Pharmacokinetic Flashcards
LO
- Define drugs pharmacodynamics and pharmacokinetics
- Develop understanding of basic concepts of ADME
- Introduce basic concepts of pharmacokinetics
o Absorption
o Distribution
o Metabolism
o Elimination - Define the common pharmacokinetic parameters
o Volume of distribution
o Clearance
o Elimination half life - Understand important optimal therapeutic response
What is meant by pharmacokinetics?
- The mathematical description, prediction and understanding of the time-course of drugs (and their metabolites) in the body
- By in the body, we mean plasma concentrations (time-course is time in circulatory system)
What is meant by pharmacodynamics?
The study of the biochemical and physiological effects of drugs and the mechanism of their actions on the body
Define the terms pharmacokinetics and pharmacodynamics and how they are denoted?
* Pharmacokinetics is the study of **‘what the body does to a drug’ **
* Pharmacodynamics is often summarised as the study of **‘what a drug does to the body’ **
* Pharmacodynamics is sometimes abbreviated to ‘PD’, while pharmacokinetics can be referred to as **‘PK’ **
What is ADME an acronym for in pharmacokinetics?
ADME is the acronym in pharmacokinetics for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compounds within the body
Define Biopharmaceutics
Biopharmaceutics can be defined as the study of the physical and chemical properties of drugs and their proper dosage as related to the onset, duration, and intensity of drug action
What are the processes that define biopharmaceutics?
o (Liberation)- about the formulation of the drug
o Adsorption **
o Distribution **
o Metabolism
o **Excretion **
Frequently referred to as (L)ADME
What is the difference between PK and clinical PK?
- Remember: PK- the study and characterisation of the time course of drug ADME and the relationship to these processes to the time course of the therapeutic and toxicological effects of the drug
- Clinical PK- use of these principles to enhance safe and effective management of the patient
What are there links between with the pharmacokinetic models?
What are the types of pharmacokinetic models and briefly describe them?
*** Empirical: **use of mathematical equations
*** Physiological: **major tool for prediction of in vivo PK from in vitro data
*** Compartmental: **number compartments defined by concentration over time data
o One compartment assumes drug distributed fully throughout body- the simplest model, drug distributed in an equal way throughout the body
o **Two compartment **assumes simple model of drug absorption and elimination
Describe the one compartment IV bolus
- All drugs initially distribute into a central compartment (Vc)(blood stream/ circulation) before distributing into the peripheral compartment (Vt).
- If a drug rapidly equilibrates with the tissue compartment, then, for practical purposes, we use a one-compartment model which uses only one volume term, the apparent volume of distribution, Vd
- Assuming blood entered blood stream and being widely distributed in the blood stream
One compartment model example
- Distribution phase for **aminoglycosides **is only 15-30 mins
- A one-compartment model is best used to describe the behaviour of the drug
Whats an example of a two compartment model?
- Vancomycin is the classic examples of a two-compartment model
- Distribution phase is 1-2 hours
- Plasma concentration time curve may be more accurately represented by a 2-compartment model
- Distributed to major organs immediately after administration before then distributing around the whole body after distribution equilibrium
Summarise the pharmacokinetics pathway from administration of agonist or antagonist to response and the factors which can effect each of the processes
PK at the molecular level
- PK takes place at molecular level, a process we can only estimate
- Very dynamic process
- Black dots= drug molecules (some may be bound to proteins, if bound to proteins they can’t leave blood stream, so only free drug which can move)
- Drug will leave blood stream and distribute to other places of the body i.e., metabolised by liver, eliminated, go to site of action
- Measuring in plasma concentration time curve is a very dynamic process
- Some drugs may go back to tissues before elimination again
Why is ADME and PK important?
- To prevent negative patients’ outcomes
- Ignorance leads to ‘drug disasters’ e.g., Multaq (dronedarone)
- Primary cause of withdrawal of drugs
- A prominent components of marketing strategy
Preventable negative patient outcomes (PNPO)
(Don’t necessarily need to know just be aware)
- Unnecessary drug therapy (drug without indication)
- Improper drug selection (wrong medication)
- Sub-therapeutic dosage
- Over-dosage
- Adverse drug reaction
- Drug interaction(s)
- Failure to take/receive drug (inappropriate compliance)
- High-income countries, 1/10 patients harmed receiving hospital care: nearly 50% of them being preventable
- Globally, 4/10 patients harmed in primary and outpatients’ health case, 80% preventable
- Most detrimental errors and related to diagnosis, prescription, and the use of medications
- In OECD countries, 15% total hospital activity and expenditure is from adverse events
- No necessarily that drug isn’t working but that they wrong drug could be being used
Example of drug on marker with serious side effects- example
-
Zocor (simvastatin) is a cholesterol- lowering drugs that has been linked to rhabdomyolysis and myopathy (muscle injuries)
o As well as other serious side effects such as kidney failure, liver problems, and interstitial lung disease (ILD)
Multaq (dronedarone)
- Multaq (dronedarone)treats abnormal heart rhythm (atrial fibrillation or atrial flutter)
- Marketed as drug reduces risk of being hospitalised for these heart problems (French Pharm company)
- Jan 2011 FDA issued drug safety alert for Multaq concerning severe liver injury (liver failure) requiring liver transplantation
- July 2011 FDA issues second (different) drug safety alert: data indicating 2-fold increase in death; 2-fold increases stroke and hospitalisation for heart failure
- Dec 2011 FDA said multaq increased risk serious cardiovascular events, including death, when used by patients in permanent atrial fibrillation (AF)
- Sept 2012 FDA approved label changes for multaq for types of lung disease such as pneumonitis and pulmonary fibrosis due to serious side effects of multaq use
Usefulness of PK for drug development: can answer Q with PK information about a drug
- Is the drug effective by mouth?
- Which organs is the drug exposed to?
- How long does it stay in the body?
