Pharmacokinetics Flashcards
(116 cards)
1
Q
What is pharmacology?
A
Pharmacology is the study of drug action.
2
Q
What is pharmacodynamics?
A
Pharmacodynamics is the study of what the drug does to the body.
3
Q
What is pharmacokinetics?
A
Pharmacokinetics is the study of what the body does to the drug.
4
Q
What is the half-life of a drug in pharmacokinetics?
t1/2
A
The half-life of the drug is the time it takes to remove half of the current concentration of drug from the body.
5
Q
What is the MEC?
A
The minimum effective concentration - minimum conc. needed for therapeutic effect.
6
Q
What is the MTC?
A
The minimum toxic concentration - anything above this level causes side effects and toxicity.
7
Q
Drugs can have a narrow therapeutic window. Therapeutic drug monitoring is needed in this case. Describe what narrow therapeutic window means.
A
A drug with a narrow therapeutic window has a very small range between the concentration at which the drug exerts a therapeutic effect and the concentration at which toxicity may occur.
8
Q
What is meant by the term plasma concentration?
A
The concentration of the drug in the blood.
9
Q
Two or more drugs can interact and cause potentiation. What does that mean?
A
Potentiation means that the interaction can cause one drug to increase the effect or concentration of the other drug giving rise to toxicity and side effects.
10
Q
Two or more drugs can interact and cause antagonism. What does that mean?
A
Antagonism means that the interaction can cause one drug to lower the effect or concentration of the other causing a sub-therapeutic effect (below MEC).
11
Q
In general, how does a pharmacokinetic drug interaction occur?
A
These occur when one drug alters the absorption, distribution, excretion or metabolism of another drug which may result in an increase or decrease in the amount of the drug.
12
Q
Describe first-order elimination.
A
This is when a constant fraction of the drug is eliminated per unit time.
(Linear kinetics)
CONSTANT FRACTION, PERCENTAGE, PROPORTION ELIMINATED PER UNIT TIME = ALWAYS FIRST ORDER.
13
Q
Describe zero-order elimination.
A
This is when a constant amount of the drug is eliminated per unit time.
(Non-linear kinetics)
AMOUNT not proportion.
14
Q
What does enteral route of administration mean and give examples?
A
Enteral routes of administration include those where the drug is absorbed from the GI tract.
Oral, rectal, buccal and sublingual.
15
Q
What does parenteral route of administration mean and give examples?
A
Parenteral routes of administration is interpreted as injecting directly into the body.
Sub-cutaneous, intra-muscular and intravenous.
16
Q
Why may bioavailability of drug be less than 100% when administering via parenteral route?
A
Because enzymes on the way to the bloodstream can breakdown the drug.
17
Q
List the advantages of oral administration.
A
Most convenient route of access for systemic circulation.
Cheap and safe.
Preferred route by most patients.
Large surface area in the GI tract for absorption.
18
Q
List the disadvantages of oral administration.
A
Can have a delayed/variable absorption (variable - each person has different absorption levels) First-pass effect may be significant. Can cause GI upset causing nausea etc. Not suitable for all patients. Unsuitable for acid-labile drugs.
19
Q
Where are drugs mainly metabolised?
A
Liver
20
Q
Why is an initial higher dose given at the start of a treatment course?
A
Given to achieve adequate therapeutic levels rapidly before reducing the dose to a maintenance dose.
21
Q
Describe sublingual administration.
A
The drug is administered under the tongue and diffuses across the mucous membranes, into the systemic circulation.
22
Q
List the advantages of sublingual administration.
A
Has a rapid onset of action.
Bypasses first pass effect as there is a rich blood supply underneath the tongue.
Avoids gastric acid - good for acid-labile drugs.
23
Q
List the disadvantages of sublingual administration.
A
Inconvenient for long-term use.
Limited to certain types of drugs.
24
Q
How is the drug given in buccal administration?
A
The drug is placed between the gum and cheek.
25
Buccal tablets are often harder than sublingual tablets.
These are designed to dissolve slowly.
| Takes longer to disintegrate.
26
List the advantages of buccal administration.
Has a rapid onset of action.
