Pharmacology and prescribing 2 Flashcards

Question

how does lipid peroxidation cause cell damage?

Answer 1

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

Answer 2

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

Answer 3

- ROS are cytotoxic, both directly and through lipid peroxidation - important in excitotoxicity and neurodegeneration

Answer 4

GSH redox cycle

Answer 5

- 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

Answer 6

- 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

Answer 7

- by oxidising species that alter sulfhydryl groups reversibly - by covalent interaction

Answer 8

catalytic activity of many enzymes

Answer 9

- cytoskeletal protein actin GSH reductase | - Ca2+ transporting ATPases in the plasma membrane and ER

Answer 10

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

Answer 11

- sustained rise in cell Ca2+ | - this compromises cell viability

Answer 12

- 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)

Answer 13

DNA, proteins/peptides, lipids and carbohydrates

Answer 14

- mutagenic chemicals covalently bond to DNA | - non-mutagenic chemicals form covalent bonds with macromolecules

Answer 15

- 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

Answer 16

- binding to protein can produce an immunogen | - binding to DNA can cause carcinogenesis and teratogenesis

Answer 17

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

Answer 18

plasma aspartate transaminase

Answer 19

isoniazid, phenytoin

Answer 20

chlorpromazine and androgens

Answer 21

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

Answer 22

N-acetyl-p-benzoquinone imine (NAPBQI)

Answer 23

- 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

Answer 24

- regeneration of GSH from GSSG depends on the availability of cysteine - intracellular availability of cysteine can be limiting

Answer 25

acetylcysteine or methionine

Answer 26

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

Answer 27

halothane hepatitis

Answer 28

- 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)

Answer 29

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

Answer 30

- renal failure | - proteinuria

Answer 31

- papillary necrosis | - chronic renal failure

Answer 32

NSAIDs and ACE inhibitors

Answer 33

- 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

Answer 34

- 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

Answer 35

- 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

Answer 36

- 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

Answer 37

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

Answer 38

carcinogenic compounds that interact directly with DNA

Answer 39

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

Answer 40

- 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

Answer 41

- 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

Answer 42

reversion from mutant to wild-type form

Answer 43

- 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

Answer 44

- measurements of mutagenesis in mouse lymphoma cells | - assays for chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells

Answer 45

- drugs that act on DNA (i.e. cytotoxic and immunosuppressant drugs) - sex hormones

Answer 46

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

Answer 47

``` thalidomide penicillamine warfarin phenytoin valproate cytotoxic drugs ethanol retinoids ACE inhibitors ```

Answer 48

carbamazepine | tetracycline

Answer 49

``` corticosteroids androgens oestrogens stilbestrol aminoglycosides ```

Answer 50

phocomelia, heart defects, gut atresia

Answer 51

loose skin etc

Answer 52

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

Answer 53

cleft palate and congenital cataract - rare

Answer 54

masculinsation in female and testicular atrophy in male, respectively

Answer 55

vaginal adenosis in female fetus and vaginal or cervical cancer

Answer 56

cleft lip/palate, microcephaly, mental retardation

Answer 57

neural tube defects

Answer 58

retardation of fetal head growth

Answer 59

hydrocephalus, cleft palate, neural tube defects etc

Answer 60

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

Answer 61

fetal alcohol syndrome

Answer 62

hydrocephalus etc

Answer 63

oligohydramnios, renal failure

Answer 64

unlike the wild type, it cannot grow without histidine

Answer 65

- involves chronic dosing of groups of animals - is expensive and time-consuming - doesn't readily detect epigenetic carcinogens