- How is the drug removed from the body?
- What factors influence its handling?
- What is the appropriate route of administration?
- What are appropriate doses (animals/volunteers/ patients)?
- How should that drug be formulated?
- Which drug interaction are likely to be important?
What are some reasons for withdrawal in drug development in the UK?
What do drugs act on in the body?
Drugs act on specific proteins at the cell membrane called receptors
What are the 4 main drug actions at receptors (these receptors are found in the brain)
o Stimulation through direct receptor action (agonist)
o **Depression through direct receptor action (inverse agonist)
o Blocking/ antagonist drugs binds to receptor but does not activate
o Partial agonist** drugs bind to receptor and has some activity, depending on dose and recipient
What are the time curves for IV plasma concentration and oral plasma concentration?
- Time curve for IV bolus drug administration for plasma concentration
- Effect doesn’t follow same time curve, peak effect sometimes occurs after peak concentration
red= IV
green= oral
Whats the relationships between dose rate and effect?
rate at which drug gets to receptor impacts the rate at which an effect occurs
What are the general mechanisms of drug action?
- Block the action of specific enzymes
- **Inhibit cell transport **mechanisms
- Exchange/ replace substance or accumulating them to form a reserve
- Directly beneficial chemical reaction as in free radical scavenging
- **Directly harmful **chemical reaction to damage or destroy cells (act on cell wall proteins of bacteria- lysis)
Give an example of drugs that inhibit enzymes and how it works?
**Disulfiram: Antabuse **
o Aldehyde dehydrogenase is a polymorphic enzyme responsible for oxidation aldehydes to carboxylic acids, which leave the liver and metabolised by muscle and heart
o Three different types of these enzymes: ALDH1, 2 and 3
o Given to alcoholics to support non-drinking as the effects are not very nice so try to get alcoholics to stop drinking
• Disulfiram is a drug which is given to people with chronic alcoholism
• Alcohol pathway
• Alcohol –> acetaldehyde (via alcohol dehydrogenase) –> acetate (via acetaldehyde dehydrogenase (ALDH)
• This drug works by inhibiting ALDH and leads to an increase of the toxic alcohol-related compound
• Which leads to severe side effects in those who drink
What is “Asian flush” or “oriental flushing syndrome” ?
- ALDH2 plays a crucial role in maintaining low blood levels of acetaldehyde during alcohol oxidation
- Intermediate structures in this pathway can be toxic and can damage health if not eliminated
- high blood levels acetaldehyde can cause facial flushing, headache, palpitations, light headedness, and general symptoms hangover
Deficiency in ALDH
Tell me about disulfiram treatment
- ALDH2 inhibited by disulfiram
- Prescribed to abstinent alcohol dependent people
- If drink during treatment get high levels of acetaldehyde: become violently ill
- Several drugs (antibiotic metronidazole) cause a similar “disulfiram-like reaction”
What kind of effects can psychoactive drugs have?
Stimulate and depress
Give an example of a stimulatory psychoactive drug and its effects
Stimulate e.g., cocaine
o Speed up body mechanisms
o Increase heart rate, blood flow
o Respiratory rate increased
o BP raised
o Increased attention spam
o Increased ability to focus
o Increased ability to concentrate
o Increased alertness
Give an example of a depressive psychoactive drug and its effects
Depress e.g., alcohol, marijuana, benzodiazepine
o Slow down body
o Decreased heart rate, blood flow
o Respiratory rate depressed
o Analgesia
o Sedation
o Peacefulness
o Decreased alertness
PK and PD in addiction
- Important as addicts tend to use drug doses much higher than safe recommended levels
- No quality control of material- so purity an issue
- Monitor and publish adverse events
- Poly drug use and interactions
What is therapeutic drug monitoring?
The way in which we use PK and PD to optimise drug therapy for individuals
Define Therapeutic drug monitoring (TDM)
The use of drug concentrations, pharmacokinetic principles, and pharmacodynamics factors to optimise drug therapy individual patients
Draw the concentration-time graphs for IV plasma and oral dose
Draw the blood level time curve after single oral administration and label the sections
What drugs require TDM?
- Possess a narrow therapeutic index
- Poor correlation between dose and effect
- Good correlation between serum concentration and effect
What is the goal of drug therapy?
Drugs requiring routine monitoring
(dont need to learn)
Define absorption
And the route of administration is the key factor in determinig what?
- Defined as: the process by which unchanged drug proceeds from the site of administration to the general circulation (site of measurement)
- Route of administration is the key factor in determining the **rate and extent of absorption **
What are two sites of administration?
Give examples for each?
Intravascular (placement of a drug directly into the blood stream)
o IV or inter-arterially
Extra vascular
o Oral
o Sublingual
o Buccal rectal
o Conjunctival
o Dermal
o Intramuscular
o Auricular
o Subcutaneous
Absorption can occur from other sites, what are these sites and why is absorption able to occur here
* Lungs when substances are smoked or inhaled (cannabis, salbutamol)- absorption is almost complete as for IV use- lungs are a good site of absorption because they have good blood stream associated with it, large surface area
* Mucous membranes (nasal insufflation- snorting cocaine)- snorting drugs are effective because it is easy access to blood stream, mucous membrane enables drugs to pass easily
* Sublingual and buccal (buprenorphine, nitro-glycerine like vasodilators)- under tongue, and in mouth, good blood supply, easily absorbed
* Skin patches (oestrogens, fentanyl, nicotine)- less effective but good for patches
*** Rectally **(suppositories morphine)- good blood supply
Define Biopharmaceutics?
o Influence of dosage form on the therapeutic activity of a drug
o Study of the relationship between the physical and chemical properties of a drug and its dosage form
o Study of the biological effects observe following administration
What is the therapeutic response of a drug dependent upon?
Therapeutic response of a drug is dependent upon an adequate concentration of the drug being first** achieved **and then **maintained ** at the site(s) of action
What is Biopharmaceutics concerned with?
