Pharmacokinetics Flashcards
(79 cards)
1
Q
Explain the ADME scheme
A
2
Q
Drug passages across the biological membrane: Types of diffusion
A
Diffusion 1:
- Diffusion of un-ionized drugs is the most common and most important mode of traversing biological membranes; drugs difffuse passively down their concentration gradient.
- only the un-ionized form of drug can diffuse across biological membranes
Diffusion of drugs that are weak electrolytes:
- the degree of ionization of a weak acid or base is determined by the pK of the drug and pH of its environment accordin to the Henderson-Hasselbalch equation
- When the pK of a drug equals the pH of surroundings, 50% ionization occurs.
3
Q
What is the bioavailability of a drug?
A
Is the fraction of drug (administered by any route) that reaches the bloodstream unaltered.
4
Q
What does it mean when a measurment is expressed as the letter F?
A
- A measurment of the extent of a therapeutically active drug that reaches the systemic circulation and is available at the site of action is expressed as the letter F
5
Q
What is Absolute bioavailability?
A
it measures the availability of the active drug in systemic circulation adter non-intravenous administration (i.e after oral, rectal, transdermal, sc administration)
6
Q
How do we determine absolute bioavailability of a drug?
A
By a pharmacokinetic study to obtain a plasma drug concentration vs. time plit and area under curve (AUC) for the drug after both IV and non-IV administration
7
Q
How will the bioavailability of a drug given IV be?
A
It will habe an absolute bioavailability of F=1 while drugs given by other routes usually have an absolute bioavailability of less than one. (explained from the graph)
8
Q
What is Relative bioavailability?
A
This measures the bioavailability of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route.
9
Q
The absolute bioavailability of a drug administered by an extravascular route?
A
is usually less than one (F<1)
10
Q
What are the factors that can influence the Bioavailability?
A
- Poor absorption: from the GI tract or from application site
- Degradation or metabolism of the drug prior to absorption or due to hepatic –> first-pass effect
- whether a drug is taken with or without food will affect oral absorption
- other drugs taken concurrently may alter abosrption and metabolism –> interactions
- intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora
- disease states affacting liver metabolism or GI function will also have an effect.
11
Q
Sites of absorption by Oral administration:
A
Stomach:
- lipid-soluble drugs and weak acids, which are normally un-ionized at the low pH of gastric contents, may be absorbed directly from the stomach.
- weak bases and strong acids are not normally absorbed from this site, since they tend to be protonated at the pH of gastric contents. (ion trapping - accumulation)
Small intestine:
- Is the primary site of absorption of most drugs because of the very large surface area across which drugs, including partially ionized weak acids and bases, may diffuse.
- acids are normally absorbed more extensively from the small intestine than from the stomach, even though the intestine has a higher pH.
12
Q
What is the Noyes-Whitney equation?
A
It describes the rate of dissolution of oral administrated drugs.
13
Q
Factors that may alter absorption from the GI:
A
- Gastric emtpying: decreased emptying = decreased rate of aborption
- GI blood flow: difference between “blood flow limited” and “blood flow independent”
- Stomach acid and inactivating enzymes
- interaction with food or other drugs
- inert ingredients in oral preparation sor the special formulation
- the first-pass effect influences drug absorption by metabolism in the liver by biliary secretion
14
Q
Oral administration:
Tabel with location in the stomach, pH, membrane, blood supply, surface area, transit time, by-pass liver
A
15
Q
General considerations of parenteral administration:
A
- Parenteral generally results in more predictable bioavailability than oral administration
- With IV administration the drug is injected directly to the blood stream without absorption = 100% bioavailable
- its the most rapid means of introducing drugs to the body
- IM and SC: drugs can enter the capillaries directly thorugh pores between endothelial cells
- Depot preparations for sustained release may be administered by IM or SC routes, but some preparations may cause irritation and pain.
16
Q
Inhalation administration:
A
- results in rapid absorption because of the large surface area and rich blood supply of the alveoli.
- frequently used for gaseous anasthetics, but it is generally not practical.
- may be used for drugs that act on the airways, such as epinephrine and glucocorticoids to treat bornichal asthma.
17
Q
Intrathecal administration:
A
usefull for drugs that do not readily cross the blood-brain barrier
18
Q
Rectal administration:
A
- mnnimizes first-pass metabolism and may be used to circumvent the nausea and vomiting that sometimes result from oral administration
19
Q
Sublingual - Buccal administration:
A
useful for drugsh with high first-pass metabolism, such as nitroglycerin, since hepatic metabolism is bypassed.
