MT 1 Flashcards
1
Q
Agonist and types of agonists
A
-Agonists: molecules that by binding to their targets cause a change in the activity of targets.
o Full agonists: bind to and activate their targets to the maximal extent possible.
o Partial agonists: produce a submaximal response upon binding to their targets.
o Inverse agonists: cause constitutively active targets to become inactive.
2
Q
Antagonist and types of antagonists
A
-Antagonists: inhibit the ability of their targets to be activated (or inactivated) by agonists.
o Competitive antagonists: Drugs that directly block the binding site of a physiologic agonist
o Noncompetitive (allosteric)/uncompetitive antagonists: drugs that bind to other sites on the target molecule, and prevent the conformational change required for receptor activation (or inactivation)
* Require receptor activation by an agonist before they can bind to a separate allosteric binding site
3
Q
Major types of drug receptors
A
- Ligand-gated ion channels
- Voltage-gated channels
- G-protein-coupled receptors
- Receptor-activated Tyrosine kinases
- Intracellular nuclear receptors
4
Q
Ligand-gated ion channels
- Mechanism
- Example
A
- Drugs can bind to ion channels, causing an alteration in the channel’s conductance.
- Eg: Acetylcholine - nicotinic receptor (nonspecific Na+/K+ transmem. ion channel). Only 2 states: Open and Closed
- Mechanism: ACh interacts with nicotinic receptors -> open channels -> permit passage of ions (mostly Na+) -> Na+ current -> membrane depolarization -> resulting in the release of Ca2+ -> muscle contraction -> hydrolysis of ACh by AChE results in muscle cell repolarization
5
Q
Voltage-gated channels
A
(Sodium channels)
- Are able to become refractory / inactivated -> The channel’s permeability cannot be altered for a certain period of time.
- During this period, the channel cannot be reactivated for a number of milliseconds, even if the mem.pot.returns to a voltage that normally stimulates the channel to open -> State-dependent binding
6
Q
Two important classes of drugs which act by altering the conductance of ion channels
A
- Local anesthetics: block the conductance of Na+ ions through voltage-gated Na+ channels in neurons, preventing AP-propagation and pain perception (nociception).
- Benzodiazepines: inhibit neurotransmission in the CNS by potentiating the ability of the neurotransmitter GABA to increase the conductance of Cl-ions across neuronal membranes, preventing AP propagation and pain perception.
7
Q
G-protein-coupled receptors
A
G-protein-coupled receptors
-Heptahelical receptors spanning the plasma membrane are functionally coupled to intracellular G proteins.
-Types:
o Gαs (Gα stimulatory)-coupled receptors: Histamine (H2) and β-Adrenoceptors (1+2)
o Gαi (G inhibitory)-coupled receptors: (Somatostatine) α2-Adrenoceptors
o Gq (and G11)-coupled receptors: Serotonin, Histamine (H1) and α1-Adrenoceptors
8
Q
Gαs (Gα stimulatory)-coupled receptors
A
- Histamine (H2)-receptors: (brain, heart, vascular SMs, leukocytes, and parietal cells). Activation increases gastric acid prod, causes vasodilation, and generally relaxes SMs.
- β-Adrenoceptors: (post-junctional effector cells). Epinephrine/Adrenaline
• β1-receptors (excitatory): mediate incr. contractility (cardiac muscle) and HR, fat cell lipolysis
• β2-receptors (inhibitory): mediate vasodilation and intestinal, bronchial, and uterine SM-relaxation
9
Q
Gαi (G inhibitory)-coupled receptors
A
- Somatostatine
- Inhibit adenylyl cyclase, leading to reduced cAMP prod.
- α2-Adrenoceptors: prejunctional adrenergic nerve terminals.
- Prejunctional inhibition of release of norepinephrine and other neurotransmitters (α2)
- α2-Receptors activate (Gi) (like muscarinic M2-cholinoceptors)
10
Q
Gq (and G11)-coupled receptors
A
- Serotonin
- Histamine (H1)-receptors: brain, heart, bronchi, GI tract, vascular SMs, and leukocytes. Incr in diacylglycerol and IC Ca2.
- In the brain: incr wakefulness.
- In vessels: causes vasodilation and incr in permeability.
- α1-Adrenoceptors: postjunctional effector cells, vascular SM (excitatory)
- α-Adrenoceptors mediate vasoconstriction (α1), GI-relaxation (α1), mydriasis (α1)
- α1-receptors activate (Gq) (like muscarinic M1 and M3 cholinoceptors)
11
Q
Receptor-activated Tyrosine kinases
A
- Insulin
- Drugs can bind to the EC domain of a transmem. receptor and cause a change in signaling within the cell by activating or inhibiting an enzymatic IC domain of the same receptor molecule.