Bypasses first pass effect as drug gets absorbed through oral mucosa and enters directly into the bloodstream.
Avoids gastric acid - good for acid-labile drugs.
27
List the disadvantages of buccal administration.
Inconvenient for long-term use.
| Limited to certain types of drugs.
28
Prochlorperazine is a drug used in buccal administration and sold under the name Buccastem. What is it used for and what is the benefit of it being a buccal drug?
Used to treat nausea and vomiting associated with migraines. Since the tablet isn't swallowed, it avoids the drug being brought up if vomiting occurs.
29
List the advantages of rectal administration.
PARTIALLY avoids first-pass metabolism.
Avoids destruction by gastric acid and digestive enzymes.
Useful for patients unable to take drugs orally - if unconscious or vomiting.
30
List the disadvantages of rectal administration.
May irritate the rectal mucosa.
| Issues with patient acceptability.
31
Rectal drugs can be used for local and systemic effects. Give two examples.
Local effect - for haemorrhoids
| Systemic effect - relieve pain - paracetamol suppository
32
Explain why the rectal route of administration has a reduced first pass effect?
The rectal route partially bypasses first pass metabolism because two-thirds of the veins draining the rectum lead directly into the systemic circulation whereas one-third would lead to the hepatic portal system.
33
Give three examples of rectal formulations.
Suppositories, enema, rectal foam.
34
Why does intravenous administration give 100% bioavailability?
Drug is directly injected into venous blood via the peripheral vein so no absorption stage required for a systemic effect.
Intramuscular and subcutaneous require an absorption stage.
35
List the advantages of IV administration.
NB: IV must be administered by healthcare professionals
No first pass effect so 100% bioavailability.
Avoids digestion by enzymes and gastric acid.
Easy to titrate the dose - can control how many millilitres of drug you are going to give.
36
List the disadvantages of IV administration.
Cost.
Patient acceptability - phobia of needles.
Risk of sepsis and embolism.
37
Subcutaneous
This is a parenteral route of administration.
Its injection under the dermis into the subcutis/fatty tissue.
Commonly for insulin - patients are encouraged to rotate the site they use for injections and using same site can cause irritation.
Patient can be trained by healthcare professional to inject themselves.
38
List the advantages of subcutaneous administration.
No first pass effect.
Avoids digestion by enzymes and gastric acid.
Easy to titrate the dose - can control how many millilitres of drug you are going to give.
39
List the disadvantages of subcutaneous administration.
Pain at site of injection.
| Patient acceptability - phobia of needles.
40
List the advantages of intramuscular administration.
NB: There is no risk of embolism and sepsis as injection is not directly into a vein.
No first pass effect.
Avoids digestion by enzymes and gastric acid.
Easy to titrate the dose - can control how many millilitres of drug you are going to give.
41
List the disadvantages of intramuscular administration.
Pain at site of injection.
| Patient acceptability - phobia of needles.
42
Intramuscular
Injection into the muscle.
Easier to administer than IV.
Typical route for vaccines, adrenaline, morphine and diazepam.
Site of injection will influence absorption.
43
Respiratory
Involves the delivery of drugs locally to the lungs and anesthetic gases (affects CNS).
Can cause local or systemic effects.
44
List the advantages of respiratory route of administration.
No first-pass effect.
Rapid absorption.
Lungs provide a large area for absorption.
45
List the disadvantages of respiratory route of administration.
Some inhalation devices are expensive.
| Inhaler must be used correctly for effect = inhaler technique.
46
3 types of respiratory inhalers: inhaler, nebuliser, anesthetic gases. Describe these.
Inhaler - local effect in the lungs, causes bronchodilation, allows airways to open up allowing patient to breathe more easily.
Nebuliser - local effect in lungs
Anesthesia - given as gas, given via respiratory route but moves to CNS for systemic effect.
47
Skin.
For local and systemic effects.
Local: ointments, creams, gels, pastes.
Does not need to be absorbed into the systemic circulation to have a local effect, some may get absorbed.
Systemic: transdermal patches e.g. contraception, HRT, NRT, analgesia.
Can provide a steady delivery rate.
