drug effects on organogenesis?

A

gestation period: 17-60 days
main cellular processes: division, migration, differentiation, death
affected by: teratogens

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94
Q

what are the drug effects on histogenesis and functional maturation?

A

gestation period: 60 days to term
main cellular processes: division, migration, differentiation, death
affected by: micellaneous drugs (e.g. alcohol, nicotine, antithyroid drugs, steroids) - interfere with supply of nutrients

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95
Q

what are the effects of thalidomide?

A

producing, at therapeutic dosage, virtually 100% malformed infants when taken in the first 3-6 weeks of gestation

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96
Q

when was thalidomide introduced? what as?

A
  • in 1957
  • as a hypnotic and sedative with a feature of being less hazardous in overdosage than barbituates
  • recommended for use in pregnancy
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97
Q

when did suspicion of thalidomide’s teratogenicity arise?

A

1961

- reports of a sudden increase in the incidence of phocomelia

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98
Q

what are the effects of thalidomide teratogeneisis on different days of gestation?

A

21-22: malformation of ears and cranial nerve defects
24-27: phocomelia of arms
28-29: phocomelia of arms and legs
30-36: malformation of hands and anorectal stenosis

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99
Q

what are the teratogenic effects of cytotoxic drugs?

A
  • alkylating agents (e.g. chlorambucil and cyclophosphamide) and antimetabolites (e.g. azathioprine and mercaptopurine) cause malformations and often lead to abortion
  • folate antagonists (e.g. methotrexate) produce much higher incidence of major malformations
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100
Q

what are retinoids used for?

A

vitamin A derivatives

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101
Q

what are the teratogenic effects of retinoids/etretinate?

A

etretinate has marked effects on epidermal differentiation; is a known teratogen and causes a high proportion of serious abnormalities (notably skeletal deformities) in exposed fetuses

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102
Q

what is the mechanism of etretinate? what is an implication of this?

A
  • accumulates in subcutaneous fat and is eliminated extremely slowly, detectable amounts persisting for many months after chronic dosing is discontinued
  • women should avoid pregnancy for at least 2 years after treatment
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103
Q

what is an active metabolite of etretinate?

A

acitretin

- equally teratogenic, but tissue accumulation is less pronounced and elimination may be more rapid

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104
Q

what heavy metals cause teratogenesis?

A

lead, cadmium and mercury all cause fetal malformation in humans

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105
Q

where does the main evidence for heavy metal teratogenesis come from?

A

Minimata disease, named after the locality in Japan where an epidemic occurred when the local population ate fish contaminated with methylmercury that had been used as an agricultural fungicide

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106
Q

what does Minimata disease lead to?

A

impaired brain development in exposed fetuses results in cerebral palsy and mental retardation, often with microcephaly

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107
Q

what is the mechanism for mercury causing teratogenic effects?

A

mercury/other heavy metals inactivate many enzymes by forming covalent bonds with sulfhyfryl and other groups; this is responsible for developmental abnormalities

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108
Q

what are antiepileptic drugs causing teratogenic effects? how does epilepsy affect fetuses?

A
  • congenital malformations are increased 2-3 fold in babies of epileptic mothers treated with 2+ antiepileptic drugs during first trimester
  • phenytoin, valproate, carbamazepine, lamotrigine and topiramate
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109
Q

what teratogenic effects does warfarin have?

A
  • first trimester: associated with nasal hypoplasia and various CNS abnormalities, affecting 25% of exposed babies
  • last trimester: must not be used because of the risk of intracranial haemorrhage in baby during delivery
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110
Q

what is a hapten?

A

a small molecule which, when combined with a larger carrier such as a protein, can elicit the production of antibodies which bind specifically to it

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111
Q

what does the formation of an immunogenic conjugate between a small molecule and an endogenous protein require?

A

covalent bonding

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112
Q

what are immunological mechanisms of adverse drug reactions?

A
  • reactive metabolites, rather than the drug itself, are responsible. produced during drug oxidation or by photoactivation in the skin
  • reactive metabolites can also be produced by action of toxic oxygen metabolites generated by activated leukocytes
  • reactive moiety may interact to form an immunogen with nuclear components rather than proteins
  • conjugation with a macromolecule is usually essential
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113
Q

what are drugs that cause anaphylactic shock?

A
  • penicillins (75% of anaphylactic deaths)
  • enzymes e.g. asparaginase
  • therapeutic monoclonal antibodies
  • hormones e.g. corticotropin
  • heparin
  • dextrans
  • radiological contrast agents
  • vaccines
  • other serological products
  • local anaesthetics
  • antispetic chlorhexidine
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114
Q

what can drug-induced haemotological reactions be caused by?

A

type II, III, or IV hypersensitivity

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115
Q

what drugs is haemolytic anaemia associated with?

A

sulfonamides and related drugs, and with an antihypertensive drug, methyldopa

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116
Q

what is agranulocytosis?

A

complete absence of circulating neutrophils

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117
Q

what are characteristics of drug-induced agranulocytosis?

A
  • usually delayed 2-12 weeks after beginning drug treatment but may then be sudden in onset
  • often presents with mouth ulcers, a severe sore throat or other infection
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118
Q

what drugs are associated with agranulocytosis?

A

NSAIDs (especially phenylbutazone, carbimazole and clozapine) and sulfonamides and related drugs (e.g. thiazides and sulfonylureas)

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119
Q

what drugs is thrombocytopenia caused by?

A
  • reduction in platelet numbers

- can be caused by type II reactions to quinine, heparin and thizide diuretics

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120
Q

what is aplastic anaemia?

A

anaemia with associated agranulocytosis and thrombocytopenia

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121
Q

what is aplastic anaemia caused by?

A

drugs (notably chloramphenicol) can suppress all three haemopoietic cell lineages

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122
Q

what is a reactive metabolite of halothane? what is its action?

A

trifluoracetylchloride

- couples to a macromolecule to form an immunogen

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123
Q

how can cells affected by allergic liver damage be killed?

A
  • halothane-protein antigens can be expressed on the surface of hepatocytes
  • destruction of the cells occurs by type II hypersensitivity reactions involving killer T cells, and type III reactions can contribute
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124
Q

what are examples of other hypersensitivity reactions caused by drugs?

A
  • caused by type IV hypersensitivity
  • rashes can be antibody mediated but are usually cell mediated; range from mild reuptions to fatal exfoliation
  • Stevens-Johnson syndrome is a severe generalised rash that extends into the alimentary tract
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125
Q

are what is a side effect? how does it differ from ADRs?

A
  • an unintended effect of a drug related to its pharmacological properties
  • can include unexpected benefits of treatment
  • can describe minor and predictable ADRs
  • side effects can be beneficial, e.g. PDE5 inhibitors improve urinary flow
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126
Q

what are the types of effects caused by ADRs?

A 
toxic effects (beyond therapeutic range)
collateral effects (therapeutic range)
hypersusceptibility effects (below therapeutic range)
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127
Q

what are examples of toxic effects from ADRs? what can they be caused by?

A
  • nephrotoxicity with high doses of aminoglycosides e.g. gentamycin
  • dysarthria and ataxia with lithium toxicity
  • cerebellar signs and symptoms
  • caused by too high dose, reduced drug excretion by impaired renal or hepatic function or by interaction with other drugs
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128
Q

what are examples of collateral effects caused by ADRs?

A
  • beta blockers causing bronchoconstriction
  • broad spectrum antibiotics causing c. diff. and pseudomembranous colitis
  • caused by standard therapeutic doses
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129
Q

what are examples of hypersusceptibility reactions caused by ADRs? what can they be caused by?

A
  • anaphylaxis and penicillin

- sub therapeutic doses

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130
Q

what are symptoms of mild and severe ADRs?

A

mild: nausea, drowsiness, itching rash
severe: respiratory depression, neutropenia, catastrophic haemorrhage, anaphylaxis

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131
Q

what is an example of a time independent reaction (ADRs)?

A
  • occur at any time during treatment

- e.g. INR increase when erythromycin is administered with warfarin

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132
Q

what are types of time dependent reactions due to ADRs? give examples for each

A
  • rapid reactions (red man syndrome due to histamine release with rapid administration of vancomycin)
  • first dose reactions (hypotension and ACE inhibitors)
  • early reactions (nitrate induced headache)
  • intermediate reactions (delayed immunological reactions e.g. Stevens-Johnson syndrome with carbamazepine)
  • late reactions (adverse effects of corticosteroids, seizures on withdrawal of long term benzodiazepine
  • delayed reaction (thalidomide and phocomelia)
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133
Q

what are type C ADRs? give examples

A

chronic

  • osteoporosis and steroids
  • analgesic nephropathy
  • steroids and iatrogenic Cushing’s syndrome
  • colonic dysfunction due to laxatives
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134
Q

what are type D ADRs? give examples

A

delayed

  • malignancies after immunosuppression
  • teratogenesis
  • carcinogenesis e.g. cyclophosphamide and bladder cancer
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135
Q

what are type E ADRs? give examples

A

end of treatment/abrupt drug withdrawal

  • opiate withdrawal syndrome
  • glucocorticoid abruptly withdrawn leads to adrenocortical insufficiency
  • withdrawal seizures when anti-convulsants are stopped
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136
Q

what are type F ADRs?

A

failure of therapy

- failure of OCP in presence of enzyme inducer

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137
Q

what are patient risk factors for ADRs?