- Biopharmaceutics is concerned with onset, intensity (i.e., amount) and duration (i.e., length of time) of a drug at its site(s) of action
- Onset, intensity, and duration are all influenced by the rate at which a drug enters the body
What are the mechanisms of absorption?
Absorption from formulation:
Solid drug –> drug in solution –> absorbed drug (drug has to be in solution before it can be absorbed)
What happens when absorption permeability rate is limited?
When absorption permeability rate limited **drug is mostly dissolved before absorption complete **
What happens when absorption drug release rate is limited?
When absorption drug release rate limited will be very little drug at absorption site; absorption delayed until dissolution occurs
What must the drug be in to be absorbed?
solution
How does transcellular permeation occur by?
o Passive diffusion
o Active transport
o Facilitated transport
Vascular absorption predominated as blood flow is greater than what?
lymph flow
Is paracellular absorption passive or active?
Passive
Tell me the following about passive diffusion
What is rate of absorption dependent upon?
What are the rate limiting steps?
**rate of absorption dependent upon **
concentration gradient across membrane –> surface area –> permeability constant
**rate limiting steps **
perfusion rate= very small molecules, membrane not barrier (passage depend on blood flow)
permeability factor= polar hydrophobic compounds (some antibiotics) insensitive to blood flow dependent on membrane
What is the permeability constant determined by?
o physiochemical properties of the molecule
o nature of membrane (thickness membrane varies from tissue to tissue) that is distance between surface of absorption and blood capillary
o partition coefficient of the compounds
o the more lipid the drug the better it will be absorbed
Most drugs that are administered orally act how?
Systemically
What can be an issue with oral absorption?
Sometimes a drug is intended to act locally (eye, lungs etc) so systemic absorption becomes a safety issue
Getting the drug to the small intestine- the major site of absorption
Many factors can influence how well and how quickly a drug is absorbed from the small intestine.
Tell me some of these factors
(a) gastric emptying (GE) and effect of food
(b) intestinal motility/ transit
(c) blood flow
(d) presence of other drugs
(e) degradation and metabolism
Gastric emptying
What is the function of the stomach?
store, mix and reduce the gastric contents to a slurry
empty its contents in a controlled manner to the small intestine
good correlation between GE and peak plasma concentrations of many drugs
Gastric emptying
The emptying of the contents of the stomach into the intestine- may alter the rate (and extent) of absorption
o small intestine (SI) is the main site of drug absorption
o important how quickly drug ‘arrives’ in SI
o large number of factors influence GE
What are some of these factors which influence GE?
o presence or absence of food and/or fluid
o physical state of stomach contents e.g. type of food, quantity, size, temperature, viscosity
o presence of drugs (alcohol decreases GE, while metoclopramide- to treat nausea- increases GE)
o disease states e.g., gastric ulcer decreases GE, duodenal ulcer increases GE
o emotional state- depressed decreases, aggression increases GE
o exercise- life style factors
Gastric emptying
What is the effect of food on GE and drug absorption?
the presence of food can:
decrease absorption (extent and possibly rate)
delay absorption (decrease rate- not extent)
increase absorption (increase extent, may alter rate)
have little or no effect
note that there is a large intra- and inter-subject variation
note the presence of food can influence absorption due to factors other than GE- reasons not always well understood
Gastric emptying
Give examples of when absorption is decreased or delayed
**Decrease absorption (extent) **
e.g., fatty meal reduced ethanol absorption from stomach by 50%
retention of captopril in stomach reduces absorption
**Delayed absorption **
e.g., cephadrine (an antibiotic) absorbed slower due to their delayed entry into the small intestine
Tell me about the small intestine and effects with GE and absorption
o absorption works best here on all accounts
o large surface area (microvilli 200M2)
o good blood supply (1L blood/min compared to 150mL/min stomach)
o permeability to drugs greater
o thus GE is important
Tell me about intestinal motility/ transit?
- SI is major site of absorption
- Residence time in SI is important
- Transit down SI towards colon is very reproducible- 1-2 cm/s
- Transit time is especially important for:
o Sustained release (SR) and coated products
o Drugs which are absorbed at specific sites in intestine
o Drugs which dissolve slowly
Tell me about blood flow and gastric emptying
- GIT highly vascularised (good blood supply)
- However, a reduced blood flow may increase absorption of actively absorbed drugs e.g., phenylalanine (an amino acid)
- Procainamide (an anti-arrhythmic drug)- slowly and incompletely absorbed in patients with acute myocardial infarction
Tell me about GE and intestinal transit
- Food especially fat slows down gastric emptying
- Hastening gastric emptying quickens absorption
- About 30 mins drug to dissolve in stomach
- Anticholinergics- slow gastric emptying
- Metoclopramide- hastens emptying
- Binding- ion exchange resins (cholestyramine) bind several acidic drugs (e.g., warfarin, aspirin)
- Drugs competing for the same transporter
Absorption may be affected by enzymatically mediated drug metabolism that can occur in the:
a. Intestinal wall
b. The lumen of the intestine due to the presence of microbes in the gut used to treat ulcerative colitis and Crohn’s disease e.g., sulphasalazine (salicyclic acid derivative)
Whats the pH partition hypothesis?
Whats the effects of PKa?
Tell me about the ph partition hypothesis with GI absorption
o weak acids absorbed more rapidly from the stomach at pH 1.0 than at pH 8.0
o weak bases are absorbed more rapidly from the stomach at pH 8.0 than at pH 1.0
o small intestine
absorption of acids much quicker from the less acidic small intestine
What is meant by first pass metabolism?
The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation.
- a drug must pass sequentially through the gut wall, through the liver, before entering the general circulation (bioavailability)
- drugs may be destroyed by the acid in the stomach
- enzymes in GI tract
What are biologics?