48
List the advantages of transdermal patches.
NB: Absorption is required.
Patient compliance - if patch is for 7 days etc, patient doesn't need to remember to take medication each day.
Can be removed if side effects occur.
Discreet - hidden under clothing.
49
List the disadvantages of transdermal patches.
Local irritation.
50
What is the definition of absorption?
Absorption is the movement of the drug from the site of application into the bloodstream.
Apart from IV administration, every route of administration requires absorption for a systemic effect.
51
Which two routes will not have an absorption stage?
Topical
| IV
52
Solubility of the drug in aqueous and lipid environments will determine the degree of passive diffusion.
The oral tablet/capsule must be soluble in GI fluid but also soluble at the lipid bilayer of the GIT membrane to undergo passive diffusion. So a degree of lipid solubility is required.
53
Describe how drug solubility affect passive diffusion, facilitated diffusion and active transport?
For passive diffusion the only driving force is the concentration gradient. Therefore, the drug molecules undergoing passive diffusion must have aqueous and lipid solubility.
Facilitated diffusion requires a concentration gradient but drug doesn't have to dissolve in lipid membrane as it is transported by a carrier protein.
Active transport can occur against the concentration gradient and doesn't require drug to have lipid solubility as it is pumped.
54
What is pKa?
The pKa of a drug is the pH at which the drug molecule is 50% in its ionised form.
55
What three physicochemical properties affect absorption?
Size of molecule
Solubility
pKa
56
How does the physicochemical property, solubility affect absorption?
Drug must be soluble in the GI fluid i.e. have aqueous solubility.
Drug must be soluble in the GI membrane i.e. have lipid solubility to allow for passive diffusion to occur.
57
How does the physicochemical property, pKa affect absorption?
Basic drugs are unionised at high pH values above the pKa.
Acidic drugs are unionised at low pH values below the pKa.
The ratio of unionised and ionised forms is determined by the pH.
58
How does the size of molecules/particles affect absorption?
Small particles are absorbed more easily than larger ones as they can penetrate the GI membranes easier.
59
How does first-pass metabolism occur in the gastrointestinal mucosa?
The drug is absorbed from the apical surface of the GI mucosa and will be in contact with GI enzymes within the GI epithelia. These CYP450 enzymes can breakdown drug before reaching systemic circulation. This is first-pass metabolism.
60
P-glycoproteins are found at the apical surface of GI cells. These inhibit the absorption of lipid soluble drugs even if they have adequate lipid solubility. Why?
This process is called P-glycoprotein efflux.
P-glycoproteins bind to certain drugs and expel them back out into the GI contents thus inhibiting absorption. These drugs will eventually be eliminated from the body so no therapeutic effect.
61
What are P-gp substrates?
| P-gp = P-glycoproteins
These are drugs that undergo P-gp efflux.
62
Drugs can induce or inhibit the expression of P-gp. Describe what inducers and inhibitors are and what they do.
P-gp inducers will increase the expression of P-gp efflux pump and so increase the amount of drug expelled back into the gut so decreases the amount of drug being absorbed into the systemic circulation.
P-gp inhibitors will decrease the expression of P-gp efflux pump and so decrease the amount of drug expelled into the GI contents so increases the amount of drug being absorbed into the systemic circulation.
63
Name two drugs which are P-gp substrates.
Digoxin - treats heart conditions e.g. AF.
| Dabigatran - anticoagulant.
64
Name two drugs which are P-gp inducers.
Carbamazepine - treats epilepsy and neuropathic pain.
| St. John's wort - treats depression.
65
Name two drugs which are P-gp inhibitors.
Amiodarone - treat cardiac dysrhythmias.
| Verapamil - Ca channel blocker treats high bp.
66
P-gp is usually a protective mechanism. Suggest how?
Prevents non-self/foreign molecules from entering the bloodstream/systemic circulation.
67
What does the term bioavailability/ fractional availability (F) mean?
NB: it is reported as a proportion i.e. fraction or %
This is the proportion of an administered dose that is absorbed chemically unchanged into the systemic blood circulation.
68
List factors affecting oral bioavailability.
