Unit 2 Flashcards
What are pharmacokinetics?
ADME principles:
- Drug chemistry
- Drug interactions
- Normal and abnormal body function
ADME =
Absorption, Distribution, Metabolism, Excretion
Absorption is preceded by disintegration/dissolution of drugs at the site of administration
What are the ADME principles?
ABSORPTION
How will it get in?
DISTRIBUTION
Where will it go?
METABOLISM
How is it broken down?
EXCRETION
How does it leave?
Pharmacokinetics is a balancing act. What are some of the questions we ask?
How much drug do we need to give?
What effect do we want?
What side-effects are we trying to avoid?
Questions dependent on innate drug chemistry:
- How are we giving the drug?
- How does the drug move around the body?
- How quickly is the drug eliminated?
What does drug distribution depend on? How can we decide the distribution?
Drug distribution depends on drug chemistry and method of administration.
We can decide the drug distribution by altering drug formulation and administration to target specific tissues
What is important about drug movement around the body?
Drug movement around the body is dynamic:
- Drug dose. Drug in solution at absorption site
- plasma-free drug ⇌ protein-bound drug
- Organs of bio-transformation form drug metabolites
- Site of action (target molecule) Bound ⇌ Free
- Tissue reservoirs Free ⇌ Bound
- Organs of excretion remove drug + metabolites
What is water solubility?
Water is the universal solvent in biological systems and drugs need to be in aqueous solution:
- At the site of action to be able to achieve absorption
- To be distributed within the body
- At the site of action to be able to interact with a target molecule (e.g. receptor)
- To enable transport (in the circulation) to organs of excretion and metabolism
However, drugs must also be, to some extent, lipid soluble to cross cell membranes
Describe water vs lipid solubility:
Water is the universal solvent in biological systems.
Drugs need to be in aqueous solution:
- At the site of administration to achieve absorption
- To be distributed around the body
- At the site of action to be able to interact with the target molecule (e.g. a receptor)
- To enable passage (in the circulation) to organs of excretion and metabolism
HOWEVER,
Drugs with some lipid solubility:
- Cross cell membranes easily by passive diffusion
- Distribute into fatty tissue
- Will easily get to sites of actions within cells
- Will easily reabsorb from the kidney and therefore will need to be metabolised prior to excretion.
Why is the presence of drugs in plasma of significance?
The presence of drugs in plasma is of primary significance, except when the drug acts locally at the site of application or injection
BECAUSE
The (active) drug is only available for distribution to the site(s) of action, and for passage to the organs of excretion and metabolism, when it is in solution in plasma.
How do drugs move across cell membranes?
Most drugs are small molecules (molecular weight <1000). They pass across cell membranes by:
Passive diffusion along a concentration gradient (lipid soluble drugs)
Active or facilitated transport
- Pinocytosis
- Aqueous channels
- Carrier mediated transport (may be energy dependent)
What is pinocytosis?
Pinocytosis is a form of endocytosis, a cellular process by which cells internalize extracellular fluid and solutes into vesicles within the cell.
How do drugs move into/out of the circulation?
Drugs cross the vascular endothelium primarily through gaps between the cells - called FENESTRATIONS
The gaps are packed with a matrix of proteins that act to retain molecules of high molecular weight
What are some factors affecting drug movement?
Properties of the drug:
Molecular weight: High molecular weight (met) compounds will remain at the site of administration
Lipid solubility: Lipid soluble drugs pass readily across cell membranes
Chemical nature: Drugs can be neutral, acidic or basic, polar or non-polar and the degree of ionisation therefore varies
What is drug ionisation?
Influences the ability to cross cell membranes;
Weakly acidic or basic drugs (MOST):
- Partially ionised at physiological pH. The unionised fraction readily crosses cell membranes
Neutral drugs: 100% unionised;
- Readily cross-cell membranes
Strongly acidic or basic drugs: 100% ionised:
- Polar molecules that do not readily cross cell membranes
How does pH affect absorption?
