General principles Flashcards

1
Q

Which of the following drugs has a half-life of 6 hours?

A Diazepam
B Aspirin
C Digoxin
D Atenolol

A

D

Explanation
Aspirin’s t1/2 is 15 minutes (0.25 hrs)

Atenolol t1/2 is 6.1hrs

Digoxin’s t1/2 is 39hrs

Diazepam’s t1/2 43hrs.

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2
Q

Regarding irreversible antagonists, which of the following statements is correct?

A Can be displaced by increasing efficacy of agonist
B Require regeneration of receptors for further agonist action
C Can be displaced by increasing concentration of agonist
D Can be displaced by increasing potency of agonist

A

B

Explanation
Competitive antagonists can be overcome by sufficiently high concentration of agonists.

Irreversible antagonists cannot. Consequently, the duration of action of such an irreversible antagonists relatively independent of its own rate of elimination and more dependent upon the rate of turnover of receptor molecules

Note: this question can present as an EMQ: stem: results in a receptor being unavailable for binding of an agonist

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3
Q

Calculate an IVI Phenytoin loading dose for a 70 kg male; Target concentration 10 mg/L, Vd 0.5 L/kg

A 3500 mg
B 350 mg
C 300 mg
D 400 mg

A

B

Explanation
Loading dose

e: (Vd X target concentration)/bioavailability

Bioavailability in this case is 1 as it is given IVI

0.5L/kg in a 70kg man -35L.

The LD = (35 X 10)/1

35 x 10=350

Note that in the textbook Phenytoin is given a Vd of 45L (in a 70kg man)

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4
Q

Which of the following is an example of a phase I reaction?

A Acetylation
B Sulphation
C Glucuronidation
D Hydrolysis

A

D

Explanation
Phase one reactions are hydrolysis, oxidation and reduction.

Phase two reactions are glucuronidation, acetylation, glutathione conjugation, glycine conjugation, sulfate conjugation, methylation, and water conjugation

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5
Q

How many mg in 2ml of a 0.5% weight per volume solution?

A 5mg
B 10mg
C 1 mg
D 100mg

A

B

Explanation

1%=1000mg in a 100ml solution is the starting point.

0.5%=500mg in 100ml solution.

Therefore 1ml=5mg.

Therefore 2ml=10mg

Extra:

15ml of a 0.5% Prilocaine solution would equal 75mg

An easier way-100% solution is 1g in 1mL (equivalent to 1kg in 1L) 1% solution is 10mg in 1mL 0.5% solution is 5mg in 1mL Therefore 2ml=10mg

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6
Q

Which of the following statements is correct?

The volume of distribution…

A Is proportional to half life
B Is calculated by dividing the amount of drug by it’s clearance
C If high suggests homogeneous distribution throughout tissues
D Abnormal accumulation of body fluids does not effect VD

A

A

Explanation
Vd is an apparent volume.

The volume of distribution= amount of drug in the body/ concentration of the drug in blood or plasma.

Drugs with a high VD have higher extravascular concentrations than intravascular and are not homogenously distributed. Drugs that are completely retained within the vascular compartment would have minimum possible volume of distribution equal to the plasma component in which they are distributed, e.g., 0.04L/KG body weight or 2.8L/70kg

T1/2 = (0.7 x Vd) / CL

Abnormal collection of body fluids: oedema, ascites, pleural effusion, can markedly increase the VD of drugs that are hydrophilic and have normally low volumes of distribution-e.g., Gentamycin. (It has to do with the decreased plasma protein pool and binding capacity, leading to an increase of unbound free drug that can move into these fluid collections)

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7
Q

Calculate the half life of Digoxin in a 70 kg patient with a renal clearance of 9L/h and volume distribution of 500 L/70kg

A 32 hours
B 28 hours
C 39 hours
D 44 hours

A

C

Explanation
T1/2 = (0.693 x VD)/CL

T1/2= (.693 x 500)/9

T1/2=39 hours

Note: If you used 0.7 instead of 0.693 to work out the calculation in your head, T1/2=38.88 which is close to the half life given in the textbook (39)

Other facts of digoxin: oral bioavailability-70%, 25 bound in plasma, VD=500L/70kg. Digoxin’s bioavailability is increased by antibiotics like erythromycin- gut flora changes reduce gut bacterial metabolism of the digoxin

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8
Q

What is the half life of Lignocaine?

