Theme 1: Drug absorption and distribution (L1-6) Flashcards
1
Q
What is pharmacokinetics?
A
Drugs in motion
2
Q
How are drug concentrations determined in different compartments?
A
Translocation of drug molecules (properties)
Chemical transformation (metabolism)
3
Q
How can drugs move around the body?
A
Bulk flow transfer
Diffusional transfer
4
Q
What are the different mechanisms of diffusional transfer?
A
Hydrophobic diffusion barrier
Aqueous diffusion
5
Q
What are the properties of the vascular endothelium?
A
Acts as a filter
Gaps filled with protein matrix - tightly packed
Protein matrix used as MW filter
6
Q
What are fenestrations?
A
small openings or pores in cell membranes, blood vessel walls, etc.
7
Q
What do fenestrations allow?
A
Drugs to exchange freely between blood and interstitium in the liver
8
Q
Which drugs are transported in the brain capiliaries?
A
Charged drugs cannot travel
Lipid-soluble and carrier mediated ones can travel
9
Q
Why are charged drugs unable to travel in the blood capiliaries?
A
Because they have tight junctions
10
Q
What are the main drug pharmacokinetics?
A
Diffusion through the lipid
Combinations with a transmembrane carrier protein
11
Q
What are the different drug transfers across cell membranes?
A
Diffusion through lipid
Through aqueous pores
Combinations with transmembrane carrier protein
Pinocytosis (macromolecules)
12
Q
Which substances are most likely to diffuse through lipid?
A
Non-polar substances
13
Q
What is the equation using the permeability coefficient?
A
P=ΔC/J
J - number of molecules crossing membrane per unit area in time
ΔC - Concentration gradient
14
Q
What is the most important factor when considering permeability?
A
Partition coefficient
15
Q
Which drugs are most likely to exist intracellularly?
A
Lipophilic drugs (highly lipid soluble)
16
Q
How can rate of absorption of drugs in the gut and other tissues be determined?
A
From LogKow
17
Q
What are the different forms drugs can appear in?
A
Weak acids or bases
18
Q
Which drugs are most likely to penetrate cell membranes?
A
Unionised forms of the drugs (most likely weak bases)
19
Q
How is the pH of a compartment determined?
A
Using the ratio of charged:uncharged drug concentration
20
Q
How is pKa determined in weak acids?
A
pKa= pH + log[AH]/[A-]
21
Q
How is pKa determined for weak bases?
A
pKa= pH + log[BH]/[B]
22
Q
Which drugs are more lipid soluble?
A
Uncharged drugs
23
Q
What does ionisation impact?
A
Drug permeability across membranes
Steady-state distribution of drug molecules between compartments
24
Q
What is the pH partition mechanism?
A
pH changes in different body compartments which causes effects on pharmacokinetics of WA and WB
25
How are ionised forms not completely impermeable?
Due to carrier mediated transport
26
Why are body compartments never in equilibrium?
As there is constant motion of substances across the membrane
27
What are the consequences of pH partition mechanism?
Urinary acidification and alkalisation (acidification increased excretions WB decreased WA)
Plasma pH (increased = extractions of weakly acidic drugs from CNS to plasma)
28
What can be used to combat drug overdose (e.g. aspirin)?
Using urinary alkalinisation helps increase excretion
29
How does urinary alkalinisation increase aspirin excretion?
Uncharged aspirin(salicylate) allows crossing of membrane meaning it is reabsorbed into systemic circulation having detrimental effects
Charged aspirin reduces reabsorption
30
What are the 2 different types of carrier-mediated transport?
Passive and active
31
What are the negative properties of carrier-mediated transport?
It is saturable
Can be inhibitied
32
What is Fanconi syndrome in the use of cisplatin?
OCT2/3 transporter uptakes lots of cisplatin which accumulates in the cell (due to polymorphism in certain individuals)
This is toxic as there is a low efflux into the urine meaning cell death takes place causing renal failure
33
How can Fanconi syndrome use with cisplatin be combatted?