A
  • gender (F>M)
  • elderly
  • neonates
  • polypharmacy (21% 5 or more drugs)
  • genetic predisposition
  • hypersensitivity/allergies
  • hepatic/renal impairment
  • adherence problems
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138
Q

what are drug risk factors for ADRs?

A
  • steep dose-response curve
  • low therapeutic index
  • commonly causes ADRs
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139
Q

what are causes for ADRs? give examples

A
  • pharmaceutical variation (eosinophilia-myalgia syndrome with L-tryptophan)
  • receptor abnormality (malignant hyperthermia with general anaesthetics)
  • abnormal biological system unmasked with drug (primaquine induced haemolysis in patients deficient in glucose 6-phosphate dehydrogenase)
  • abnormalities in drug metabolism (isoniazid induced peripheral neuropathy in people deficient in N-acetyl transferase)
  • immunological (penicillin induced anaphylaxis)
  • drug-drug interactions (increased incidence of hepatitis when isoniazid is prescribed with rifampicin)
  • multifactorial (halothane hepatitis)
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140
Q

what is idiosyncrasy?

A

inherent abnormal response to a drug

- rare but serious

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141
Q

what can idiosyncrasy be caused by? give examples

A

genetic abnormality/enzyme deficiency
- X linked enzyme deficiency
- G6PD deficiency + primaquine leads to haemolysis and haemolytic
anaemia

abnormal receptor activity

  • malignant hyperpyrexia with general anaesthetics
  • huge rise in Ca2+ conc. -> increased muscle contraction -> increased metabolic activity -> increased body temp
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142
Q

when should we suspect an ADR?

A
  • symptoms soon after a new drug is started
  • symptoms after a dosage increase
  • symptoms disappear when the drug is stopped
  • symptoms reappear when the drug is restarted
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143
Q

what are the most common drugs to have ADRs?

A
  • antibiotics
  • antineoplastics
  • cardiovascular drugs
  • hypoglycaemics
  • NSAIDs
  • CNS drugs
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144
Q

what are the most common systems to be affected by ADRs? give examples of effects

A

GI, renal, haemorrhagic, metabolic, endocrine, dermatologic

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145
Q

what are common symptoms of ADRs?

A
  • dystonic reactions, serotonin syndrome, neuroleptic malignant syndrome
  • thyroid abnormalities
  • pulmonary fibrosis
  • torsades de pointes
  • liver failure
  • bone marrow aplasia
  • GI bleeding
  • avascular necrosis
  • rhabdomyolysis
  • skin rashes
  • Stevens-Johnsons syndrome
  • toxic epideral necrolysis
  • photosensitivity
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146
Q

what are common ADRs?

A 
confusion
nausea
balance problems
diarrhea
constipation
hypotension
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147
Q

can ADRs be avoided?

A
  • 30-50% are preventable
  • drug interactions
  • inappropriate medication
  • unnecessary medication
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148
Q

what is the MHRA? what does it do?

A

Medicines and Healthcare products Regulatory Agency

  • responsible for approving medicines and devices for use
  • watch over medicines and devices and take actions (e.g. drug withdrawal) to protect the public promptly if there is a problem
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149
Q

what is the yellow card scheme?

A
  • introduced in 1964
  • world’s first ADR reporting scheme
  • collects spontaneous reports
  • collects suspected ADRs
  • is a voluntary reporting scheme
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150
Q

what are strengths of the yellow card scheme?

A
  • acts as an early warning system for identification of previously unrecognised reactions
  • provides information about factors which predispose patients to ADRs
  • allows comparisons of ADR profiles between produces within the same therapeutic class
  • continual safety monitoring of a product throughout its life span
  • works rapidly, easily accessible, cheap
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151
Q

what are weaknesses of the yellow card scheme?

A
  • cannot provide estimates of risk as true number of cases is underestimated and total number of patients exposed is unknown
  • relies on ADR being recognised
  • not all ADRs are reported (10% of serious reactions are)
  • may be stimulated by promotion and publicity
  • reporting high for newly marketed drugs and falls off over time
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152
Q

what are reasons for underreporting of ADRs?

A 
ignorance
diffidence
fear
lethargy
guilt
ambition
complacency
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153
Q

why should we report ADRs?

A
  • important for patient safety
  • to identify ADRs not identified in clinical trials
  • to identify new ADRs ASAP
  • to compare drugs in the same therapeutic class
  • to identify ADRs in at risk groups
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154
Q

what should be reported on a yellow card?

A
  • all suspected reactions for: herbal medicines and black triangle drugs
  • all serious suspected reactions for: established drugs, vaccines, contrast media and drug interactions
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155
Q

what does the black triangle mean?

A

indicates that a medicine is undergoing additional monitoring

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156
Q

what types of preparation are black triangles assigned to?

A
  • contains a new active substance; new medicines or vaccines authorised on or after Jan 2011
  • is a biological medicine, e.g. a vaccine or a medicine derived from plamsa (blood)
  • has been given conditional approval/approved under exceptional circumstances
  • the company that markets the medicine is required to carry out additional studies
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157
Q

what is a serious reaction?

A
  • fatal
  • life threatening
  • disabling or incapacitating
  • results in hospitalisation
  • prolongs hospitalisation
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158
Q

who can report on a yellow card?

A

doctors, dentists, coroners, pharmacists, nurses, midwives, health visitors, radiographers, optometrists, patients

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159
Q

what information should be included on a yellow card?

A
  • suspected drug
  • suspected reaction
  • patient details
  • reporter details
  • additional useful information
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160
Q

what is hypersensitivity?

A

objectively reproducible symptoms or signs, initiated by exposure to a defined stimulus at a dose tolerated by normal subjects and may be caused by immunologic (allergic) and non-immunologic mechanisms

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161
Q

what is immediate and delayed drug hypersensitivity?

A

immediate < 1hr (utricarial rash, anaphylaxis)

delayed > 1hr (other rashes, hepatitis, cytopenias)

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162
Q

what is type 1 hypersensitivity?

A

acute anaphylaxis

  • prior exposure to the antigen/drug
  • IgE antibodies formed after exposure to molecule
  • IgE becomes attached to mast cells or leucocytes, expressed as cell surface receptors
  • reexposure causes mast cell degranulation and release of substances e.g. histamine, prostaglandins, leukotrienes, PAF
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163
Q

what are the signs of anaphylaxis?

A
  • occurs within minutes and lasts 1-2 hours
  • vasodilation
  • increased vascular permeability
  • bronchoconstriction
  • utricaria
  • angioedema
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164
Q

what are type 2 hypersensitivity reactions?

A

antibody dependent cytotoxicity

  • drug or metabolite combines with a protein
  • body treats it as a foreign protein and forms antibodies (IgG, IgM)
  • antibodies combine with the antigen and complement activation damages the cells e.g. methyl-dopa-induced haemolytic anaemia, pemphigus
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165
Q

what are type 3 hypersensitivity reactions?

A

immune complex mediated

  • antigen and antibody form large complexes and activate complement
  • small blood vessels are damaged or blocked
  • leucocytes attracted to site of reaction release pharmacologically active substances leading to an inflammatory process
  • includes glomerulonephritis, vasculitis
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166
Q

what are type 4 hypersensitivity reactions?

A

lymphocyte mediated

  • antigen specific receptors develop on T-lymphocytes
  • subsequent administration leads to local or tissue allergic reaction
  • contact dermatitis, Stevens-Johnson syndrome
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167
Q

what are drugs commonly implicated in hypersensitivity reactions?

A 
aspirin
penicillins and cephalosporins
sulfonamides
nitrofurans
anticonvulsants
griseofulvin
allopurinol
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168
Q

what is non immune anaphylaxis?

A
  • previously called anaphylactoid reactions
  • due to direct mast cell degranulation
  • some drugs recognised to cause this
  • no prior exposure
  • clinically identical to the immunological mechanism
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169
Q

what is the management of anaphylaxis?

A
  • commence basic life support, ABC
  • stop drug if infusion
  • adrenaline IM 500micrograms (300mcg epipen)
  • high flow oxygen
  • IV fluids
  • IV antihistamine (chlorphenamine 10mg)
  • IV hydrocortisone (100-200mg)
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170
Q

what antihistamine and hydrocortisone doses are given?

A

IV chlorphenamine 10mg

IV hydrocortisone 100-200mg

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171
Q

what is the action of adrenaline?

A
  • vasoconstriction: increase in peripheral vascular resistance, increased BP and coronary perfusion via alpha 1 adrenoceptors
  • positive ionotropic and chronotropic effects on the heart by stimulation of beta 1 adrenoceptors
  • reduced oedema and bronchodilation via beta 2 adrenoceptors
  • attenuates further release of mediators from mast cells and basophils by increasing intracellular cAMP
172
Q

what are medicinal risk factors for hypersensitivity?

A

protein or polysaccharide based macromolecules

173
Q

what are host risk factors for hypersensitivity?

A
  • females > males
  • EBV, HIV
  • previous drug reactions
  • uncontrolled asthma (not atopy)
174
Q

what are genetic risk factors for hypersensitivity?

A
  • certain HLA groups

- acetylator status

175
Q

what are the clinical criteria for allergy to drug?

A
  • does not correlate with pharmacological properties of the drug
  • no linear relation with dose
  • reaction similar to those produced by other allergens
  • induction period of primary exposure
  • disappearance on cessation
  • reappears on reexposure
  • occurs in a minority of patients on the drug
176
Q

what is the mechanism of NSAIDs?