- Drug from gut may go straight into the liver via HPV = first pass effect.
- Drug may not dissolute/disintegrate so cannot be absorbed.
- Stomach can chemically breakdown drug by gastric acids and digestive enzymes.
- If drug is polar it cannot enter bloodstream as it cannot bypass the lipid membrane.
- Drug may bind to another component within the GI tract so absorption is inhibited
- Drug may undergo first pass metabolism due to GI enzymes.
- Drugs may undergo bacterial or enzymatic attack.
69
Vascularity can affect absorption. How?
Vascularity refers to how much blood is flowing to a particular area. The higher the blood flow, the higher the rate of drug absorption.
70
Define distribution.
Distribution is the movement of drug backwards and forwards between blood and the various tissues of the body.
71
What are the 5 factors affecting distribution?
```
Binding to macromolecules - plasma and tissue proteins
Ion trapping
Ability to undergo passive diffusion
P-glycoproteins
Regional blood flow
```
72
Explain how drug-plasma protein complexes and drug-tissue protein complexes prevent the distribution of drugs reaching the target organ.
If drug binds to albumin (plasma protein) in the blood, it cannot bypass the lipid bilayer to reach target organ because albumin is not lipid soluble. Bound drug is unable to undergo passive diffusion - trapped on one side of membrane unable to distribute to the other side. Similar thing can happen with tissue proteins. Overall outcome would depend on the binding affinity of the drug to the plasma/ tissue protein.
73
How does displacement work in terms of drugs binding to plasma proteins?
The strength of the binding depends on the association constant of the drug. Drugs with a higher association constant can displace those having a lower association constant.
74
There are many types of plasma proteins. Globulins and albumin are most significant. Describe albumin. Albumin concentrations fall in patients with liver
cirrhosis, why?
Albumin is the most abundant plasma protein.
Acidic drugs mainly bind to albumin.
The concentrations of albumin fall in liver cirrhosis because liver produces albumin. The clinical significance of this is increased concentrations of free drug - resulting in toxic/adverse effects.
75
There are many types of plasma proteins. Globulins and albumin are most significant. Describe globulins e.g. α1-acid glycoprotein. Levels of this protein can rise in acute infection. What is the impact of this?
Basic drugs mainly bind to α1-acid glycoprotein and other globulins.
The rise in α1-acid glycoprotein can result in a lower concentration of free drug thus a reduced pharmacological effect causes a sub-therapeutic effect in the patient.
76
Describe the blood-brain barrier
The BBB is a highly permeable, selective barrier which separates blood from the extracellular fluid in the CNS.
It is formed by endothelial cells, connected by tight junctions and astrocytes develop capillaries.
It protects the brain from most pathogens and toxins.
The BBB also has P-glycoproteins as a defense mechanism to prevent entry of drugs and toxins into the brain.
77
Antibiotics cannot enter the blood-brain barrier so suggest how you would treat an infection in the brain.
Drugs can be injected into the cerebrospinal fluid and can enter the brain by crossing the blood-cerebrospinal fluid barrier.
78
What is volume of distribution?
The volume of distribution is the tendency of a drug to distribute out of the blood and into the tissues.
Small volume of distribution = drug stays in blood rather than moving into tissues.
Large volume of distribution = drug moves into tissues from blood.
79
Adalimumab is a monoclonal antibody with a small volume of distribution. Explain why?
This drug is a protein with a very high molecular weight and thus is restricted to the plasma compartment in the body so doesn't distribute out into other organs. Tends to stay in blood due to high molecular weight.
80
Warfarin is an anti-coagulant and blood thinning drug with a small volume of distribution. Explain why?
Warfarin tends to strongly bind to plasma proteins which cannot bypass lipid bilayers thus remains within blood without distributing to target organs.
81
Gentamicin is an antibiotic drug with a small volume of distribution. Explain why?
Gentamicin is a highly polar molecule and so cannot bypass the lipid bilayer to distribute into tissues and organs thus remains in the blood.
82
Digoxin is a drug used to treat heart conditions with a large volume of distribution. Explain why?