Using renal handling by administrating an uptake blocker
This stops accumulations in PCT cell
34
What are examples of drugs using other carrier mediated transport systems?
Levodopa: transported by the carrier responsible for phenylalanine
Fluorouracil: transported by carrier for natural pyrimidines (thymine & uracil)
Iron: carrier system in jejunum
Calcium: vitamin D-dependent carrier system
35
What are other factors that impact pharmacokinetics?
Binding of plasma proteins
Partition into body fat and other tissues
36
What are the different routes of drug administration?
Oral
Sublingual
Rectal
Application to epithelial surface
Inhalation
Injection (subcutaneous, intramuscular, intravenous and intrathecal)
37
What happens to drug absorption from the intestine?
Passive transfer-rate determined by ionisation and lipid solubility of drug molecules
38
What are the main factors affecting GI absorption of drugs?
GI motility
Splanchnic blood flow (intestine, pancreas and spleen)
Particle size formulation (drug delivery)
Physiochemical factors (ionisation and hydrophobicity)
39
What external factors does GI motility effect?
Migraine, diabetic and neuropathy (gastric stasis, dec absorption)
Malabsorptive states, GI diseases (dec absorption usually)
Coeliac disease (dec. thyroxine and digoxin absorption, inc propranolol, cotrimoxazole and cephalexin absorption)
Drugs (muscarinic receptors)
Food (dec absorption, exceptions)
40
What are the major effects of particle size and formulation on drug absorption?
Preparation (tablet, capsule, coating etc.) have major effect on absorption
Designed to meet specific therapeutic needs
41
What is digoxin?
It is used to treat heart failure and atrial fibrillation
It has a narrow therapeutic window
The absorption differs from patient to patient
42
What are examples of different drug-drug interactions
Tetracycline and Ca2+
Bile acid bring resins interact with warfarin, thyroxine
43
What are examples of drugs that are malabsorbed?
Vancomycin (C.difficile treatment)
Mesalazine (Crohn’s treatment)
Olsalazine (ulcerative colitis)
44
What is the process of drugs being absorbed via first-pass metabolism?
Dose enters in small intestine enterocytes can degrade drug but also pass through to portal vein
Liver metabolises lipophilic drugs converting them to have water soluble properties to be excreted
45
Which vessel is key in perfusion to the liver?
Portal vein (capable of 80% of perfusion)
46
Which drugs are highly extracted?
Chlormethiazole
Ergotamine
Glyceryl trinitrate
Labetalol
Lignocaine
Morphine
Pethidine
Propranolol
47
Which drugs have intermediate extraction?
Aspirin
Codeine
Quinidine
Nortriptyline
48
Which drugs are lowly extracted?
Diazepam
Digitoxin
Isoniazid
Paracetamol
Procainamid
Theophylline
Warfarin
49
Which factors affect systemic availability?
Amount of drug that reaches systemic circulation intact
Rate at which it reaches systemic circulation (pharmaceutical and GI)
Extent depends of absorption and pre-systemic metabolism
50
What are important factors to consider in dose response curves?
Cmax, Tmax and AUC
51
What are the benefits of using skin in pharmacology?
It is an effective barrier against MOs and loss of water
Allows permeation of drugs from topically applied creams and ointments in quantities producing systemic actions
52
What are the problems with transdermal delivery?
Variability in administration through the skin - lack of precision regarding real dose absorbed
53
What are the therapeutic objectives of transdermal delivery?
Lack of drug dosage (ointments and creams)
Ointments containing nitroglycerin need multiple application
Variable amount and duration of drug
54
How does amount and duration of a cream/ointment impact delivery?
Differences in area of skin covered with ointment
Thickness of ointment layer
55
What are new topical dosage forms?
Transdermal patches - correct dosage lasting a prolonged period of time
56
Why are transdermal therapies more advantageous?
No troublesome side effects and unreliable therapeutic action with repetitive dosage
Patients are often more compliant
No frequent dosing needed as can be used over a prolonged time period
No gastric irritation
57
What are downfalls to transdermal patches?