(rarely in Veterinary medicine; eg uses for analeptics, sedatives)
20
Q
Topical administration:
A
- widely used when a local effect is desired or to minimize systemic effects, especially in dermatology and ophthalmology.
- preparations must be non-irritating.
- drugs administered topically may sometimes produce systemic effects.
21
Q
What is Distribution?
A
- It is a branch of PK which describes the reversible transfer of drug from one location to another within the body
22
Q
The process of distribution:
A
- the compund needs to be carried to its effector site, most often via the bloodstream
- drug distribution is the process which a drug leaces the blood stream and enters the extracellular fluids and tissues, or is the movement of a drug from the bloodstream to various tissues of the body
- From there, the compound may distribute into tissues and organs, usually to differing extents.
23
Q
The distribution of a drug between tissues is dependent on:
A
- permeability between tissues (between blood and tissue in particular)
- blood flow and perfusion rate of the tissue
- the ability of the drug to bind plasma proteins and tissue
24
Q
What is the VD of a drug?
A
- The Volume Distribution (VD) of a drug is a property that quantifies the extent of distribution
- “Volume of Distribution” is the volume of total body fluid into which a drug “appears” to distribute.
- it is defined as: the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration.
- Volume of distribution is determined by administering a known dose of drug (expressed in units of mass) IV and measruing the initial plasma concentration (mass/volume)
25
What is important for distribution if the site of action is intracellular?
A drug must diffuse accross the cellular membranes, and in this case lipid solubility is imprtant for effective distribution
26
What is the importance of blood flow in the distribution?
- in most tissues, drugs can leave the circulation readily by diffusion across or between capillary endothelial cells. Thus, the initial rate of distribution of a drug depends heavily on blood flow to various organs.
Bran, liver, kidney \> muscle, skin \> fat, bone
- at equilibrium the amount of drug in an organ is related to the mass of the organ and its properties, as well as to the properties of the drug.
27
What is Drug Redistribution?
- it descripves when the relative distributon of a drug in the body changes with time.
- this is usually seen with highly lipphilic drugs such as Thiopental that initially enter tissues with high blood flow (eg the brain) and then quickly redistribute to tisses with lower blood flow (eg skeletal muscle and adipose tissue)
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factors affecting drug distribution:
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Distribution: Binding of drugs by plasma proteins
- Drugs in the plasma may exist in the free form or may be bound to plasma proteins or other blood components, such as RBC´s.
- the extent of plasma protein binding is highly variable and ranges from virtually 0% to more than 99% bound, depending on the specific drug. Binding is generally reversible.
- only the free drug diffuses thorugh capillary walls; extensive binding retards the rate at which the drug reaches its site of action and may prolong duration of action
- some plasma proteins bind many different drugs, while other proteins bind only one or a limited number
- ef: serum albumin tends to bind many acidic drugs, while alpha1-acid glycoprotein and globulins tends to bind many basic drigs.
- there are a few, if any, documented changes in a grud´s effect due to changes in plasma protein binding.
30
Distribution: Proteins with potenital binding sites for Various Drugs:
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Barriers to drug distribution:
1. Blood-brain barrier:
- ionized or polar drugs distribute poorly to the CNS, including certain chemotherapeutic agents and toxic compunds, because they must pass thorugh, rather than between, endothelial cells.
- inflammation, eg from meningitis, mau increase the ability of ionized, poorly soluble drugs to cross the blood-brain barrier.
2. Placental barrier:
- lipid soluble drigs cross the placental barrier more easily than polar drugs; drugs with a molecular weight of less than 600 pass the placental barrier better than øarger molecules.
- consider mother - foetus
- drug transporters (eg P-glycoprotein transporter) transfer drugs out of the foetus.
32
Standard values of volumes of fluid compartments in an average:
33
Features of Volume of Distribution:
VD values for most drugs do not represent their actual distribution in body fluids. The use of VD values is primarily conceptual, that is:
- Drugs that distribute extensively have relatively large VD values and vice versa
- A very low VD value may indicate extensive plasma protein binding of the drug
- A very high value may indicate that the drug is extensively bound to tissue sites.
- among other variables, VD may be influenced by age, sex, weight, and disease processes (eg. oedema, ascites)
34
What is Biotransformation?
a major mechanism for drug elimination; most drugs undergo biotransformation, or metabolism, after they enter the body.
- Compounds begin to be broken down as soon as they enter the body. As metabolism occurs, the initial (parent) compound is converted to new compunds called metabolites.
