Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Primary Pharmacology > Variability in drug response > Flashcards

Variability in drug response Flashcards

1
Q

Define tachyphylaxis

A

Repeated administration of a drug is associated with a rapid decrease in response to that drug over a short time period

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Give an example of tachyphylaxis

A

E,g, ephedrine or metaraminol leads to depletion of noradrenaline stores
Most common mechanism is depletion of stores of a transmitter before resynthesis can take place

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is desensitisation?

A

De-sensitisation refers to chronic loss fo response over a longer period and may be cause by structural change in receptor morphology or by absolute loss of receptor numbers. Often used synonymously with tachyphylaxis —> beta receptor depletion in the use of adrenaline

Give an example

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Define tolerance

A

Increased doses of a drug are required to produce the same effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What mechanisms have been postulated for tolerance occuring (5)

A
  • Decreased receptor density
  • Structural changes in receptor morphiology changing affinity
  • Altered response to drug receptor activation
  • Enzyme induction —> decreased quantity of drug reaches the site of action
  • Development of physiological compensatory mechanisms
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Give an example of pharmacological tolerance and the different ways it effects primary reason for use, modifications of this tolerance and side effects

A
  • Opioids
    ◦ Cross tolerance
    ◦ Analgesia - decreased duration of analgesia and then decreased intensity of analgesia
    ◦ Euphoria
    ◦ Respiratory depression - tolerance slower less than the analgesia
    ◦ Less tolerance to constipation and miosis
  • Nitrates - sulfhydryl groups on vascular smooth muscle become depleted
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Define addiction

A

Repetitive compulsive use of psychoactive substances known by the user to be harmful

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Define dependence

A

Physical or psycho.logical state associated with withdrawal symptoms when the drug administered is abruptly ceased
E.g. opioids with halo one exaggerating symptoms, and the symptoms are abolished by a small dose of an opioid

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Outline what idiosyncracy is in the context of drug effects, mechanisms (3) and key characteristics (2)
Examples (4)

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Adverse drug reactions can be divided into? (2)
Involvement of genetics? Relationship to dose? Mechanisms 2/3
Example

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Define hypersensitivity reactions

A

exaggerated or inappropriate immune response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Histamine structurally is what?

A

Low molecular weight, endogenous amine synthesised in tissued by decarboxylation of histidine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What receptors does histamine act on?

A

H1
H2
H3

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

H1 receptor activation causes what? (4)

A
  1. Smooth muscle contraction in resp + GIT
  2. Increase release of prostacyclin from endothelial cells AND release of nitric oxide
  3. CVS central - slow AVN conduction, coronary vasoconstriction
  4. Peripheral vasodilation, increased capillary perameability
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

H2 receptor activation causes what?

A
  1. Bronchodilation
  2. Gastric - increased H+ secretion
  3. Cardiac 0 increased HR and contractility, coronary vasodilation
  4. Peripheral vasodilation and increased permeability
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

H3 receptor does what

A

decreases synthesis and reelase of histamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Seratonin structurally is what? Synthesised from?

A

Monoamine neurotransmitter

Synthesed from L trytophan

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Receptor subtypes for seratonin

A

5HT3 ligand gated ion channel

5HT1, 2, 4,5 6, 7 GPCR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Bradykinin is structurally what?

A

small autocoids, polypeptide of low molecular weight synthsed from kininogens which are plasma alpha 2 globulins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What are the functions of Prostaglandins?

A
  1. Pain - inflammation, sensitise peripheral nerve endings
  2. Mediated pyrogenic response and inflammation
  3. GIT - decreased gastric acid secretion, increased protective mucous secretion
  4. Renal blood flow regulation

PGI2 - bronchodilates, vasodilates. plt aggregation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What is a type 2 hypersensitivty reaction? e.g.