If applied to the wrong area it could result in a different therapeutic effect
58
What is the scopolamine drug delivery system?
Application to skin
Drug diffusion in direction of concentration gradient
Energy source: difference in drugs chemical potential between the reservoir and system’s exterior
Constancy of rate delivered assured as long as drug present in excess in reservoir
59
What are examples of transdermal patches?
Transderm-Nitro (nitroglycerin)
Catapres TTS (clonidine)
Estraderm (estradiol)
Nicorette (nicotine)
60
What are the drug delivery advantages of transdermal delivery?
Reduced dosage frequency
Short-half life drugs
Simplified patient compliance
More consistent treatment of chronic disorders
61
What are the GI tract advantages of using transdermal drug delivery?
Prevention of unpredictable absorption
Avoidance of gastric irritation
62
Why are there other ways of injecting drugs?
Because large molecules cannot survive in certain deliveries
63
How is IV drug administration useful?
It is the fastest and most certain
High concentration drugs
Enters right segment of the heart and lungs then systemic circulation
64
What does rate of injection dictate?
The peak drug concentration reaching the tissues - avoids high plasma concentrations (could reach deadly concentration, out of therapeutic window)
65
What do subcutaneous and intramuscular injections rate of absorption depend on?
Site of injection
Local blood flow
Drug formulation
66
Which type of drug administration has faster effects than oral?
Subcutaneous and intramuscular
67
What is intrathecal injection?
It is into the thecal sac (subarachnoid space) around the spinal chord using a lumbar puncture needle
68
What are examples of intrathecal injection?
Methotrexate - treat childhood leukaemia
Local anaesthetics (butivacane)
Opiate anaesthetics
Baclofen - (GABA analogue) treat muscle spasm from a chronic neurological disease
Some antibiotics (aminoglycosides) - nervous system infections with bacteria resistant to antibiotics
69
What diseases does inhalation drug treatment help?
Asthma, bronchitis emphysema and lung cancer
70
Why is inhalation advantageous as a method of drug delivery?
Rapid action
Minimise systemic absorption (avoids wastage)
Minimise side effects (βagonists and glucocorticoids)
71
What are properties of drug administration via inhalation?
Rapid delivery across mucous membranes of RT and pulmonary epithelium
Effects occur rapidly
Used for drugs that are gases or can be dispersed in aerosol (powder into liquid)
Effective in respiratory disease
72
What is asthma?
Inflammation
Mucus production
Bronchospasm
73
What are the symptoms of asthma?
Shortness of breath
Wheezing
Tightness of chest
Coughing at night/ after physical activity
Waking at night with symptoms (uncontrolled)
74
What are the different triggers?
Strong smells
Smoke
Colds/flu
Dust
Pets
Hot/cold weather
Car exhaust
Pollens
Air pollution
75
What is the first line of treatment of asthma?
Adrenergic agonists and glucocorticoids (inhalation)
β-agonists (pirbuterol, terbutaline, albuterol and salmeterol) - potential bronchodilators
76
What are the pharmacological properties of β-agonists used for bronchodilation?
Relax airway smooth muscle directly
Rapid onset of action (15-30mins)
Relief for 4-6 hours
Little stimulation of other receptors
77
How can corticosteroids be used to treat asthma?
Decrease number and activity of cells in airway inflammation
Inhaled eliminates the use of oral
No direct effect on airways smooth muscle
Prolonged inhalation reduces hyper-responsiveness of airway smooth muscle
78
What are disadvantages of inhaled drugs?
Incorrect technique can cause failure in response to treatment
79
Why does technique matter when inhaling drugs?
To ensure the drug reaches appropriate target
When not used correctly a large fraction can be deposited in the mouth and pharynx or swallowed
80
How are corticosteroids useful in asthma treatment?
Undergo extensive 1st pass metabolism, therefore small amount reaches systemic circulation - minimises side effects
10-20% reaches airway
81
What are spacers?
