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FRACP > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Factors affecting the pharmacokinetics of a drug

A

Absorption
Distribution
Metabolism
Elimination

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2
Q

AUC - what does this represent in pharmacokinetics

A

Area under the curve (drug concentration y axis vs time x axis) - represents extent of absorption and bioavailability of a drug

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3
Q

pharmacokinetics vs pharmacodynamics

vs pharmacogenetics

A

Kinetics - study of the absorption, distribution, and elimination (by metabolism and excretion) of drugs.

Dynamics- study of the effect a drug has on a human body (ie the pain effect of a particular analgesic medication in children)

Genetics - genetic factors and their influence on drug metabolism and development of drug receptors (ie CYP450)

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4
Q

Factors affecting drug absorption

A

pH
gastric emptying
Both influenced by level of maturation of organ systems (absorption of diff drugs will be different in neonates vs children vs teens)

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5
Q

List factors in neonates that affect the absorption of medications compared with older children

A

Delayed gastric emptying and intestinal motility
Higher stomach pH
Reduced bile acid synthesis

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6
Q

Neonatal skin absorption

A

Thinner stratum corneum -> incr absorption of topical preparations

Increased skin perfusion -> incr absorption

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7
Q

Define bioavailability

How to calculate the bioavailability of a drug?

IV vs oral bioavailability

A

How much of the drug is absorbed and reaches the systemic circulation (ie 100mg is taken orally but only 60mg is absorbed and reaches systemic circulation so bioavailability is 0.6)
- Dependent on absorption and first pass metabolism

Calculates fraction (F) of administered drug dose that reaches systemic circulation in unchanged form

F = AUC (oral) / AUC (IV)

Bioavailability of IV drugs should be 100% vs oral drugs lower (incomplete absorption, undergoes first pass metabolism in gut, liver or excreted in bile)

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8
Q

Volume of distribution - definition

A

Volume that would accomodate all the drugs in the body if the concentration was the same as in plasma

Alterations can change half life of drugs because larger volumes require longer to be eliminated

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9
Q

Distribution - factors affecting this in neonates/younger children

A
  1. Pre-school children have LARGER volume of distribution (incr total body water content) for water soluble drugs compared with adults (sometimes require HIGHER dose of drug/loading dose). Lipophilic drugs have larger volume of distribution in infants (~12mo) due to increased fat
  2. Younger children have reduced protein binding c/w adults -> excess free unbound [drug] -> A/E/toxicity at lower [drug] and also results in higher Vd c/w adults
  3. Immature BBB so greater distribution of drugs to CNS
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10
Q

Metabolism - describe the phases

A

Mostly occurs in Liver
Also occurs to much lesser degree in lungs, kidneys and walls of GIT

  • Phase I - oxidative mainly (also reduction or hydrolysis), driven by CYP450. enzymes low at birth but levels increase w age.
  • Phase II - conjugation (glucuronidation, sulphation, methylation, acetylation, glutathionylation) -> excretion by kidneys

NOTE - some drugs undergo phase II then I, or just phase II OR phase I

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11
Q

Metabolism in neonates vs odler children

A

Liver enzymes generally low at birth, increase w age

Lower body temp can impair enzyme activity

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12
Q

What is first pass metabolism?

A

A phenomenon in which a drug gets metabolized at a specific location (usually LIVER) in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation. This effect can become augmented by various factors such as plasma protein concentrations, enzymatic activity, and gastrointestinal motility.

Note that IV medications are injected directly into systemic circulation so are not subject to the ‘first pass’ effect - 100% reaches systemic circulation. This will be reduced when the drug is administered orally, resulting in higher oral dose requirements.

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13
Q

What enzyme is responsible for caffeine metabolism?

A

CYP1A2

Note- reduced levels of this enzyme in neonates so limited metabolism, requires only once daily dosing in this age group

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14
Q

Erythromycin - effect on cyp450

A

CYP450 inhibitor

thus affects clearance of other drugs also metabolised by CYP450 but doesn’t affect their bioavailability

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15
Q

Factors affecting renal elimination

A

GFR
Tubular secretion
Tubular reabsorption

Also

  • GA
  • Postnatal age
  • Weight

Note- kidney function is immature at birth -> eGFR increases with age
-> require dose reduction in younger children

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16
Q

Clearance and Rate of elimination formulas

First vs zero order kinetics

A

Clearance of drug = Cl renal + Cl hepatic + CL lung + CL other

= Rate of elimination / [medication in the plasma] = mg/L

FIRST ORDER KINETICS (majority of drugs)
So rate of elimination is directly proportional to the amt of drug in the body. Thus there is an exponential DECREASE in the amt of drug in the body over time.