Answer 66

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

Answer 67

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

Answer 68

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

Answer 69

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

Answer 70

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

Answer 71

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

Answer 72

1961 | - reports of a sudden increase in the incidence of phocomelia

Answer 73

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

Answer 74

- 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

Answer 75

vitamin A derivatives

Answer 76

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

Answer 77

- 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

Answer 78

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

Answer 79

lead, cadmium and mercury all cause fetal malformation in humans

Answer 80

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

Answer 81

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

Answer 82

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

Answer 83

- 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

Answer 84

- 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

Answer 85

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

Answer 86

covalent bonding

Answer 87

- 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

Answer 88

- 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

Answer 89

type II, III, or IV hypersensitivity

Answer 90

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

Answer 91

complete absence of circulating neutrophils

Answer 92

- 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

Answer 93

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

Answer 94

- reduction in platelet numbers | - can be caused by type II reactions to quinine, heparin and thizide diuretics

Answer 95

anaemia with associated agranulocytosis and thrombocytopenia

Answer 96

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

Answer 97

trifluoracetylchloride | - couples to a macromolecule to form an immunogen

Answer 98

- 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

Answer 99

- 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

Answer 100

- 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

Answer 101

``` toxic effects (beyond therapeutic range) collateral effects (therapeutic range) hypersusceptibility effects (below therapeutic range) ```

Answer 102

- 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

Answer 103

- beta blockers causing bronchoconstriction - broad spectrum antibiotics causing c. diff. and pseudomembranous colitis - caused by standard therapeutic doses

Answer 104

- anaphylaxis and penicillin | - sub therapeutic doses

Answer 105

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

Answer 106

- occur at any time during treatment | - e.g. INR increase when erythromycin is administered with warfarin

Answer 107

- 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)

Answer 108

chronic - osteoporosis and steroids - analgesic nephropathy - steroids and iatrogenic Cushing's syndrome - colonic dysfunction due to laxatives

Answer 109

delayed - malignancies after immunosuppression - teratogenesis - carcinogenesis e.g. cyclophosphamide and bladder cancer

Answer 110

end of treatment/abrupt drug withdrawal - opiate withdrawal syndrome - glucocorticoid abruptly withdrawn leads to adrenocortical insufficiency - withdrawal seizures when anti-convulsants are stopped

Answer 111

failure of therapy | - failure of OCP in presence of enzyme inducer

Answer 112

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

Answer 113

- steep dose-response curve - low therapeutic index - commonly causes ADRs

Answer 114

- 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)

Answer 115

inherent abnormal response to a drug | - rare but serious

Answer 116

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

Answer 117

- 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

Answer 118

- antibiotics - antineoplastics - cardiovascular drugs - hypoglycaemics - NSAIDs - CNS drugs

Answer 119

GI, renal, haemorrhagic, metabolic, endocrine, dermatologic

Answer 120

- 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

Answer 121

``` confusion nausea balance problems diarrhea constipation hypotension ```

Answer 122

- 30-50% are preventable - drug interactions - inappropriate medication - unnecessary medication

Answer 123

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

Answer 124

- introduced in 1964 - world's first ADR reporting scheme - collects spontaneous reports - collects suspected ADRs - is a voluntary reporting scheme

Answer 125

- 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

Answer 126

- 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

Answer 127

``` ignorance diffidence fear lethargy guilt ambition complacency ```

Answer 128

- 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

Answer 129

- all suspected reactions for: herbal medicines and black triangle drugs - all serious suspected reactions for: established drugs, vaccines, contrast media and drug interactions

Answer 130

indicates that a medicine is undergoing additional monitoring

Answer 131

- 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

Answer 132

- fatal - life threatening - disabling or incapacitating - results in hospitalisation - prolongs hospitalisation

Answer 133

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

Answer 134

- suspected drug - suspected reaction - patient details - reporter details - additional useful information

Answer 135

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

Answer 136

immediate < 1hr (utricarial rash, anaphylaxis) | delayed > 1hr (other rashes, hepatitis, cytopenias)

Answer 137

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

Answer 138

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

Answer 139

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

Answer 140

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

Answer 141

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

Answer 142

``` aspirin penicillins and cephalosporins sulfonamides nitrofurans anticonvulsants griseofulvin allopurinol ```

Answer 143

- 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

Answer 144

- 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)

Answer 145

IV chlorphenamine 10mg | IV hydrocortisone 100-200mg

Answer 146

- 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

Answer 147

protein or polysaccharide based macromolecules

Answer 148

- females > males - EBV, HIV - previous drug reactions - uncontrolled asthma (not atopy)