- Receptors that possess intrinsic tyrosine kinase activity.
- Ligand binding causes conformational changes in the receptor.
- Autophosphorylate tyrosine -> activation.
12
Q
Intracellular nuclear receptors
A
- Cortisol
-Drugs can diffuse through the plasma mem. and bind to cytoplasmic or nuclear receptors.
-Ligands: lipophilic, can diffuse rapidly through the plasma membrane.
o Absence of ligand: inactive receptors, because of interaction with chaperone proteins (HSP-90).
o Binding of ligand: structural changes in the receptor facilitate dissociation of chaperones, entry of receptors into the nucleus, hetero- or homodimerization of receptors, and high affinity interaction with the DNA of target genes.
13
Q
Tachyphylaxis
A
Repeated administration of the same dose of a drug results in a reduced effect of the drug over time.
14
Q
Desensitization
A
Decreased ability of a receptor to respond to stimulation by a drug or a ligand.
- Homologous: decr response at single type of receptor
- Heterogenous: decr response at two or more types of receptors
15
Q
Inactivation
A
Loss of ability of a receptor to respond to stimulation by a drug or ligand
16
Q
Down-regulation
A
Repeated or persistent drug-receptor interaction results in a removal of the receptor from sites where subsequent drug-receptor interactions could take place.
- Prolonged receptor stimulation by ligand induces the cell to endocytose and sequesters receptors in endocytic vesicles, resulting in cellular desensitization, by decr the number of receptors. If subsides, the receptors can be recycled to the cell surface and thereby rendered functional again.
- Cells also have the ability to alter the level of synthesis of receptors and thereby to regulate the number of receptors available for drug binding.
17
Q
Beta-adrenergic receptor regulation
A
a) Repeated or persistent stimulation of the receptor by agonist -> phosphorylation of amino acids at C-terminus of the receptor -> decr adenylyl cyclase (effector) activity.
b) Binding of Beta-arrestin also leads to receptor sequestration. The receptor can then be recycled and reinserted into the plasma membrane.
c) Prolonged receptor occupation by agnost can lead to receptor down-regulation and eventual receptor degradation. Cells can also reduce the surface receptors
18
Q
Neostigmine, Physostigmine
A
Indirect-acting parasympathomimetic agents inhibit AChE and increase ACh levels at both muscarinic and nicotinic cholinoceptors
19
Q
Which inhibitor does these enzymes have:
- AchE
- Cyclooxygenase
- Xanthine oxidase
- Dihydrofolate reductase
- DNA polymerase
- ACE
A
- AchE: Neostigmine
- Cyclooxygenase: Aspirin
- Xanthine oxidase: Allopurinol
- Dihydrofolate reductase: Trimethoprim, Methotrexate
- DNA polymerase: Cytarabine
- ACE: Enalapril
20
Q
Which false substrate does these enzymes have…
- Dihydrofolate reductase
- DNA polymerase
A
- Dihydrofolate reductase: Methotrexate
2. DNA polymerase: Cytarabine
21
Q
Antimetabolite action
A
S-phase specific drugs, structural analogues of essential metabolites and interfering with DNA synthesis -> Cytarabine, Fluorouracil, Mercaptopurine, Thioguanine.
22
Q
Antacids
A
Weak bases that partially neutralize gastric acid.
o Reduce pain associated with ulcers and may promote healing.
o Act nonspecifically by absorbing or chemically neutralizing stomach acid.
o Eg: Sodium bicarbonate, Magnesium hydroxide
23
Q
Osmotic agents
A
o Salt-containing osmotic agents: Mg-sulphate, Mg-citrate, Mg-hydroxide, sodium phosphates.
o Salt-free osmotic agents: glycerin, lactulose -> Alter water and ion balance by changing the osmolarity in the nephron directly
24
Q
Metal-chelating agents
A
Usually contain two or more electronegative groups that form stable coordinate-covalent complexes with cationic metals that can then be excreted from the body.
o EDTA: administered im or by iv infusion as the disodium salt of calcium.
o Deferoxamine: specific iron-chelating agent that binds with ferric ions to form ferrioxamine; it also binds to ferrous ions.
25
What is the fraction of receptors in each state dependent on at equilibrium?
The dissociation constant Kd (intrinsic property of any given drug–receptor pair). Kd = Koff/Kon.
26
When does maximum drug–receptor binding occur?
When [LR]= [Ro] -> [LR]/[Ro] = 1.