Tell me about them
Proteins as drugs (biologics)
- absorption proteins (e.g., monoclonal antibody) given orally minimal
o due to extensive degradation
o poor intestinal permeability - most often given IV or IM
- absorption large proteins drugs (>20,000 Da) slow and via lymph
- half-life rate limited by absorption
What is Bioavailability (F)?
Is the proportion of drug (parent drug usually) that reaches the systemic circulation after oral compared to IV administration
IV administration: bioavailability= 1 (100%)- instantaneous for bolus intravenous administration
Other routes of administration= <1
Which is best? What would you choose to ease your pain?
Methadone, F=0.85
Diamorphine, F= 0.25
Morphine, F=0.45
Methadone as has the highest F
What is absolute bioavailability and how can it be calculated?
Assessed with ref to IV dose
F is measured by comparing the area under the curve (AUC) for oral against IV doses from zero to the time point for which elimination is complete
F= Dose/ AUC (iv) x AUC/ Dose (oral)
When comparing routes of administration, we try to determine amount of drug remaining to be absorbed (non-disintegrated/ dissolved dose) . How is this calculated?
This is calculated **amount absorbed relative to amount released **
Draw and label the blood level time curve after single oral administration
If administration compound is a prodrug, what is F and IV?
F measured on active metabolite
IV ref is to active metabolite
What is relative bioavailability used for?
Used when no IV data available
Used to compare F between formulations of drug given by route (tablet Vs intramuscular solution)
What are the uses of bioavailability?
Bioequivalence studies (for quality assessment)
Clinical trials (batch testing before marketing drug)
Generic substitution when produce comes off patent (calculation is usually innovators product and new preparation should be <20% different)
Comparison of routes of administration
Absolute bioavailability vs relative bioavailability
A drug must pass sequentially through what before entering the general circulation?
A drug must pass sequentially through the gut wall, through the liver, before entering the general circular (bioavailability)
Drugs absorbed after oral ingestion pass through what?
What can happen in this ‘first-pass’?
Drugs absorbed after oral ingestion pass through mesenteric circulation into the liver
In this “first-pass” drugs can be substantially metabolised
What can lead to reduced oral bioavailability?
Formulation: time taken for absorption
Poor intestinal permeability (general polar drugs like H2 antagonist Ranitidine; IV excreted unchanged; oral 66% absorbed 3-4h after admin)
Molecular w’t> 400g/nole (gentamycin)
Competing reaction (acid hydrolysis or enzymes)
* Hepatic extraction (first pass effect) that is drugs may be metabolised in the liver before reaching circulation
* Examples of such drugs include
o Desipramine, dextropropoxyphene, ketamine, lidocaine, morphine, nicotine, papaverine
What can increase oral bioavailability?
What strategies are there for improving absorption?
Alter physiochemical properties of the molecule
* Absorption weak acids and bases increases if use a salt form
Change formulation
Administer by different route
Do drugs which are readily metabolised by liver enzymes usually have a higher or lower F?
Lower F
What can first pass metabolism reduce and what can it metabolise the drug to?
- First-pass metabolism reduces the pharmacological action of the parent drug
- First-pass metabolism can metabolise a drug to its active form (pro drug)
Bioavailability (F) explained
- F= the fraction of dose reaching the systemic circulation as intact drug: F= FG.FH
FG= fraction reaching splanchnic circulation intact
FH= Fraction avoiding ‘First-pass’ hepatic extraction (= 1 – EH)
What is extraction ratio?
ER: magnitude of first pass (hepatic) effect
o **ER= CLH / Q **
o Where** Q is hepatic blood flow** (usually about 90L per hour {1500 ml/min})
o Systemic drug bioavailability (F) may be determined from the extent of absorption (f) and the extraction ratio (ER):
**F= f x (1-ER) **
Extraction ratio (ER) is the fraction of drug that is removed from the blood or plasma as it crosses the eliminating organ (e.g. liver or kidney).
Another pharmacokinetic term is absorption rate (Ka)
What is this and the different orders?
o Dependent on site of administration and drug formulation
o Zero order: drug absorption rate is independent of amount remaining in gut
o First order: drug absorption rate is proportional to the drug concentration dissolved in the gastrointestinal tract
Tell me about absorption rate: first order
And the different equations associated
o **Rate of absorption= Ka. Aa **
Where Ka is the drug absorption rate constant which reflects drug permeability
Aa is amount remaining to be absorbed
o The drug absorption **half-life t1/2a= 0.693/Ka **
o **Aa= F.De-Ka.t **
Where F is the fraction of the administered D (dose) that is available to be absorbed
Ka = ln(2) / t1/2a
Influence of Ka
Pharmaceutical formulation can be used to improve absorption, tell me how this can be done?
** Aspirin** (acetylsalicylic acid) one of the first synthetic pro drugs
* Produced to overcome taste and GI irritation of parent dutg salicyclic acid
* Was designed to be rapidly hydrolysed in body
* Dissolution time (surface area, solubility, pH and stirring)
** Coat tables** (erythromycin) so resistant to stomach acid (enteric coated products) but not intestinal fluids
**Retention in stomach ** of poorly soluble drugs (grisefulvin-antifingal agent) Eat with fatty food
Rapid release of controlled release forms
Absorption in older patients
Drug absorption is theoretically reduced in the order patients
* Due to loss of mucosal intestinal surface
* Decrease in GI blood flow
* Reduced gastric acidity
pH- brief notes
Define distribution
What can the rate and extent of distribution be derived from?