A
  • exert their effects by inhibiting cyclo-oxygenase, which catalyses the synthesis of prostaglandins and thromboxane from arachidonic acid
  • COX-1 is constituitively present in normal cells whereas COX-2 is induced by inflammatory cells
  • inhibition is the most likely mechanism for analgesia
  • ratio of COX-1 and COX-2 inhibition will determine side effects
177
Q

what is the action of cyclooxygenase (COX)?

A

catalyses the synthesis of prostaglandins and thromboxane from arachidonic acid

178
Q

where are COX-1 and COX-2 present?

A
  • COX-1 is constitutively present in normal cells

- COX-2 is induced by inflammatory cells and is targeted by NSAIDs

179
Q

what are contraindications to NSAIDs?

A
  • active or recurrent GI bleeding
  • active or recurrent GI ulceration related to NSAID use
  • severe heart failure
  • patients with an allergy to aspirin
  • should be avoided in renal failure and dehydration
180
Q

when should NSAIDs be used with caution?

A
  • allergic disorders
  • cardiac impairment
  • cerebrovascular disease
  • coagulation defects
  • connective-tissue disorders
  • Crohn’s disease (may be exacerbated)
  • elderly (risk of side effects and fatalities)
  • heart failure
  • ischaemic heart disease
  • peripheral arterial disease
  • risk factors for cardiovascular events
  • ulcerative colitis
  • uncontrolled hypertension
181
Q

how can NSAIDs affect asthmatics?

A
  • 8-20% of adult asthmatics experience bronchospasm following ingestion of aspirin and other NSAIDs
  • reaction is potentially fatal
  • asthmatics with chronic rhinitis or a history of nasal polyps are at greater risk
182
Q

how can NSAIDs affect renal function?

A
  • in healthy individuals, there is little damage
  • in at risk patients they cause renal dysfunction
  • occurs through the inhibition of the biosynthesis of prostaglandins involved in the maintenance of renal medullary blood flow
  • neonates and the elderly are at risk, and patients with heart, liver and renal disease or a reduced circulating blood volume
  • acute interstitial nephritis is a less common cause of renal impairment and often becomes apparent after many months of NSAID use
183
Q

how is metformin cleared and excreted?

A

cleared by active tubular secretion and is excreted unchanged in the urine

184
Q

what is the elimination half-life of a drug?

A

the time required for the serum concentration of the drug to decrease by 50%

185
Q

what precautions do you need to take if a patient on metformin is undergoing a radiological investigation with IV contrast?

A
  • risk of lactic acidosis (mortality of 30-50%)
  • the serum creatinine must be measured within the preceding month
  • if creatinine is normal and a low volume of contrast (up to 100ml) to be administered no special precaution is required
  • if more than 100mls of contrast is used IV or is given intraarterially then metformin should be withheld for 48 hours before
  • if serum is raised and contrast is needed, metformin should be withheld for 48 hours before and after contrast and serum should be measured before restarting metformin
186
Q

in what ways can a prescription for metformin be altered to mitigate the effects of reduced renal impairment?

A
  • drugs that are predominantly excreted unchanged in the urine may require a dose adjustment in renal impairment
  • important for drugs with a narrow therapeutic index
  • reduce the dose or lengthen the dosing interval or both
  • some drugs are less effective in renal impairment and should be substituted if needed
187
Q

what is opium?

A

an extract of the juice of the poppy Papaver somniferum that contains morphine and other related alkaloids

188
Q

what is nociception?

A

the mechanism whereby noxious peripheral stimuli are transmitted to the CNS
- pain is a subjective experience associated with nociception

189
Q

what are PMNs? what are their role?

A

polymodal nociceptors

  • main type of peripheral sensory neuron that responds to noxious stimuli
  • most are non-myelinated C fibres whose endings respond to thermal, mechanical and chemical stimuli
  • release glutamate (fast transmitter) and various peptides acting as slow transmitters
190
Q

what are C fibres?

A
  • non-myelinated

- endings respond to thermal, mechanical and chemical stimuli

191
Q

what chemical stimuli act on PMNs to cause pain?

A
  • bradykinin
  • protons
  • ATP
  • vanilloids (e.g. capsaicin)
  • sensitised by prostaglandins
192
Q

what is the role of TRPV1 receptors?

A
  • responds to noxious heat as well as to capsaicin-like agonists
  • lipid mediator anandamide is an agonist at TRPV1 receptors, and an endogenous cannabinoid-receptor agonist
193
Q

where do nociceptive fibres terminate?

A

terminate in the superficial layers of the dorsal horn, forming synaptic connections with transmission neurons running to the thalamus

194
Q

what is the structure of morphine?

A
  • phenanthrene derivative with two planar rings and two aliphatic ring structures
  • occupy a plane roughly at right angles to the rest of the molecule
195
Q

what are the most important parts of the morphine molecule for opioid activity?

A

free hydroxyl on the benzene ring that is linked by two carbon atoms to a nitrogen atom

196
Q

what are some opioid analgesic compounds?

A
  • heroin
  • morphine
  • naloxone
  • codeine
  • oxycodone
  • buprenorphine
  • pentazocine
  • pethidine
  • fentanyl
  • methadone
197
Q

what variants of the morphine molecule have been produced by substitution at one or both of the hydroxyls?

A
  • diamorphine, 3,6-diacetylmorphine
  • codeine 3-methoxymorphine
  • oxycodone
198
Q

how is naloxone produced from morphine?

A

substiution of a bulky substituent on the nitrogen atom of the morphine
- antagonist activity

199
Q

what are the different types of opioid receptor?

A
  • delta
  • kappa
  • mu
  • nociceptin (NOR)
  • zeta (ZOR)
200
Q

what type of receptor is the opioid receptor?

A

inhibitor GPCRs, with opioids as ligands

201
Q

what endogenous opioids are there?

A
  • dynorphins
  • enkephalins
  • endorphins
  • endomorphins
  • nociceptin
202
Q

what is an opioid?

A

any substance, whether endogenous or synthetic, that produces morphine-like effects that are blocked by antagonists e.g. naloxone

203
Q

what is an opiate?

A

compounds e.g. morphine and codeine that are found in the opium poppy

204
Q

what is a narcotic analgesic?

A
  • old term for opioids

- narcotic is the ability to induce sleep

205
Q

what are some important morphine-like agonists?

A
  • diamorphine
  • oxycodone
  • codeine
206
Q

what are the main groups of synthetic analalogues of opioids? give examples for each

A
  • piperidines (e.g. pethidine and fentanyl)
  • methadone-like drugs
  • benzomorphans (e.g. pentazocine)
  • thebaine derivatives (e.g. buprenorphine)
207
Q

how can opioid analgesics be administered?

A

orally, by injection or intrathecally

208
Q

what are endorphins?

A

large family of endogenous opioid peptides

- have a tyrosine residue at the N-terminus

209
Q

what are the functional effects associated with the u/MOPr opioid receptor?

A
  • supraspinal, spinal and peripheral analgesia
  • respiratory depression
  • pupil constriction
  • reduced GI motility
  • euphoria
  • sedation
  • physical dependence
210
Q

what are the functional effects associated with the delta/DOPr opioid receptor?

A
  • spinal analgesia
  • respiratory depression
  • reduced GI motility
211
Q

what are the functional effects associated with the kappa/KOPr opioid receptor?

A
  • spinal and peripheral analgesia
  • pupil constriction
  • reduced GI motility
  • dysphoria and hallucinations
  • sedation
212
Q

what are the functional effects associated with the ORL1/NOPr opioid receptor?

A
  • spinal analgesia
  • catatonia
  • reverse supraspinal analgesic effects of endogenous and exogenous u/MOPr
213
Q

what type of GPCR are opioid receptors?

A

Gi/Go

214
Q

what are endogenous opioid peptides for opioid receptors?

A
  • beta-endorphin
  • leu-enkaphalin
  • met-enkephalin
  • dynorphin
  • orphanin FQ/nociceptin
215
Q

what are some agonist research tools for opioid receptors?

A
  • DAMGO
  • DPDPE
  • enadoline
  • Ro64-6198
216
Q

what are some antagonist research tools for opioid receptors?

A
  • CTOP
  • naltrindole
  • nor-binaltorphimine
  • SB 612111
217
Q

what endogenous peptides, research agonists and antagonists have activity at u/MOPr opioid receptors?

A
  • beta-endorphin
  • leu-enkephalin
  • met-enkephalin
  • dynorphin
  • DAMGO (agonist)
  • CTOP (antagonist)
  • nor-binaltorphimine (antagonist)
218
Q

what endogenous peptides, research agonists and antagonists have activity at delta/DOPr opioid receptors?

A
  • beta-endorphin
  • leu-enkephalin
  • met-enkephalin
  • dynorphin
  • DPDPE (agonist)
  • naltrindole (antagonist)
  • nor-binaltorphimine (antagonist)
219
Q

what endogenous peptides, research agonists and antagonists have activity at kappa/KOPr opioid receptors?

A
  • beta-endorphin
  • leu-enkephalin
  • met-enkephalin
  • dynorphin
  • enadoline (agonist)
  • naltrindole (antagonist)
  • nor-binaltorphimine (antagonist)
220
Q

what endogenous peptides, research agonists and antagonists have activity at ORL1/NOPr opioid receptors?

A
  • orphanin FQ/nociceptin
  • Ro64-6198 (agonist)
  • SB 612111 (antagonist)
221
Q

what receptor mediates the major pharmacological effects of morphine, including analgesia?