A

IgG or IgM bind to a cell surface antibody –> classical pathway of complement activation leading to cell lysis, phagocytosis and inflammation

e.g. HUS, HITTS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What is the difference between anaphylaxis and non allergy anaphylactoid reactions

A

Anaphylaxis - IgE mediated mast cell degranulation, requiring prior sensisation, live threatening and dose independent

Anaphylactoid - mast cell degranulation by substances, no prior exposure, less severe and more linked to dose

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What allergies/reactions can latex cause

A

Irritatnt contact dermatitis
Anaphylaxis
Delayed hypersensitivity reaction

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

If you were to characterise mechansism of drug reactions into 3 groups how would you do it?
1/ provide example
2. 4
3. 4 types of response

A

Physicochemical
* Pharmaceutical - thiopental + succ —> precipitate
* Chelation - tetracyclines +calcium —> decreased absorption

Pharmacokinetic
* Absorption e.g. second gas effect
* Distribution - compete for the same protein binding sites
* Metabolism - enzyme induction and inhibition
* Excretion - compete for the same active transport system

Pharmacodynamic
* Antagonism
* Summation - net effect is equal to the sum of the individual effects
◦ Combination of 2 drugs with identical mechanism of action
◦ E.g. two different opioids
* Potentiation
◦ One drug increases the effect of another
◦ One fo the drugs has no independent action on its own
◦ E.g. aminoglycosides increase competitive neuromuscular blockade
* Synergism
◦ The net effect is more than the sum of the individual effects
◦ Combination of drugs that exert similar effects but have different mechanisms of action
◦ E.g. NSAID and opioids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Describe an example fo absorption mediated variations due to drug interactions? Give an example of a drug affected? How to increase and decrease drug availability

A
  • ABC (ATP binding cassette) family has a protein within it called the multi-drug resistant protein transporter known as p-glycoprotein (PGP) which is found in gut mucosa and the BBB
  • Many cytotoxic, anti microbial and other drugs are ubstrates for PGP and unable therefore the penetrate the BBB
  • E.g. anticoagulatant Dabigatran
  • Coadminstration of PGP inhibits e.g. amiodarone, verapamil will increase Dabigatran bioavailability and therefore risk of adverse events while inducers e.g. rifampicin will reduce bioavailability
  • PGP inhibitors and inducers also happen often to be inducers and inhibitors of CYP3A4
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What is metabolised by CYP2B6

Inducers

Inhibitor

A

Propofol
Methadone
Ketamine
Cyclophosphamide (induces itself)
Clopidogrel

Inhibited by clopidogrel
Phenobarb and SMOKING induces metabolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Propofol is metabolised by which enzyme

A

CYP2B6
CYP2C9

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What are the drugs metabolised by CYP2C9

Inducers
inhibitors

A

Propofol
Phenytoin
Parecoxib
Celecoxib
Losartan
S warfarin

INduced by brbituarates and rifampicin

Inhibited by amiodarone, azoles, macrolides, metronidazole and trimethorpim

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

CYP2C19 metabolism

inducers
inhibitors

A

Losartan
Diazepam
Phenytoin
Omeprazole
Clopidogrel

Induced by barbituares and rifampicin
Inhibited by fluconazole

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

CYP2D6 metabolism

inducers
Inhibtors

A

Codeine/oxycodone/tramadol
Flecainide
Metoprolol
TCAs, Fluoxetine, Clozapine

Paroxetine and fluoxetine inhibit
histamine receptor antagonsits -0 cimetidine inhibit, amiodarone, inhibits
7% genetic absence

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

CYP3A4 metabolism

inducers
Inhibitors

A

Diazepam, temazepam, midazolam

Fentanyl, alfentanil, methadone
Paracetamol

Lignocaine

Vecuronium

Amidoarone, diltiazem, nifedipine, sprionolactone, verapamil, sildenafil, statins

Cortisol, cyclosporin, tacrolimus

Macrolides

Inducers
- Phenytoin, barbituates, carbamazpeine
- Glucocorticoids
- Rifampicin
- St Johns wart
- Mifepristone and atorvastatin

Inhibitors
- Abx - clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole, ritonivir
- Grapefruit juice
- Diltiazem

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

CYP1A2 metabolites
Inducers

A

PCM
Caffeine
Tamoxifen
Warfarin 12% increase inrequirement
Clopidogrel
Theophylline
Olanzapine, fluvoxamine

Inducers - smoking, cruciferous vegetables, omeprazole

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

Characterize a phase 1 reaction

A

Non synthetic, non specific conversion of parent drug to a oplar metabolite by introducing or unmasking a functional group e.g OH, NH2, SH increasing polarity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