- Distribution refers to the **reversible transfer of drug from one location to another within the body **
- Definitive information on distribution of a drug in the body requires measurements in various tissues- difficult in humans
- Rate and extent of distribution can however be derived from blood or plasma
Several factors determine distribution pattern of a drug over time
o Ability of drug to cross the tissue membranes
o Extent of binding blood/tissues
o Partitioning into lipid/adipose tissue
Tissue concentration depends on…
o Physio-chemical properties of drug
Lipid solubility relates to ability to cross the BBB
o Blood flow
The intravenous route is characterised by the volume of distribution(V)
Intravenous route
* Rapidly places drug in blood
o Speeds up time to target site
* Distribution phase
o Time period in which drug in all tissues comes into equilibrium with that in plasma
* Characterised by
o Volume of distribution (V)
Whats an assumption with the distribution phase and tell me about this
Assumption: one compartment model
* The drug in blood is in rapid equilibrium with drug in the extra vascular tissues
* The drug concentration may not be equal in each tissue of fluid however, we will assume that they are always proportional to the concentration of drug in the blood
* This is not an exact representation however, it is useful for several drugs to a reasonable approximation
What is another assumption you make with distribution and what is this?
**Rapid mixing **
o We also need to assume that the drug is mixed instantaneously in blood or plasma
o The actual time taken for mixing is usually very short, within a few minutes
o In comparison with normal sampling times, it is insignificant
We usually don’t sample fast enough to see drug mixing in the blood
Whats another assumption for distribution following a one compartmental model and rapid mixing?
First order kinetics
Tell me about the first order kinetic assumption
**Linear model **
o We will assume that drug follows first order kinetics (dose dependent)- higher the dose the higher the concentration in blood stream
o First order kinetics means that the rate of change of drug conc by any process is directly proportional to the drug conc remaining to undertake that process
o If linear
If we double the dose, the conc will double at each time point
o Remember first order kinetics is an assumption of a linear model not a one compartment model
o Zero-order (constant elimination rate)
How do most drugs pass through the membrane?
Via diffusion
Tell me the different ways in which drugs can pass through the membrane and what these processes are?
o Passive diffusion- molecules move down a concentration gradient with movement because of the kinetic energy of the drug molecules
o Characterised by absence of competition between molecules and lack saturation
**o Carrier mediated system **
o Characterised by saturability, specificity, and competition inhibition
o Passive facilitate diffusion e.g., glucose transport
Glucose moves down concentration gradient as a passive process
At high plasma glucose con rate of transport glucose reaches a maximum
**o Active transport **
Distinguishing feature is the net movement of a drug against a concentration gradient, which can be large
Maintenance of this gradient requires metabolic energy
E.g., angiotensin-converting enzyme inhibitors via the dipeptide transport system
Distribution can be rate-limited by what?
**Perfusion or permeability **
* Some tissue membrane present “no” barrier to distribution (lipophilic drugs)
* Perfusion varies from 10mL/min/mL for lungs to 0.025 mL/min/mL resting muscle or fat
* Well perfused tissues take up a drug much more rapidly than poorly perfused ones
Tissue uptake of a drug is known as what?
Extravasation
Permeability-rate limitation arises particuarly for what?
The differences in ease of entry are a function of what?
For polar drugs diffusing across tightly knit lipoidal membranes
Differences in ease of entry are a function of both
o Lipid-to-water partition coefficient
o Degree of ionisation
What do acids/bases exist in solution as?
An equilibrium between unionised and ionised drugs
Whats the pH partition hypothesis?
PH partition hypothesis
o Only unionised non-polar (lipophilic) drugs penetrate the tissue cell membrane
o Increased accumulation of drug on side of membrane where pH favours ionised form
o At equilibrium concentration of unionised species is equal on both sides
Lipid-to-water partition coefficient,pH
o pH of gastric fluid varies 1.5-7.0
o urinary pH varies 4.5-7.5
o pH blood 7.5
With the Lipid-to-water partition coefficient what is the unionised form assumed?
unionised form is assumed to be lipophilic enough to transverse membranes- if not no transfer occurs irrespective of pH
The unionised fraction is controlled by pH and PKa of the drug according to what?
o **Henderson-Haselbalch equation **
o Thus for acids
**pH = Pka + Log10 (increased conc/ unionised conc) **
Henderson-Hasselbalch equation examples
Using warfarin as an example
o warfarin is an acid with pKa 4.8 that has equimolar concentration of unionised and ionised forms at pH 4.8
o that is 50% drug is unionised at pH 4.8
o only unionised drugs can transverse membranes
o at pH 5.8 the ratio is 10:1 in favour of the ionised drug (91% ionised)
o at pH 3.8 ionised 9% and unionised are 91%
Distribution of acidic drugs
- knowledge Pka is important
- very weak acids such as paracetamol (Pka 9.5), morphine (Pka 9.9) and essentially unionised at all pH values
o **Here the durg distribution (transport) is rapid ** - Acids with pKa 3.0-7.5 are subject to dramatic changes in rate of transport with** change in pH **
- Acids Pka <2.5 has very low unionised fraction and transport across even gut membrane is **very slow **
Distribution of basic drugs
- A base must be very weak pKa <5 for transport to be independent of pH
o E.g., caffeine (Pka 0.8) - Bases pH 5-11 will be transported dependent upon pH (amphetamine, methadone)
- At low pH of gastric fluids strong bases are in **ionised form and transport is slow **
**Question? **
Why on measuring total tissue concentration, does the general aesthetic thiopental enter the brain mush more rapidly than it does in the muscle tissue: yet, for penicillin the opposite is true
o Thiopental more lipid
o Drugs that enter BBB are best in lipophilic form, this is not the same issue for muscle tissue
o Thiopental likely to be a lipophilic drug, suggests that penicillin (an antibiotic) is a big molecules
What are many drugs bound to?
Plasma and tissue proteins
Whats the most important plasma protein?
albumin
Dynamic processes can affect what of protein binding?
“free”: drug concentration
What drug is pharmacologically active?