A

u/MOPr

222
Q

what type of activity does morphine have at the u/MOPr?

A

partial agonist; lower intrinsic efficacy than full agonist

223
Q

what type of activity do codeine and dextropropoxyphene show at opioid receptors?

A
  • weak agonists

- maximal effects, both analgesic and unwanted, are less than that of morphine

224
Q

what type of activity do buprenorphine show at opioid receptors?

A
  • partial agonist
  • dissociates slowly from opioid receptors
  • induces less respiratory depression than other opioids
  • very potent drug
  • can antagonise the effect of other opioids by its high affinity and low efficacy
225
Q

what type of activity does pentazocine show at opioid receptors?

A
  • kappa agonist
  • u antagonist (or weak partial agonist)
  • drugs with kappa agonist tend to cause dysphoria rather than euphoria
226
Q

what is action of opioid receptors on the cell?

A
  • promote opening of potassium channels and inhibit opening of voltage-gated calcium channels
  • decrease neuronal excitability (due to increased K+ conductance causing hyperpolarisation) and reduce transmitter release (inhibition of Ca2+ entry)
  • inhibitory effect
  • inhibit adenylyl cylase and activate the MAP kinase (ERK) pathway
227
Q

what is the action of u/MOPr receptors?

A
  • most of the analgesic effects of opioids

- major unwanted effects (respiratory depression, constipation, euphoria, sedation and dependence)

228
Q

what is the action of delta/DOPr receptors?

A
  • receptor activation results in analgesia

- can be proconvulsant

229
Q

what is the action of kappa/KOPr receptors?

A
  • analgesia at the spinal level
  • sedation, dysphoria and hallucinations
  • some analgesics are mixed kappa agonists/u antagonists
230
Q

what is the action of ORL1 receptors?

A
  • antiopioid effect (supraspinal)
  • analgesia (spinal)
  • immobility and impairment of learning
231
Q

how do opioids increase activity in some neuronal pathways?

A

disinhibition
- cause excitation of projection neurons by suppressing the activity of inhibitory interneurons that tonically inhibit the projection neurons

232
Q

what causes the different behavioural responses seen with selective agonists for each type of opioid receptor?

A

heterogenous anatomical distributions across the CNS

233
Q

what are the sites of opioid receptors?

A
  • widely distributed in the brain and spinal cord
  • effective as analgesics when injected in minute doses into specific brain nuclei (e.g. insular cortex, amygdala, hypothalamus, PAG region and RVM and the dorsal horn of the spinal cord)
  • evidence that supraspinal opioid analgesia involves endogenous opioid peptide release at supraspinal and spinal sites
  • release of serotonin (5-HT) from descending inhibitory fibres
  • surgical interruption of the descending pathway from the RVM to the spinal cord reduces analgesia induced by morphine given to supraspinal sites; both sites contribute to analgesia
  • at spinal level, morphine inhibits transmission of nociceptive impulses through the dorsal horn and suppresses nociceptive spinal reflexes; can act presynaptically to inhibit release of neurotransmitters from primary afferents in the dorsal horn and postsynaptically to reduce excitability of dorsal horn neurons
234
Q

how does morphine cause analgesia in the CNS?

A
  • effective in acute and chronic pain
  • less effective in neuropathic pain than in pain associated with tissue injury inflammation or tumour growth
  • antinociceptive
  • reduces affective component of pain
  • supraspinal action, possibly at level of limbic system, which is involved in the euphoria-producing effect
235
Q

how can morphine cause hyperalgesia in the CNS?

A
  • pain sensitisation or allodynia
  • can appear as a reduced analgesic response to a given dose of opioid
  • should not be confused with tolerance, which is a reduced responsiveness due to u-receptor desensitisation and occurs with other opioid-induced behaviours in addition to analgesia
236
Q

what are the mechanisms of morphine causing hyperalgesia in the CNS?

A
  • peripheral, spinal and supraspinal components
  • PKC and NMDA receptor activation
  • P2X4 receptor expression in microglia is upregulated resulting in BDNF release, TrkB signalling and downregulation of the K+/Cl- cotransporter KCC2
  • in mice in which BDNF has been deleted from microglia, hyperalgesia to morphine doesn’t occur, but antinociception and tolerance are unaffected
237
Q

how can opioid-induced hyperalgesia be reduced?

A
  • reduced by ketamine (NMDA antagonist), propofol, alpha2-adrenoceptor agonists and COX2 inhibitors
  • switching to another opioid can reduce hyperalgesia (methadone; weak NMDA receptor antagonist)
238
Q

what are characteristics of euphoria caused by opioids (morphine)?

A
  • morphine causes a powerful sense of contentment and wellbeing
  • agitation and anxiety associated with a painful illness or injury are reduced
  • if morphine or diamorphine (heroin) is given IV, there is a sudden rush likened to an abdominal orgasm
239
Q

what does euphoria produced by morphine depend on?

A
  • depends on circumstances
  • in distressed patients, it’s pronounced
  • in chronic pain patients, it causes analgesia with little or no euphoria
  • some patients report restlessness rather than euphoria
240
Q

what mediates euphoria caused by opioids?

A
  • u/MOPr receptors
  • kappa/KOPr activation produces dysphoria and hallucinations
  • doesn’t occur with codeine or pentazocine to any marked extent
  • antagonists at the kappa receptor have antidepressant properties
241
Q

how do opioids cause respiratory depression?

A
  • results in increased arterial PCO2
  • occurs with a normal analgesic dose of morphine or related compounds
  • patients in severe pain may have reduced degree of respiratory depression
  • mediated by u/MOPr
  • not accompanied by depression of the medullary centres controlling CV function; better tolerated than depression caused by a barbituate
242
Q

what is the depressant effect of respiratory depression associated with?

A
  • decrease in sensitivity of respiratory centres to arterial PCO2
  • inhibition of respiratory rhythm generation
243
Q

what detects changes in PCO2? what does hypercapnia lead to?

A

chemosensitive neurons in a number of bran stem and medullary nuclei

  • increased arterial CO2 (hypercapnia) normally results in a compensatory increase in minute ventilation rate (Ve)
  • in some chemosensitive regions, opioids exert a depressant effect on the hypercapnic response, making the increase in Ve insufficient to counteract increased CO2
244
Q

where do respiratory movements originate from? how can opioids affect this?

A
  • pre-Boetzinger complex (rhythm generator) within the ventral respiratory column of the medulla
  • u/MOPr are located here, and local injection of opioid agonists decreases respiratory frequency
245
Q

what is an antitussive effect?

A

cough suppression

246
Q

how is antitussive effect increased by opioids?

A
  • does not correlate closely with the analgesic and respiratory depression action of opioids
  • increasing substitution on the phenolic hydroxyl group of morphine increases antitussive relative to analgesic activity
  • codeine and pholcodine suppress cough in subanalgesic doses but cause constipation
247
Q

what opioids have an antitussive effect?

A
  • codeine and pholcodine suppress cough in subanalgesic doses
  • cause constipation
248
Q

what is dextromethorphan? what are its effects? where does it act?

A
  • dextro-isomer of the opioid analgesic levorphanol
  • no affinity for opioid receptors and its cough suppression is not antagonised by naloxone
  • uncompetitive NMDA receptor antagonist and has putative actions at delta receptors
  • works at various sites in the brain stem and medulla to suppress cough
  • antitussive, neuroprotective and has analgesic action in neuropathic pain
249
Q

how do opioids cause nausea and vomiting?

A
  • occur in up to 40% of patients to whom morphine is given
  • doesn’t seem to be separable from the analgesic effect
  • usually transient and disappear with repeated administration
  • in some they persist and can limit compliance
  • site of action is the area postrema (chemoreceptor trigger zone), a region of the medulla where chemical stimuli of many kinds may initiate vomiting
250
Q

what area, when stimulated by chemicals/opioids, can cause nausea and vomiting?

A 
area postrema (chemoreceptor trigger zone)
- region of the medulla where chemical stimuli may initiate vomiting
251
Q

how do opioids cause pupillary constriction?

A

caused by u and kappa receptor-mediated stimulation of the oculomotor nucleus

252
Q

how can opioid-induced pupillary constriction be diagnostic?

A
  • pinpoint pupils are an important diagnostic feature in opioid poisoning, because most other causes of coma and respiratory depression produce dilation
  • tolerance doesn’t develop to the pupillary constriction induced by opioids
  • can be observed in opioid-dependent drug users who have been taking opioids for some time
253
Q

what are effects of opioids on the GI tract?

A
  • increase tone and reduce motility
  • > constipation
  • delay in gastric emptying may reduce absorption of other drugs
  • pressure in biliary tract increases due to contraction of the gall bladder and constriction of the biliary sphincter
  • rise in intrabiliary pressure can cause a transient increase in concentration of amylase and lipase in the plasma
254
Q

what mediates the effects of opioids on the GI tract?

A
  • action of morphine on visceral smooth muscle is probably mediated mainly through intramural nerve plexuses, because the increase in tone is reduced or abolished by atropine
  • partly mediated by a central action, as intracerebroventricular injection of morphine inhibits propulsive GI movements
255
Q

what are opioid antagonists that do not cross the BBB? what is their action?

A
  • methylnaltrexone bromide and alvimopan
  • developed to reduce unwanted peripheral side effects of opioids e.g. constipation w/out significantly reducing analgesia or precipitating withdrawal in dependent individuals
256
Q

what are other effects of opioids?