27
Kd
Equilibrium dissociation constant for a given drug–receptor interaction
= The conc of ligand at which 50% of the available receptors are occupied
28
What does Lower Kd mean?
= tighter drug–receptor interaction (higher affinity)
29
1. More potent drugs
| 2. More efficacious drugs
1. More potent drugs: those having higher affinity for their receptors (lower Kd)
2. More efficacious drugs: those causing a higher proportion of receptors to be activated.
30
Difference bw. partial agonists and full agonists
Both bind to the same site of the receptor, but partial agonists can reduce the response produced by a full agonist, ie. can act as a competitive antagonist = “mixed agonistantagonists.”
31
Classification of antagonists
1. Receptor antagonist:
a) Active site binding: prevents the binding of agonist to the receptor
-Reversible antagonists: competetive
-Irreversible antagonists: noncompetetive
b) Allosteric binding: either alters the Kd for agonist binding or prevents the conformational change required for receptor activation.
Both noncompetetive:
-Reversible antagonists
-Irreversible antagonists
2. Non-receptor antagonist: Inhibits the ability of an agonist to initiate a response without binding to the receptor for agonist.
a) Chemical antagonists: inactivate an agonist (by modifying or sequestering it) before it has the opportunity to act
b) Physiologic antagonists: cause a physiologic effect opposite to that induced by the agonist.
32
Difference bw. competetive and noncompetetive antagonists
- Competitive antagonist: reduces the potency of an agonist, without affecting the agonist’s efficacy.
- Noncompetitive antagonist: reduces the efficacy of an agonist.
33
Types of dose–response relationships
-Graded dose–response relationships
34
Graded dose–response relationships
Describe the effect of various doses of a drug on an individual
35
Graded dose–response curves
Effect of drug as function of its concentration.
36
Potency (EC50)
Concentration at which the drug elicits 50% of its maximal response
37
Efficacy (Emax)
The maximal response produced by the drug.
State at which receptor-mediated signaling is maximal and, therefore, additional drug will produce no additional response.
38
Quantal dose-response relationships
- Describe the effect of various doses of a drug on a population of individuals
- Fraction of population responding to a given dose of a drug as a function of the drug dose.
39
Median effective dose (ED50)
Effectiveness.
| Dose at which 50% of animals exhibit a therapeutic response to a drug
40
Median toxic dose (TD50)
Toxicity (adverse effect)
| Dose at which 50% of animals experience a toxic response
41
Median lethal dose (LD50):
Lethality (lethal effect)
| Dose at which 50% of animals die
42
ED50
Dose at which 50% of animals respond to a drug
43
EC50
Dose at which a drug elicits a half-maximal effect in an individual animal.
44
Therapeutic Window
| "Small therapeutic window"
Range of doses (concentrations) of a drug that elicits a therapeutic response, without unacceptable adverse effects (toxicity), in a population of patients.
-Small therapeutic window: plasma drug levels must be monitored closely to maintain effective dosing without exceeding the level that could produce toxicity.
45
Therapeutic Index (TI)
- "Large TI"
- "Small TI"
Ratio that quantities the therapeutic window
TI = [TD50] / [ED50]
-Large TI: a large/“wide” therapeutic window (for example, a thousand-fold difference between the therapeutic and toxic doses)
-Small TI: a small/“narrow” therapeutic window (for example, a twofold difference between the therapeutic and toxic doses).
46
Drugs can be toxic, because of?
o Genetic predisposition
o Nonselective action
o Inappropriate use or administration of the drug
47
FACTORS INFLUENCING DRUG TOXICITY
- Age, genetic makeup, preexisting conditions, dose administered, and other drugs the patient may be taking.
- Drug metabolism, genetic factors
48
Types of adverse effects
```
1. “On-target” adverse effects: Result of the drug binding to its intended receptor, but:
o At an inappropriate conc.
o With suboptimal kinetics
o In the incorrect tissue
2. “Off-target” adverse effects: Caused by the drug binding to a target or receptor for which it was not intended.
3. Production of toxic metabolites
a) Non-covalent interactions
b) Defense mechanisms
4. Production of harmful immune response
a) Hypersensitivity responses
b) Idiosyncratic responses
```
49
Lipid peroxidation
- Type of adverse effect, with non-covalent interactions of toxic metabolites production.
- Peroxidation of unsaturated lipids initiated by reactive metabolites or by reactive oxygen species
50
Example of adverse effect - defense mechanisms which produces toxic metabolites
- Generation of toxic reactive oxygen species
- Depletion of glutathione (GSH)
- Modification of sulfhydryl groups
51
Types of hypersensitivity responses
-Type I (immediate hypersensitivity): results from production of IgE after exposure to Ag. Subsequent exposure to the Ag -> mast cells degranulation -> release of inflam. mediators (Histamine, leukotriens) -> bronchoconstriction, vasodilatation, inflammation.