ZERO ORDER KINETICS

  • Rate of elimination is CONSTANT regardless of [drug]
    ex: phenytoin, warfarin, aspirin
  • Straight diagonal line decrease on graph (y axis [drug] vs x axis time)
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17
Q

Features of short vs long half life

A

Short
Quick acting but wear off fast
Need to give more frequently

Long

  • longer onset of action
  • but effects persist for longer
  • dosed less frequently
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18
Q

How many half lives to achieve steady state concentration?

A

5x

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19
Q

what parameter is most important in determining steady-state?

A

Half-life of a drug (5x half lifes to reach steady state)

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20
Q

Steady state concentration

A

Drug in = drug out (rate of absorption = rate of clearance)

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21
Q

Relative GC activity/potency of the following steroids:

Pred
Methylpred
Cortisol
Dexamethasone
Fludrocortisone

What is the physiological steroid dose?

A

D-MP(F)H (potent -> weak)
1,5,6,10,25

Dexametasone = 1mg
Methylpred = 5mg
Pred = 6mg
(Fludrocortisone = 10)
Hydrocortisone = 25mg

Physiological steroid = hydrocortisone 10mg/kg/m^2/day

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22
Q

Factors affecting distribution of a drug

A
  1. Blood flow to an area
  2. Capillary permeability
  3. Degree of plasma protein binding (only unbound molecules are free to diffuse to tissues whereas bound drug has to stay in plasma)
  4. Apparent Volume of distribution = dose administered/plasma concentration
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22
Q

What is phase II metabolism?

A

Conjugation mostly by liver

(glucuronidation, sulphation, methylation, acetylation, glutathionylation) -> excretion by kidneys

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23
Q

Apparent Volume of distribution = formula?

What does a high vs low Vd indicate?

A

Vd = dose administered/plasma concentration

(high Vd >16 = distributed amongst ECF
vs low Vd <3 = distributed only in plasma)

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24
Q

What is phase I metabolism?

A

Occurs in liver
Oxidative mainly (also reduction or hydrolysis), driven by CYP450. enzymes low at birth but levels increase w age.
Makes lipophilic drugs water soluble for excretion in urine

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25
Q

Fluconazole - effect on p450 system?

A

p450 inhibitor

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26
Q

Rifampicin - effect on p450 system?

A

CYPp450 inducer

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27
Q

Routes of excretion and elimination

A

Kidneys - metabolised substances now hydrophilic are passed in urine

Faeces - not absorbed, passes directly out of body in stool

Bile - substance absorbed in GIT then enters enterohepatic circulation and is excreted in bile/ducts into intestine -> passes out in stool

Inhaled anaesthetics are eliminated via lungs

Sweat
Saliva
Breast milk
Tears

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28
Q

Elimination vs excretion

A

EliMination - passage of Metabolised substance

Excretion - passage of UNmetabolised substance

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29
Q

mechanism for
a) penicillin resistance
b) macrolide and fluoroquinolone resistance
of Streptococcus pneumoniae?

A

a) altered penicillin binding proteins

b) to alteration in binding site on RNA/ DNA gyrase respectively

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30
Q

Which anti epileptics require serum level monitoring?

A

phenytoin, phenobarbitone and sometimes carbamazepine

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31
Q

What effect do anti-epileptic medications have on CYP450?

A

The majority are CYP inducers (phenobarbitone, carbamazepine, oxcarbazepine, phenytoin)

EXCEPT Valproate which is an inhibitor

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32
Q

What effect do azole antifungals (vori, posa)

Have on CYP450?

A

Inhibitors

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33
Q

What effect does
grapefruit juice
Have on CYP450?

A

Inhibitor

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34
Q

What effect do Ca channel blockers (verapamil, diltiazem)

Have on CYP450?

A

Inhibitors

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35
Q

what effect does clarithromycin have on CYP450?

A

Inhibitor

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36
Q

What effect do
steroids
Have on CYP450?

A

inducers

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37
Q

What effect does
St Johns wart
Have on CYP450?

A

Inducor

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38
Q

What effect does
topiramate
Have on CYP450?