A 120 minutes
B 10 minutes
C 30 minutes
D 60 minutes

A

A

Explanation
Lignocaine has a t1/2 of 1-2 hours.

Note: in older editions, it writes that lignocaine has a half life of 1-2 hours. The latest edition reports that it has an elimination half life of 1-2 hrs (1.6hrs) and may be increased to 6hrs in patients with liver failure

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9
Q

Which of the following statements regarding the bioavailability of a drug is correct?

A Is 70% for orally administered Digoxin.
B Must be 100% if given by inhalation.
C Is high if the drug is hydrophilic.
D Is equal to 1 minus the extraction ratio (ER)

A

A

Explanation
Inhalation gives a bioavailability of 5 to <100%. Hydrophilic and lipophilic drugs can have low rates of bioavailability. Too lipophilic, the drug will not be soluble enough to cross the water layer adjacent to the cell. The bioavailability of the drug (F) can be predicted from the extent of absorption (f) and the extraction ration (ER).

F=f x (1-ER).

e.g.morphine is almost completely absorbed (f=1) so that the loss in the gut is negligible. However the heaptic extraction ration for morphine is 0.67 (morphine clearance diided by hepatic blood flow). Therefore 1-0.67=0.33

F= 1 X 0.33=0.33-the bioavailability of morphine is expected to be 33%

100% bioavailability is only via intravenous administration

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10
Q

Which of the following is an example of Type 1 biotransformation reaction

AGlucuronidation
B Methylation
C Acetylation
D Hydrolysis

A

D

Explanation

Phase one reactions are hydration, oxidation and reduction. Phase two reactions are glucuronidation, acetylation, glutathione conjugation, glycine conjugation, sulfate conjugation, methylation, and water conjugation

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11
Q

Which of the following statements regarding Naloxone is false?

A Naloxone is a pure antagonist
B Naloxone has equal affinity for mu, kappa and delta receptors
C Tolerance to naloxone does not develop
D Intravenous administration reverses opioid effects in 1-2min

A

B

Explanation
Naloxone is a pure antagonist. It has a very high affinity for mu receptors and a lower affinity for the other receptor binding sites but can also reverse agonists at deltas and kappa sites. Naloxone has a half life of 1-2 hours when given by injection and 10 hours when taking via the oral route. Although naloxone is well absorbed via the oral route it undergoes rapid first pass metabolism. IVI administration reverses opioid toxicity in 1-3 minutes. There is no tolerance to the antagonistic action of these agents, nor does withdrawal of naloxone after chronic administration precipitate an abstinence syndrome

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12
Q

With regard to properties of a drug, which of the following statements is correct?

A TD50 is the concentration of a drug necessary to produce toxic effects 50 % of the time
B Efficacy is the maximum response produced by a drug
C Spare receptors are present if Kd 50 is the same as EC 50.
D Potency is the same as affinity.

A

B

Explanation

Spare receptors are present if the EC50<Kd.

Potency: how much of a drug that is required to produce an effect.

Affinity: how tight the drug binds to its receptors.

TD50 is the dose required to produce toxic effects in 50% of patients.

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13
Q

Which of the following is an example of a phase II biotransformation?

A Hydrolysis
B Oxidation
C Reduction
D Methylation

A

D

Explanation
Phase one reactions are hydration, oxidation and reduction.

Phase two reactions are glucuronidation, acetylation, glutathione conjugation, glycine conjugation, sulfate conjugation, methylation, and water conjugation

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14
Q

Regarding t1/2, which of the following statements is true?

A Has no relation to protein binding
B It can be poor predictor of clearance
C Is not affected by age
D Is not related to Vd

A

B

Explanation
T1/2 = 0.7 x VD/CL. There is a relation to the Vd. Disease states can affect T1/2. Renal impairment, which occurs in 2/3 of the elderly, will lengthen the half-life of most drugs.