Most drugs are either weak acids or weak bases
Weak acids (HA):
HA ⇌ H+ + A-
unionised ⇌ ionised
Weak bases (B):
BH+ ⇌ B
ionised ⇌ unionised
UNIONISED: More readily absorbed
IONISED: Less readily absorbed
What is the Henderson-Hasselbalch equation?
pKa is the dissociation constant of a drug. When pH = pKa, A- = Ha, and B = BH+
pKa = pH + Log10 (protonated species / non-protonated species)
ACIDS: pKa = pH + log10 (HA/A-)
BASES: pKa = pH + log10 (BH+/B)
EXAMPLE: Effect of pH on drug on ionisation state in acid and alkali environments - Stomach + kidney and Pancreas
pKa = pH + log10 (HA/A-)
HA ⇌ A- + H+
Stomach: Low pH (~2)
Kidney: low pH (~2-4)
MOST DRUG IN HA, UNIONISED FORM
Pancreas: high pH (~7.5-8)
MOST DRUG IN A-, IONISED FORM
What is diffusion/ion trapping of weak acids and bases?
This can occur when the pH differs on two sides of a membrane
- Weak acids are trapped in an ionised form in alkaline fluids
- Weak bases are trapped in an ionised form in acidic fluids
Summarise ionisation, solubility and transport in drugs:
UNIONISED (lipid soluble) molecules readily pass across lipid membranes
IONISED molecules do not easily pass across lipid membranes
The extent to which a drug is ionised, and therefore the rate and extent of its absorption (and distribution), is influenced by:
The pKa of the drug and local pH
How well will aspirin, heparin and loperimide be absorbed?
Aspirin:
Mol. Wt: 180g/mol
Water soluble
(Weak acid)
Heparin:
Mol. Wt: 15kDa
Water soluble
(Strong acid)
Loperimide:
Mol wt: 477g/mol
Lipid soluble
(strong acid or base, depending on formulation)
ASPIRIN
Will cross well. Bioavailability 80-100%
HEPARIN
Big (large molecular weight) will absorb very slowly. Therefore not administered orally (is a blood thinner so will be intravenously administered). Bioavailability 0% from GIT
LOPERIMIDE
High lipid solubility but isn’t absorbed well. Bioavailability 0.3% p-glycoprotein substrate
So what is drug absorption influenced by?
Route of administration
- Drugs can be given orally or parenterally
The route is determined primarily by the:
- Properties of the drug
- Therapeutic objective e.g. the need for;
Rapid onset of action
High plasma concentration
Long term administration
Restriction to a local site
Examples of uses for locally administered drugs:
Skin
Mucous membranes
Pinna
Intramammary
Oral
Epidural
Intra-articular
Rumen (retain devices)
Skin
- Flea treatment
Mucous membranes
- Eye drops
Pinna
- Antibiotics for ear infection
Intramammary
- Antibiotics for mastitis
Oral
- GIT problems, eg diarrhoea
Epidural
- Analgesics + local anaesthetics
Intra-articular
- Joint infection or inflammation
Rumen (retain devices)
- Sustained or pulsed release of anthelmintics
What are the physiological variables affecting drug absorption?
pH at site of absorption
Area of absorbing surface (e.g. following oral administration, most drug absorption occurs in the intestines. A reduction in the surface area for absorption will decrease the amount of drug absorbed)
Local blood flow (e.g. decreased perfusion will reduce the rate of diffusion of a drug from the site of administration
What is bioavailability as a measure of absorption?
Bioavailability is:
The fraction of the administered dose that reaches the systemic circulation in an active form
It is expressed as a percentage of the total administered
What is bioavailability?
Bioavailability = area under the curve of oral dose / area under the curve of IV dose
Takes NO account of the rate of drug absorption therefore:
- Two drugs may have the same bioavailability but the peak plasma concentration will be higher if one is absorbed more rapidly
- A difference in the peak concentration achieved may affect the therapeutic effect
What can drugs distribute into?
Once absorbed from the site of administration drugs can distribute into:
Plasma (if a drug has been given intravenously it will, of course, already be present in plasma)
Extracellular fluid (ECF)
- Interstitial fluid
- Transcellular fluid
Intracellular fluid (ICF)
What is drug distribution in body compartments?
Volume of distribution, Vd, is a measure of the volume of fluid required to contain the total amount of drug at its plasma concentration
If the body was a compartment, the drug would be the same thoroughout.
What is greater Vd reflected by?