-Type II (antibody dependent cytotoxic hypersensitivity): drug binds to cells and is recognized by an Ab -> lysis of cell by complement fixation/action of cytotoxic T cells/ phagocytosis by macrophages -> Rare adverse responses to several drugs (penicillin, quinidine)
-Type III (immune complex-mediated hypersensitivity): Ab are formed against soluble Ag. Ag-Ab complexes are deposited in tissues -> Serum sickness: leukocytes and complement are activated within the tissues
-Type IV (delayed-type hypersensitivity): activation of TH1 and cytotoxic T cells. A substance acts as a hapten and binds to host proteins (contact dermatitis).
- The first exposure does not produce a response
- The subsequent dermal exposures can activate Langerhans cells, which migrate and activate T cells. The T cells return to the skin and initiate an immune response.
(latex allergies)
52
“Cytokine storm”
Repeated exposure to a drug recognized as a foreign substance causes a massive immune response.
Can lead to fever, hypotension, and organ failure.
53
What is required for the four types of hypersensitivity responses
Prior exposure to a substance
54
Autoimmune reactions
The organism's immune system attacks its own cells
| Eg. Procainamide can cause a lupus-like syndrome by inducing antibodies to DNA.
55
Idiosyncratic responses
Rare adverse effects for which no obvious mechanism is apparent.
-Difficult to explain and often difficult to study in animal models, precisely because the genetic variation that may be causing the adverse response is not known.
56
Pharmacokinetic properties: ADME
o Absorption: process of a substance entering the body.
o Distribution: dispersion/dissemination of substances through fluids/tissues
o Metabolism: transformation of substances and daughter metabolites.
o Excretion: elimination of substances from the body.
ADME influence drug levels and kinetics of drug exposure to tissues -> performance and pharmacological activity of a drug.
57
TRANSPORT MECHANISMS OF DRUGS
1) Transcellular transport
a. Diffusion
b. Filtration
c. Facilitated diffusion
d. Active transport
e. Pinocytosis
2) Intercellular transport
58
Transcellular transport
Across cell-membranes, layers or membrane-pores
o Semipermeable/Selective membrane: allows certain molecules or ions to pass through it by diffusion or facilitated diffusion. (Lipid bilayer)
o Permeability may depend on: solute size, solubility properties, and chemistry.
59
What does the Rate of passage depends on
pressure, concentration and temperature of molecules/solutes, permeability of the membrane to each solute.
60
Which is the most permeable to small, uncharged solutes?
Phospholipid bilayer
61
What is diffusion influenced by?
- Lipid–water partition coefficient of the drug = Ratio of solubility in organic solvent / solubility in aqueous solution.
- Absorption increases as lipid solubility (partition coefficient) increases.
62
What is the degree of ionization of a weak acid or base determined by?
pK of the drug and pH of its environment (Henderson-Hassel Balch equation).
63
ABSORPTION
Movement of a drug into the bloodstream
64
Phases of absorption
1. Administration of drug in a specific route and dosage. The drug must be absorbed before any medicinal effects can take place. (drug's pharmacokinetic profile)
2. Has to be taken in to the bloodstream (via mucous surfaces)
3. Uptake into the target organs or cells (cf. drug distribution)
65
Which factors will reduce the extent of absorption after administration?
Factors such as poor compound solubility, chemical instability in stomach, and inability to permeate intestinal wall
66
What is the determining the compound's bioavailability?
Absorption
67
Bioavailability (F)
= Fraction of drug that reaches the bloodstream unaltered (IV = 1).
= Measurement of the extent of a therapeutically active drug that reaches the systemic circulation and is available at the site of action.
68
Absolute bioavailability
Availability of the active drug in systemic circulation after non-IV administration.
69
Relative bioavailability
Measures the bioavailability of a certain drug when compared with another formulation of the same drug
(i.e. Absolute Bioavailability if other formulation is IV)
70
Factors influencing Bioavailability
These factors reduce the availability of drugs prior to their entry into the systemic circulation.
o Poor absorption from the GI-tract or from application site
o Degradation or metabolism of the drug prior to hepatic absorption
o First-pass effect
o Whether a drug is taken with or without food will affect oral absorption
o Other drugs taken concurrently may alter absorption and metabolism interactions
o Intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora.
o Disease states affecting liver metabolism or GI-function
71
DISTRIBUTION
= reversible transfer of drug from one location to another within the body.