They can be used for inhaled drugs by depositing particles into chamber and allowing them to travel into the airways
82
What is Sodium cromoglycate and nedocromil sodium?
They are prophylactic anti-inflammatory agents
Manage acutely attacks of asthma (not bronchodilators)
83
What is Theophylline?
A potent bronchodilator
Narrow therapeutic window, overdose leads to seizures and arrythmias
High drug-drug interaction
84
Why would prolonged release of inhaled drugs be advantageous?
Current ones have a short half-life
Prolongs pharmacological effect
New approaches have been made in developing new formulations
85
How can biodegradable polymers be used to deliver inhaled drugs?
They can act like particles and prolong the release of drugs
Surfactants can be used which can cause even more prolonged release
86
Which factors of formulation can affect bioavailability in oral dosing?
Also known as pharmaceutical availability
Rate of disintegration (some drugs are pre-dissolved)
Rate of dissolution of drug particles in intestinal fluid
87
What are the physical factors affecting pharmaceutical availability?
Tablet compression and excipients (rate of disintegration)
Other tablet excipients (interaction with gastric juice, too motile = little absorption)
Form of the drug (crystalline is more stable therefore dissolves slowly), counter ion effects
Particle size (smaller dissolve more quickly)
88
What is an example of an excipient?
Sorbitan
Emulsifying agent for different drugs and their administration
89
Describe bioequivalence
It is when 2 formulations of a drug have comparability bioavailability and similar times to achieve peak plasma concentration
90
When are drugs bioinequivalent?
When they have significant differences in bioavailability
91
What are the parameters measures in plasma concentration-time curves?
Cmax, tmax, AUC, onset time=MEC(minimal effective concentration), therapeutic range and duration of action
92
What is therapeutic equivalence?
Two similar drugs have comparable efficacy (size of effect) and safety
93
What is an example of bioequvalence impacting patients?
Phenytoin caused toxicity by a change in formation from calcium phosphate to lactose
Increased dissolution took place which enhanced the rate of bioavailability forming a dangerous release profile (increased cmax and tmax)
94
How is the route of administration determined?
By therapeutic objective (slow or fast onset)
Properties of the drug (small, soluble, biological)
95
How can absorption of insulin in drug formulation change?
Physical state (crystalline or not)
Zinc or protein content (prolonging release)
Nature and pH of buffer suspension
96
What are examples of types of insulin that have different rates of absorption?
Insulin BP - soluble and amorphous
Rapid onset and short duration of action
Ultralente insulin - large crystals + high zinc, suspended in solution of sodium acetate/chloride
Onset action ~7h and duration ~36h
97
How can the object used to suspend the drug affect diffusion rate?
Could be retarded by using thick oils by slowing diffusion
98
What are examples of objects impacting diffusion rate during drug delivery?
Vasopressin tannate in oil - diabetes insipidus
Fluphenazine decanoate in oil - schizophrenia
99
How can different administrations impact dosing of the same drug?
Can impact the plasma concentration (e.g. phenytoin)
100
What is diabetes insipidus?
It is the formation of less vasopressin which causes an increase in Na+ and H2O release
101
How can local injections have different formulations in local anaesthetics?
Some formulations contain adrenaline
Vasoconstriction at site of injection
Prevents drug getting carried away by circulation from site of injection
Prolonging the effect of the local anaesthetic
102
How can administration avoiding 1st pass metabolism impact drug dose?
To have direct effect on their site of action
103
What are examples of administration avoiding 1st pass metabolism with changed formulation?
Glyceryl trinitrate - 10x less dose required compared to oral, rapid therapeutic effect
Glyceryltrinitrate, hyoscine, oestradiol - transdermal patches creating a prolonged effect
104
How can oral formulation be changed to control release?
Delayed release and slow release drug formulation (e.g. enteric coated aspirin - release delayed until tablet reaches small intestine)
Reduced risk of gastric erosion (formulations of quinidine, less frequent administration)
105
What are other examples of slow release formulations?