Fate of phase 1 products

A

◦ Many phase 1 products are not eliminated rapidly and undergo a subsequent reaction (phase 2) in which an endogenous substrate such as glucoronic acid, sulfuric acid, acetic acid or amino acid combines with the newly incorporated functional group to form a highly polar conjugate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

If you were to class phase 1 reactions into 3 main reaction types

A

Oxidation
Reduction
Hydorlysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

What is an example of a phase 1 oxidation reaction

A

Removal of electorns from moelcules, the most common

Liver predominant but also occurs in mucosa, lung, brain, kkidney

Demethylation (diazepam), hydroxylation (midazolam), desulfation of thiopental

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

Reduction of species is a phase 1 or 2 metabolism reaction? e.g.>

A

Phase 1
P450 driven
GTN is an example

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

What is reduction

A

The gain of electrons

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

What is a non oxidation/reduction phase 1 reaction?

A

hydrolysis

A moelcule is cleaved into 2 parts byt he addition of H20
Not P450 driven
Plasma cholinesterases, non specific esterases and red cell esterases do this

e.g. Succinylcholine, remifentatnil, esmolol, LA (esters)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

Where are non specific esterases found?

A

Cytoplasm of muscle and liver

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

What is the microsomal oxidation system? Where is it found? What is it derived from? What 2 microsomes are key?

A

Drug metabolising enzymes are oftne located in the lipophilic endoplasmic reticulum of hte liver, lamellar membanes reform into vesicles called microsomes which retain morphologica and functional characteristics of intact membrane of the endoplasmic reticulum

2 microsomes key
- Flavoproetin NADPH cytochrome P450
- Haemoprotein - terminal oxidase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

What dos p450 refer to

A

wavelenght of absorption of light when in reduced form and combined with carbon monoxide

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

Where is cyp450 enzymes

A

Smooth ER of hepatocytes
Gut mucosa
Lungs
Kidneys
Brain

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

What is the rbeakdown of frequency of each fo the major subfamilies of CYP 450

A

◦ CYP1A2 - 15%
◦ CYP2A6 - 4%
◦ CYP2B6 - 1%
◦ CYP2C9 - 20% of human liver P450 content
◦ CYP2D6 - 5% of human liver P450 content
‣ Multiple mutations, genetic polymorphisms
‣ 5-15% of the population are poor metabolisers
‣ Codeine, tramadol, oxycodone
◦ CYP2E1 - 10% of human liver P450 content
‣ Fluorine containing volatile metabolism
◦ CYP3A4 - 30% of P450 liver P450 content
‣ 50% of prescription drugs metabolised by the liver
‣ Midazolam, alfentanyl

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

What does carbamazapine enhance the metabolism of?

A

Clonazepam
itraconazole
Carbamazepine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

What does phenytoin enhance the metabolism of

A

Cortisol, dexamethasone

Digitoxin
Itraconazole
Theophyllline

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

Ritonavir effects metabolism of?

A

Midazolam

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

Rifampicin affects metabolism of

A

Glucocorticoids, prednisone
Propanolol, metoprolol
Anticoagulants
Digitoxin
Methadone

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

Barbituates and phenobarbitol afffect metabolism of

A

Coumarin anticoagulants
Digitoxin
Itraconazole
Phenytoin
Chloramphenicol
Chlorpromazine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

What is an example of a liver enzyme inhibitor? MOA?

A
  • Imidizolecontaining drugs e.g.cimetidine, ketoconazole bind tightly to P450 heme iron and reduce the metabolism of endogenous substrates
  • Macrolides e.g. erythromycin are metabolised by CYP3A to metabolites that complex the cytochrome P450 heme iron and render it catalytically inactive
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

How do liver enzyme inducers work? (2)

A

either enhance P450 synthesis or reduce is degredation
* Accelarates substrate metabolism and decrease pharmacological action OR exacerbates metabolite mediated toxicity

52
Q

What is a phase 2 reaction? What characteristics the substrates and the products? e.g.?

A

Conjugation or coupling synthetic reactions with endogenous substances to yeild more water soluble conjugates

Either parent drugs or phase 1 metabolites, sometimes phase 2 comes before phase 1.