- Only **free **(non-bound) drug us pharmacologically active
Examples of drugs which are highly protein bound are
o Phenytoin (90%) are warfarin (99%)
o Small concentration free drug in plasma
o When the free drug has acting on target, the found drug will unbind from protein to maintain the effect of the free drug, whether that be long or short
Plasma protein binding examples
- Note only unbound drug fraction is able to bind to target site (active)
- Examples
o 100% unbound= lithium
o 20% unbound= quinidine
o 3%- 10%= methadone
o 2% unbound= oxazepam
o 0.5% unbound warfarin
conditions of altered binding, when is albumin decreased?
o Liver cirrhosis
o Serious burns to body
o Pregnancy
o Less protein = less binding = more free protein (transient effect)
Conditions of altered binding, when is Alpha1-acid glycoprotein increased?
o Myocardial infarction
o Surgery
o Crohn’s disease
o Trauma to body
o Rheumatoid arthritis
o more protein = more binding = less free protein (transient effect)
The fraction of the drug in the body located in the plasma depends on?
binding to both plasma and tissue
A drug may have great affintiy for plasma proteins but may still be located where?
A drug may have great affinity for plasma proteins but may still be located primarily in tissue if the tissue has an even greater affinity than that of plasma e.g., methadone
Distribution of plasma-protein bound drugs is restricted to where?
Whereas alcohol, distributes equally where?
Distribution of plasma-protein bound drugs (warfarin) restricted to plasma and extracellular fluid, whereas alcohol distributes equally into the total body water
When does multiple equilibria occur?
Multiple equilibria occur in plasma where drug can bind to various proteins
What do acidic and basic drugs bind to?
- Acidic drugs common bind to albumin
- Basic drugs bind to alpha1- acid glycoprotein
Where can binding also occur?
- Within tissue binding can also occur
- There may be partition into adipose tissue (fat)
Distribution of drugs into tissue depeneds on a number of factors. What are these factors
o Blood flow to tissues
o Partition co-efficient of the drug between blood and the tissue
o Degree of ionisation of the drug at plasma pH
o Molecular size of drug
o Extent binding to plasma, tissue proteins
Define volume of distribution, Vd
o Proportionality constant that relates the amount of drug in the body to the drug concentration in blood/plasma
- Mathematical ‘fudge’ factor where amount ‘A’ of drug in the body is related to ‘C’ concentration drug in plasma
- V Is not a physiological volume
- Never < blood or plasma volume but it can be much larger than total body water volume for some drugs
Vd
What is total body water comprised of?
What is the volume of total body water?
What does it assume?
**Total body water (TBW) **
o Assume a 70kg ‘man’
o Body is 60% water
o Density of water= 1kg/L
o Therefore, 70kg x 1L/kg x 0.6= 42L
For the body water compartments, what is the following…
Initial plasma concentration?
TBW?
Tissues/ fluids outside blood stream comprise main water compartment?
- Drug administered intravenously distributed immediately into blood
o Initial plasma concentration= dose /4L - Drug may be distributed the TBW (total body water)= 42 L
- Tissues/ fluids outside blood stream comprise main water compartment= 37 L
Define the apparent volume of distribution, V?
o V reflects the amount of drug left in the blood after all the drug has been absorbed; that is, the concentration in plasma after distribution of dose administered is complete
o V indicates the extent of tissue distribution
Magnitude V provides the extent of drug distribution but not the location of drug whats the volume of distribution if…
The drug is ‘held’ in the blood stream
Very little drug reamins in the blood stream
If drug is ‘held’ In the blood stream it will have a small volume of volume of distribution
If very little drug remains in blood stream has a large volume of distribution
What units is V expressed in?
L or L/Kg
Whats a simple equation which can be used to describe V?
**V= Ab/Cp **
V= the apparent volume of distribution
Ab= amount of drug present in the body
Cp= plasma concentration of the drug
What is apparent V a function of?
Apparent V is a function of the Pka (lipid vs water solubility) of the drug and extent to which plasma and tissue binding occurs
Plasma protein binding (Gibaldi and Koup 1981)
- Of note with plasma protein binding is variability within and between patients
- Degree binding expressed as a ratio bound-to-total drug concentration
o Ratio limit= 0 – 1.0 (0.9= highly bound)
o Fraction drug unbound in plasma = fu
Fu= Cu/C **
Where Cu= drug unbound in plasma;
Concentration drug in plasma= Cp**
o Binding is a function of the affinity of the protein for the drug
The rate of presentation to the tissue is the product of what?
blood flow= Q and arterial blood conc= Ca
Rate of presentation= Q.CA
How do you calculate the net rate of extravasation?
The net rate of extravasation is the difference between rates of presentation and leaving where Cv is the emergent venous concentration
**Net rate of uptake= Q.(CA – CV) **
What can therefore be used as one compartment?
- Blood and tissue can be viewed as one compartment (if no impediment to movement into tissue)
- Then: Cv is in equilibrium with that in tissue, CT
How can you estimate the fraction of drug in and outside of systemic circulation?
- Can estimate the fraction of drug in and outside of systemic circulation if know plasma volume (Vp) and volume of distribution (v)
**o Amount in plasma= Vp x concentration (Cp)
o Amount in body= V x C
o Fraction drug in plasma is Vp/V ** - V is larger than plasma compartment (>4L) only indicates that drug is present in tissues or fluids outside the department; actual sites can not be determined from this value
Summary for part III
Summary
* All drugs initially distribute into a the blood stream, which is known as the central compartment (Vc) before distributing into the tissues also known as the peripheral compartment (Vt)
* If a drug rapidly equilibrates within tissue compartment, then, for practical purposes, we use a one-compartment model which uses only one volume term, the apparent volume of distribution, V
Apparent volume of distribution (V) for intravenous bolus dose
Calculating V
- Need to know details for drug administration
o Amount administered (dose); units (mg, ug) - Need to know results of drug analysis
o Concentration of drug present (mg/L,ng/ml)
o Concentration= dose/V
Can rearrange to calculate V
A clinical example:
* A 30mg dose of the antidepressant Nortriptyline is administered to a patient iv
* A sample of blood drawn for analysis immediately after dosing shows a plasma concentration of 25µg/L
* What is the volume of distribution of this drug?