- Process by which a drug leaves the bloodstream and enters the extracellular fluids and tissues
72
The distribution of a drug between tissues depends on?
o permeability bw tissues (esp. bw blood and tissues)
o blood flow and perfusion rate of the tissue
o ability of the drug to bind plasma proteins and tissue.
73
What is important for effective distribution?
Lipid solubility: Intracellular site of action: The drug must diffuse across cellular membranes
74
Initial rate of distribution of a drug depends heavily on?
Blood flow to various organ: brain, liver, kidney > muscle, skin > fat, bone
75
At equilibrium/steady state: what is the amount of drug in organ is related to?
o the mass of the organ and its properties
| o the properties of the specific drug
76
How does drug redistribution work?
The relative distribution of a drug in the body changes with time. The highly lipophilic drugs will initially enter tissues with high blood flow (e.g., brain) and then quickly redistribute to tissues with lower blood flow (e.g., skeletal muscle, adipose tissue).
77
Factors affecting drug distribution
- Medicinal substance: Dose, application route
- Rate of distribution: Membrane permeability, blood perfusion
- Extent of distribution: Lipid solubility, pKa, plasma protein binding, Intracellular binding
78
What can extensive binding do?
It retards the rate at which the drug reaches its site of action and may prolong duration of action.
79
Barriers to drug distribution
-Blood-Brain Barrier (BBB): ionized or polar drugs distribute poorly to the CNS (because they must pass through, rather than bw, endothelial cells)
-Placental barrier (PB) :
o Lipid-soluble drugs cross the placental barrier more easily than polar drugs
o Drugs with molecular weight <600 pass PB better than larger molecules.
80
What can increase the ability of ionized, poorly soluble drugs to cross BBB?
Inflammation
81
Volume of distribution (VD)
= volume of total body fluid into which a drug “appears” to distribute. (quantifies the extent of distribution)
-volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration
82
Determination of VD (liter)
By administration of a known dose of drug (mass) iv and measuring the initial plasma conc (mass/volume):
Vd = amount of drug administered (mg)/initial plasma conc Co (mg/L)
-Co: determined by extrapolation from the elimination phase
83
Features of volume of distribution
- What does a very low/very high Vd indicate?
- What is Vd influenced by?
Vd values for most drugs do not represent their actual distribution in body fluids.
- 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.
- Vd may be influenced by age, sex, weight, and disease processes (e.g., edema, ascites).
84
Biotransformation
Major mechanism for drug elimination after it enters the body
- Compounds begin to be broken down as soon as it enter the body
- Initial/parent compound is converted to new compounds
- It ends pharmacologic action of parent drug and, via excretion, increases removal of drug
85
Xenobiotics
Compound with no metabolic function that, since it can’t be used as foods by the organism, can be harmful if accumulated in cells.
-Synthetic drugs, natural poisons and antibiotics
86
Which stages is the system of xenobiotic-enzymes?
o Oxidizes the xenobiotic (phase I)
| o Conjugates water-soluble groups onto the molecule (phase II).
87
The majority of small-molecule drug metabolism is carried out how?
In the liver by redox enzymes, termed cytochrome P450 enzymes.
88
Possible consequences of biotransformation
Production of:
- inactive metabolites (most common)
- metabolites with increased or decreased potencies
- metabolites with qualitatively different pharmacologic actions
- toxic metabolites
- active metabolites from inactive pro-drugs.
89
What causes decreased tubular reabsorption?
Increased polarity of metabolites -> more rapid rate of clearance because of possible secretion by acid or base carriers in the kidney
90
What is biotransformation catalyzed by?
Specific enzyme systems, which may also catalyze the metabolism of endogenous substances (steroid hormones)
91
What can biotransformation be affected by?
Many parameters:
- prior administration of the drug or other drugs
- diet
- hormonal status
- genetics; diseases
- age
- developmental status (very elderly and very young may be more sensitive to drugs)
- liver function)
92
Classification of biotransformation reactions
1. Phase I (non-synthetic) reactions = enzyme-catalyzed biotransformation of drug without any conjugations.
o Oxidations, reductions, hydrolysis reactions
o Cytochrome P-450, aldehyde and alcohol dehydrogenase, deaminases, esterases, amidases, and epoxide hydratases
2. Phase II (synthetic) reactions = enzyme-catalyzed combination of drug (or drug metabolite) with endogenous substance = Conjugation reactions.
93
What does phase II of biotransform. reactions require
o A functional group - active centre - site of conjugation with endogenous substance.
o Energy indirectly for synthesis of “activated carriers,” the form of the endogenous substance used in conjugation reaction (e.g., UDP-glucuronate).