- Biotransformation, which almost always produces metabolites that are more polar than the parent drug, usually terminates the pharmacologic action of the parent drug and, via excretion, increases removal of the drug from the body.
35
What are Xenobiotics?
- all organisms are constantly exposed to compound that they cannot use as foods and would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called Xenobiotics
36
How are Xenobiotics detoxified?
- Xenobiotics such as synthetic drugs, natural poisons and antibiotics are detoxified by a set of xenobiotic-metabolizing enzymes.
- these include Cytochrome P450 oxidases, UDP-glucuronosyl transferases, and Glutathione S-transferases.
- This system of enzymes acts in two stages to firstly oxidize the xenobiotics (phase 1) and then conjugate water-soluble groups onto the molecule (phase 2)
- the majority of small-molecule drug emtabolism is carried out in the liver by redox enzymes, termed cytochrome P450 enzymes
37
Possible consequences of biotransformation include:
the production of inactive metabolites (most common), metabolites with:
- increased or decreased potencies
- metabolites with qualitatively different pharmacologic actions
- toxic metabolites
- active metabolites from inactive prodrugs
38
Why does metabolites lead to a more rapid rate of clearance?
- metabolites are often more polar than the parent compounds and this increased polarity may lead to a more rapid clearance,
- because of possible secretion by acid or base carriers in the kidney it may also lead to decreased tubular reabsorption
39
Biotransformation of drugs is variable and can be affected by many parameters, such as:
- Prior administration of the drugs in question or of other drugs; diet, hormonal status, genetics, diseases (eg decreased in cardiac of pulmonary disease), age and developmental status (the very elderly and very young may be more sensitive to drugs, because of decreased or undeveloped levels of drug-metabolizing enzymes), and liver function (in case of severe liver damage).
40
Classification of Biotransformation reactions:
1. Phase 1 (nonsynthetic) reactions:
- involve enzyme-catalyzed biotransformation of the drug without any conjugates.
- includes: oxidations, reductions and hydrolysis reactions; they frequently introduce a functional group (eg. OH-) that serves as the active centre for sequential conjugation in a phase 2 reaction.
2. Phase 2 (synthetic) reactions:
- include conjugation reactions, which involve the enzyme-catalyzed combination of a drug (or drug metabolite) with an endogenous substance.
- phase 2 reactions require a functional group - an active centre - as the site of conjugation with the endogenous substance.
- phase 2 reactions require energy indirectly for the synthesis of "activated carriers", the form of the endogenous substance used in the conjugation reaction (eg. UDP-glucuronate)
41
Enzymes catalyzing phase 1 biotransformation reactions include:
- Cytochrme P-450, aldehyde and alcohol dehydrogenases, deaminases, esterases, amidases and epoxide hydratases
42
Enzymes catalyzing phase 2 biotransformation reactions include:
- Glucuronly transferase (glucuronide conjugation), sulfotransferase (sulfate conjugation), transacylases (amino acid conjugation), acetulases, ethylases, methulases and glutathione transferase.
43
Selected inducers and inhibitors of Cytochrome P-450 (CYP) enzymes 1:
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Selected inducers and inhibitors of Cytochrome P-450 (CYP) enzymes 2:
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Cytochrome P-450 catalyzes numerous reactions, including:
- Aromatic and aliphatic hydrocylations
- dealkylations at nitrogen, sulphur, and oxygen atoms
- heteroatom oxidations at nitrogen and sulphur atoms
- reductions at nitrogen atoms
- and ester and amide hydrolysis
46
What are the CYP3A subfamily resposible for?
- for up to half of the total cytochrome P-450 in the liver and accounts for approx. 50% of the metabolism of clinically important drugs.
- CYP3A4 is a particular abundant enzyme
47
Cytochrome P-450 monooxygenase Localization:
- primarily the liver, which has the greatest specific enzymatic activity and the highest total activity
- gut, lung, skin, kidneys
- adrenals, ovaries and testis, and tissues involved in steroidogenesis and steroid metabolism.
- the enzymes subcellular location is the Endoplasmic reticulum
- Lipid membrane location facilitates the metabolism of lipid soluble drugs
48
Cytochrome P-450 monooxygenase Mechanism of reaction:
- in the overall reaction, the drug is oxidized and oxygen is reduced to water.
- reducing equivalents provided by Nicotinamide adenine dinucleotide phosphate (NADPH), and generation of this cofactor is coupled to cytochrome P-450 reductase.