What does large V 1200L tell us about Nortriptyline?
Preferentially distributed in tissues not found in large concentration in blood must be lipophilic drug
Examples of apparent V for some drugs
- Value of V determined mainly by perfusion and protein binding by seldom has true physiological meaning
- For instance…
- Flurosemide V= 15L (highly protein bound)
- Ethanol V= 35L (distributed in body fluids)
- Digoxin extensively distributed and bound in extravascular tissues V= 450L
Vd or V is the factor which accounts for what?
Vd or V is the factor that accounts for all of the drug in the body and can be used to estimate the loading dose
What are loading doses used to achieve?
Whats the formula for a loading dose?
Loading doses are used to rapidly** achieve the desired plasma drug concentration **
Loading dose= (Vd)(Cp/(S)(F)
o Where Vd is the apparent Vd;
o Cp desired plasma concentration.
o S- salt factor 1 unless state (when a drug is administered in its parent form S= 1.0)
o F= bioavailability
In pharmacokinetics, a loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose. A loading dose is most useful for drugs that are eliminated from the body relatively slowly, i.e. have a long systemic half-life
If drug is known to be distributed into TBW, what dose (MG) is needed to obtain an initial plasma level of 5 mg/L in patient weighing 70Kg?
At a target concentration of 7.5mg/L of Theophyline is required by a 60kg patient. What is the loading dose given the following: Vd= 0.5 L/Kg; CL= 0.04 L/Kg/hr; T1/2 =9.3 hrs
Calculate an oral loading dose for digoxcin for a 70 kg man to produce a plasma concentration of 1.5 ng/ml, bioavailability 0.62, salt= 1, Vd is 7.3 L/Kg
What is the formula for volume of distribution?
Define **metabolism **
Irreversible biotransformation of drugs in the body–> typically involves making it more polar to enhance renal excretion
The function of drug metabolism is to convert lipophilic compounds (the parent drug) into more polar, hydrophilic compounds (metabolites) that can easily be dissolved in an aqueous environment such as blood, bile, or urine to thus efficiently be excreted from the body.
What nature of the drug is beneficial for absorption and distribution but not so beneficial for elimination?
**Lipophilic nature **is a bonus for absorption and distribution but a disadvantage for elimination
What does the process of metabolism involve?
Process involves changing lipophilic compounds into hydrophilic products (water soluble)
Biochemical process usually enzymatic
Metabolism is the major mechanism for ending the pharmacological activity of a drug. Few drugs will remain unchanged in the body. What are the most common pathways for biotransformation during metabolism?
- Most common pathways for biotransformation are oxidation, and reduction (phase 1 reactions)
**Occurs primarily in the liver **in 2 steps: Phase 1 oxidation and phase II conjugation
Conjugation usually comes last (phase 2 reactions)
What does drug metabolism in the liver depend on?
o Blood flow to the liver (QH)
o Activity of the enzyme in the liver
- Liver enzymes will chemically alter the drug to form ‘metabolites’ which are…?
o Inactive or
o Equally or more active than the parent drug e.g., allopurinol (treatment of gout)- active metabolite oxipurinol
Metabolism pathways
What is the elimination half-life (T1/2)?
What is it useful in estimating?
- **The time taken for the plasma concentration to decrease by half (50%) **
- Useful in estimating: **time to reach steady state concentration **
- Time for plasma concentration fall after dosing is stopped e.g., if patient has overdosed
- Frequency of dosing interval
Whats the formula to calculate half life?
What does the elimination half-life of a drug depend on and what its relationship to this?
What is Half-life a property of?
As it is independent of concentration, it is a property of first order processes
Elimination half-life
Why is a portion of an orally administered drug dose inactivated by the liver before reacing the systemic circulation and target organ?
Due to hepatic metabolism
Blood concentration- time curve after bolus IV injection
What stage is not present with bolus IV injection?
- No absorptive stage- only distribution and elimination
- The drug is immediately available (F=100%) upon administration i.e., a t=0
- All other routes of administration require an absorptive stage before the drug reaches the systemic circulation
Upon IV administration the fate of the drug mainly depends upon what?
And what assumptions can be made?
- Upon IV administration the fate of the drug mainly depends upon:
Rate of elimination (Ke); Rate of metabolism (Km) - We can make some assumptions:
o If Ke and Km are large- drug is rapidly cleared
o If Ke and Km are small- drug is slowly cleared
With single oral administration of a drug, what does a drug have to cross and what is this called? What t=? is the drug admnitered at?
- Drug has to cross the small intestinal membrane before it reaches the systemic circulation: **rate of absorption important (Ka) **
- Therefore, the drug is administered** t=0 **
o No drug is present in the systemic circulation (unlike IV administration)
In regard to single oral adminstration, what is the time lag?
- Period of time before drug begins to appear in the systemic circulation is known as Time lag
The Ka and Ke follow what kinetics order with single oral administration?
- Rate of absorption (Ka) and rate of elimination (Ke) follow first order kinetics I.e., depend on the concentration of the drug at the absorption site and in the blood circulation
Plasma concentration time curve after single oral administration
Optimal blood/plasma concentration time curve after single oral administration
Whats TD90?
Whats ED90?
Whats the therapeutic window?
- TD90= toxic concentration in 90% of patients
- ED90= minimum effective concentration in 90% of patients
- Therapeutic window- lies between these two levels
*** It is generally considered that the blood drug concentrations should reside within these limits **
What are some important parameters?