94
Which enzymes of the biotransform. reactions are inducible by drugs?
Only those enzymes located in the endoplasmic reticulum
95
Cytochrome P-450 monooxygenase
Mixed function oxidase.
| The most frequently enzyme system involved in phase I reactions.
96
Which reactions does cytochrome P-450 monooxygenase catalyze?
o aromatic and aliphatic hydroxylation
o dealkylations at nitrogen, sulphur, and oxygen atoms
o heteroatom oxidations at nitrogen and sulphur atoms
o reductions at nitrogen atoms; and ester and amide hydrolysis
97
CYP3A subfamily
o Responsible for up to half of total CYP-450 in liver
| o Accounts for approximately 50% of metabolism of clinically important drugs.
98
Localization of drug metabolism
- Primarily in liver: greatest specific enzymatic activity and highest total activity,
- Also found in many other tissues: adrenals, ovaries and testis, tissues involved in steroidogenesis and steroid metabolism.
- Subcellular location: endoplasmic reticulum.
- Lipid membrane location: facilitates the metabolism of lipid-soluble drugs.
99
Mechanism of drug metabolism
-Overall reaction = Aromatic hydroxylation
o Drug is oxidized and oxygen is reduced to water
o Reducing equivalents are provided by NADPH
o Generation of this cofactor is coupled to cytochrome P-450 reductase.
100
Genetic polymorphisms
Clinically important in CYP-450s, particularly CYP2C and CYP2D.
These enzymes have substantially different properties (Vmax or Km).
101
Induction of drug metabolism
- By drugs and endogenous substances, such as hormones.
- Any given drug preferentially induces 1 form CYP-450 or a particular set of P-450s.
- A drug may induce its own metabolism and that of other drugs catalyzed by the induced P-450.
- Can be caused by wide variety of clinically useful drugs
102
Inhibition of drug metabolism
- Competitive or non-competitive reduced metabolism of other drugs or endogenous substrates.
- Can be caused by a number of commonly used drugs
- Major source of drug–drug interactions.
103
Glucuronyl transferase
Set of enzymes with unique but overlapping specificities, involved in phase II reactions.
- Catalyzes conjugation of glucuronic acid to variety of active centers
o -OH, -COOH, -SH, and -NH2.
104
EXCRETION - ELIMINATION
= Removal of compounds and their metabolites from body, usually through the kidneys (urine) or in feces.
105
Incomplete excretion
Accumulation of foreign substances adversely affecting the normal metabolism.
106
Routes of excretion
- Urine, feces (e.g., unabsorbed drugs, drugs secreted in bile), saliva, sweat, tears, milk (possible transfer to neonates), and lungs (alcohols and anesthetics)
- The kidney is the major site of excretion for most drugs.
- Some drugs are secreted by liver cells into the bile, pass into the intestine, and are eliminated in the feces
- Drugs may be also be reabsorbed from the intestine (i.e., undergo enterohepatic circulation) -> prolonged persistence of a drug in the body
107
Net renal excretion of drugs
Result of three separate processes:
The amount of drug filtered at the glomerulus
+ the amount of drug secreted by active transport mechanisms in the kidney
– minus the amount of drug passively reabsorbed throughout the tubule.
108
How is most drugs filtrated?
Low molecular weights -> freely filtered from plasma at glomerulus
109
What reduces the filtration?
-Serum protein binding (plasma proteins too large to be filtered)
110
Glomerular filtration rate
30–40% < during newborns' 1st year of life than in adults
111
Where does secretion happen?
Kidney proximal tubule
| = two transport systems secreting drugs into the ultrafiltrate: one for organic acids and a second for organic bases.
112
What does secretion require?
Energy for active transport against a concentration gradient
113
Where does reabsorption happen?
Throughout the tubule
114
Which compounds need active reabsorption?
Endogenous compounds (such as glucose)
115
Which compounds have simple passive diffusion for reabsorption?
Un-ionized form of drugs (weak acids and bases).
116
Reabsoprtion rate depends on?
o lipid solubility and pK of drug
| o conc. gradient of drug bw urine and plasma
117
Reabsorption may be affected by?
Alterations of urinary pH, (also affect elimination of weak acids/bases by affecting the degree of ionization).