A
  • morphine releases histamine from mast cells by an action unrelated to opioid receptors (pethidine and fentanyl don’t do this)
  • histamine release can cause local effects, e.g. urticaria and itching, and systemic effects, e.g. bronchoconstriction and hypotension (affects asthma patients)
  • hypotension and bradycardia occur with large doses of most opioids, due to action on the medulla
  • spasms of ureters, bladder and uterus
  • opioids exert complex immunosuppressant effects (long term use)
257
Q

what are the main pharmacological effects of morphine?

A
  • analgesia
  • euphoria and sedation
  • respiratory depression
  • suppression of cough
  • nausea and vomiting
  • pupillary constriction
  • reduced GI motility, causing constipation
  • histamine release, causing itch, bronchoconstriction and hypotension
258
Q

what are the most troublesome unwanted effects of morphine?

A

nausea and vomiting, constipation and respiratory depression

259
Q

what does acute overdosage with morphine produce?

A

coma and respiratory depression

260
Q

how is diamorphine cleaved?

A
  • inactive at opioid receptors

- rapidly cleaved in the brain to 6-acetylmorphine and morphine

261
Q

what is codeine converted into?

A

also converted to morphine but more slowly, by liver metabolism

262
Q

what is tolerance? when does it develop?

A
  • an increase in the dose needed to produce a given pharmacological effect
  • develops within a few days during repeated administration
  • drug rotation is used clinically to overcome loss of effectiveness
  • likely to depend on receptor occupancy level; degree of tolerance may reflect the response being assessed, the intrinsic efficacy and the dose being administered
263
Q

what is physical dependence?

A

state in which withdrawal of the drug causes adverse physiological effects

264
Q

what pharmacological effects of morphine does tolerance affect?

A
  • extends to analgesia, emesis, euphoria and respiratory depression
  • affects constipation and pupil-constriction much less, so they will still be present with higher doses
265
Q

what does tolerance result from?

A
  • desensitisation of the u opioid receptors (at level of drug target)
  • long-term adaptive changes at the cellular, synaptic and network levels
  • cross-tolerance occurs between drugs acting at the same receptor, but not between opioids that act on different receptors
266
Q

what are symptoms of abstinence syndrome?

A
  • irritability
  • diarrhoea
  • weight loss
  • body shakes, writhing, jumping, aggression
  • restlessness
  • runny nose
  • shivering
  • piloerection
267
Q

what may cause abstinence syndrome?

A
  • noradrenergic pathways emanating from the LC
  • alpha2-adrenoceptor agonist clonidine can be used to alleviate symptoms
  • rate of firing of LC neurons is reduced by opioids and increased during abstinence syndrome
  • reduced by giving NMDA receptor antagonists
268
Q

what are uses, route of administration, pharmacokinetic aspects and main adverse effects of morphine?

A

uses
- acute and chronic pain

routes of administration

  • oral, including sustained release form
  • injection
  • intrathecal

pharmacokinetic aspects

  • half life 3-4hrs
  • converted to active metabolite (morphine-6-glucuronide)

main adverse effects

  • sedation
  • respiratory depression
  • constipation
  • nausea and vomiting
  • itching (histamine release)
  • tolerance and dependance
  • euphoria
269
Q

what is the active metabolite of morphine?

A

morphine-6-glucuronide

270
Q

what are uses, routes of administration, pharmacokinetic aspects and main adverse effects of diamorphine (heroin)?

A

uses
- acute and chronic pain

routes of administration

  • oral
  • injection

pharmacokinetic aspects
- acts more rapidly than morphine due to rapid brain perfusion

main adverse effects

  • sedation
  • respiratory depression
  • constipation
  • nausea and vomiting
  • itching (histamine release)
  • tolerance and dependance
  • euphoria
271
Q

what are uses, routes of administration, pharmacokinetic aspects and main adverse effects of hydromorphone?

A

uses
- acute and chronic pain

routes of administration

  • oral
  • injection

pharmacokinetic aspects

  • half life 2-4hrs
  • no active metabolites

main adverse effects

  • sedation (less)
  • respiratory depression
  • constipation
  • nausea and vomiting
  • itching (histamine release)
  • tolerance and dependance
  • euphoria
272
Q

what are uses, routes of administration, pharmacokinetic aspects and main adverse effects of oxycodone?

A

uses
- acute and chronic pain

routes of administration

  • oral, including sustained-release form
  • injection

pharmacokinetic aspects
- half-life 3-4.5hrs

main adverse effects

  • sedation
  • respiratory depression
  • constipation
  • nausea and vomiting
  • itching (histamine release)
  • tolerance and dependance
  • euphoria
273
Q

what are uses, routes of administration, pharmacokinetic aspects and main adverse effects of methadone?

A

uses

  • chronic pain
  • maintenance of addicts

routes of administration

  • oral
  • injection

pharmacokinetic aspects

  • long half-life (>24hrs)
  • slow onset

main adverse effects

  • sedation
  • respiratory depression
  • constipation
  • nausea and vomiting
  • itching (histamine release)
  • tolerance and dependance
  • euphoria (less)
  • accumulation may occur
274
Q

what are uses, routes of administration, pharmacokinetic aspects and main adverse effects of pethidine?

A

uses
- acute pain

routes of administration

  • oral
  • intramuscular injection

pharmacokinetic aspects

  • half life 2-4hrs
  • active metabolite (norpethidine) may account for stimulant effects

main adverse effects

  • sedation
  • respiratory depression
  • constipation
  • nausea and vomiting
  • itching (histamine release)
  • tolerance and dependance
  • euphoria
  • anticholinergic effects
  • risk of excitement and convulsions
275
Q

what are uses, routes of administration, pharmacokinetic aspects and main adverse effects of buprenorphine?

A

uses

  • acute and chronic pain
  • maintenance of addicts

routes of administration

  • sublingual
  • injection
  • intrathecal

pharmacokinetic aspects

  • half life 12hrs
  • slow onset
  • inactive orally due to first-pass metabolism

main adverse effects

  • as morphine but less pronounced
  • respiratory depression not reversed by naloxone
  • may precipitate opioid withdrawal
276
Q

what is the active metabolite of pethidine?

A

norpethidine

277
Q

what are uses, routes of administration, pharmacokinetic aspects and main adverse effects of pentazocine?

A

uses
- mainly acute pain

routes of administration

  • oral
  • injection

pharmacokinetic aspects
- half life 2-4hrs

main adverse effects

  • psychotomimetic effects (dysphoria)
  • irritation at injection site
  • may precipitate opioid withdrawal effect
278
Q

what are uses, routes of administration, pharmacological aspects and main adverse effects of dipipenone?

A

uses
- moderate to severe pain

routes of administration
- oral

pharmacokinetic aspects
- half life 3.5hrs

main adverse effects

  • effects similar to morphine
  • psychosis
279
Q

what are uses, routes of administration, pharmacological aspects and main adverse effects of fentanyl?

A

uses

  • acute pain
  • anaesthesia

routes of administration

  • intravenous
  • epidermal
  • transdermal patch

pharmacokinetic aspects
- half life 1-2hrs

main adverse effects

  • sedation
  • respiratory depression
  • constipation
  • nausea and vomiting
  • itching (histamine release)
  • tolerance and dependance
  • euphoria
280
Q

what are the uses, routes of administration, pharmacological aspects and main adverse effects of remifentanil?

A

uses
- anaesthesia

routes of administration
- IV infusion

pharmacokinetic aspects

  • half life 5mins
  • very rapid onset and recovery

main adverse effects
- respiratory depression

281
Q

what are the uses, routes of administration, pharmacological aspects and main adverse effects of codeine?

A

uses

  • mild pain
  • effective only in mild pain
  • also used to suppress cough
  • dihydrocodeine is similar

routes of administration
- oral

pharmacokinetic aspects

  • acts as prodrug
  • metabolised to morphine and other active metabolites

main adverse effects

  • mainly constipation
  • no dependence liability
282
Q

what are the uses, routes of administration, pharmacological aspects and main adverse effects of dextropropoxyphene?

A 
uses
- mild pain
- no longer recommended
routes of administration
- mainly oral

pharmacokinetic aspects

  • half life 4hrs
  • active metabolite (norpropoxyphene) with half life 24hrs

main adverse effects

  • respiratory depression
  • may cause convulsions (maybe by action of norpropoxyphene)
283
Q

what is the active metabolite of dextropropoxyphene?

A

norpropoxyphene

  • half life 24hrs
  • may cause convulsions
284
Q

what are uses, routes of administration, pharmacologic aspects and main adverse effects of tramadol?

A

uses

  • acute (mainly postop) and chronic pain
  • tapentadol is similar

routes of administration

  • oral
  • IV

pharmacokinetic aspects

  • well absorbed
  • half life 4-6hrs
  • weak agonist at opioid receptors
  • inhibits monoamine uptake

main adverse effects

  • dizziness
  • may cause convulsions
  • no respiratory depression
285
Q

what are the components of dependence?

A
  • physical dependence, associated with withdrawal syndrome and lasting for a few days
  • psychological dependence, associated with craving and lasting for months or years; rarely occurs in patients being given opioids as analgesics
286
Q

what drugs does physical dependence occur with?

A

u/MOPr antagonists

287
Q

what is the mechanism of tolerance?

A

involves receptor desensitisation; not pharmacokinetic in origin

288
Q

what drugs precipitate withdrawal syndrome?

A

u/MOPr antagonists

289
Q

what drugs can be used to relieve opioid withdrawal symptoms?