A

Inducor

tx migraines and also

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39
Q

How does codeine work?

A

Is a prodrug that is converted via CYP2D6 via oxidation to morphine which gives the sedative affect

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40
Q

Ethosuximide - MOA and indication for use?

What effect does it Have on CYP450?

A

T-type calcium channel blocker
tx abence seizures

CYP450 Inducer

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41
Q

What antibiotics are active against pseudomonas?

A 
Augmentin/timentin
Gentamicin
Tazocin (Piperacillin/tazobactam)
Ceftazidime (the only cephalosporin)
Ciprofloxacin
Tobramycin
Amikacin
Aztreonam (monobactam specifically targeted at GNB, doesn't cover GPB)
Carbapenems - broadest of all beta lactams (imipenem, meropenem etc)
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42
Q

which cephalosporin is active against pseudomonas

A

Ceftazadime

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43
Q

Why should bactrim not be given to patients on long-term immunosuppression with MTX?
What is the treatment?

A

MTX and Bactrim MOA: folic acid ANTAGONIST via inhibition of dihydrofolate reductase -> reduction of folate metabolism
o Bactrim also reduces renal excretion of MTX
o Also have competitive protein binding so bactrim increases free serum levels of MTX
- Thus high potential for MTX toxicity -> feb neut and mucositis
- Antidote is FOLINIC ACID – reduced form of folic acid that supplies the necessary cofactor antagonized by MTX

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44
Q

Which abx for resistant strep pneumonia?

A

If resistant – vancomycin + ceftriaxone

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45
Q

Metabolism of carbamazepine

A

In liver by cyp450 -> renal excreted

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46
Q

Metabolism and elimination of gabapentin

A

eliminated unchanged by the kidneys (not metabolised)

47
Q

Use of warfarin in pregnancy

A

Crosses placenta. Should not be used in pregnancy unless absolutely essential. Teratogenic in 1st trimester and 2-4 weeks before due date can cause haemmhoragic cx

48
Q

Antiepileptic drugs that are eliminated unchanged by the kidneys or undergo minimal metabolism ?

A

Gabapentin, pregabalin, vigabatrin

49
Q

Use of sodium valproate in pregnancy

A

CI in pregnancy -> crosses placenta with risk of congenital malformations. Teratogen.

50
Q

Use of digoxin in pregnancy

A

Rapidly crosses the placenta and reaches equilibrium, with maternal and fetal sera having equal concentrations. Can safely be used in pregnancy. No known teratogenic effects.

51
Q

Use of muscle relaxants (vecuronium, pancuronium) in pregnancy

A

Fine to use - don’t cross placenta

Highly ionized which impedes placental transfer, resulting in minimal effects on the fetus

52
Q

Use of captopril in pregnancy

A

should NOT be used in pregnancy. Can cause IUGR, oligohydramniose, hypotension, acute renal failure and PDA.

53
Q

Nitric oxide

  • indication for use
  • MOA
  • why is the half life so short
A

Mx of pulm HTN in neonates

MOA: Nitric oxide mechanism upregulation of cyclic GMP

Degradation due to rapid binding to Hb

54
Q

MOA thiazide diuretics and what affect do they have on serum electrolytes

A

Acts on proximal distal tubule
to block Sodium reabsorption via the Na-Cl cotransporter through competition with the Cl site of the transporter

Electrolyte changes

  • Hyponatraemia,
  • Hypochloraemic alkalosis
  • Hypokalaemia
  • Hypomagnesaemia (although magesium can be normal)
  • Hypercalcaemia (increases reabsorption of Ca and thus reduces calciuria so sometimes used for tx of Ca stones)
55
Q

MOA loop diuretics

SE

A

Loop diuretics act on the Na+-K+-2Cl− symporter (NKCC2) in the thick ascending limb of the loop of Henle to inhibit sodium, chloride and potassium reabsorption. This is achieved by competing for the Cl− binding site.

SE
Electrolyte changes (hypoMg, hypoK, hypoNa, hypoCa)
Hyperuricaemia, gout
Hypotension, dehydration, postural syncope
Dyslipidaemia
AKI/raised serum Cr

56
Q

MOA allopurinol

A

inhibits xanthine oxidase which block metabolism of xanthine and hypoxanthine to uric acid
decreases the formation of new uric acid, however does not reduce acid concentration prior to treatment (ie is preventative not treatment so use rasburicase if uric acid levels already high)

57
Q

MOA rasburicase

A

Uricase (Rasburicase) or uric oxidase catalyses the oxidation of uric acid to a water soluble compound allantoin.
Lowers serum uric acid and is effective in preventing and treating hyperuricaemia and tumour lysis syndrome.