118
Renal clearance of drugs
```
The volume of plasma which get filtered of drug per unit time
CL (ml/min) = U x V/P
U=concentration of drug/ml of urine
V=volume of urine excreted/minute
P=concentration of drug/ml of plasma
```
119
GFR-Glomerular filtration rate
Drug excreted by filtration alone (e.g. insulin) (GFR = 125-130 mL/min)
120
RPC-Renal Plasma Clearance
Drug excreted by filtration and complete secretion (eg. paraaminohippuric acid, PAH) (RPC = 650 mL/min)
121
Total body clearance (CL)
Clearance due to renal elimination (CLr) + clearance due to metabolism (CLm)
CL = CLr + CLm (CL=DOSE/AUC)
o CLr = ke x VD (renal clearance)
o CLm = km x VD (metabolic clearance) -> calculated from M and AUC
122
Factors influencing renal clearance
```
o age (some mechanisms not fully developed at birth), other drugs, and disease
o renal failure: clearance may be reduced significantly -> higher plasma levels
o drugs with a narrow therapeutic index: dose adjustment may be required
```
123
Hepatic extraction of drugs
Possible thanks to liver's large size (1500 g) and high blood flow (1 mL/g/min).
124
Extraction ratio of hepatic extraction
Amount of drug removed in liver divided by amount of drug entering the organ
o Drug completely extracted by liver: extraction ratio of 1
o Highly extracted drugs: hepatic clearance approaching 1500 mL/min
125
First-pass effect
Drugs taken orally pass across membranes of GI tract into portal vein and through liver before entering general circulation.
126
What happens with the first-pass effect during Hepatic disease?
Drugs with a high first-pass extraction may reach systemic circulation in higher than normal amounts (dose adjustment required)
127
How is the bioavailability of orally administered drugs affected?
It is decreased by the fraction of drug removed by the first pass through the liver.
- Drug with a hepatic extraction ratio of 1 -> 0 % bioavailability
- Lidocaine: extraction ratio of 0.7 -> 30 % bioavailability
128
PHARMACOKINETIC MODELLING
- Simple mathematical schemes representing complex physiologic spaces or processes.
- Most commonly used pharmacokinetic models: compartmental (one-compartment and two-compartment) models.
129
Pharmacokinetics
Describes changes in plasma drug concentration over time.
130
Zero-order elimination/kinetics
Plot of the log of the plasma concentration vs. time = concave upward - a constant amount of drug will be eliminated per unit time
-May occur when therapeutic doses of drugs exceed capacity of elimination mechanisms.
131
First-order elimination
Elimination of most drugs.
- Elimination of a constant fraction of drug per unit time; rate of elimination is a linear function of the plasma drug concentration.
- Occurs when elimination systems are not saturated by the drug.
132
One-compartment open model
Following a single IV administration: Cp = Bxe^-βxt
o Cp : drug concentration in plasma,
o B : zero-time intercept with plasma drug conc in plasma (C0),
o β (ke) : elimination rate (constant)
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Elimination Half-life (T1/2)
T1/2 = ln2 / β (ln2 = O,693)
T1/2 = 0.693 x Vd/CL
= Time it takes for the plasma drug conc to be reduced by 50%.
- Applies only to drugs eliminated by first-order kinetics.
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Co
Plasma conc. at time zero: The plasma conc. at zero time. Determined by extrapolating the plasma conc. versus time curve back to the T (conc.) axis.
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Cmax
Peak plasma conc.: highest plasma conc. achieved following a single non-iv. dose of a drug.
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Tmax
Time of the peak plasma conc.: The time that the Cmax is achieved following a single non-iv. dose of a drug.
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T1/2el
Half life of elimination: Time required to eliminate 50% of any amount of drug from the body.
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AUC
Area under curve: The are under the curve in a plot of conc. of drug in plasma against time. Represents the total amount of drug absorbed by the body, irrespective of the rate of absorption.
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Two-compratment open model
More common model for distribution and elimination of drugs
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Distribution phase
Time required for drug to reach equilibrium distribution between a central compartment (plasma space), and a second compartment, (aggregate tissues and fluids) to which the drug distributes.
o Initial rapid changes in the plasma conc of a drug
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Types of compartments
- Central compartment: allows rapid, +/- instantaneous equilibrium.
* blood, interstitial fluid and highly perfused organs (heart, liver, lungs and kidneys).
* drug is both introduced and exists through the central compartment.
- Peripheral compartment: comes to equilibrium with central compartment more slowly
* less well perfused organs (skin, bone and fat).
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Intravenous administration
Cp = Axe–αxt + Bxe–βxt
- A and B : intercept terms, based on distribution (A – exponential) and elimination (B – linear) phases of the biphasic disposition curve.
- α and β : hybrid rate constant associated with the bi-exponential expression that mathematically describes the disposition curve.