Theophylline and nifedipine
106
How can unconventional formulations not always be useful?
β-antagonists already good effect on duration
Procinamide can cause neutropenia (lower levels of neutrophils)
107
What criteria do combination oral therapies have to meet?
Frequency of administration is the same
Fixed doses are therapeutically and optimally effective
108
Which combination formulas have improved compliance?
Anti-TB drugs (rifampicin + isoniazid)
Ferrous sulphate + folic acid (pregnancy)
109
Which combination formulations are easy to administer?
Triple vaccine (diphtheria, tetanus and pertussis)
110
Which combination formulations have synergistic or addictive effects?
Trimethoprim + sulphonamides
Amoxicillin + Clavulanic acid
Aspirin + codeine
Paracetamol + metoclapramide
Combined oral contraceptive
111
Which combination formulations have decreased adverse effects?
L-dopa + decarboxylase inhibitors (Parkinson’s)
Diuretics (potassium wasting/sparing)
112
What are special delivery systems?
Biologically erodible microspheres - loaded with drugs
Pro-drugs
Antibody-drug conjugates (chemo)
Packaging in liposomes (non-lipid soluble drugs)
Gene therapy
Implantable devices
113
Describe drug distribution
Process by which a drug reversible leaves the systemic circulation and enters the interstitium and/or the cells of the tissues
114
What does the transport of a drug from the interstitium depend on?
Blood flow (perfusion)
Capillary permeability
Degree of binding to plasma and tissue proteins (HSA)
Relative hydrophobicity of the drug
115
How can blood flow be distributed in different organs?
It varies widely as cardiac output is unequal in various organs
116
What is the blood flow distribution in specific organs?
Blood flow brain, liver and kidney > skeletal muscle > adipose tissue
117
What is capillary permeability determined by?
Capillary structure
Drug structure
118
How does capillary structure differ in the liver and brain?
Liver: large fenestrations, drugs exchange freely between blood and interstitium, contains slit junctions
Brain: Tight and slit junctions, lipid soluble and carrier mediated ONLY, astrocyte foot processes
119
What is a major factor of distribution of hydrophobic drugs?
Blood flow to area
120
How do drugs bind to proteins?
Reversible in a non-diffusible form
121
Describe volume of distribution (Vd)
It is a hypothetical volume of fluid the drug is disseminated to
(no physiological/physical bias)
122
What compartments is the total body water split into?
Plasma - 4L
Interstitial vol - 10L
Intracellular vol - 28L
Total = 42L
123
How much of the drug is distributed in the plasma?
Large MW/ binding to plasma proteins means the drug is trapped in the plasma compartment
4L in 70Kg individual
124
How much of the drug is distributed to the extra cellular fluid?
Low MW hydrophilic
Moves to interstitium via slit junctions
OR
unable to cross membrane of cells into intracellular fluid
14L in 70Kg individual
125
How much of the drug is distributed into the total body water?
Low MW and hydrophobic
Moves through slit junctions and crosses cell membranes into intracellular fluid
42L in 70Kg
126
What is the apparent volume of distribution?
When a drug rarely associates with only one body compartment and binding occurs to cellular components
127
What happens when drugs are bound to plasma proteins?
They are pharmacologically inactive - unable to reach target eliciting biological response
128
What is the binding capacity of albumin?
Low - 1:1, drug:albumin
High - Many:1, many drugs:albumin
129
What is albumins affinity for binding drugs?
Strongest affinity: weak acids no hydrophobic drugs
130
What is competition between drugs binding to albumin?
High capacity binding drugs can have competing affinities
131
What is the binding drugs to albumin dependent on?
Dose
Binding capacity
132
What are the 2 different classes of high capacity binding to albumin?
Class I - binding sites in excess (concentration free drug is low)
Class II - dose greater than available binding sites (concentration of free drug is significant)
133
What happens when both class I and II drugs are administered?
This can cause displacement of class I drugs which causes a rapid increase of class I plasma concentration as a new equilibrium is reached
Can cause different toxicological and pharmacological effects