Generally metabolites polar, renally excreted, often inactive. Morphine 6 glucoronide would be an exception however

53
Q

How are phase 2 reactions facilitated? Where in the cell?

A

Transferases - UDP glucuronosyl transferase (UGT) the most dominant, work int he cytosol and microsomes

54
Q

How do phase 2 reactions compare to phase 1

A

faster, conjugation and coupling sythetic reactions

55
Q

What are examples of phase 2 reaction types

A

◦ Glucoronidation - morphine, propofol
◦ Sulphation - BDZ, propofol
◦ Acetylation - hydralazine
◦ Methylation - catecholamines

56
Q

COmpring phase 1 and 2 which loses activity in renal failure earlier

A

Phase 1

57
Q

Plasma esterases do what? High or low capacity? Foudn where?

A

Non microsomal enzymes in the liver and RBC
Hydrolyse ester bonds
High capacity enzymes

58
Q

3 examples of plasma esterases and their metabolites

A

◦ Plasma cholinesterase
‣ Succinylcholine, mivacurium,ester LA
◦ Non specific plasma esterases
‣ Remifentanil, atracurium
◦ RBC esterases
‣ Esmolol

59
Q

List 5 drug factors affecting hepatic metabolism of drugs

A

Lipid solubility
Ionisation
protein binding
Competition of enzyme metabolism
Saturatable enzyme metabolism

60
Q

Give 4 social patient factors that can be determined from history that affect drug metabolism in the liver? Give 4 factors that further affect metabolism

A
  1. Age
  2. Obesity
  3. Pregnancy
  4. Social- smoking. diet, alcohol
  5. Genetic polymorphism - slow and fast acetylation, succylcholine apnoea
  6. Hepatic blood flow
  7. Enzyme induction or inhibition
  8. Hepatic disease
61
Q

Give 3 hepatic enzyme inhibitors

A

Cimetidine
Omeprazole
Antidepressants
Erythromycin
Grapefruit juice

62
Q

Give 3 liver enzyme inducers

A

Barbituates
Phentyoin
Carbamazapine
Tobacco
Alcohol

63
Q

What is Michaelis Mentin kinetics

A
  • Enzyme kinetics - equating reaction velocity to substrate concentration for the below system
64
Q

Draw a graph representing the effect of two interacting drugs reprresenitng additive, antagonitic and synergitic effects

A
65
Q

What effect does alcohol have on metabolsim of drugs?

A

Enzyme inducer so icnreases their etabolism

66
Q

What effect does cigarette smoking have on metabolism of drugs?

A

Increases as is a liver enzyme indcuer

67
Q

Describe factors which influence drug distribution to the foetus

A
  1. Lipid solubility - placental membrane derived from foetal capillaries and synctiotrophoblast and is phospholipid in nature. Pethidine high lipid solubility thyen metabolised and accumula;tes
  2. Free drug concentration
  3. Placental blood flow
  4. pKa - foetal pH is lower than in the mother –> lignocaine has a lower pKa so is more lipophilic at lower pHs reducing trapping in foetus, however Bupivocaine is the opposite
68
Q

How does noenatal/infant pharmacodynamics differ to adults

3

A
  1. Immmature NMJ until 2 months of age - smaller ACh reserves, myasthenia response to muscle relaxants nad more sensitive to non depolarising agents
  2. Increased MAC
  3. NSAIDs close ductus
69
Q

Pharmacokinetic changes in infants/noenates comparted to adults
A - 3(
D - 4
M - 2
E - 1

A

Absorption
1. Oral absorption - delayed gastric emptying and slower intestinal transit time. Slower but increased absorption of drugs
2. IM - small muscle mass, hihg CO so fast onset
3. Voltailes - faster onset, due to VA: FRC BUT increased cardiac output reduced onset

Distribution
1. Increased Vd - increased TBW, increased BV (ECF > ICF)
2. Reduced plasma protein binding - albumin, alpha 1 acid gluycoprtoein
3. Increased cardiac output
4. Immature BBB

M
1. Immature active enzymes - despite liver size being rrelatively larger, maturitiy reached by 2 years
2. Decrease plasma cholinesterase but SCh not prolonged in action

E
1. Immature renal function in first 6 months <10% of adult

70
Q

How does being a noenate affect absorption of drugs (3)