A

long acting u/MOPr agonists e.g. methadone and buprenorphine

290
Q

what drugs are much less likely to cause physical or psychological dependence?

A

certain opioid analgesics, e.g. codeine, pentazocine, buprenorphine and tramadol

291
Q

what is the plasma half-life of most morphine analogues?

A

3-6hrs

292
Q

what is the metabolism of morphine?

A
  • hepatic metabolism is the main mode of inactivation, usually by conjugation with glucuronide at the 3- and 6-OH groups
  • glucoronides constitute a considerable fraction of the drug in bloodstream
  • morphine-6-glucuronide is more active as an analgesic than morphine itself
  • morphine-3-glucuronide may antagonise the analgesic effect of the morphine, but has little/no affinity for opioid receptors
293
Q

how is morphine inactivated during metabolism?

A
  • hepatic metabolism
  • conjugation with glucuronide at the 3- and 6-OH groups
  • glucoronides constitute a considerable fraction of the drug in bloodstream
  • produces morphine-6-glucuronide and morphine-3-glucuronide
294
Q

what is the action of morphine-6-glucuronide?

A

morphine-6-glucuronide is more active as an analgesic than morphine itself

295
Q

what is the action of morphine-3-glucuronide?

A

morphine-3-glucuronide may antagonise the analgesic effect of the morphine, but has little/no affinity for opioid receptors

296
Q

how are morphine metabolites excreted?

A
  • morphine glucuronides are excreted in the urine (dose needs to be reduced in cases of renal failure)
  • glucuronides reach the gut via biliary excretion, where they’re hydrolysed, most of the morphine being reabsorbed (enterohepatic circulation)
297
Q

why do morphine-like drugs have a longer duration of action in neonates?

A
  • neonates have low conjugating capacity
  • morphine congeners should not be used in the neonatal period or used as analgesics in childbirth, because even a small degree of respiratory distress can be hazardous
298
Q

what is an alternative to morphine-like drugs for neonates and childbirth?

A

pethidine

299
Q

what is the metabolism of morphine analogues that have no free hydroxyl group in the 3 position?

A
  • e.g. diamorphine, codeine
  • converted to morphine (accounts for all or part of their pharmacological activity)
  • with heroin, the conversion occurs rapidly in aqueous solution and in the brain
  • with codeine, the effect is slower and occurs by metabolism in the liver
300
Q

what are the advantages of administering morphine intrathecally?

A
  • very effective analgesia
  • used by anaesthetists
  • sedative and respiratory depressant effects reduced, but not completely avoided
301
Q

what are features of patient-controlled analgesia?

A
  • treatment of chronic or postop pain
  • provided with an infusion pump that they control
  • maximum possible rate of administration is limited to avoid acute toxicity
  • patients show little tendency to use excessively large doses and become dependent
  • dose is adjusted to achieve analgesia w/out excessive sedation; reduced as pain subsides
  • reduces anxiety and distress, and decreases analgesic consumption
  • patients often experience sudden, sharp increases in level of pain (breakthrough pain); touch-sensitive transdermal patches containing potent opioids e.g. fentanyl that rapidly release drug into bloodstream
302
Q

what is breakthrough pain? how is it treated?

A
  • in chronic pain, esp. cancer pain, patients often experience sudden, sharp increases in level of pain
  • therapeutic need to be able to increase rapidly the amount of opioid being administered
  • touch-sensitive transdermal patches containing potent opioids e.g. fentanyl that rapidly release drug into the bloodstream
303
Q

what is used to treat opioid overdose?

A

naloxone (opioid antagonist)

  • shorter biological half-life than most opioid agonists
  • given IV
  • must be given repeatedly to avoid respiratory depressant effect of agonist reoccuring once naloxone has been eliminated
  • failure to respond to naloxone suggests a cause other than opioid poisoning for the comatose state
  • danger of precipitating a severe withdrawal syndrome
304
Q

should naloxone be given more than once to treat opioid overdose? why/why not?

A

must be given repeatedly to avoid respiratory depressant effect of agonist reoccuring once naloxone has been eliminated

305
Q

how can naloxone act as a diagnostic test?

A

failure to respond to naloxone suggests a cause other than opioid poisoning for the comatose state

306
Q

why is there individual variability for sensitivity to opioid analgesics?

A

altered metabolism or altered sensitivity of the receptors

307
Q

what can cause reduced responsiveness to morphine?

A
  • mutation in genes e.g. drug transporter, P-glycoprotein, glucuronyltransferase that metabolises morphine and the u/MOPr
  • mutations of cytochrome P450 (CYP) enzymes influence metabolism of codeine, oxycodone, methadone, tramadol and dextromethorphan
  • genotyping could be used to identify opioid resistant individuals
308
Q

what is diamorphine? how do its characteristics affect its function?

A
  • 3,6-diacetylmorphine
  • prodrug; its high analgesic potency is attributable to rapid conversion to 6-monoacetylmorphine and morphine
  • greater lipid solubility, so crosses the BBB more rapidly than morphine
  • less emetic than morphine
  • greater solubility
  • exerts same respiratory depressant effect as morphine, and if given IV, more likely to cause dependence
309
Q

what is diamorphine converted into?

A
  • chemical formula is 3,6-diacetylmorphine

- it is a prodrug; its high analgesic potency is attributable to rapid conversion to 6-monoacetylmorphine and morphine

310
Q

what is the advantage of diamorphine over morphine?

A

only advantage is its greater solubility; allows smaller volumes to be given orally, subcutaneously or intrathecally

311
Q

what is codeine? how does it compare to morphine?

A

3-methoxymorphine

  • more reliably absorbed by mouth than morphine
  • has only 20% or less of the analgesic potency
  • used as an oral analgesic for mild types of pain
  • metabolised to morphine and undergoes glucuronidation in the liver
  • little or no euphoria; rarely addictive
  • same degree of respiratory depression as morphine
  • constipation
  • marked antitussive activity
312
Q

why are some of the population resistant to the analgesic effect of codeine?

A

10%; lack the demethylating enzyme that converts it to morphine

313
Q

what is codeine often combined with?

A

paracetamol in proprietary analgesic preparations

314
Q

what are fentanyl, alfentanil, sufentanil and remifentanil? what are their uses?

A
  • highly potent phenylpiperidine derivatives
  • actions similar to morphine, but with more rapid onset and shorter duration of action
  • used in anaesthesia/intrathecally
  • patient-controlled infusion systems and in severe chronic pain
  • rapid onset is advantageous in breakthrough pain
315
Q

what is the duration of action of methadone? why is it longer than morphine’s?

A
  • plasma half-life >24hrs

- increased duration due to drug being bound in the extravascular compartment and is slowly released

316
Q

how is methadone used to treat addiction?

A
  • treating heroin addiction

- wean addicts from heroin by giving regular oral doses of methadone; an improvement if not a cure

317
Q

what are the other sites of action of methadone in the CNS?

A
  • block of potassium channels, NMDA receptors and 5-HT receptors that may explain its CNS side effect profile
  • interindividual variation in the response to methadone, due to genetic variability between individuals in metabolism
318
Q

what are additional effects of pethidine (meperidine)? how does it compare to morphine?

A
  • causes restlessness rather than sedation
  • additional antimuscarinic action that may cause dry mouth and blurring of vision as side effects
  • similar euphoric effect
  • equally liable to cause dependence
  • duration of action is the same/slightly shorter
319
Q

what is the metabolism of pethidine?

A
  • partly N-demethylated in the liver to norpethidine
  • norpethidine has hallucinogenic and convulsant effects
  • these effects become significant with large oral doses of pethidine, producing an overdose syndrome different to that of morphine
320
Q

how does pethidine interact with monoamine oxidase inhibitors? what causes this?

A
  • severe reactions, e.g. excitement, hyperthermia and convulsions have been seen
  • due to inhibition of an alternative metabolic pathway, leading to increased norpethidine formation
321
Q

how does etorphine compare to morphine?

A
  • morphine analogue
  • more than 1000 times more potent
  • used in animals
322
Q

what is buprenorphine? what are its actions?

A
  • partial agonist on u/MOPr
  • produces strong analgesia
  • can produce mild withdrawal symptoms in patients dependent on other opioids
  • long duration of action
  • difficult to reverse with naloxone
323
Q

what is mechanism of action of tramadol?

A
  • weak agonist at u/MOPr
  • weak inhibitor of monoamine reuptake
  • secondary effect in analgesia as a serotonin and norepinephrine reuptake inhibitor
  • psychiatric reactions have been seen
324
Q

what is pentazocine? what are its effects?

A
  • mixed kappa agonist/u antagonist with analgesic properties similar to morphine
  • marked dysphoria, with nightmares and hallucinations, rather than euphoria
325
Q

what is loperamide? what are its effects?

A
  • opioid that is extruded from the brain by P-glycoprotein
  • lacks analgesic activity
  • inhibits peristalsis, used to control diarrhoea
326
Q

what are some opioid antagonists?

A
  • naloxone
  • naltrexone
  • methylnaltrexone bromide
  • alvimopram
327
Q

what is naloxone? what is its affinity? what is its action?

A
  • first pure opioid antagonist
  • affinity for all three classic opioid receptors (u > kappa > delta)
  • locks actions of endogenous opioid peptides and those of morphine-like drugs
328
Q

what are the effects of naloxone?