Digoxin has a high affinity for the tissue proteins within the heart therefore binds strongly to the proteins. This allows easy movement from the blood into the cardiac tissue for treatment.
83
Doxepin is a drug used to treat insomnia with a large volume of distribution. Explain why?
Doxepin is a lipid soluble molecule so can bypass the lipid bilayer and distribute into tissues easily.
84
Chloroquine is a drug used to treat malaria with a large volume of distribution. Explain why?
Chloroquine binds strongly to DNA so will move from blood into tissues easily.
85
Most drug metabolism occurs in the liver. What is metabolism?
Metabolism is the enzymatic conversion of one chemical compound to another.
-metabolic processes will convert the drug into a more water-soluble compound by increasing its polarity allowing it to be excreted.
86
Benzylpenicillin and insulin are not given via oral route due to first pass metabolism in the stomach. Explain how this happens?
Both drugs are hydrolysed by the acidic conditions in the stomach and the presence of enzymes such as proteases.
87
What are hepatocytes?
The functional cells that form the liver.
88
What enzymes and reactions does phase 1 metabolism involve?
NB: resulting metabolites are often pharmacologically active.
Involves a group of enzymes called cytochrome P450 (CYP450).
Reactions: Oxidation, reduction, demethylation, hydrolysis, hydroxylation, dealkylation.
Metabolites formed are polar for easy renal excretion.
89
What reaction is demethylation and hydroxylation?
Demethylation: CH3 group metabolised by CYP enzyme.
Hydroxylation: addition of hydroxyl/OH group into molecule by CYP enzyme.
90
Describe phase 2 metabolism.
NB: resulting metabolites are often inactive.
Phase 2 metabolism involves conjugation reactions resulting in conjugates formed.
- The drug molecule or phase 1 metabolite is joined together with another molecule.
91
What is the phase 2 metabolite like?
Phase 2 metabolite is increased in size, polarity and aqueous solubility to promote renal excretion.
92
What is a prodrug?
A prodrug is a compound that must undergo chemical conversion via metabolic processes to become a pharmacologically active drug.
One of its metabolites has the therapeutic responses needed.
93
Pharmacist can advise you to avoid the concurrent used of grapefruit juice with simvastatin. Why might this be?
Some components of grapefruit juice inhibit the activity of CYP3A4 in the gut wall. This reduces the metabolism of simvastatin.
Clinical implication: toxicity --> rhabdomyolysis = muscle damage and muscle death.
94
A patient was given metronidazole to treat an dental infection and was told to avoid alcohol during the course of treatment and 48 hours after. Why?
Metronidazole and alcohol causes an interaction. Metronidazole inhibits the action of enzymes which metabolise alcohol. This results in accumulation of toxic metabolites leading to acidosis. Typical symptoms are nausea, vomiting, neck and face flushing.
95
Drugs and CYP450 enzymes.
Drugs can induce or inhibit the action of CYP450 enzymes and other enzymes resulting in lowered or raised drug plasma concentrations in the blood. Can cause sub-therapeutic or toxic effects.
96
Carbamazepine and ciclosporin must not be given together as risk of organ transplant rejection is high. How does this happen?
Carbamazepine is used to treat epilepsy and nerve pain. Ciclosporin is an immunosuppressant given to organ transplant patients to prevent rejection. Carbamazepine induces the CYP450 enzymes involved in breakdown of ciclosporin causes the drug to be broken down more quickly. This increase in metabolism results in a sub-therapeutic effect. Results in organ transplant rejection.
97
What is excretion in terms of drugs?
Excretion is the physical and irreversible removal of drugs or their metabolites from the body.
98
Drugs are excreted mainly via the renal system. How does the drug or metabolite enter the renal tubules?
By glomerular filtration or active secretion in the tubules i.e. active transport.
Active secretion is a more effective mechanism for renal excretion compared to glomerular filtration as drugs bound to plasma proteins or larger molecules cannot go through this method.
Although the drug or metabolite can be reabsorbed back into the bloodstream from the renal tubules by passive diffusion.
99
What happens to drugs/metabolites remaining in the tubules?