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Extravascular administration
Triexponential equation: Cp = -Nxe-kaxt + Axe–αxt + Bxe– βxt
Ka: absorption rate constant (considerably greater in value than the other two)
Axe-αxt: absorption into compartment 1 (blood)
Bxe-βxt: terminal elimination in compartment 2 (tissues)
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What is noncompartmental PK analysis dependent on?
Highly dependent on estimation of total drug exposure.
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Total drug exposure is estimated how?
Estimated by Area Under the Curve methods
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How can Plasma concentration (C)–time and (n) profile be described?
In terms of Slopes and Heights (i), Areas and Moments (SHAM)
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Repeat administration
Repeated administration of drug eliminated by first-order kinetics: increase of average plasma conc until mean steady-state level is reached
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Interval of time required to reach steady state
5x T1/2
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Steady state
Average plasma conc and range of fluctuations above and below that level
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Fluctations of steady state
o high point of the steady state range shortly after dose administration
o low point immediately before administration of the dose.
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How can the magnitude of fluctuations be controlled?
By the dosing interval:
o A shorter dosing interval decreases fluctuations
o A longer dosing interval increases them.
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Loading dose
-Needed when therapeutic conc of drug in plasma must be achieved rapidly (e.g. life-threatening situation)
-Loading dose = Desired drugplasma x VD
(amount or mass) = (mass/volume) x (volume)
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Criterias to remain a steady state
The dose rate must be equal the elimination rate;
o elimination rate = CL x Drugplasma
o dose rate = CL x Desired Drugplasma
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Maintenance dose rate
Dose of a drug required per unit time to maintain a desired steady-state level in the plasma to sustain a specific therapeutic effect (mg/hour)
-Maintenance dose rate = Desired drugplasma x Clearance (CL)
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Factors influencing drug action
```
-Species, subspecies, bloodlines
o Receptorial
o Absorption
o Distribution
o Metabolism
o Gut flora
-Health status, condition
o Fever
o Diarrhoea
o Dosage
o Route of application
o Feeding (type and composition of feed)
o Gender/Sex
o Age
-Tolerance (according to multiply application): Subject's reaction to drug decreases
-Dependence, abuse (~ according to multiply application)
o Habituation
o Addiction
-Idiosyncrasy (single, first application)
-Allergy – Anaphylaxis (~according to multiply application)
```
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What is allergy caused by?
Caused by an over-sensitive immune system.
| Does not often happen the first time patient takes a medication, but the next time taking that medication.
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Types of medicines causing allergy
antibiotics, hormones, anticonvulsants, NSAIDs
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Factors maintaining drug allergy
contamination of skin, inhalation – contamination of airways, depot preparations, chronic diseases, atopy
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Allergic reactions types
Type I : Immediate or anaphylactic reaction
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Anaphylaxis
Systemic, immediate hypersensitivity reaction due to the IgE-mediated release of mediators from mast cells and basophils
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Anaphylactoid (or pseudo-allergic) reactions
Clinically similar event not mediated by IgE. (unknown mechanism)
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Factors affecting drug disposition and response in the elderly
- Absorption:
1. Altered physiology?
2. Clinical consideration?
1. Altered physiology: Decr. Gastric acid secretion, incr. gastric pH, decr. GI blood flow, pancreatic trypsin and GI motility
2. Clinical consideration: altered dissolution rate, possible decr. Absorption rate, time of onset delayed
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Factors affecting drug disposition and response in the elderly
- Body composition:
1. Altered physiology?
2. Clinical consideration?
1. Altered physiology: Decr. total body water and lean body weight, incr. body fat (female > male)
2. Clinical consideration: polar drugs tend to have decr. Vd, lipid soluble drugs incr. Vd
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Factors affecting drug disposition and response in the elderly
- Protein binding:
1. Altered physiology?
2. Clinical consideration?
1. Altered physiology: Decr. serum albumin, incr./same 1-GP and gamma globulin, decr/same RBC binding
2. Clinical consideration: incr/same free fraction of acidic drugs, decr. free fraction of basic drugs
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Factors affecting drug disposition and response in the elderly
- Metabolism
1. Altered physiology?
2. Clinical consideration?
1. Altered physiology: decr/same enzyme induction, decr. hepatic blood flow and hepatic mass, same acetylation, decr/same glucuronidation and mixed function
2. Clinical consideration: decr. metabolism and clearance influenced by environmental factors (eg. nutrition)
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Factors affecting drug disposition and response in the elderly
- Excretion
1. Altered physiology?
2. Clinical consideration?
1. Altered physiology: decr. GFR, renal plasma flow and active secretion
2. Clinical consideration: decr. renal clearance, incr. half-life