Answer 149

- certain HLA groups | - acetylator status

Answer 150

- 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

Answer 151

- 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

Answer 152

catalyses the synthesis of prostaglandins and thromboxane from arachidonic acid

Answer 153

- COX-1 is constitutively present in normal cells | - COX-2 is induced by inflammatory cells and is targeted by NSAIDs

Answer 154

- 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

Answer 155

- 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

Answer 156

- 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

Answer 157

- 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

Answer 158

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

Answer 159

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

Answer 160

- 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

Answer 161

- 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

Answer 162

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

Answer 163

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

Answer 164

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

Answer 165

- non-myelinated | - endings respond to thermal, mechanical and chemical stimuli

Answer 166

- bradykinin - protons - ATP - vanilloids (e.g. capsaicin) - sensitised by prostaglandins

Answer 167

- 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

Answer 168

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

Answer 169

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

Answer 170

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

Answer 171

- heroin - morphine - naloxone - codeine - oxycodone - buprenorphine - pentazocine - pethidine - fentanyl - methadone

Answer 172

- diamorphine, 3,6-diacetylmorphine - codeine 3-methoxymorphine - oxycodone

Answer 173

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

Answer 174

- delta - kappa - mu - nociceptin (NOR) - zeta (ZOR)

Answer 175

inhibitor GPCRs, with opioids as ligands

Answer 176

- dynorphins - enkephalins - endorphins - endomorphins - nociceptin

Answer 177

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

Answer 178

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

Answer 179

- old term for opioids | - narcotic is the ability to induce sleep

Answer 180

- diamorphine - oxycodone - codeine

Answer 181

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

Answer 182

orally, by injection or intrathecally

Answer 183

large family of endogenous opioid peptides | - have a tyrosine residue at the N-terminus

Answer 184

- supraspinal, spinal and peripheral analgesia - respiratory depression - pupil constriction - reduced GI motility - euphoria - sedation - physical dependence

Answer 185

- spinal analgesia - respiratory depression - reduced GI motility

Answer 186

- spinal and peripheral analgesia - pupil constriction - reduced GI motility - dysphoria and hallucinations - sedation

Answer 187

- spinal analgesia - catatonia - reverse supraspinal analgesic effects of endogenous and exogenous u/MOPr

Answer 188

- beta-endorphin - leu-enkaphalin - met-enkephalin - dynorphin - orphanin FQ/nociceptin

Answer 189

- DAMGO - DPDPE - enadoline - Ro64-6198

Answer 190

- CTOP - naltrindole - nor-binaltorphimine - SB 612111

Answer 191

- beta-endorphin - leu-enkephalin - met-enkephalin - dynorphin - DAMGO (agonist) - CTOP (antagonist) - nor-binaltorphimine (antagonist)

Answer 192

- beta-endorphin - leu-enkephalin - met-enkephalin - dynorphin - DPDPE (agonist) - naltrindole (antagonist) - nor-binaltorphimine (antagonist)

Answer 193

- beta-endorphin - leu-enkephalin - met-enkephalin - dynorphin - enadoline (agonist) - naltrindole (antagonist) - nor-binaltorphimine (antagonist)

Answer 194

- orphanin FQ/nociceptin - Ro64-6198 (agonist) - SB 612111 (antagonist)

Answer 195

partial agonist; lower intrinsic efficacy than full agonist

Answer 196

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

Answer 197

- 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

Answer 198

- kappa agonist - u antagonist (or weak partial agonist) - drugs with kappa agonist tend to cause dysphoria rather than euphoria

Answer 199

- 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

Answer 200

- most of the analgesic effects of opioids | - major unwanted effects (respiratory depression, constipation, euphoria, sedation and dependence)

Answer 201

- receptor activation results in analgesia | - can be proconvulsant

Answer 202

- analgesia at the spinal level - sedation, dysphoria and hallucinations - some analgesics are mixed kappa agonists/u antagonists