58
Q 
Aminoglycosides - MOA and examples of abx in this class
What bacteria is it active against?
A

Protein synthesis inhibition via inhibiting binding of tRNA at the ribosome

Active against: Gram-negative aerobes (eg pseudomonas) and some anaerobic bacilli

Ex: kanamycin, tobramycin, gentamicin, and neomycin

59
Q

Tetracyclines

A

Protein synthesis inhibition via inhibiting binding of tRNA at the ribosome

Broad spectrum

Ex: doxycycline

60
Q

MOA infliximab

Main indication

A

Monoclonal antibody against tumour necrosis factor alpha (TNF-α).

It works by binding to TNF-α, and therefore inhibits the binding of TNF-α to its receptor cells.

Used for treatment of IBD (CD)
- TNF-α is thought to be directly related to the pathogenesis of inflammatory bowel disease; so blocking receptor-binding can stop the inflammatory process.

61
Q

What drug classes are the main ones subject to tolerance over time?

A

Narcotics, alcohol, barbiturates, benzodiazepines.

62
Q

Hep C treatment and SE

A

Ribaviron (along with IFN)

Main SE to watch for is haemoragic anaemia within 2 weeks of starting medication -> this can worsen underlying cardiac disease (so avoid in pts with significant cardiac disease)

Other SE include depression; alopecia; nausea; and myalgia.

63
Q

MOA and SE of risperidone

A

The primary side effects of risperidone are:
Atypical antipsychotic
Serotonin > DA antagonism
Also alpha adrenergic antagonism

  • mild sedation
  • hypotension
  • akathisia (subjective feeling of inner restlessness w mental anguish -> unable to sit still)
  • prolactin elevation (which can cause menstrual irregularities)
  • weight gain
  • moderate risk of extrapyramidal symptoms, such as akathisia and dystonia (muscle stiffness).
  • increased dream activity.
64
Q

Main consequence of alcohol poisoning in toddlers

A

Hypoglycaemia
- Alcohol inhibits gluconeogenesis but plasma glucose can usually be maintained from glycogen breakdown.

Other: drowsiness, dysarthria, ataxic and hypoglycemia.

65
Q

Definition and formula for RELATIVE bioavailability

A

Relative bioavailability measures the bioavailability of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route. (vs absolute bioavailability when compared with IV formulation)

= (AUCA x DoseB) / (AUCB x DoseA)

66
Q

Barbituates - MOA, clinical effects and examples

A

MOA: GABA potentiator

Anaesthetic, sedative, anxiolytic, anticonvulsant and hypnotic properties (NOT analgesia effects)

Examples: thiopental and anything needing in ‘barbital’

67
Q

Hydroxychlorquine

Indications for use
SE

A

Use: malaria and cutaneous rheumatological disease (SLE and often in dermatomyositis)

SE: nausea most common; reversible corneal toxicity (dose-related), rare but irreversibly retinal toxicity

68
Q

Which anticonvulsant interacts with lamotrigine?

A
  1. Sodium valproate: valproate increases lamotrigine concentration necessitating a lower lamotrigine dose
  2. Carbamazepine: Lamotrigine may increase the concentration of carbamazepine, increasing the adverse CNS effects of carbamazepine. Carbamazepine may decrease the concentration of lamotrigine and decrease its efficacy.
69
Q

Which opiod is safe for use when breastfeeding?

A

Buprenorphine

The other agents all cross into breastmilk and have an oral ility that can cause adverse effects in a breast feeding infant. These include sedation, poor weight gain and delayed developmental milestones. They should be avoided where possible.

70
Q

MOA ondansetron and granisetron

A

Potent 5HT3 (serotonin) antagonists in the peripheral/central nervous system -> anti-nausea

71
Q

Difference between competitive and non-competitive antagonism

Graph for each of y axis ‘% max effect’ vs x axis ‘log[x]’

A

Competitive - ANTAGONIST (inhibitor/blocker) and agonist (activator) compete for the same receptor binding site. Whichever is present in higher []s occupies the binding site/wins.

Non-competitive - ANTAG occupies a DIFFERENT binding site than the agonist thus if any amt of antagonist is present, will prevent the action of the agonist (or NO amt of agonist will be able to activate the receptor) .