A

Absorption
1. Oral absorption - delayed gastric emptying and slower intestinal transit time. Slower but increased absorption of drugs
2. IM - small muscle mass, hihg CO so fast onset
3. Voltailes - faster onset, due to VA: FRC BUT increased cardiac output reduced onset

71
Q

How does being a noenate affect metabolism of drugs (2)

A

M
1. Immature active enzymes - despite liver size being rrelatively larger, maturitiy reached by 2 years
2. Decrease plasma cholinesterase but SCh not prolonged in action

72
Q

How does being a noenate affect distribution of drugs (4)

A

Distribution
1. Increased Vd - increased TBW, increased BV (ECF > ICF)
2. Reduced plasma protein binding - albumin, alpha 1 acid gluycoprtoein
3. Increased cardiac output
4. Immature BBB

73
Q

How does being elderly affect pharmacodynamics (3)

A
  1. Brain - reduced MAC, increased responisbeness of sedatives and hypnotics ?receptor mediated
  2. Heart
    a) reduced responisvenss to beta agonists, antagonits due to receptor downregulation
    b) loss of baroreceptor reflex (vasodilators more likely to cause hypotension)
  3. Interaction
    A) other medications
    B) other illnesses
74
Q

How does being elderly affect pharmacokinetics?
A - 1
D - 2
M - 2
E - 2

A

Absorption NIL
Distribution
1. Altered Vd - reduced muscle mass, and total body water. Increased fat mass for accumulation of lipid soluble drugs
2. Decreased albumin nd increased alpha 1 acid glyocprotein
Metbaolism
1. Decreased hepatic blood flow
2. Decreased hepatic enzyme activity Phase 1 > phase 2
Eliminiation
- Reduction in CrC with age
- Reduction in hepatic funciton with age

75
Q

How does being pregnant effect pharmacodynamcis? (2)

A

Decreased MAC
Increased sensitivty to LA

76
Q

Pharmacokinetics of pregnancy
A - 3
D - 2
M - 3
E - 1

A

A -
1. Delayed gastric emptying with labour, nausea and vomiting
2. Increased cardiac output - increased IM and SC absorption, faster onset of action
3. Increased minute ventilation, reduced FRC = faster volatile onset.
D -
1. Increased Vd - increased TBW and plasma volume, increased ECF and increased fat mass
2. Decreased albumin and alpha 1 acid glycoprotein
M -
1. NO change in hepatic blood flow
2. Hepatic enzyme induction by progresterone and competition for hepatic metabolism by oestrogen
3. Decreased plasma cholinesterase activity
E
1. Increased renal blood flow and GFR

77
Q

Obesity and its impact on pharmacokinetics
A - 3
D - 2
M - 4
E - 1

A

A
1. Increased GORD
2. Delayed gastric emptying
3. Increased gut perfusion due to increased cardiac output
D -
1. Increased Vd - increased fat mass, total body water, blood volume, organ mass and LBM
2. Increased alpha 1 acid glycoprotein
M
1. Increased hepatic blood flow
2. Phase 1 and 2 enzymes unchange dor increased
3. Fatty liver infiltration
E
1. Increased renal blood flow and GFR

78
Q

What are some examples of drugs which are markedly affected by cardiac failure in their clearance

A

Cardiac disease by limiting blood flow to the liver may impair disposition of drugs whose metabolism is flow limited even where they are rapid;y metabolised
* Amitryptline
* Isoniazid
* Lidocaine
* Morphine
* Propranolol
* Verapamil
* Labetalol

79
Q

How does pulmonary disease affect drug metabolsim

A

Pulmonary disease can affect drug metabolism
* Impaired hydrolysis of procainamide and procaine him those with chronic respiratory insufficiency and increased half life of anti-pyrine in those with lung cancer

80
Q

What effect does liver disease have on drug metabolism - pharmacokinetics
A -1
D - 3
M 3
E 1

A

Absorption
1. Portocaval shunting - decreased first pass metabolis, increased oral bioavailability. Important for drugs with high hepatic extraction ratio
D
- Decreased protein synthesis - decreased plasma protein binding and increased unbound fraction
- Increased Vd - fluid and Na retention, ascities, decreased plasma protein binding
- Acid base changes altering ionised fraction
M -
1. Phase 1` and 2 reaction decreased (phase 1 the most), decreased drug metabolism
2. Decreased hepatic blood flow
3. Decreased plasma cholinesterase
E
- Decreased biliary excretion