Half-life is related to volume of distribution (t1/2 = 0.69 x Vd/clearance), which in turn is related to protein binding.

Web sources say the protein binding can affect the half-life of a drug. The bound portion may act as a reservoir or depot from which the drug is slowly released as the unbound form. Since the unbound form is being metabolized and/or excreted from the body, the bound fraction will be released in order to maintain equilibrium.

Note: From current textbook- Plasma protein binding is often mentioned as a factor playing a role in pharmacokinetics, pharmacodynamics, and drug interactions. However, there are no clinically relevant examples of changes in a drug disposition or effects that can be clearly ascribed to changes in plasma protein binding. The clinical importance of plasma protein binding is only to help interpretation of measured drug concentrations.

Extra:

Half-life is dependent on both clearance and volume of distribution, such that a decrease in clearance, or an increase in volume of distribution will prolong the half-life and lead to a longer dosage interval.

Medications with increased clearance or decreased volume of distribution will have shorter half-lives and require more frequent dosing.

Since half-life is dependent on both clearance and volume of distribution, if there is a similar increase in both clearance and volume, there will be no change in the half-life for the drug as is the case for midazolam and metoprolol.

Half-life is the time it takes for the drug concentration to be reduced in half and is useful in determining dosing frequency. Because half-life is determined by both Vd and clearance, it may be increased by an issue with either one. Therefore clearance and Vd may be predictors of half-life not the other way round.

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15
Q

Regarding efficacy, which of the follwing statements is correct?

A It is the drugs ability to produce 50% of its maximal effect
B It can be measured with a quantal dose response curve
C Partial agonists have higher maximal efficacy than full agonists
D It is the maximum effect a drug can bring about regardless of dose

A

D

Explanation
Efficacy: The maximum effect a drug can bring about, regardless of dose. Efficacy is measured by a graded dose response curve and not a quantal dose response curve. By definition partial agonists have a lower efficacy than full agonists

Potency: the dose or concentration required to bring about 50% of a drug’s maximal effect

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16
Q

10 ml of 1% weight to volume is equal to:

A 1000 mg
B 1 mg
C 10 mg
D 100 mg

A

D

Explanation
1%=1000mg in a 100ml solution is the a starting point.

Therefore 1ml=10mg.

Therefore 2ml=20mg

Therefore 10ml=100mg

Note: These questions seems to follow the local anaesthetic solution makeup/concentration. This is how I then calculate the answer.

Local anaesthetics

A solution expressed as 1% contains 1g of substance in each 100mls. The number of mg/ml can easily be calculated by multiplying the percentage strength by 10. Therefore a 1% solution of lignocaine contains 10mg/ml of solution. A 0.25% solution of bupivacaine has 2.5mg/ml.

Another starting point: 1g/mL = 100% in weight for volume measures (based on water’s density being 1g/mL)

17
Q

Regarding therapeutic index, which of the following statements is correct?

A Potent drugs are more likely to h have a high therapeutic index.
B It is the ratio of ED50/LD50
C It is the ratio of TD50/ED50
D High therapeutic index means a drug is dangerous

A

C

Explanation
Therapeutic index (TI) is relationship of the dose of a drug required to produce a desired effect to that which produces an undesirable effect. TI= Median toxic dose (TD50)/median effective dose (ED50). Drugs with a high TI are safer. Potency of drugs has no relationship to the TI

The therapeutic index and therapeutic window are related, but not the same. Ti= TD50/ED50 => Ratio, high ratio means effective dose much lower than toxic dose (corollary is that there is significant margin of safety) Therapeutic window= Minimum toxic dose-Minimum effective dose. => Range over which we assume drug can be safely used

18
Q

Regarding pharmacodynamics which of the following statements is true?

A Efficacy is measured by gram-for-gram effect
B Potency is maximal drug effect.
C Potency is dose of maximal effect.
D Efficacy is the maximal effect of a drug

A

D

Explanation
Potency is the dose required to bring about 50% of the drug’s maximal effect. Efficacy is only measured by a graded dose response curve and not by a quantal dose response curve

19
Q

Which of the following drugs induce the CYP450 enzymes?