72
Q

Define potency vs efficacy

A

Potency - Amt of drug that is required to produce a particular effect

Efficacy - maximum effect that can be achieved by a drug

73
Q

What medication is contraindicated in the prevention of recurrent SVT in Wolff-Parkinson-White due to the risk of potentiating accessory pathway conduction?

A

Digoxin

74
Q

What medication is used in congestive heart failure to reduce afterload.

A 
Ace inhibitors (ex rampipril)
Furosemide to lesser degree (mainly reduces preload)
75
Q

Atenolol - MOA and SE

A

Beta blocker
These include bradycardia (slow heartbeat), severe hypotension with shock, acute heart failure, hypoglycemia and bronchospastic reactions.

76
Q

Atropine

Indicaitons
MOA
SE

A

Indications: anti-sialagogue/anti-vagal effect, organophosphate/muscarinic poisoning, and bradycardia

MOA: antimuscarinic that works through competitive inhibition of postganglionic acetylcholine receptors and direct vagolytic action, which leads to parasympathetic inhibition of the acetylcholine receptors in smooth muscle. The end effect of increased parasympathetic inhibition allows for preexisting sympathetic stimulation to predominate, creating increased cardiac output and other associated antimuscarinic side effects as described herein.

SE are antiSLUD: xerostomia, blurred vision, photophobia, tachycardia, flushing, and hot skin. Constipation, difficulty with urination, and anhidrosis

78
Q

Flecainide

MOA
Indicaitons
SE

A

MOA - Antiarrythmic Na channel blocker -> slows the upstroke of the cardiac action potential -> slows conduction of the electrical impulse within the heart, i.e. it “reduces excitability”.

Indications: VT or SVT

SE: toxicity -> marked prolongation of the PR interval and widening of the QRS duration on the surface ECG; heart failure; torsades de points; can be associated w ILD.

79
Q

Adenosine

MOA
Indications

A

‘AdeNOsine’ sounds like ‘AV Node’ -> acts on AV node

Anti-arrhymic.
Indications: SVT, cardiac stress testing

  • Binds to A1 receptors (G protein coupled -> cAMP) in cardiac AV node, significantly reducing conduction time and thus slowing HR via 2 methods:
  • K channel activator -> K efflux -> hyperpolarization of the resting membrane potential
  • Inhibits L-type Ca channels -> prevents Ca influx -> suppression of calcium-dependent action potentials
  • Requires a longer time for depolarization to occur and thus slows down conduction
79
Q

MOA Digoxin
Indications
CI
SE

A

Indications - SYSTOLIC heart failure w reduced EF and comorbid AF (not first line for AF)
Sx control only; doesn’t improve mortality

CI: heart block and VF

Binds and inhibits Na/K ATPase on cardiac myocite

  • > Prevents intracellular Na exiting and extracellular K entering cardiac myocyte -> incr I/C [Na] and incr E/C [K]
  • > High IC Na leads to high
  • > Leads to inactivation of Na/Ca exchanger and prevents Ca secretion out of myocyte -> high IC [Ca]
  • > Incr intracellular Ca ions -> increases force of heart contraction.

Toxicity: Hyperkalaemia, nausea/vomiting/GI sx, frequent PVCs or bidirectional VT, bradyarrhythmias, hypotension, shock; AKI

80
Q

MOA Digoxin
Indications
CI
SE

A

Increases force of heart contraction
Indications - SYSTOLIC heart failure w reduced EF and comorbid AF (not first line for AF)
Sx control only; doesn’t improve mortality

CI: heart block and VF

Binds and inhibits Na/K ATPase on cardiac myocite

  • > Prevents intracellular Na exiting and extracellular K entering cardiac myocyte -> incr I/C [Na] and incr E/C [K]
  • > High IC Na leads to inactivation of Na/Ca exchanger and prevents Ca secretion out of myocyte -> high IC [Ca]
  • > Incr intracellular Ca ions -> increases force of heart contraction.