Answer 203

- antiopioid effect (supraspinal) - analgesia (spinal) - immobility and impairment of learning

Answer 204

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

Answer 205

heterogenous anatomical distributions across the CNS

Answer 206

- 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

Answer 207

- 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

Answer 208

- 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

Answer 209

- 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

Answer 210

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

Answer 211

- 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

Answer 212

- 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

Answer 213

- 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

Answer 214

- 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

Answer 215

- decrease in sensitivity of respiratory centres to arterial PCO2 - inhibition of respiratory rhythm generation

Answer 216

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

Answer 217

- 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

Answer 218

cough suppression

Answer 219

- 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

Answer 220

- codeine and pholcodine suppress cough in subanalgesic doses - cause constipation

Answer 221

- 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

Answer 222

- 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

Answer 223

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

Answer 224

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

Answer 225

- 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

Answer 226

- 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

Answer 227

- 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

Answer 228

- 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

Answer 229

- 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)

Answer 230

- 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

Answer 231

nausea and vomiting, constipation and respiratory depression

Answer 232

coma and respiratory depression

Answer 233

- inactive at opioid receptors | - rapidly cleaved in the brain to 6-acetylmorphine and morphine

Answer 234

also converted to morphine but more slowly, by liver metabolism

Answer 235

- 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

Answer 236

state in which withdrawal of the drug causes adverse physiological effects

Answer 237

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

Answer 238

- 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

Answer 239

- irritability - diarrhoea - weight loss - body shakes, writhing, jumping, aggression - restlessness - runny nose - shivering - piloerection

Answer 240

- 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

Answer 241

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

Answer 242

morphine-6-glucuronide

Answer 243

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

Answer 244

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

Answer 245

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

Answer 246

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

Answer 247

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

Answer 248

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

Answer 249

norpethidine

Answer 250

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

Answer 251

uses - moderate to severe pain routes of administration - oral pharmacokinetic aspects - half life 3.5hrs main adverse effects - effects similar to morphine - psychosis

Answer 252

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

Answer 253

uses - anaesthesia routes of administration - IV infusion pharmacokinetic aspects - half life 5mins - very rapid onset and recovery main adverse effects - respiratory depression