A
  • given on its own, it has very little effect in normal subjects; produces rapid reversal of the effects of morphine and other opioids
  • little effects on pain threshold under normal conditions
  • causes hyperalgesia under stress or inflammation, when endogenous opioids are produced
  • inhibits acupuncture analgesia, which is associated with the release of endogenous opioid peptides
  • analgesia produced by PAG stimulation is prevented
329
Q

what are the main uses of naloxone?

A
  • treat respiratory depression caused by opioid overdosage
  • to reverse the effect of opioid analgesics
  • labour and respiration of newborn baby
330
Q

what are the pharmacokinetic aspects of naloxone?

A
  • given IV
  • effects produced immediately
  • rapidly metabolised by the liver
  • effect lasts 2-4hrs
  • may have to be given repeatedly
331
Q

what is the use of naltrexone?

A
  • very similar to naloxone
  • much longer duration of action (half life about 10hrs)
  • may be used in addicts who have been detoxified, because it nullifies the effect of a dose of opioid
  • slow-release subcutanoeus implant
  • effective in reducing alcohol consumption in heavy drinkers
  • beneficial effects in septic shock
  • treats chronic itching (pruritus) in chronic liver disease
332
Q

why can naltrexone be effective in reducing alcohol consumption in heavy drinkers?

A

part of the high from alcohol comes from the release of endogenous opioid peptides

333
Q

what are methylnaltrexone bromide and alvimopan?

A

u/MOPr antagonists that don’t cross the BBB
- used in combination with opioid agonists to block unwanted effects, most notably reduced GI motility, nausea and vomiting

334
Q

how is morphine affected by first-pass metabolism? how is dosage affected by this?

A
  • 50% of oral (enteral) morphine is metabolised by first pass metabolism
  • halve dose if giving it subcutaneous, IM, IV (parenterally) etc
  • single dose lasts 3-4hrs
335
Q

what is potency?

A
  • measure of drug activity expressed in terms of the amount required to produce an effect of given intensity
  • whether a drug is strong or weak; how well the drug binds to the receptor, the binding affinity
336
Q

what is efficacy?

A

relative ability of a drug-receptor complex to produce a maximum functional response

337
Q

what is the affinity?

A

how avidly a drug binds its receptor or how the chemical forces that cause a substance to bind its receptor

338
Q

how are receptors affected in tolerance to opioids?

A

downregulation of receptors with prologed use

339
Q

how long does opioid withdrawal last for?

A

starts within 24hrs, lasts about 72hrs

340
Q

what is the dose of naloxone? how is it titrated?

A

400ug/ml

  • titrate to effect: dilute 1ml in 10ml saline
  • one ampule of a drug is usually the right adult dose
341
Q

what are features of opioid use in chronic non-cancer pain?

A
  • lose effectiveness fairly quickly (within weeks)
  • in a large study, 50% of patients who were on opioids for non-cancer pain at 12 weeks were still on them 5 yrs later
  • addiction leads to manipulative behaviour
  • marketed aggressively by the drug companies in the US for chronic non-cancer pain in the late 90s
  • huge problem in the US
342
Q

what are pharmacogenetics of opioids? how does this relate to codeine metabolism?

A
  • codeine is a prodrug; needs to be metabolised by cytochrome CYP2D6 to morphine to work
  • CYP2D6 activity is decreased in 10-15% of the Caucasian population, and is absent in a further 10% of this population
  • codeine will have a reduced or absent effect in these people
  • CYP2D6 is overactive in 5% of this population; may be at increased risk of respiratory depression with codeine
343
Q

when should morphine not be used?

A
  • be careful in patients with <30% renal failure (creatinine clearance < 30)
  • morphine-6-glucuronide is more potent than morphine and is renally excreted; may accumulate in renal failure
  • reduce dose and timing interval
  • use oxycodone instead
344
Q

what is the metabolism of tramadol?

A
  • prodrug
  • needs to be metabolised by CYP2D6 to o-desmethyl tramadol to be active
  • won’t be effective in 10% of patients
345
Q

what does tramadol interact with?

A

SSRIs, tricyclic antidepressants and MAOIs, sometimes fatally

346
Q

what is the definition of pharmacokinetics?

A

the action of drugs in the body including absorption, distribution, metabolism, excretion

347
Q

what is the definition of absorption?

A

the process of transfer from the site of administration into the general or systemic circulation

348
Q

what are the different routes of administration?

A

oral, intravenous, intraarterial, intramuscular, subcutaneous, inhalational, topical, sublingual, rectal, intrathecal

349
Q

what are the different methods of passage across membranes?

A
  • passive diffusion through the lipid layer
  • diffusion through pores or ion channels
  • carrier mediated processes
  • pinocytosis
350
Q

what are features of passive diffusion?

A
  • drugs can move passively down concentration gradient
  • need to have degree of lipid solubility to cross phospholipid bilayer directly e.g. steroids
  • rate of diffusion proportional to conc gradient, the area and permeability of the membrane and inversely proportional to thickness
351
Q

what are ABCs? how many do humans have?

A

ATP binding cassettes

49 ABCs

352
Q

what is an example of an ABC?

A

P-gp, aka Multi Drug Resistance as it removes a wide range of drugs from cytoplasm to the extracellular side
- inhibits P-gp and so increases concentration of anti cancer drugs in the cytoplasm

353
Q

how many SLCs do humans have?

A

over 300 members of the SLC (solute carrier) superfamily

354
Q

what is an example of an SLC?

A

OAT1 (organic anion transporter)

  • found in kidney
  • secretes penicillin and uric acid
  • probenicid blocks it, leading to uric acid being excreted
355
Q

what is pinocytosis?

A
  • form of carrier mediated entry into the cytoplasm
  • usually involved in uptake of endogenous macromolecules,can be involved in uptake of recombinant therapeutic proteins
  • drugs e.g. amphotericin can be taken up into liposome for pinocytosis
356
Q

what are features of drug ionisation?

A
  • basic property of most drugs that are either weak acids or basis
  • ionisable groups are essential for mechanism of action of most drugs as ionic forces are part of ligand receptor interaction
  • drugs with ionisable groups exist in equilibrium between charged (ionised) and uncharged forms
357
Q

what does the extent of drug ionisation depend on?

A

strength of the ionisable group and the pH of the solution

358
Q

what are most water soluble/lipid soluble drugs?

A

ionised form of drug is most water soluble and unionised is lipid soluble

359
Q

what is the PKa of a drug?

A
  • dissociation or ionisation constant

- pH at which half of the substance is ionised and half is unionised

360
Q

where are weak acids and bases best absorbed?

A

weak acids best absorbed in the stomach

weak bases best absorbed in the intestine

361
Q

what are features for oral absorption?

A
  • easiest and most convenient for many drugs
  • large surface area and high blood flow of small intestine can give rapid and complete absorption of oral drugs
  • many obstacles for drug to overcome before it reaches the systemic circulation
362
Q

what are determinants of oral absorption?

A
  • drug structure
  • drug formulation
  • gastric emptying
  • first pass metabolism
363
Q

how does drug structure affect oral absorption?

A
  • drug needs to be lipid soluble to be absorbed from the gut
  • highly polarised drugs tend to be only partially absorbed with much passed in faeces
  • some drugs unstable at low pH or in presence of digestive enzymes
364
Q

how does drug formulation affect oral absorption?

A
  • the capsule or tablet must disintegrate & dissolve to be absorbed.
  • most do so rapidly
  • some formulated to dissolve slowly (modified release MR) or have a coating that is resistant to the acidity of the stomach (enteric coating- EC)
365
Q

how does gastric emptying affect oral absorption?

A
  • rate of gastric emptying determines how soon a drug taken orally is delivered to small intestine
  • can be slowed by food or drugs (e.g antimuscarinics such as Oxybutinin) or trauma
  • can be faster if had gastric surgery e.g gastrectomy or pyloroplasty
366
Q

what are the four major metabolic barriers for drugs to reach circulation?

A
  • intestinal lumen
  • intestinal wall
  • liver
  • lungs
367
Q

how are drugs absorbed in the intestinal lumen?

A
  • contains digestive enzymes that can split peptide, ester & glycosidic bonds
  • peptide drugs broken down by proteases (Insulin)
  • colonic bacteria hydrolysis & reduction of drugs
368
Q

how are drugs absorbed in the intestinal wall?

A
  • walls of upper intestine rich in cellular enzymes e.g. Mono amine oxidases (MAO)
  • luminal membrane of enterocytes contains efflux transporters such as P-gp which may limit absorption by transporting drug back into the gut lumen
  • extensive bowel surgery “short gut syndrome” – poor oral absorption as little surface left and rapid transit time
369
Q

how is hepatic first pass metabolism avoided?

A

by giving drug to region of gut not drained by splanchnic e.g. mouth or rectum (GTN)

370
Q

how are drugs absorbed by transcutaneous routes?

A
  • human epidermis effective barrier to water soluble compounds.
  • limited rate & extent of absorption of lipid soluble drugs. Need potent, non irritant drugs.
  • slow and continued absorption useful with transdermal patches e.g. Fentanyl patch 72 hourly in chronic pain/palliative care
371
Q

how are drugs absorbed by intradermal and subcutaneous routes?

A
  • avoids barrier of stratum corneum
  • mainly limited by blood flow
  • small volume can be given
  • use for local effect (e.g. local anaesthetic) or to deliberately limit rate of absorption (e.g. long term contraceptive implants)
372
Q

how are drugs absorbed by intramuscular routes?