The solutes/drug molecules within the renal tubules remain and flow to collecting ducts, ureter and then bladder to be excreted as urine. Renal excretion is promoted by increased polarity and increased size (larger molecules cannot undergo reabsorption).
100
Active secretion process can strip the drug from plasma protein binding sites.
Because the affinity of many substances for the active transport system is much greater than plasma protein binding affinity.
Drugs and metabolites move from the blood into the peritubular capillaries and into the renal tubules.
101
How does urine pH influence drug excretion?
In alkaline urine, acidic drugs are more easily ionised.
In acidic urine, alkaline drugs are more easily ionised.
Urine pH can be manipulated to control the excretion of certain drugs from the body e.g. aspirin overdose, sodium bicarbonate given to increase urine pH.
102
NSAIDs such as ibuprofen should not be given with lithium as it can result in lithium toxicity. How does this happen?
NSAIDs inhibit the synthesis of renal prostaglandins which are required to control the process of blood flow/renal perfusion. Renal blood flow is reduced which reduces the amount of drug reaching the kidney thus the amount of drug being excreted is reduced. This causes an accumulation of lithium causing toxicity.
103
Rate of elimination = Mass x K.
| What is K?
K = the elimination rate constant = This expresses the rate of drug elimination as the proportion of body load being eliminated per unit time.
104
What is the relationship between half life and elimination rate constant?
t1/2 = 0.693/K
| Patient's liver and kidney function affects half-life.
105
What does the area under a concentration-time curve mean?
Area under the curve gives us a measure of exposure that patient has had to the drug. Units: mghL-1.
Higher the dose, higher the concentration, higher the area under the curve.
106
AUC and bioavailability (F) are related.
F1/F2 = AUC1/AUC2.
Proportional relationship.
Absolute bioavailability = comparing IV to oral dose
Relative bioavailability = comparing similar doses = capsule and tablet.
107
What is the extraction ratio, E?
The extraction ratio of an organ of elimination can be viewed as the measure of the organ's relative efficiency in eliminating the drug from the systemic circulation over a single pass through the organ.
Extraction ratio close to 0 = most of the drug escapes elimination during a single pass through the organ.
Extraction ratio close to 1 = most of the drug gets eliminated through a single pass through the organ.
108
What is the equation used to find extraction ratio, E?
E = Cin - Cout / Cin.
| Answer given as decimal or percentage.
109
What is clearance?
Clearance is the volume of blood that is effectively cleared of drug per unit time.
110
Clearance is related to extraction ratio and hepatic blood flow. Write an equation that ties all of this together.
Cl = QH x E
Increasing clearance decreases AUC.
2 litres of blood flow through the liver per minute in a healthy person.
111
Write an equation tying clearance, volume of distribution and elimination rate constant together.
K = Cl/V
112
Paracetamol overdose can cause liver injury. What is the toxic metabolite formed and explain the mechanisms.
NAPQI is a toxic metabolite formed from phase 1 metabolism of paracetamol which is hepatotoxic and causes hepatic necrosis.
At therapeutic doses, NAPQI is conjugated by glutathione (phase 2) giving a non-toxic metabolite.
However, in overdose, the amount of NAPQI formed is greater than that of intracellular glutathione. NAPQI can then bind to hepatocytes.
113
What is are antidotes for paracetamol overdose?
Activated charcoal administered orally to patients within 1 hour of ingestion.
OR acetylcysteine infused within 24 hours of ingestion - most effective if given within 8 hours.
114
What is the mechanism of activated charcoal to treat paracetamol overdose?
Activated charcoal can bind to any drug remaining within the GIT. Paracetamol will adsorb to the surface of the activated charcoal preventing further absorption.
It is often given in combination with sorbitol which is sweet and is a laxative - aids the excretion of drug via faeces.
115
What is the mechanism of acetylcysteine to treat paracetamol overdose?
Acetylcysteine is a precursor of glutathione so maintains the intracellular glutathione levels which can inactivate NAPQI by conjugation.
It works by protecting the liver if infused - reducing the risk of liver damage.
116
Name drugs with a narrow therapeutic window.
Digoxin, ciclosporin, lithium, gentamicin, theophylline, phenytoin, warfarin.