- the overall reaction for aromatic hydrocylation can be described as:
Drug + O2 + NADPH + H+ --\> Drug - OH + NADP+ + H2O
49
Cytochrome P-450 monooxygenase Genetic polymorphism:
- Genetic polymorphism of several clinically important CYP-450s, particularly CYP2C and CYP2D, is a source of variable metabolism in humans, indlucing differences among radical and ethnic groups.
- these enzymes have substantially different properties (Vmax or Km)
50
Cytochrome P-450 monooxygenase Induction:
- Induction is brought up by drugs and endogenous substances, such as hormones.
- any given drug preferentially induces one form of Cytochrome P-450 or a particular set of P-450s
- When caused by drugs, induction is pharmacologially important as a major source of drug interactions.
- a drug may induce its own metabolism (metabolic tolernace) and that of the other drugs catalyzed by the induved P-450
- Induction can be caused by a wide variety of clinically useful drugs (drug-drug interactions), such as: phenobarbital, omeprazole, rifampin, carbamazepine, and St. John´s wort.
51
Cytochrome P-450 monooxygenase - Inhibition:
- Competitive or non-competitive inhibition of CYP-450 activity can result in the reduced metabolism of other drugs or endogenous substrates such as testosterone.
- inhibition ccan be caused by a number of commonly used drugs, including Cimotidine, fluconazole, fluoxetine, and eryhromycin, and is another major source of drug - drug interactions.
- some of the same drugs that inhibit CYP3A4 can inhibit the drug efflux transporter P-glycoprotein (eg. amiodarone, clarithromycin, erythromycin, ketoconazole).
52
General features of Glucuronyl transferase:
(metabolism - biotransformation)
- it is a set of enzymes with unique but overlapping specificity that are involved in phase 2 reactions.
- it catalyzes the conjugation of glucuronic acid to a variety o active cetners, including -OH, -COOH, -SH, and -NH2
53
Mechanism of reaction of Glucuronyl transferase:
- UDP-glucoronic acid, the active gluvuronide donor, is formed from UTP and glucose-1-phosphate
- Glucuronyl transferase then catalyzes the conjugaton to the active center of the drug
54
Location and induction of Glucuronyl transferase:
- It is loated in the endoplasmic reticulum.
- it is the only ohase 2 reaction that is inducible by drugs and is a possible dite of drug interactions.
55
Routes of excretion:
- urine, faeces (e.g unabsorbed drugs and drugs secreted in bile)
- saliva, sweat, tears, milk (with possible transfer to neonates)
- and lungs (e.g alcohols and anaesthetics)
Any route may be important for a given drug, but the kidney is the major site of excretion for most drugs.
56
What is the Net renal excretion of drugs?
- it is the result of three separate processes: the amount f drug filtered at the glomerulus, plus the amount of drug secreted by active transport mechanisms in the kidney, less the amount of drug passively reabsorbed throughout the tubule.
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Filtration of drugs:
- most drugs have low molecular weight an are thus freely filtered from the plasma at the glomerulus.
- serum protein binding reduces filtration because plasma proteins are too large to be filtered
- the flomerular filtration rate is 30-40% lower during newborn´s firs year of life than adults
58
Secretion of drugs:
- the kidney proximal tubule contains two transport systems that may secrete drugs into the ultrafiltrate
- one for organic acids and a second for organic bases
- these systems require energy for active transport against a concentratin gradient; they are a site for potential drug-drug interactions because drugs may compete with each other for binding to the transporters
- plasma protein binding does not normally have a large effect on secretion because the affinity of the transport systems for most drugs is greater than the affinity of plasma binding proteins
59
Reabsorption of drugs:
- may occur throughout the tubule; some compounds, including endogenous compounds such as glucose, are actively reabsorbed.
- reabsorption of the un-ionized form of drugs that are weak acids and bases can occur by simple passive diffusion the rate of which depends on the lipid solubility and pK of the drug and also on the concetration gradient of the drug between urine and the plasma.
- Reabsorption may be affected by alterations of urinary pH, which also affect elimination of weak acids or bases by affecting the degree of ionization.
- Eg: acidification of the urine will result in a higher proportion of the un-ionized form of an acidic drug and will facilitate reabsorption
60
Renal clearance of drugs:
- a drug eccreted by filtration alone (eg insulin) will have a clearance equal to the glomerular filtration rate (GFR; 125-130 mL/min)
- A drug excreted by filtration and complete secretion (eg. para-aminohippuric acid PAHA) will have a clearance equal to renal plasma clearance 650mL/min
- clearance values between 130 and 650 mL/min suggest that a drug is filtered, secreted and partially reabsorbed.