81
Q

How does hepatic disease affect pharmacodynamics

A

Increased sensitivity to hypnotics and sedatives

82
Q

Renal disease effect on pharmacokinetics
A - 1
D - 2
M - 1
E - 2

A

Absorption
- Increased urea delays gastric emptying
Distribution
1. Increased Vd due to fluid retention and reduced plasma proteins. Higher loading doses may be required
2. Avid base changes alter the ionised fraction and protein bidning
M
- Uraemic toxins inhibit enzymes and drug transporters
E - Decreased drug clearance and drug accumulation, decreased dose and increased dosing interval
- Increased urea affects osmotic changes

83
Q

How to calculate the dose required based on renal dysfunction

A

= usual dose x impaired clearance / normal clearance

84
Q

How does cardiac failure influence pharmacokinetics?
A 2
D - 3
M 2
E 1

A

Absorption
1. Decreased gut perfusion
2. Decreased cardiac output
- Reduces concentration gradient between blood and alveolus, alveolar partial pressure rises more quickyl and faster uptake of volatiles
Distribution
1. Decreased Vd - increased drug concentrations, increased CNS sensitivtiy. SMaller loading doses
2. Decreased cardiac output slower arm to brain circulation time
3. Increased alpha1 acid glycoprotein in acute cardiac failure - basic drugs reduced binding
Metabolism
- reduction in hepatic blood flow
- Hepatic metabolic pathways may be altered
Elimination
- Decreased renal blood flow

85
Q

What are non genetic variables influencing drug metabolism?

5

A

◦ Age
‣ Increased susceptibility to toxic and pharmacological activity occurs at the extremes of age
‣ Drug metabolism plays a role along with absorption, distribution and elimination
◦ Sex
‣ Ethanol, propranolol, benzodiazepaines, oestrogen and salicylates all may have sex dependent variation inmetabolism
◦ Liver size and function
◦ Body temperature
◦ Nutritional and environmental factors
‣ Charcoal broiled foods and cruciferous vegetables are known to induced CYP1A enzymes
‣ Grapefruit juice inhibits the CYP3Ametabolism of coadminstrered drugs
‣ Cigarette smokers metabolise some drugs more avidly because of enzyme induction

86
Q

Define a genetic polymorphism

A
  • Inherited differences in enzyme structure that alter the way drugs are metabolised in the body

‣ Occupancy of a variant allele of a gene at a population frequency of >1% resulting in altered expression or functional activity of a gene product

Contribute to significant differences in the metabolic rate by up to 30x

87
Q

Outline genetic variability of phase 1 - 3 examples

A

‣ Phase 1
* Often autosomal recessive
* Debrisoquinsparteine oxidation
◦ 3-10% of caucasians
◦ Autosomal recessive
◦ CYP2D6 dependent oxidations of debrisoquin and other drugs (tamoxifen- failed activation to active metabolite)
◦ Faulty expression fo the P450 protein due to mRNA splicing or protein folding conferring a poor metaboliser phenotype ]

  • Ultra rapid CYP2D6 variation
    ◦ Ethiopians and Saudi Arabians in 1/3
    ◦ Need higher doses of nortriptyline; and metabolises codeine much faster
  • Stereoselective aromatic 4 hydroxylation of anticonvulsant me-phenytoin
    ◦ CYP2C19
    ◦ Autosomal recessive in 3-5% of Caucasian’s and 20% of Japanese
    ◦ Normal = S mepheytoin is hydroxilated by CYP2C19 at the 4 position of the phenyl ring before glucoronidation and rapid excretion in the urine whereas R-mephenytoin is slowly N-demethylated to nirvanol and active metabolite
    ‣ Extensive metabolisers may show higher levels of tamoxifen and clopidogrel which are prodrugs activated by this mechanism
    ◦ Poor metabolisers lack the hydroxylase activity leading both S and R me-phenytoin e anti omens to be N-demthylated to nirvanol accumulating at high doses —> sedation, ataxia
  • Other genetic factors affect warfarin, and other CYP2C9 substances e.g. phenytoin, losartan, NSAIDs
88
Q