Greater Vd is reflected by lower drug concentration.
a) After injection the drug could just stay in the circulation
b) The drug could distribute into extracellular fluid, reducing the plasma concentration
c) The drug could distribute into total body water; if it does the concentration of drug in the plasma will be lower than if it had just distributed into the circulation and ECF
How do we calculate Vd?
Vd = Q Dose (total amount of drug in the body; mg/kg) / Cp Plasma concentration (usually µg or ng/ml)
How can we interpret the volume of distribution?
Vd VERY LOW (0.05 to 0.1 L/kg): Drug confined to the plasma compartment (large molecules)
Vd LOW (0.2 L/kg): Drug confined to the plasma and interstitial space (highly polar molecules which penetrate membranes poorly)
Vd INTERMEDIATE (0.6 L/kg): Drug enters total body water (crosses membranes)
Vd VERY HIGH (>1 L/kg): Drug concentrates in fat or binds to a site within a tissue or cell
TOTAL BODY WATER = APPROX 0.6 L/kg
Why is it important to know the Volume of distribution of a drug?
- It enables you to predict whether the drug selected for administration is likely to reach the target site at effective concentrations
- The Vd can be used to determine the loading dose necessary to achieve a target plasma concentration
What is Vd?
The ability of a drug to leave the circulation and enter interstitial fluid (and then to cross cell membranes) can be influenced by:
- Size
- Plasma protein binding
- Endothelial cell barrier function
- Ion trapping
- Lipid solubility
What do we know about plasma protein binding?
Once a drug has entered the vascular compartment, it may circulate bound to plasma albumin and globulin
The plasma protein bound and free drug in the circulation are in equilibrium
Normally only the free drug crosses the endothelial cell barrier
Drug + Plasma protein
t = 0 total concentration
t = n total concentration and unbound concentration
What are some variations in plasma protein?
Drug binding to plasma protein occurs to a variable extent (from 0% to 99%)
There are species difference in the extent to which a drug is plasma protein bound
Displacement can occur if two extensively plasma protein-bound drugs are given together
What are the consequences of drug-plasma protein binding?
Pharmacodynamics:
The protein-bound fraction is pharmacologically inactive
Pharmacokinetics:
Only the free portion of a protein-bound drug will readily leave the circulation/be ultra-filtered in the kidney
Toxicity:
In a few individuals, the drug-protein complex may be recognised as ‘foreign’ i.e. behaves as an antigen, causing a hypersensitivity reaction on second exposure
Interactions:
Competition between drugs or endogenous compounds for protein binding can occur which may lead to unwanted effects
Summarise drug distribution:
Drug can distribute in plasma, interstitial fluid or trancellular fluid (ECF compartments) and intracellular fluid (ICF)
Volume of distribution can be calculated from plasma concentration, and used to predict this distribution
Drug chemistry, particularly plasma protein binding, is the major determinant of drug distribution
What is drug metabolism?
Most drugs require metabolism prior to elimination from the body
This converts drugs into more water-soluble compounds and aids their elimination
Some drug metabolites are biologically active
Some drugs are administered as inactive, pro-drugs and must be metabolised to an active form
What are the sites of metabolism?
The LIVER is the main site of drug metabolism
Some drugs may be metabolised in other tissues e.g. PLASMA, wall of the GASTROINTESTINAL TRACT, LUNG and KIDNEY
What is the process of metabolism?
Drugs metabolised in the liver must be able to cross the liver cell membrane to reach the microsomal enzymes
The main enzymes involved in drug metabolism in the liver are the mitochondrial mixed function oxidase enzymes, otherwise known as cytochrome P-450 or CYP enzymes
What are the phases in metabolism?
Hepatic metabolism is normally biphasic
PHASE 1:
Convert lipophilic molecules into more polar molecules
PHASE 2:
Add a conjugating group to the molecule to increase polarity, decrease lipophilicity, and therefore aid drug excretion
STEP BY STEP
1. Drug
2. Phase 1: oxidation, reduction, hydrolysis
3. Metabolite
4. Phase 2: Conjugation. Addition of e.g. glucuronic acid, glycine, sulphate, acetyl
5. Conjugate
What is first pass metabolism?
Some drugs are extensively metabolised in the wall of the gastrointestinal tract or in the portal blood or in the liver before they reach the systemic circulation
First pass metabolism affects the absorption of orally administered drugs