A Sulphonylureas
B Grape fruit juice
C Fluconazole
D Erythromycin

A

A

Explanation
Inhibitors of CYP450 enzymes

Clarithromycin, diltiazem, erythromycin, fluconazole, grapefruit juice, ketoconazole, ritonavir, isoniazid, acute alcohol binging, cimetidine, ciprofloxacin, omeprazole, metronidazole

Inducer of the CYP450 enzymes

Barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin, St John’s Wort, ethanol (chronic) and charcoal broiled foods, griseofulvin, sulphonylureas (websourced- USMLE)

Note: in the current TB, it states that INH is an enzyme inducer

Extra:

Enzyme Inhibitors: SICKFACES.COM + Grapefruit

Sodium valproate; Isoniazid (noting current text states inducer); Cimetidine; Ketoconazole; Fluconazole; Alcohol (binge); Chloramphenicol; Erythromycin; Sulphonamides; Ciproflox; Omeprazole; Metronidazole.

Enzyme inducers: CRAP GPs

Carbamazepine; Rifampicin; Alcohol (chronic); Phenytoin; Griseofulvin; Phenobarbitone; Sulphonylureas

20
Q

Which drug has a half life of 6hrs

A Acetaminophen
B Disopyramide
C Diazepam
D Atropine

A

B

Explanation
This question is taken form a table in section 1-basic principles

Diazepam > 40hrs

Atropine= 4.3hrs

Acetaminophen=2hrs

Others:
atenolol-6.1hrs,
fluoxetine-53hrs,
amoxicillin-1.7hrs, ciprofloxacin-4.1hrs,
digoxin-50hrs
clonidine-12hrs
cyclosporin - wide range reported, up to 20 hours

21
Q

The type of metabolism which leads to the accumulation of toxic metabolites in a paracetamol overdose is?

A Hydroxylation
B Methylation
C Sulphation
D Glucuronidation

A

A

Explanation
Acetaminophen metabolism by hepatocytes by 1. about 90% undergoing glucuronidation/sulfation to inactive metabolites (saturable phase 2 rxns). Glucoronidation and sulfation are adequate for metabolism of therapeutic doses of paracetamol metabolism. 2. About 2% cleared by urine unchanged. 3. In overdose, glucuronidation/sulfation will be exhausted and remaining acetaminophen undergoes CYP oxidation (this is a hydroxylation reaction) to become toxic intermediate NAPQ1- TOXIC 4.. NAPQ1 can either be detoxified by gluthatione to mercapturic acid OR undergo cell death—> Hepatotoxicity.

Acetaminophen is conjugated to harmless glucuronide and sulfate metabolites when it is taken in normal doses. If large overdose is taken, the metabolic pathway gets overwhelmed and a P450 dependent system converts some of the drug to a reactive intermediate NAPQI. If the gluthathione stores are exhausted (in an overdose), NAPQI binds with proteins in the hepatocytes inducing liver damage.

Example of P450-dependent oxidation reactions: hydroxylation, N-dealkylation, O-dealkylation, N-oxidation, S-oxidation and deamination. Other type I reactions: oxidation P450 independent systems, reductions and hydrolyses.

Example of phase II reactions: glucuronidation, acetylation, glutathione conjugation, glycine conjugation, sulfate conjugation and methylation.

22
Q

How many mmol/l of Sodium does 1L of 3% saline contain?

A 600mmol/L
B 450mmol/L
C 500mmol/L
D 550mmol/L

A

C

Explanation
It contains exactly 513mmol/l

Remember 1% NACL of 100ml solution = 1g of NACL in that solution

0.9% NACL of 100ml solution= 0.9g of NACL

0.9% NACL of 1000ml solution= 9g of NACL

3% NACL of 1000ml solution= 30g of NACL

There are 154mmol and 9 grams in 1L of 0.9% NACL.