- Time of onset of action
- Time to reach peak concentration (Tmax)
- Peak concentration (Cmax)
- Intensity
- Duration of action
- The desired properties of the various parameters depend upon the condition being treated e.g.,
o Migraine- requires a short onset of action is desirable
o Arthritis- rapid onset is not critical
What is the rate of metabolism in the liver and the rate of elimination from the kidney is summarised by?
by the variable elimination rate constant (kelim)
What do most metabolism and elimination process operate by ?
Most metabolism and elimination process operate by first order processes- that is rate depends on concentration of drugs present
As most metabolism and elimination processes operate by first order processes, what is it important to use? How can this be done? What equation describes this?
- Therefore, important to use drug concentration at a specific time rather than over/ any time
- One way to do this is to collect plasma samples at set time intervals to obtains graph of plasma concentration over time
- Can be described by decay equation Cp= Cp e-kt
Plasma elimination half life
How many half-lives does it usually take to eliminate a drug from the body?
Kelim- elimination rate constant- can also be calculated by clearance and volume of distribution, give the formula?
- Usually takes 5-7 half-lives for a drug to be eliminated from the body
- Kelim- elimination rate constant- can also be calculated by clearance and volume of distribution
- T1/2 – 0.693 x (V/CL)
o Where CL is the clearance
o Where V is volume of distribution
How can drugs be eliminated from the body?
What is excretion and where does it primarily occur?
- Irreversible loss of drug or metabolite from the body
- Primarily via kidney (also bile, faeces, sweat, saliva, tears, expired air and breast milk)
Define clearance
May be defined as: volume per unit time (blood or plasma) that would be completely freed of drug to account for the elimination
What can clearance refer to?
May refer to: blood CLb or plasma CLp or Cb, Cp or Cu concentration of unbound or free drug, depending on the concentration measured
1. Most drugs follow first order (linear) kinetics
2. Some drugs follow zero-order (saturation) kinetics
Clearance is additive and is a function of elimination by all participating organs such as liver or kidney. Whats the formula for systemic clearance?
What is clearance usually constant over the therapeutic concentration range?
o Drug elimination systems are not saturated- therefore the absolute rate of elimination is a linear function of the drugs plasma concentration
o Important for insuring appropriate long-term drug dosing- correct stead-state drug concentrations
Tell me about renal clearance?
- Clearance of unchanged drug and metabolites
- Kidneys: most important organs for unchanged drug/ drug metabolites elimination
- Water-soluble compounds exhibit more efficient renal excretion compared to lipid soluble compounds
Clearance
Linking all components together
Total clearance formula?
What is the extraction ratio?
- Extraction ratio (ER) is fraction of drug presented to the elimination organ which is cleared after a single pass through the organ
- Some drugs excreted or metabolised so efficiently that most drug is removed
- Protein acts as transport system and clearance becomes dependent upon blood flow
- ER tends decrease when blood flow increases
What is a high extraction ratio?
- High enzyme activity
- Cause must plasma bound drug to be stripped off during transit through organ
- Intrinsic function enzyme is key
- Blood flow limits whole thing
What is a Low extraction ratio?
- Enzyme sluggish and metabolises drug at slow rate compared to blood flow
- Enzyme remains attached to protein
- Extend binding key factor
Examples of High, medium and low extraction ratio
What is Qh altered by ?
What is CLuint altered by?
Factors which alter clearance
- Body weight and body surface area
- Plasma protein binding
- High extraction ratio
- Renal function
- Hepatic function
- Decreased cardiac output
Hepatocyte
Plasma protein binding
- Fraction free drug does not vary with the drug concentration because binding sites far exceeds number drug molecules
- Controlled by binding affinity of the drug
- Plasma protein concentration
Displacement drug from plasma binding sites
- Often misunderstood
- Along will only lead to a temporary/ transient and modest increase in free drug concentration and effect
- Clinically significant interactions ascribed to it (e.g., warfarin/ phenylbutazone) can be explained by **inhibition of drug metabolism
**
Drugs most likely to elicit an increase in effects are those?
o >90% bound
o Low volume of distribution (<10L)
o Narrow therapeutic index
o High extraction/ parenteral route
What effects a drugs steady state?
What are the two things that affect how much drug accumulates between the first dose and a dose at steady state
- **Elimination constant or half life **
o We cannot control the half-life dosing interval - **The dosing interval **
o The dosing interval can be adjusted to suite the patients need
The goal of drug therapy is the ensure that the Css falls where?
Repeated drug administration results in drug accumulation that eventually reaches what?
What happens to the Css in the following circumstances?
* Dosing interval < drug half-life
* Dosing interval= half life
* Dosing interval > half-life
- **Dosing interval < drug half-life **–> Css will be much higher than concentration after first dose
- Dosing interval= half-life –> Css will be twice as high as the concentration after the first dose
- Dosing interval > half-life –> Css will be similar to the concentration after the first dose (because the drug is almost completely washed out before the next dose is given)
Drug levels must be maintained within certain limits to achieve what?
**o Maximum effectiveness
o Limit toxicity (min effective concentration- MEC)
o Minimise toxic concentration (MTC) **
- Must consider drug accumulation
- Time to reach steady state is a function of drug accumulation
When are loading doses usually only given?
Loading doses for narrow therapeutic drugs should only be administered where?
Formula for loading dose?
- Loading dose usually only given when an urgent need
- Loading doses for narrow therapeutic drugs should only be administered in clinical settings
- Lidocaine example of drug that would require a fast loaded dose due to treatment of life-threatening arrythmias
- LD= Cp x Vd
- Conboard is included when patients already taking the drug
Whats a maintenance dose?
- When an estimate of CL can be used to calculate the rate of administration or maintenance dose to produce a desired average plasma concentration at steady state
- Maintenance dose=
o (CL L/Hr)(CPs save) / (S) (F)
o L/ Hr – T= one hour
o S is purity of drug salt factor
o F is bioavailability
Example
**Explain these terms **
* PD
* ER
* CL
* C
* H
* R
* Extravasation