61
Total body clearance (Cl):
- can be separated into clearance due to renal elimination, Cl, and clearance due to metabolism, Clm
- Clm = Km x VD (metabolic clearance)
- Cl = Clr + Clm
- Metabolic Clerance calculated from M and AUC and Cl = DOSE / AUC
62
Factors influencing renal clearance:
- age (some mechanisms of excretion may not be fully developed at the time of birth), other drugs and disease.
- in the presence of renal failure (resulting in higher plasma levels)
- for those drugs with a narrow therapeutic index, dose adjustment may be required.
63
Hepatic extraction of drugs:
- General extraction by the liver occurs because of the livers large size (1500g) and high blood flow (1 mL/g/min)
- the extraction rate is the amount of drug removed in the liver divided by the amount of drug entering the organ; a drug completely extracted by the liver would have an extraction ratio of 1.
- highly extracted frugs can have a hepatic clearance approaching 1500 mL/min
64
What are the First-pass effect?
- drugs taken orally pass across membranes of the GI tract into the portal vein and through the liver before entering the general circulation
- in the presence of a hepatic disease, drugs with a high first-pass extraction may reach the systemic circulation in higher than normal amounts, and dose adjustment may be required.
65
Bioavailability of orally administered drugs is decreased by?
- the fraction of drug removed by the firs pass thorugh the liver.
- eg: a drug with a hepatic extraction ratio of 1 would have 0% bioavailabilty;
- a drug such as lidocaine, with an extraction ratio of 0,7, would have 30% bioavailability
66
What are the Pharmacokinetic models?
- they are relatively simple mathematical schemes that represent complex physiologic spaces or processes.
- the most commonly used are Compartmental (one-compartment and two-compartment...) models.
67
What is the Non-compartmental PK analysis?
- It is highly dependent on estimation of total drug exposure (based on AUC) and highly dependent on the blood/plasma sampling schedule.
68
What is the Zero-order elimination?
- in this model, the plot of the log of the plasma concetration versus time will be concave upward, and a constant amoung of drug will be eliminated per unit time (e.g 10 mg of drug will be elininated every 8 hours)
- zero-order elimination may occur when therapeutic doses of drugs exceed the capacity of elimination mechanisms.
69
What is the First-order elimination?
- accounts for elimination of most drugs.
- it refers to the elimination of a constant fracion of drug per unit time;
- that is the rate of elimination is a linear function of the plasma drug concentration
- First-order elimination occurs when elimination systems are not saturated by the drug
- drug elimination is firs order;
70
What are the One-copartment open model?
- the body is seen as one continous fluid phase, into which drug is administered, and through which it diffuses.
- the term "open" describes the continous loss of drugs from the compartment due to metabolism and excretion.
- the openness of the body causes drug molecules to disengage from receptors and so terminated drug action.
71
Mathematical formula of One-compartment open model:
72
Elimination Half-life (T 1/2):
- Half life is the time it takes for the plasma drug concentration to be reduced by 50%
- this concept applies only to drugs eliminated by first-order kinetics.
- half-life is determined from the log plasma drug concentration versus time profile for drugs fitting a one-compartment model or from the elinimation phase for drugs fitting the two-compartment model.
- as long as the dose administered does not exceed the capacity of the elinimation systems (i.e the dose does not saturate those systems), the half-life will remain constant.
- the slope of the semilogarithmic plot is k, where k is the rate constant of elimination and has units of time-1, and the incercept on the y axis is C0.
73
Calculation of Half-life:
74
Pharmacokinetic parameters:
- C0, Cmax, Tmax, T 1/2el, AUC
75
Two-compartment open model:
- is a more common model for distribution and elimination of drugs.
- initial rapid changes in the plasma concentrtion of a drug are observed because of a distriution phase, the time required for the drug to reach an equilibrium distribution between a central compartment, such as the plasma space, and a second compartment, such as the aggregate tissues and fluids to which the drug distributes.
- after distribution, a more linear decrease in the log drug concentration is observed if the elimination phase is first order.
- for drugs that obey a two-compartment model, the value of C0 obtained by extrapolation of the elimination phase is used to calculate Vd, and the elimination rate constant, k, is obtained from the slope of the elimination phase.
76
The central compartment:
- allows rapid, more or less instantenous equilibrium.
- it can be though of as the blood, interstitial fluid and highly perfused organs such as heart, liver, lungs and kidney.
- the drug is both introduced and exists through the central compartment.
77
The peripheral compartment:
- comes to equilibrium with the central compartment more slowly, and can be though of as less well perfused organs such as skin, bone and fat.
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Non-compartmental PK analysis:
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