Phase 2 variants in metabolism seen in what 3 examples

A
  • Succinylcholine is metabolised only half as rapidly in persons with genetically determined deficiency in plasma-cholinesterase (BCHE)
    ◦ Hydrolysis in the plasma is catalysed by non specific enzyme plasma cholinesterase
    ◦ Autosomal recessive genes found
    ◦ This increases the risk of prolonged respiratory paralysis (succinylcholine apnoea)
    * TPMT
    ◦ Encountered in 1:300 Europeans resulting in rapidly degraded mutant enzyme and consequenct deficient S methylation of aromatic and heterocyclic sulfhydryl compounds which is required for detoxification
    ◦ This increases the risk of this purine drug induced fatal haematopoeiteic toxicity
    * UGT polypmorphisms - Gilberts syndrome
    * Acetylation is a phase 2 metabolic pathway in the liver, drugs metabolised by N-acetyltransferase type 2 (NAT2) include hydralazine and isoniazid
    ◦ Genetically different isoenzymes of NAT2 that acetylate at a slow or fast rate
89
Q

Define isomer

A

Compounds with the same atomic formula and same molecular weight but different structural arrangements

90
Q

Structural isomer includes what types? What is a structural isomer? Define each subgroup

A

Same atomic formula but DIFFERENT order of atomic bonds

Positional isomers - atoms occupy different positions on identical carbon skeleton
Chain isomers
Functional group isomers
Tautomerism - a type opf strutcural isomer were balance between two isomers is determined by surrounding pH
e.g. Thiopental - enol form is water soluble, keto form lipid soluble

91
Q

What is a stereoisomer

A

Same atomic formulae, same bond structure, different 3 dimensional configuration

92
Q

What are the types of stereoisomer

A

Geometric - cis and trans

Optical isomers
- Enantiomer - L and D OR S and R
- Diastereoisomers

93
Q

What is a geometric isomer? What subclassifications

A

Dissimilar groups attached to two atoms linked by structurally rigid bond e.g. double bone or ring

Cis - same side
Trans - opposite side

e.g. mivacurium

94
Q

What is an optical isomer

A

One or more chiral centres

95
Q

What is a chiral centre

A

Carbon atom or quaternary ntirogen surrounded by 4 different chemical groups

96
Q

Enantiomer

A

A compound that is a mirror image of each other around a chiral centre

97
Q

What are the subtypes of enantiomers

A

D +/- or L - or (-)
According to direction of rotation of the plane on polarised light

R and S
According to direction in whcioh groups with increasing MW are organised about a chiral centre

98
Q

What is a racaemic mixture

A

Preprations containing equal amounts of two enantiomers e.g. bupivocaine, atropine, volatiles (except sevo)

99
Q

Enantiopure preparations

A

Single enantiomer e.g. S ketamine, dexmeditomidine, S bupivocaine or S ropivocaine

100
Q

Diastereoisomers

A

Compounds containing more than one chiral centre e.g. atracurium

101
Q

INcidence of malignant hyperthermia

A

1:5000 to 1:50 000

102
Q

Inheritence pattern of MH

A

autosomal cominant

103
Q

What is the MOA of MH

A

Ryanodine receptor mutation on chromosome 19 on the sarcoplasmic reticulum which mediate release of Ca from the sarcoplasmic reticulum

Abnormal RY R leads to excessive efflux of Ca and generalised muscle rigidity, increasing ATP consumption to return Ca into sarcoplasmic reticulum –> increased CO2, heat and lactate –> cell lysis –> myoglobinaemia, hyperkalaemia, acidosis

104
Q

What causes MH

A

Succinylcholine and volatile anaesthetic agents

105
Q

What 3 subtypes of ryanidine receptor are there?