Answer 254

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

Answer 255

``` 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)

Answer 256

norpropoxyphene - half life 24hrs - may cause convulsions

Answer 257

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

Answer 258

- 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

Answer 259

u/MOPr antagonists

Answer 260

involves receptor desensitisation; not pharmacokinetic in origin

Answer 261

u/MOPr antagonists

Answer 262

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

Answer 263

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

Answer 264

- 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

Answer 265

- 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

Answer 266

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

Answer 267

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

Answer 268

- 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)

Answer 269

- 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

Answer 270

- 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

Answer 271

- very effective analgesia - used by anaesthetists - sedative and respiratory depressant effects reduced, but not completely avoided

Answer 272

- 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

Answer 273

- 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

Answer 274

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

Answer 275

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

Answer 276

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

Answer 277

altered metabolism or altered sensitivity of the receptors

Answer 278

- 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

Answer 279

- 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

Answer 280

- chemical formula is 3,6-diacetylmorphine | - it is a prodrug; its high analgesic potency is attributable to rapid conversion to 6-monoacetylmorphine and morphine

Answer 281

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

Answer 282

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

Answer 283

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

Answer 284

paracetamol in proprietary analgesic preparations

Answer 285

- 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

Answer 286

- plasma half-life >24hrs | - increased duration due to drug being bound in the extravascular compartment and is slowly released

Answer 287

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

Answer 288

- 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

Answer 289

- 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

Answer 290

- 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

Answer 291

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

Answer 292

- morphine analogue - more than 1000 times more potent - used in animals

Answer 293

- 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

Answer 294

- 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

Answer 295

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

Answer 296

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

Answer 297

- naloxone - naltrexone - methylnaltrexone bromide - alvimopram

Answer 298

- 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

Answer 299

- 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

Answer 300

- treat respiratory depression caused by opioid overdosage - to reverse the effect of opioid analgesics - labour and respiration of newborn baby

Answer 301

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

Answer 302

- 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

Answer 303

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

Answer 304

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

Answer 305

- 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

Answer 306

- 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

Answer 307

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

Answer 308

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

Answer 309

downregulation of receptors with prologed use

Answer 310

starts within 24hrs, lasts about 72hrs

Answer 311

400ug/ml - titrate to effect: dilute 1ml in 10ml saline - one ampule of a drug is usually the right adult dose

Answer 312

- 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

Answer 313

- 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

Answer 314

- 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

Answer 315

- prodrug - needs to be metabolised by CYP2D6 to o-desmethyl tramadol to be active - won't be effective in 10% of patients

Answer 316

SSRIs, tricyclic antidepressants and MAOIs, sometimes fatally

Answer 317

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

Answer 318

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

Answer 319

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

Answer 320

- passive diffusion through the lipid layer - diffusion through pores or ion channels - carrier mediated processes - pinocytosis

Answer 321

- 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

Answer 322

ATP binding cassettes | 49 ABCs

Answer 323

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

Answer 324

over 300 members of the SLC (solute carrier) superfamily

Answer 325

OAT1 (organic anion transporter) - found in kidney - secretes penicillin and uric acid - probenicid blocks it, leading to uric acid being excreted

Answer 326

- 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

Answer 327

- 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

Answer 328

strength of the ionisable group and the pH of the solution

Answer 329

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

Answer 330

- dissociation or ionisation constant | - pH at which half of the substance is ionised and half is unionised

Answer 331

weak acids best absorbed in the stomach | weak bases best absorbed in the intestine

Answer 332

- 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

Answer 333

- drug structure - drug formulation - gastric emptying - first pass metabolism

Answer 334

- 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

Answer 335

- 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)

Answer 336

- 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

Answer 337

- intestinal lumen - intestinal wall - liver - lungs

Answer 338

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

Answer 339

- 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

Answer 340

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

Answer 341

- 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

Answer 342

- 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)

Answer 343

- 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)

Answer 344

- 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!

Answer 345

- 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.

Answer 346

- 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

Answer 347

- 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.

Answer 348

- 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

Answer 349

- cytotoxic chemo with DNA | - cannot reenter the circulation and is equivalent to elimination

Answer 350

- 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

Answer 351

by returning drug molecules to the circulation

Answer 352

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

Answer 353

- 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

Answer 354

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

Answer 355

transformation of the drug molecule into a different molecule

Answer 356

molecule is expelled in liquid, solid or gaseous waste

Answer 357

- 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

Answer 358

- 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

Answer 359

- 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

Answer 360

CYP1 to CYP4

Answer 361

smoking and alcohol - more rapid drug metabolism

Answer 362

cimetidine and grapefruit

Answer 363

alcohol dehydrogenase

Answer 364

monoamine oxidase

Answer 365

xanthine oxidase

Answer 366

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

Answer 367

- 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

Answer 368

- 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

Answer 369

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

Answer 370

time take n for a concentration to reduce by one half

Answer 371

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

Answer 372

- 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

Answer 373

F= AUC oral/AUC iv

Answer 374

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

Answer 375

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

Answer 376

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

Answer 377

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

Answer 378

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

Answer 379

rate constant of equilibrium

Answer 380

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

Answer 381

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

Answer 382

a balance between drug input and elimination

Answer 383

4-5 half lives

Answer 384

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

Answer 385

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)

Answer 386

rate of elimination = CL x Css at steady state the rate of infusion also equals this

Answer 387

Css = rate of infusion/CL CL = rate of infusion/Css

Answer 388

loading dose = Css x Vd

Answer 389

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

Answer 390

maintaining the steady state achieved by the loading dose | - Css = D x F/t x CL

Answer 391

ACE inhibitor

Answer 392

- 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

Answer 393

- 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

Answer 394

- 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

Answer 395

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

Pharmacology and prescribing 2 Flashcards

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