Toxicity: Hyperkalaemia, nausea/vomiting/GI sx, frequent PVCs or bidirectional VT, bradyarrhythmias, hypotension, shock; AKI

82
Q

Tocilizumab

MOA
Indications

A

monoclonal antibody directed against the IL 6 receptor

Indicaitons:
Covid 19 ventilated patients - reduces mortality
RA
JIA 
Systemic scleroderma assoc ILD
83
Q

Infliximab MOA and indications

A

chimeric monoclonal antibody that binds to TNF alpha

Indicaitons

  • moderate to severely active Crohn disease
  • ulcerative colitis
  • active rheumatoid arthritis
  • ankylosing spondylitis
  • psoriatic arthritis
83
Q

Define ‘therapeutic index’ of a drug and what is the formula

A

Therapeutic index (or ratio), is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects.

= toxic dose of a drug for 50% of the population / the therapeutic dose for 50% of the population

84
Q

Anakinra MOA

A

IL1 inhibitor daily SC injection

Indicaitons

  • RA
  • Familial Mediterranean Fever - colchicine-resistant
  • JIA
  • Kawasaki resistant to IvIG
86
Q

Pimecrolimus

Indication for use

MOA

SE

A

=Elidel cream
Topical preparation is 2nd line for eczema

MOA: calcineurin inhibitor -> blocks T cell proliferation and preventing release of inflammatory cytokines.

SE: local irritation, burning sensation, itch, erythema, skin infections

87
Q

Which pharmacokinetic concept best explains the increase in drug concentrations of drugs with high hepatic extraction ratios in pts w cirrhosis vs the healthy general population?

A

Increased Bioavailability - Systemic bioavailability is a product of absorption and first pass metabolism. Liver disease decreases first pass metabolism and so increases bioavailability.

Cirrhosis may lead to portosystemic shunts, reduced protein synthesis (for binding) and decreased activity of a number of important drug metabolising enzymes, which will result in increased bioavailability of orally administered flow limited drugs. The oral bioavailability of a number of drugs with intermediate to high hepatic extraction ratios has indeed been shown to be significantly increased in patients with liver cirrhosis

87
Q

Main risk of ibuprofen poisoning

A

Renal failure - may be delayed onset so recheck 6-8 hrs

88
Q

Sx of DRESS

Which viral infection and which anticonvulsant is associated?

A

Clinical presentation:

  • Long latency period between drug exposure and disease onset (2-8 weeks)
  • Prolonged course despite cessation of drug
  • Frequent association with reactivation of latent HHV6
(DRESS FFEES)
Fever 38-40
Facial oedema
Eosinophilia
Enlarged LNs
Skin eruption – progresses to diffuse, confluent erythema

Carbamazepine
HLA-B*58:01 (Han Chinese) strongly associated with allopurinol associated DRESS

89
Q

CYP inhibitors

A 
Azoles
Macrolide abx (-mycin)
Cimetidine
Valproate
Ca ch blockers (verapamil, diltiazem)
Grapefruit juice
90
Q

HLA1502

What anticonvulsant is assoc w DRESS/SJS/TEN in this genetic group?

A

Carbamazepine (also oxcarbazepine, phenobarbital and phenytoin)
HLA1502 highest in asian population (10%; Han Chinese, Thai)

91
Q

CYP inducers

A

anti-epileptics EXCEPT VALPROATE

  • > phenobarbitone
  • > carbamazepine
  • > oxcarbazepine
  • > phenytoin
  • > ethosuximide
  • > topiramate

Rifampicin
Steroids
St Johns wart

93
Q

In acute paracetamol overdose, which mechanisms may result in hepatoxicity?

A
  1. Metabolism of paracetamol by cytochrome p450 to NAPQI (phase I Metabolism) which is HEPATOTOXIC -> usually then is conjugated (detoxified) by glutathione. in paracetamol overdose the liver conjugation system is overwhelmed and glutathione is depleted and the NAPQI accumulates causing liver toxicity -> ALF
93
Q

What do we measure in clinical practise as a surrogate for target site concentration of a drug?

A

Serum plasma concentrations
-> specifically, trough concentrations is a surrogate for the AUC, which is a surrogate for the target site concentration

94
Q

Carbamazepine SE

A 
Maculopapular rash
Hepatotoxicity
Leukopenia/ pancytopenia (BM suppression)
Hyponatraemia 
Rash (3-5%)
– SJS (HLAB1502-Asians)
- DRESS
95
Q

Which anticonvulsant drug therapies is likely to cause the most harm in pregnancy?

A

Na Valproate

96
Q

AUC differs between individuals based on what PK variables? (2)

A

Drug clearance (with incr clearance, the AUC decreases)

Bioavailability (how much of the drug gets into systemic circulation)

97
Q

What factors impact drug CLEARANCE?