There are thus 17mmol and 1 gram in 1L of 0.1% NACL

Therefore 30 grams requires 513mmol in 1L of 3% NACL (30 X 17)

Alternative approach:

3% = 30mg/ml = 30 g/L solution of NaCl NaCl molar mass = 23 + 35.5 g/mol = 58.5 g/mol It follows that in 3% NaCl = 30g/L = 30/58.5 mol/L = 0.513mol/L = 513mmol/L. Therefore 0.9% NaCl is known to contain 154mmol/L 3% NaCl would then contain 3/0.9 x 154 = 513mmol/L

23
Q

Which of the following is equal to the molar mass of a substance divided by its valence?

A Osmolality
B Daltons
C Molecular wieght
D Equivalents

A

D

Explanation
Equivalents: The concept of electrical equivalents is important as many of the important solutes in the body are in the form of charged particles. One equivalent (eq) is 1 mol of an ionized substance divided by its valence. One mole of NACL dissociates into 1 eq of Na and 1 eq of Cl. One equivalent of Na =23grams but 1equivaent of Ca is 40g/2=20grams. Electrical equivalence is not the same as chemical equivalence

24
Q

Phase 3 drug trials involve the following guidelines

A Monitoring the marketed drug safety in actual large numbers
B The drug effect on healthy volunters with small trial numbers
C A retrospective case specific analysis
D Specific patient selection within populations expressing the disease intended for treatment with large trial numbers

A

D

Explanation
Phase 1= the effects of a drug as a function of dose in a small group of healthy volunteers (25-50). If however, the drug is suspected to have significant side effects/toxicity, volunteers with the disease are used instead.

Phase2= the drug is studied for the first time in patients with the target disease to determine its efficacy. A small number of patients are studies in great detail (100-200). This stage is usually done in a university/hospital setting.

Phase 3= the drug is evaluated in much larger number of patients >1000 to further establish safety and efficacy. Information gathered in 1,2,3 trials are used to minimize errors caused by placebo effect, variable course of disease etc.

Phase 4= the drug has been approved for marketing. The drug is monitored under actual conditions of use in a large number of patients

25
Q

Regarding potency, which statement is correct?

A Potency of a drug depends only on the affinity (Kd) of receptors for binding the drug
B The smaller the EC50, the greater the potency of the drug
C Potency refers to the concentration of a drug to produce 100% of its maximal effect
D The clinical effect of a drug depends on its potency

A

B

Explanation
Potency of a drug depends in part on the affinity (Kd) of receptors for binding the drug and in part on the efficiency with which drug-receptor interaction is coupled to response. A drug is more potent if its EC50 is less than that of another drug’s EC50. Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s MAXIMAL effect. The clinical effect of a drug depends not on its potency (EC50) but on its maximal efficacy and its ability to reach the relevant receptors

26
Q

Which of the following opioid analgesia is not metabolised by isoenzyme CYP2D6?

A Hydrocodone
B Fentanyl
C Codiene
D Oxycodone

A

B

Explanation
Codeine, oxycodone and hydrocodone undergo metabolism in the liver by P450 isoenzyme CYP2D6, resulting in the production of metabolites of greater potency. Fentanyl is metabolised by CYP3A4 isoenzyme

27
Q

Verapamil acts on this type of plasma membrane channel

A Ligand regulated-transmembrane receptor
B Ligand gated ion channel
C Voltage gated ion channel
D Secondary messenger

A

C

Explanation
Voltage gated ion channels

This question can present as an EMQ

Voltage gated ion channels do not bind neurotransmitters directly but are controlled by membrane potential; such ion channels are also important drug targets. Verapamil inhibits voltage gated calcium channels that are present in the heart and in the vascular smooth muscle, producing antiarrhythmic effects and reducing blood pressure without mimicking or antagonising any known endogenous transmitter

28
Q

Which of the following stages of a drug trial examines the effects and side effects of a drug in a population with the disease?

A Phase 3
B Phase 1
C Phase 4
D Phase 2

A

D

effects, drug interactions

Pharmacoeconomics to gather data in support of the use

Comparative effectiveness and community based research (sometimes described as Phase V trials)

Trial combinations with existing products

Source: www.tga.gov.au

Phases of clinical trials

Clinical trials of biomedical interventions typically proceed through four phases.

Phase I Clinical Trial
Phase I clinical trials are done to test a new biomedical intervention for the first time in a small group of people (e.g. 20-80) to evaluate safety (e.g. to determine a safe dosage range and identify side effects).

Phase II Clinical Trial
Phase II clinical trials are done to study an intervention in a larger group of people (several hundred) to determine efficacy (that is, whether it works as intended) and to further evaluate its safety.

Phase III Clinical Trial
Phase III studies are done to study the efficacy of an intervention in large groups of trial participants (from several hundred to several thousand) by comparing the intervention to other standard or experimental interventions (or to non-interventional standard care). Phase III studies are also used to monitor adverse effects and to collect information that will allow the intervention to be used safely.

Phase IV Clinical Trial
Phase IV studies are done after an intervention has been marketed. These studies are designed to monitor the effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use over longer periods of time. They may also be used to investigate the potential use of the intervention in a different condition, or in combination with other therapies.

Source: https://www.australianclinicaltrials.gov.au/

Extra:

Wikipedia

Phase 1

Dose-ranging on healthy volunteers for safety

Phase 2

Testing of drug on participants to assess efficacy and side effects.

Phase 3

Testing of drug on participants to assess efficacy, effectiveness and safety.

Phase 4

Post marketing surveillance in public

29
Q

What is meant by the term therapeutic index?

A The ratio of the median effective dose to the median toxic dose
B The minimum dose at which a drug has a clinically relevant effect
C The ratio of the median toxic dose to the median effective dose
D The difference between the minimum toxic dose and minimum therapeutic dose

A

C

Explanation
Therapeutic index is the ratio of TD50 / ED50 for some therapeutically relevant effect.

TD50 = median toxic dose (dose at which 50% experience toxic effects)

ED50 = median effective dose (dose at which 50% exhibit specified quantal effect)

Therapeutic window is the range between the minimum toxic dose and minimum therapeutic dose, and is of greater practical value in choosing a dose for a patient.

30
Q

What occurs to the dose-response curve when a fixed concentration of a competitive antagonist is added?

A Increased EC50
B Decreased Emax
C Decreased EC50
D Increased Emax

A

A

Explanation
EC50 is the concentration of a drug required to produce 50% of the drugs maximal effect. Emax is the maximum possible effect of a drug, regardless of dose required to produce that effect. Competitive antagonists increase the amount of concentration required to produce a given effect, therefore addition of a competitive antagonist causes an increased EC50 on the dose-response curve. There is no change to Emax with addition of competitive antagonists.

31
Q

Potency is:

A The concentration or dose of a drug required to produce 50% of the drugs maximal effect
B The concentration or dose of a drug required to produce a toxic effect in 50% of exposed subjects
C Proportional to therapeutic index
D The maximal effect of a drug regardless of dose

A

A

Explanation
Efficacy is the maximal effect of a drug regardless of dose - potency is the concentration or dose of a drug required to produce 50% of the drugs maximal effect

The concentration or dose of a drug required to produce 50% of the drugs maximal effect is known as EC50 or ED50. The concentration or dose of a drug required to produce a toxic effect in 50% of exposed subjects is TD50. TD50 is proportional to therapeutic index.

Extra:

What is drug potency and efficacy? Potency is the amount of drug necessary to produce a biological response of a certain magnitude. Efficacy is the ability of the drug to produce a response by the activation of the receptor

32
Q

Which of the following drugs is a CYP-enzyme inhibitor?

A Amoxicillin
B Carbamazepine
C Clarithromycin
D Rifampicin

A

C

Explanation
Macrolide antibiotics are CYP-enzyme inhibitors. Carbamazepine and rifampicin are CYPenzyme inducers.

Extra:

Enzyme Inhibitors: SICKFACES.COM + Grapefruit

Sodium valproate; Isoniazid (noting current text states inducer); Cimetidine; Ketoconazole; Fluconazole; Alcohol (binge); Chloramphenicol; Erythromycin; Sulphonamides; Ciproflox; Omeprazole; Metronidazole.

Enzyme inducers: CRAP GPs

Carbamazepine; Rifampicin; Alcohol (chronic); Phenytoin; Griseofulvin; Phenobarbitone; Sulphonylureas