A
  • depends on blood flow and water solubility
  • increase in either enhances removal of drug from injection site
  • can make a Depot injection by incorporating drug into lipophilic formulation which releases drug over days or weeks (e.g Flupenthixol)
373
Q

how are drugs absorbed by intranasal routes?

A
  • low level of proteases and drug metabolising enzymes
  • good surface area
  • can be used for local (e.g. decongestants) or systemic (e.g. desmopressin) effects….or both with Cocaine!
374
Q

how are drugs absorbed by inhalational routes?

A
  • large surface area & bllod flow BUT limited by risks of toxicity to alveoli and delivery of non volatile drugs
  • largely restricted to volatiles such as general anaesthetics and locally acting drugs such as bronchodilators in asthma
  • asthma drugs non volatile so given as aerosol or dry powder.
  • old study showed only approx 5% delivered to small airways.
375
Q

what is the definition of distribution? how does it occur?

A
  • the process by which the drug is transferred reversibly from the general circulation to the tissues as the blood concentration increases and then returns from the tissues to the blood when the blood concentration falls
  • occurs by passive diffusion across cell membranes for most lipid soluble drugs
  • once equilibrium is reached any process that removes the drug from one side of the membrane results in movement to restore that equilibrium
376
Q

what happens during distribution?

A
  • with IV drug injection there is a high initial plasma concentration and the drug may rapidly enter well perfused tissue such as brain, liver & lungs…
  • the drug will continue to enter less well perfused tissues lowering the plasma concentration…
  • the concentrations in the highly perfused tissues then decrease.
377
Q

what is the action of protein binding for drugs?

A
  • plasma or tissue proteins
  • reversible or irreversible
  • commonest reversible binding occurs with plasma protein albumin
  • lowers free concentration of drug and can act as a depot releasing the bound drug when the plasma concentration drops through redistribution or elimination
378
Q

what are examples of irreversible protein binding of drugs?

A
  • cytotoxic chemo with DNA

- cannot reenter the circulation and is equivalent to elimination

379
Q

how are drugs distributed in the brain?

A
  • lipid soluble drugs easily pass from blood to brain
  • water soluble drugs enter slowly despite good blood supply
  • BBB due to tight junctions, smaller number and size of pores in the endothelium and the layer of astrocytes
380
Q

how do efflux transporters protect the brain?

A

by returning drug molecules to the circulation

381
Q

how are drugs removed from the brain?

A

by diffusion into plasma, active transport in the choroid plexus or elimination in CSF

382
Q

how are drugs distributed within the fetus?

A
  • lipid soluble drugs readily cross the placenta
  • placental blood flow relatively low, so slow equilibration with foetus
  • large molecules do not cross placenta
  • foetal liver has low levels of drug metabolising enzymes, so relies on maternal elimination
383
Q

what is the definition of elimination?

A

the removal of drugs activity from the body via metabolism and/or excretion

384
Q

what is the definition of metabolism?

A

transformation of the drug molecule into a different molecule

385
Q

what is the definition of excretion?

A

molecule is expelled in liquid, solid or gaseous waste

386
Q

what happens in metabolism of lipid soluble drugs?

A
  • necessary
  • converted to water soluble products that are readily removed in the urine (if they remain lipid soluble they would be reabsorbed)
  • metabolism produces one or more new compounds which may show differences from parent drug
387
Q

what are phase 1 reactions?

A
  • involve the transformation of the drug to a more polar metabolite
  • this is done by unmasking or adding a functional group (e.g. OH, NH2, SH)
  • oxidations are commonest reactions, catalysed by cytochrome P450
  • degradative reaction
  • mainly microsomal
  • metabolites formed may be smaller, polar/non polar, active/inactive
388
Q

what are phase 2 reactions?

A
  • involves formation of a covalent bond between the drug or its phase 1 metabolite and an endogenous substrate (conjugation)
  • conjugates phase 1 metabolite with glucuronic acid, sulfate, acetyl methyl groups
  • microsomal, mitochondrial and cytoplasmic
  • products are usually larger, polar, water soluble and inactive, and readily excreted by kidneys
  • synthetic reaction
389
Q

what cytochrome P450s are involved in drug metabolism?

A

CYP1 to CYP4

390
Q

what can induce CYP enzymes?

A

smoking and alcohol - more rapid drug metabolism

391
Q

what drugs and foods can induce or inhibit P450 enzymes?

A

cimetidine and grapefruit

392
Q

what is ethanol metabolised by?

A

alcohol dehydrogenase

393
Q

what is noradrenaline inactivated by?

A

monoamine oxidase

394
Q

what inactivates 6-mercaptopurine?

A

xanthine oxidase

395
Q

what is excreted in fluids, solids and gases?

A

fluids: low molecular weight polar compounds (urine, bile, sweat, tears, breast milk)
solids: faecal elimination important for high molecular weight compounds excreted in bile
gases: expired air important for volatiles

396
Q

what is first order kinetics?

A
  • a drug given iv is rapidly distributed to the tissues.
  • by taking repeat plasma samples the fall in the plasma concentration with time can be measured.
  • often the decline is exponential – a constant fraction of the drug is eliminated per unit of time
397
Q

what is zero order kinetics?

A
  • if an enzyme system that removes a drug is saturated the rate of removal of the drug is constant and unaffected by an increase in concentration
  • ethanol follows zero order kinetics once alcohol dehydrogenase has been saturated
398
Q

what does plotting the logarithm of concentration (lnC) on y axis against time on x axis produce?

A
  • straight line with downhill slope
  • slope = -k
  • intercept gives concentration at time 0 = ln[A0]
399
Q

what is the definition of half life?

A

time take n for a concentration to reduce by one half

400
Q

what is the definition of bioavailability? what is the bioavailability of IV and oral drugs?

A

fraction of the administered drug that reaches the systemic circulation unaltered (F)

  • IV drugs have F=1 as 100% of drug reaches circulation
  • oral drugs may have F<1 if incompletely absorbed or undergo first pass metabolism
401
Q

how is bioavailability determined?

A
  • by measuring plasma concentration after oral and IV doses

- cannot measure at a single point in time as IV and oral routes have different concentration/time profiles

402
Q

what does F =?

A

F= AUC oral/AUC iv

403
Q

what is the definition of distribution? what does the distribution of water soluble and lipid soluble drugs depend on?

A

rate and extent of movement of a drug into and out of tissues from blood

  • water soluble drugs rate of distribution depends on rate of passage across membranes
  • lipid soluble drugs rate of distribution depends on blood flow to tissues that accumulate drug
404
Q

what is the apparent volume of distribution Vd?

A

the extent of distribution of the drug; determines the total amount of drug that has to be administered to produce a particular plasma concentration

405
Q

what is the equation for Vd?

A

Vd = total amount of drug in body (dose)/plasma concentration

406
Q

what does low or high Vd suggest?

A

low suggests may be confined to circulatory volume, high may be distributed in total body water

407
Q

what is the definition of clearance?

A

the volume of blood or plasma cleared of drug per unit time

408
Q

what is K?

A

rate constant of equilibrium

409
Q

what is an equation for K?

A

K = CL/Vd

410
Q

what is an equation for clearance?

A

CL = dose/AUC for IV drug

CL = dose x F/AUC for oral drug with bioavailability of less than 1

411
Q

what are repeated drug doses used for?

A

used to maintain a constant drug concentration in the blood and at the site of action for therapeutic effect

412
Q

what is steady state (Css)?

A

a balance between drug input and elimination

413
Q

how many half lives does it take to reach 95% of Css with IV infusion?

A

4-5 half lives

414
Q

how will a drug with slow elimination take to reach steady state?

A

a drug with slow elimination will take a long time to reach steady state and it will accumulate high plasma concentrations before elimination rate rises to match drug infusion

415
Q

how does Vd affect Css?

A

a high Vd can also lead to a delay in reaching Css as t1/2 is also dependent on Vd (t1/2 = 0.693Vd/CL)

416
Q

what does rate of elimination =?

A

rate of elimination = CL x Css

at steady state the rate of infusion also equals this

417
Q

how can Css and CL be calculated?

A

Css = rate of infusion/CL

CL = rate of infusion/Css

418
Q

what does D x F/t =?

A

CL x Css

419
Q

what does CL x Css =?

A

D x F/t

420
Q

what is an equation for loading dose?

A

loading dose = Css x Vd

421
Q

what is the aim of a loading dose?

A

giving a high initial dose this loads the system and shortens the time to steady state

422
Q

what is the aim of a maintenance dose?

A

maintaining the steady state achieved by the loading dose

- Css = D x F/t x CL

423
Q

what is ramipril?

A

ACE inhibitor

424
Q

what is the action of ACE inhibitors?

A
  • ACE converts angiogtensin I to potent vasoconstrictor angiotensin II which also stimulates the release of aldosterone
  • ACE inhibitors cause vasodilation and potassium retention and salt and water retention
425
Q

when should renal function be checked during the use of ACE inhibitors?

A
  • checked before starting them
  • 2-4 weeks after any increase in dose
  • renal function should be checked periodically during treatment, esp. if there is pre-existing renal impairment, as hyperkalaemia can occur
426
Q

what is ACE inhibitor cough?

A
  • occurs in 10-30% of patients taking them
  • chronic cough thought to occur due to accumulation of kinins in the lung
  • more common in women and can occur after many months of treatment
427
Q

why do afro-caribbean patients use ACE inhibitors less?

A

they commonly have low renin essential hypertension, where the RAAS is contributing little to their hypertension

Phase 2A (28 decks)

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