A

Patient size
Kidney function
Liver function

Cl = Clrenal + Clhepatic +Clother

98
Q

What do you have to consider before commencing azathioprine or 6MP in a patient?

A

doing pharmacogenetics

  • this is because there is a risk of severe azathioprine induced BM suppression in select individuals with a particular TPMT gene mutation resulting from incr production of 6MP
  • > for homozygotes with 2 dysfunctional enzymes, AVOID aza or use 1/10th dose.
  • > for heterozygotes, consider 30-70% dose reduction
98
Q

Effect of diarrhoea on tacrolimus levels

A

Can actually incr exposure/increase levels -> need to check levels to ensure not toxic

99
Q

Drugs with metabolising enzyme polymorphisms (pharmacokinetics)

A

COdeine (CYP2D9)
Voriconazole (CYP2c19)
Tacrolimus (CYP3A5)
Azathiprine (TPMT)

100
Q

Formula for elimination rate (mg/h)

A

= Clearance (Lxh) x concentration (mg/h)

101
Q

formula for maintenance dose requirement

A

= clearance x desired concentration (AUC)

102
Q

Formula for loading dose

A

= volume (L) x target concentration (mg/L)

103
Q

What is the definition of bio equivalence between drugs?

A

Maximal concentration and AUC should be within 80 and 125%

106
Q

Hysteresis loops: clockwise vs anticlockwise. what do they mean for the drug?

A

Hysteresis loop means there is a time delay between measured concentration and the effect response.

Clockwise loop (A): occurs when rapid tolerance develops (cocaine). Clinical effect for a given plasma concentration is initially high, but decreases as tolerance rapidly develops.

Anticlockwise loop (B): SLOW DISTRIBUTION of drug to site of action. Response for a given plasma concentration is initially low, but increases as the drug is distributed out of plasma to the site of action (ex: digoxin)

107
Q

Phases of drug clinical trials

A

Phase 1 - side effects/safety, HOW does it work?
Phase 2 - efficacy/does it work?
Phase 3 - efficacy compared with current available tx (30-100)
phase 4: marketing and post-marketing surveillance (larger numbers, 1000+)

108
Q

What unique SE does Rifampicin/Rifabutin have?

A

Orange tears - can stain contact lenses
Can also cause skin, tears, saliva, sweat, urine and stools to turn red-orange or orange-brown in colour

Also hepatotoxic

109
Q

What unique SE does Fusidic acid have?

A

Jaundice

110
Q

Why is chloramphenicol CI in babies?

A

Causes ‘grey baby syndrome’
-> accumulates in the baby, causing hypotension (low blood pressure), cyanosis (blue coloring of lips, nail beds, and skin from lack of oxygen in the blood), and often death

111
Q

MOA Diazoxide

A

opens ATP-dependent potassium channels on pancreatic beta cells in the presence of ATP and Mg2+, resulting in hyperpolarization of the cell and inhibition of insulin release. Diazoxide binds to a different site on the potassium channel than the sulfonylureas.

112
Q

Metformin

MOA
SE

A

Biguanide class

MOA

  • Decr gluconeogenesis
  • Incr insulin sensitivity
  • Incr LOW
  • Rarely causes hypoglycaemia

SE

  • Diarrhoea
  • B12 deficiency -> peripheral neuropathy
  • Metallic taste
  • Lactic acidosis (incr risk w renal impairment)
113
Q

Sulfonylureas (glicazide)

MOA
SE

A

MOA
- targets Beta cells to increase insulin production (doesn’t work in patients with no beta cells left ie insulin-dependent diabetics)

SE

  • Weight gain
  • Hypoglycaemia
  • GI SE
114
Q

Pioglitazone

MOA
SE

A

MOA
- reduces peripheral insulin resistance

SE

  • bone #
  • bladder cancer
  • weight gain
115
Q

Gliptins

MOA
SE

A

MOA

  • DDP4 inhibitor
  • > increases insulin secretion and lowers glucagon secretion

SE

  • headache
  • pancreatitis
  • cardioprotective!
116
Q

‘GliFlozins

MOA
SE

A

MOA

  • SGLT2 inhibitors
  • > reduces glucose reabsorption in kidneys and increases its excretion in urine

SE

  • UTIs
  • Genital pruritis
  • Back pain
  • DKA (CI in T1DM)
  • Cardioprotective!

FRACP (21 decks)

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