A

RY R 1 - skeletal
RYR 2 - myocardium
YR 3 brain

106
Q

Early clinical features of MH

A

Monitor
Increased HR
Increased ETCO2
Increased temperature
Arrhythmias

Patient
Masseter spasm after ACh
Sweating
Muscle rigidity

Tests
- Hyperkalaemia
- Metabolic and respiratory acidosis

107
Q

Late signs of MH

A

Myoglobinuria
Raised serum CK
Coagulopathy
Cardiac arrest

108
Q

How to treat MH

A
  1. Stop trigger - turn off volatile, hyperventilate with 100% O2/high gas flows and start TIVA
  2. Dantrolene
  3. Treat complications
    - HyperK
    - Hyperthermia
    - Acidosis
    - Arrhtyhmias
    - Renal protection
109
Q

How do you test for malignant hyperthermia

A

Caffeine and halothane contracture test

110
Q

Dantrolene preparation

A

20mg with 3mg mannitol in an orange powder to be reconstructed in 60ml of sterile water

Highly irritant when extravasated

111
Q

Dose of dantrolene

A

2.5mg/kg IV every 10-15 minutes up to 10mg/kg and then 1mg/kg every 4-6 hours for 24 hours after crisis

112
Q

Mechanism of dantrolene

A

Binds to RYR1 preventing Ca release uncoupling excitation contraction

No effect on muscle aciton potential

113
Q

Pharmacokinetics of dantrolene

A

Protein binding 85%
Hepatic metabolism to 5-hydroxy
T1/2 B 12 hours
Renal excretion

114
Q

What is a porphyria

A

Defect in haem synthesis - the 1st step where conjugation of succinyl CoA and glycine to gamma amino-laevulinic acid catalused by amino-laevulinic acid synthetase –> partial deficiency resulting i accumulation of porphyrin precurers

115
Q

Unsafe drugs in context of porphyrias

A

Barbituarates
Ketamine
Clonidine

Ketorolac, diclofenac

Phenytoin
Erythromycin

?Metaraminol and ephidrine
?Volatiles
?Oxycodone

116
Q

Where do you find plasma cholinesterases

A

Plasma, brain,. liver, kidneys

117
Q

Where are plasma cholinesterases synthesised

A

Liver

118
Q

T1/2 beta of plasma cholinesterases

A

8-16 hours

119
Q

Plasma cholinesterase involved in the metabolism of what 3 agents

A

SCh
Mivacurium
Ester LAs

120
Q

Describe the genetics around plasma cholinesterases

A

Chromosome 3 4 alleles
- Usual
- Atypical
- Silent/absent
- Fluoride resistant

Homozygenous patient prolonged paralysed after usual dose SCh 4-8 hours, dibucaine number 20. Ea/Ea

Heterozygotes have slightly prolonged paralysis after usual dose, 4% of people, 10-20 minute paralysis. Dibucaine number 60

96% of people normal response, dibucaine number 80

121
Q

What commonly encountered factors lead to reduced plasma cholinesterase

A
  1. Pregnancy
  2. Organ failures - liver, renal, cardiac
  3. Malingancy and malnutrition
  4. Burns
  5. Thyrotoxicosis
  6. Iatrogenic - plasmapheresis, anticholinesterases, ketamine, ester LA, OCP
122
Q

What is dibucaine?

A

Amide LA
Inhibits normal plasma cholinesterase to a greater extnet than atypical forms

Dibucaine number represents perecentage inhibition i.e. higher number = more normal plasma cholinesterase

123
Q

What is p glycoprotein?

A

A drug efflux pump in the intestine

124
Q

What inhibits P glycoprotein?

A

Verapamil
Amiodarone
Dabigatran
Ketoconazole
Erythromycin
Quinidine

125
Q

What are subtrates for P glycoprotein>

A

Digoxin
CaB
Statins
Sildenafil
Calcineurin inhibitors
Diazepam
OCP

126
Q

Warfarin affected by

A

All ABx - endogenous vitamin K production which anythign broad spectrum affects, macrolides, metrnidazole, cipro also inhibit its breakdown

PCM, ASA, NSAIDs, amiodarone, statins can also inhibit its metabolism

127
Q

QTc prolongation due to

A

Genetic/congenital
Anti-arrhtyhmics
- 1A - procainamide
- 1X flecainide
3 - sotalol and amiodarone

SSRIs, TCA and antidepressants
Antipsychotics - chlorpromazine, haloperidol, quetiapine, olanzapine

Macrolides
Hydroxychloroquine
Fluoroquinolones

Primary Pharmacology (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions