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SPMM PART A > 1.3.2 Pharmacokinetics > Flashcards

1.3.2 Pharmacokinetics Flashcards

1
Q

Which of the following factors can improve absorption of orally administered drugs?

  • Fast intestinal motility
  • High hydrophilic capacity of drug
  • None of the above
  • Presence of food in the GI tract
  • Presence of P glycoprotein
A

None of the above

The factors listed reduce rate of absorption:

  • food
  • gastric acid
  • intestinal motility e.g. having diarrhoea or vomiting can affect drug absorption.
  • highly hydrophilic drugs cannot cross the lipid cell membrane, while highly lipophilic drugs will struggle to cross the water layer in extracellular space
  • P-gylycoprotein is a reverse pump. (This can be inhibited by grape fruit.
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2
Q

A newly developed antipsychotic is said to be highly permeable across lipid membranes and so achieve very high bioavailability when given orally. Which of the following properties of the drug enable this?

  • All of the above
  • Balanced hydrophilic and lipophilic properties
  • Exists in highly ionised form predominantly
  • Low concentration gradient across membranes
  • Low protein binding
A

Balanced hydrophilic and lipophilic properties.

If highly hydrophilic, the drug cannot cross the lipid cell membrane. On the other hand if highly lipophilic, the drug is not soluble enough to cross the water layer adjacent to the cell. Balanced hydrophilic & lipophilic property is essential for high permeability.

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3
Q

Urinary acidification can help eliminate which of the following medications on overdose?

  • Amphetamines
  • Barbiturates
  • Paracetamol
  • Salicylates
  • Tricyclics
A

Amphetamines.

Acidification may help in elimination of amphetamines and phencyclidine, but often complications of such a procedure overrides any benefits.

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4
Q

A drug X is used to treat acute behavioural disturbances. It can be given orally or intravenously. 15mg of oral drug is needed for an acutely disturbed man of weight 70kgs while 10mg is sufficient if given intravenously. What is the bioavailability of IV administration of 10mg?

A

100%

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5
Q

A drug X is used to treat acute behavioural disturbances. It can be given orally or intravenously. 15mg of oral drug is needed for an acutely disturbed man of weight 70kgs while 10mg is sufficient if given intravenously. What is the bioavailability of IV administration of 10mg?

1.5mg
10.5mg
10mg
15mg
5mg

A

10mg

When a drug is administered intravenously the availability of the drug is 100%.

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6
Q

Which of the following should be considered when switching from one brand of medication to another brand?

  • Bioavailability
  • Bioequivalence
  • Clearance
  • Rate of absorption
  • Volume of distribution
A

Bioequivalence

It is a measure of comparability of plasma levels of two different formulations of the same active compound when given at same dose and same route of administration

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7
Q

What is the volume of distribution of drug A if the plasma concentration immediately after IV administration of 10mg is 0.01mg/mL?

0.1mL
1 mL
1000mL
100mL
10mL
A

1000mL

Vd =Q/Cp

Vd = volume of distribution, Q = quantity of drug
Cp = plasma concentration at time of administration ('zero time').
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8
Q

A drug X when given at a dose of 300Units is cleared from the body at a rate of 30Units per hour. When the dose is increased to 600Units it is still cleared at a rate of 30Units per hour. Which of the following is true? The drug follows

  • first order at lower doses and zero order at higher doses
  • first order kinetics
  • no specific kinetics
  • zero order at lower doses and first order at higher doses
  • zero order kinetics
A

Zero order kinetics

When the system facilitating first order clearance of drugs gets saturated, drugs follow zero order kinetics. Here a constant amount, not fraction, of drug is cleared per unit time. This means that irrespective of the amount of drug in plasma or dose of drug administered, only a fixed unit of drug is cleared by the body. As such, increasing dose might result in serious toxicity in this case.

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9
Q

Most orally administered psychotropic drugs undergo hepatic metabolism followed by renal clearance. Which of the following statement about clearance is true?

  • Clearance can occur only via urine
  • It always depends on the dose consumed
  • It helps calculating half life of a drug in the body
  • It is fixed for each individual with minor variations among drugs
  • It is the amount of drug eliminated from the body in a given time
A

It helps calculating half life of a drug in the body.

Clearance is defined as the volume of blood cleared of a particular drug in unit time.

It is specific for each drug and does not depend on drug concentration in plasma (because if concentration increases, elimination will also increase under first order kinetics).

It represents the relationship between the rate of drug elimination (t1/2) and plasma level.

For drugs with first order kinetics, clearance is constant irrespective of dose consumed because rate of elimination is directly proportional to plasma level.

Total body clearance depends on renal and non renal clearance such as sweat, bile etc.

Renal elimination without significant liver breakdown is seen in lithium, amisulpride, sulpride, gabapentin, acamprosate and amantadine.

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10
Q

A new molecule investigated for anxiety disorder failed at initial stages of animal testing as it failed to reach the brain crossing the blood brain barrier. Which of the following factors decide the degree of blood brain barrier permeability?

  • Frequency of administration of drug
  • Half life of drug
  • Lipid water partition coefficient
  • Nitrogen content of the drug
  • Time of drug administration
A

Lipid water partition coefficient.

The ability of a drug to pass blood brain barrier depends on:

  • its molecular size,
  • lipid solubility and
  • ionic status.

Unionized molecules that are freely available and less protein bound are transported across the barrier easily.

In general higher the lipid water partition coefficient, greater the ability to cross the barrier

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11
Q

A psychotropic drug is observed to undergo phase 2 metabolism directly without undergoing phase 1 reactions. Which one of the following fits with the above description best?

  • Chlordiazepoxide
  • Diazepam
  • Fluoxetine
  • Lithium
  • Lorazepam
A

Lorazepam.

Lorazepam, Temazepam and Oxazepam undergo direct phase 2 reactions.

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12
Q

Drug B is a prodrug whose metabolite is an active hypnotic agent. If drug A induces the metabolism of drug B, which of the following is true?

  • Effect of drug A will increase
  • Effects of drug B are more pronounced
  • Hypnotic effect is lost
  • Level of drug B’s metabolite falls in blood
  • No change occurs in drug effect
A

Effects of drug B are more pronounced.

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13
Q

Which of the following is an enzyme inducer?

  • Caffeine
  • Grapefruit juice
  • Paroxetine
  • Smoking
  • Valproate
A

Smoking induces CYP1A2 via PAH.

Caffeine is an inhibitor.

Paroxetine, to some extent Fluoxetine, Neuroleptics, Amitriptyline and Clomipramine inhibit

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14
Q

Some drugs such as fluoxetine move from first order to zero order kinetics in supratherapeutic doses. What happens to their t1/2 in such cases?

  • t½ becomes independent of dose
  • t½ doubles
  • t½ halves
  • t½ quadruples
  • t½ becomes dependent on dose
A

t½ becomes dependent on dose.

In very high supra therapeutic doses, saturation of enzymes can happen for drugs such as Fluoxetine, wherein first order elimination switches to become zero order..

When the system facilitating first order clearance of drugs gets saturated, drugs follow zero order kinetics.

Here a constant amount, not fraction, of drug is cleared per unit time.

This means that irrespective of the amount of drug in plasma or dose of drug administered, only a fixed unit of drug is cleared by the body.

Here the concept of half life does not hold true a ˜half life’ depends on dose administered.

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15
Q

A drug follows first order kinetics and has a t1/2 of 4 hours. In a healthy male how long will it take for this drug to reach steady state assuming no loading dose is given and the drug is administered at equal intervals regularly?

  • 1 hour
  • 10 hours
  • 2 hours
  • 20 hours
  • 4 hours
A

20 hours.

It is estimated that it takes 4-5 x t ½ for a drug to reach the steady plasma level.

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16
Q

The ratio between minimum plasma level causing toxic effect to minimum plasma level causing therapeutic effect is called as:

  • Affinity
  • Potency
  • Therapeutic index
  • Toxic dose
  • Volume of distribution
A

Therapeutic index:

It is the ratio of minimum plasma concentration causing toxic effects to that causing a therapeutic effect. This can vary according to the toxic symptom specified for a given drug

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17
Q

Under which of the following conditions interactions with drugs that alter protein binding becomes important?

  • Children
  • High altitude living
  • Lung disease
  • Obesity
  • Renal disease
A

Renal Dx.

Protein binding interactions become relevant in renal disease where proteinuria can occur.

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18
Q

Which of the following is not altered much considering pharmacokinetics in the elderly?

  • Gastric pH
  • GI absorption
  • Plasma protein binding
  • Renal clearance
  • Total body fat
A

GI absorption.

GI absorption & hepatic metabolism are not altered.

Following changes are noted

  • Increase in total body fat,
  • gastric pH is increased as acidity drops
  • reduced renal clearance,
  • Decrease in plasma protein binding &
  • decreased number of brain acetylcholine postsynaptic receptors.
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19
Q

Which of the following acts on presynaptic receptors as main mechanism of action?

  • Clonidine
  • Diazepam
  • Donepezil
  • Phenelzine
  • Propronalol
A

Clonidine, Lofexidine act at alpha2 presynaptic receptor.

20
Q

Which of the following medications must be used with caution when Fluvoxamine is prescribed?

  • Amlodipine
  • Naproxen
  • Paracetamol
  • Salbutamol
  • Theophylline
A

Theophylline.

Fluvoxamine decreases the clearance of cytochrome CYP1A2 substrates such as theophylline, leading to toxic levels when co-administered.

21
Q

Which of the following drugs has a metabolite that has the longest half-life?

  • Citalopram
  • Duloxetine
  • Fluoxetine
  • Paroxetine
  • Venlafaxine
A

Fluoxetine.

There are substantial differences in term of their half-life between Fluoxetine and others SSRIs.

The half-life of Fluoxetine and its active metabolite Norfluoxetine is respectively 2 to 4 days and 7 to 15 days, more extended than other SSRIs (approximately 1 day).

22
Q

Which of the following hypnotic drugs acts for the longest duration?

  • Nitrazepam
  • Temazepam
  • Triazolam
  • Zaleplon
  • Zolpidem
A

Nitrazepam is a long acting benzodiazepine with an elimination half life of 15-38 (mean elimination half life 26 hours)

23
Q

A patient suddenly withdraws from a medication. How many half-lives does it take for the medication to be completely excreted?

10
2
3
5
8
A

5

From a clinical standpoint, it is common to assume that a drug is effectively eliminated after 4-5 half-lives, assuming first order kinetics.

24
Q

Which of the following psychotropic will be affected most by contact with moist air?

  • Carbamazepine
  • Gabapentin
  • Olanzapine
  • Sodium valproate
  • Topiramate
A

Sodium valproate

Deliquescent salts such as valproate absorb moisture from the air

25
Q

The drug of choice for alcohol detoxification in a patient with liver disease is

  • Carbamazepine
  • Chlordiazepoxide
  • Chlormethiazole
  • Diazepam
  • Oxazepam
A

Oxazepam

Oxazepam is less likely to accumulate and cause adverse reactions in the elderly or people with liver disease.

Oxazepam may be safer than many other benzodiazepines in patients with impaired liver function because it does not require hepatic oxidation, but rather it is simply metabolized via glucuronidation.

26
Q

Which of the following drugs has its plasma levels reduced even after regular administration of the same dose for a month?

  • Carbamazepine
  • Chlormethiazole
  • Clozapine
  • Lithium
  • Valproate
A

Carbamazepine

Because it exhibits autoinduction: it induces the expression of the hepatic microsomal enzyme system CYP3A4, which metabolizes carbamazepine itself.

27
Q

Which of the following medications has the least protein-binding?

  • Clomipramine
  • Fluoxetine
  • Paroxetine
  • Valproate
  • Venlafaxine
A

Venlafaxine has a much lower protein binding (25%-30%) than do the SSRIs (80%-100%).

Thus, the free fraction of venlafaxine is much higher than the other drugs at the same total plasma drug level.

28
Q

Bioavailability is least likely to be influenced by

  • Absorption
  • Distribution
  • Excretion
  • Gender
  • Metabolism
A

Gender

Bioavailability is the fraction of an ingested dose of a drug that gains access to the systemic circulation.

It may be low because the drug is metabolised in the gut wall or liver before reaching the systemic circulation.

29
Q

Which of the following types of drug molecules is most efficiently absorbed?

  • Large, lipid soluble electrically neutral molecules
  • Large, water soluble electrically neutral molecules
  • Small, lipid soluble electrically neutral molecules
  • Small, water soluble electrically charged molecules
  • Small, water soluble electrically neutral molecules
A

Small, lipid soluble electrically neutral molecules.

To achieve a therapeutic effect most drugs need to cross at least one lipid membrane.

This will depend on size and shape of the molecule, lipid solubility and ionic charge.

Hence it is more efficient for small, water-soluble electrically neutral molecules, which can cross membranes easily.

The blood brain barrier only allows lipid soluble molecules in the brain

30
Q

There is poor oral absorption of most psychotropics in which of the following parts of the gastrointestinal system?

  • Colon
  • Ileum
  • Jejunum
  • Rectum
  • Stomach
A

Stomach.

Absorption by oral administration occurs primarily in the small bowel, though absorption of many slow or sustained release drugs occurs in the large bowel.

There is poor absorption in the acidic stomach but conversely good absorption in alkaline jejunum, ileum, colon and rectum.

31
Q

The metabolism of which one among the following follow first order kinetics?

  • Absorption of controlled release drugs
  • Alcohol
  • Depot antipsychotic
  • Oral Antipsychotic
  • Phenytoin
A

Oral Antipsychotic.

Most drugs show first order kinetics where the rate of absorption or elimination is directly proportional to the amount of drug remaining.

The concentration of a drug in the plasma will normally follow first order kinetics, decreasing in an exponential manner related to plasma concentration.

However, drugs like ethanol and Phenytoin are metabolised by zero order kinetics, their concentration decreasing in a linear fashion i.e at a constant rate irrespective of plasma concentration.

With zero-order kinetics, a fixed amount of drug is absorbed each time independent of drug concentrations and hence a small increase in drug ingestion results in a large increase in plasma concentration.

Absorption of controlled release drugs and depot antipsychotics also follow zero-order kinetics.

32
Q

The area under the curve after a single dose allows determination of the

  • Bioavailability of the drug
  • Distribution
  • Elimination
  • Metabolism
  • Plasma half life (t-1/2)
A

Bioavailability of the drug.

The AUC is proportional to the amount of drug in plasma and allows determination of fraction of dose absorbed (i.e. Bioavailability of the drug).

Low Bioavailability usually means high first pass metabolism.

T-1/2 is the time taken for the plasma concentration to fall by a half. It only applies for drugs with first order kinetics.

33
Q

Which one among the following statements is incorrect about oral route of administration?

  • Acid-resistant drugs are better absorbed
  • Lipid solubility aids absorption
  • Oral route drugs are subject to renal first pass metabolism
  • Oral route leads to variable plasma concentration because the absorption may be erratic
  • Preparations that are soluble in gastrointestinal fluids are absorbed better
A

Oral route drugs are subject to renal first pass metabolism.

Drugs taken orally are subject to metabolism by the liver (First-Pass effect).

A drug taken orally is absorbed from the gut into the enterohepatic circulation, where the liver inactivates some of the drug before even it reaches the systemic circulation, which is known as the first pass effect. It can be avoided if the drug is injected intravenously whereby the drug directly enters the systemic circulation.

34
Q

Which one among the following statements is least likely to be correct with respect to the tissue distribution of drugs?

  • Distribution is uniform across the body tissues
  • Drugs with high affinity for tissues such as fat have high volume of distribution
  • The drug distribution in plasma to various tissues depends on plasma protein binding
  • The drug distribution in plasma to various tissues depends on tissue permeability
  • Tissue distribution leads to a fall in plasma concentration
A

Distribution is uniform across the body tissues.

Drugs are not evenly distributed in the body.

There are three main compartments through which a drug may be distributed.

(1) The Vascular compartment
(2) The extra cellular compartment
(3) The intracellular compartment.

Drugs which are large molecules and those which bind tightly to plasma proteins remain in the vascular compartment;

drugs with low lipid solubility are distributed in the vascular plus the extra cellular compartment whilst lipid soluble drugs are distributed through the three compartments.

Drugs such as Phenytoin, diazepam, chlorpromazine and amitryptyline are all highly bound to plasma proteins. They are very lipophilic and once absorbed pass readily in to peripheral fat stores; from which they are gradually released long after the last dose has been administered.

35
Q

Hepatic metabolism may involve various chemical reactions. Which one of the following is not a common chemical activity seen in hepatic metabolism?

  • dealkylation
  • hydroxylation
  • oxidation
  • polymerisation
  • reduction
A

Polymerisation.

Hepatic metabolism may involve non-synthetic reactions that involve :

  • oxidation,
  • reduction,
  • hydroxylation,
  • dealkylation,
  • demethylation,
  • acetylation;

Methylation may produce active compounds (Phase 1).

The metabolism also involves synthetic reactions such as conjugation usually with glucoronic acid and sulphation which produce inactive water soluble compounds.(Phase 2)

36
Q

Which of the following enzymes are responsible for oxidative metabolism of most psychotropic drugs?

  • Aryl Sulfatase
  • Cytochrome P450 family
  • G Protein
  • Glycoprotein P
  • Monoamine Oxidase
A

The cytochrome P450 (CYP450) enzyme superfamily is the primary phase I enzyme system involved in the oxidative metabolism of drugs and other chemicals.

These enzymes also are responsible for all or part of the metabolism and synthesis of a number of endogenous com- pounds, such as steroid hormones and prostaglandins.

37
Q

Steady-state plasma concentration is usually achieved after

1-2 half-lives
10-20 half lives
2-3 half lives
4-5 half-lives
9-10 half-lives
A

4-5 half-lives

Steady state concentration is achieved after repeated doses, which lead to an equilibrium between absorption and elimination. It is usually achieved after 4-5 half-lives. The doses given at greater intervals than the half-life leads to lesser fluctuations in plasma concentration.

Attempts to reduce plasma fluctuations include using slow release (called MR for modified release or XL for extended release) preparations e.g lithium, venlafaxine or to allow long intervals between administration. e.g depot antipsychotics.

38
Q

Which of the following drugs has a higher therapeutic index than the others listed?

  • Lithium
  • Paracetamol
  • Phenytoin
  • Tricyclics
  • Type 1 antiarrythmics
A

Paracetamol.

Drugs available over the counter usually have a better therapeutic index (else they wont be sold without prescription). This does not mean that they are absolutely safe.

39
Q

The enhancement of drug effects following the repeated administration of the same dose of a drug is called as

  • Cross Tolerance
  • Habituation
  • Neuroadaptation
  • Sensitisation
  • Tolerance
A

Sensitisation.

Tolerance = the diminished response to the administration of a drug after repeated exposure.

It may be:

  • behavioural tolerance through learning to cope with the effects,
  • increased metabolism,
  • reduced receptor sensitivity or number,
  • activation of a homeostatic mechanism.

Cross-tolerance = shared tolerance among drugs with similar chemical structure.

Cross-tolerance forms the basis for a number of drug interactions (E.g. alcohol with barbiturates).

Sensitisation = the enhancement of drug effects following the repeated administration of the same dose of drug.

40
Q

Which of the following is least likely to be a pharmacokinetic property of the tricyclic antidepressants?

  • Extensive hepatic breakdown
  • Extensive protein binding in the plasma
  • Lipid solubility
  • Metabolism being reduced by smoking
  • Their activity may delay their own absorption
A
  • Metabolism being reduced by smoking

Tricyclics are rapidly and almost completely absorbed from the gut and are widely distributed in the tissues of the body.

They readily cross lipid barriers such as blood brain barrier and placenta.

They are extensively bound to plasma proteins. E.g. Imipramine 80-95%.

Smoking and barbiturates facilitate metabolism and neuroleptics inhibit metabolism.

Due to anticholinergic effects, they may reduce their own absorption (delayed gastric emptying esp. amitryptiline)

41
Q

Which of the following undergoes metabolism predominantly by first order kinetics?

  • Alcohol
  • Depot antipsychotics
  • Phenytoin
  • Thioridazine
  • Venlafaxine XL
A

Thioridazine.

Elimination of a constant quantity per time unit of the drug quantity present in the organism is called zero order kinetics.

95% of the drugs in use at therapeutic concentrations are eliminated by first order elimination kinetics.

A few substances are eliminated by zero-order elimination kinetics, because their elimination process is saturated, especially at higher doses.

Examples are Ethanol, Phenytoin, high dose Salicylates, high dose Fluoxetine, high dose Omeprazole.

Because in a saturated process the elimination rate is no longer proportional to the drug concentration but decreasing at higher concentrations.

Zero-order kinetics are also called “non-linear kinetics” in clinical pharmacology.

The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit ‘flip-flop’ kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate.

42
Q

A 69-year-old man on warfarin has come back from a holiday in France when he developed some psychiatric symptoms. He was also taking one of the following drugs. Which one of the above drugs would lead you to send him for an urgent INR?

  • Clozapine
  • Lithium
  • Olanzapine
  • St. John’s wort
  • Venlafaxine
A

St. John’s wort = inducer.

St John’s Wort leads to a reduction in the anticoagulant effect of warfarin.

Case reports of reduced anticoagulant effect and need for increased warfarin dose have been reported.

Check INR and stop St.John’s wort. Monitor INR closely as this may rise on stopping St Johns wort. The dose of warfarin may need adjusting in such situations.

43
Q

Julie is a 29-year-old woman who has recently started taking combined oral contraceptive pills. Which of the following medication could decrease the effectiveness of the contraception?

  • Amitriptyline
  • Clozapine
  • Fluoxetine
  • Lithium
  • St. John’s wort
A

St. John’s wort = inducer of cytochrome P450 isoenzyme and may reduce the efficacy of oral contraceptives.

It is associated with increased metabolism of norethindrone and ethinyl estradiol, resulting in breakthrough bleeding, follicle growth and ovulation. Therefore women using oral contraceptives should be cautioned that St.

John’s wort might interfere with contraceptive effectiveness and should consider using a barrier method of contraception if taking it concomitantly.

44
Q

A constant amount, not a fraction, of the drug compound is cleared per unit time. This is called;

  • Bioequivalence
  • First order kinetics
  • Phase 1 metabolism
  • Phase 2 metabolism
  • Zero order kinetics
A

Zero order kinetics.

When a constant fraction of drug is cleared per unit time, it is called as first order kinetics.

Thus if the ingested drug increases in quantity, more of it will be eliminated.

Most psychotropic drugs follow first order kinetics.

In zero order kinetics, a constant amount, not fraction, of drug is cleared per unit time. This means that irrespective of the amount of drug in plasma or dose of drug administered, the body clears only a fixed unit of the drug. Increasing dose might result in serious toxicity in this case.

45
Q

Which of the following antipsychotics is primarily renally excreted?

  • Amisulpride
  • Clozapine
  • Haloperidol
  • Olanzapine
  • Risperidone
A

Amisulpride is primarily renally excreted.

Nevertheless, there is limited experience of using any antipsychotics in renal disease and therefore best to avoid them if possible in well established renal failure.

46
Q

Which of the following statements about lithium is correct?

  • 70% of middle aged women develop hypothyroidism after 6-12 months of treatment
  • A third of patients treated with lithium experience at least one side effect
  • ACE inhibitors cause a reduction in lithium levels
  • Lithium levels fall within 10 days of starting a thiazide diuretic
  • NSAIDs can increase the plasma levels of lithium to >40%
A

NSAIDs increase the plasma levels of lithium (>10 to >40% in some cases)

By inhibiting the synthesis of renal prostaglandins and reducing renal blood flow.

This increases renal reabsorption of both sodium and lithium.

The levels of lithium usually increase within 10 days of a thiazide diuretic being prescribed.

ACE inhibitors can reduce thirst, which can lead to dehydration, and increase renal sodium loss, leading to increased sodium reabsorption by the kidneys, causing an increase in lithium plasma levels.

About 20% of middle-aged women develop hypothyroidism after 6-12 months of treatment.

Approximately two-thirds of patients treated with lithium experience at least one side effect.

SPMM PART A (10 decks)

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