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Definition:
the study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of action and effects of drugs with their chemical structure; also, the relationship between drug concentration and effect.
Receptor Theory
The existence of receptors was first inferred from observations of the chemical and physiological specificity of drug effects. Now receptors have been isolated biochemically and genes encoding receptor proteins have been cloned and sequenced. Receptors determine the quantitative relationship between drug dose and pharmacologic effect. Receptors are responsible for the selectivity of drug action. Receptors mediate antagonists. the actions of pharmacologic agonists and
The term receptor has been used operationally to denote any cellular macromolecule to which a drug binds to initiate its effects. Among the most important drug receptors are cellular proteins, whose normal function is to act as receptors for endogenous regulatory ligands particularly hormones, growth factors, and neurotransmitters. The function of such physiological receptors consists of binding the appropriate endogenous ligand and, in response, propagating its regulatory signal in the target cell.
Types of receptors
Intracellular receptor
Ion channels
Sajt enzimaktivitssal rendelkez transzmembrn receptor: jelfog fehrjt aktivl receptor, mely lncreakcit indt el
Drug-receptor interactions
Agonist
Receptor
Agonist-Receptor Interaction
Drug-receptor interactions
Induced Fit
Receptor
Perfect Fit!
Emax:
the maximum response of the system to the drug EC50: that concentration of drug that produces a response one-half of the maximum response
Efficacy is the maximum effect (Emax) of a drug. Potency, a comparative measure, refers to the different doses of two drugs needed to produce the same effect.
Drug-receptor interactions
Competitive Inhibition
Antagonist
Receptor
DENIED!
Antagonist-Receptor Complex
Drug-receptor interactions
Non-competitive Inhibition
Antagonist
Agonist
Receptor
DENIED!
Inhibited-Receptor
Non-competitive antagonism
Some antagonists may form covalent bonds with the receptor at the agonist binding site and, therefore, form an irreversible complex with the receptor.
Other receptor antagonists bind to the receptor at sites unrelated to the agonist binding site. Binding of this antagonist is not reversible or surmountable by increasing [agonist]. Some allosteric effects could potentiate the effects of agonists.
Because the response to B is less than that to A, saturating B reduces the overall response of the system
Partial agonism
The molecular basis is unknown. 1) The partial agonist may fit the receptor binding site well but is less able to promote the receptor conformational change leading to transduction. 2) The receptor may isomerize between 2 states: A (active) and I (inactive)
If the A form has high affinity for the agonist (L), the equilibrium will be shifted in favor of AL and full activation might be achieved. If I and A forms of the receptor share similar affinities for L, both AL and IL will be formed but only AL will produce an effect and the agonists will appear partial.
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Time Response
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Therapeutic Index
LD50 TI = ED50
Drugs safety margin Must be >1 for drug to be usable Digitalis has a TI of 2 Penicillin has TI of >100
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Influencing factors
Genetic effects
Lack of specific enzymes Lower metabolic rate
Psychological factors
Placebo effect
Pediatric Patients
Higher proportion of water Lower plasma protein levels
More available drug
Immature liver/kidneys
Liver often metabolizes more slowly Kidneys may excrete more slowly
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Geriatric Patients
Chronic disease states Decreased plasma protein binding Slower metabolism Slower excretion Dietary deficiencies Use of multiple medications Lack of compliance
Farmakolgia
Toxikolgia
experimentlis
klinikai
Farmakodinmia
Farmakokinetika
(L) A D M E R
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PROTEIN BOUND
DISTRIBUTION BIOPHASE
ELIMINATION
RECEPTOR BINDING
METABOLISM
Pharmacokinetics
Pharmacodynamics
Absorption
Movement from administration site into circulation
Factors Affecting Absorption: Absorption: Formulation factors Tablet disintegration Inert ingredient / solvent effects Solubility Drug pH Concentration Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food, other drugs
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Transport of drugs
Hydrophilic Heads
Lipid Bilayer
Hydrophobic Tails
Small, uncharged
H2O, urea, CO2, O2, N2 Glucose Sucrose H+, Na+, K+, Ca2+, Cl-, HCO3-
Swoosh!
DENIED!
DENIED!
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- Lipid: aqueous drug partition coefficients described the ease with which a drug moves between aqueous and lipid environments - Ionization state of the drug is an important factor: charged drugs diffuse-through lipid environments with difficulty. - pH and the drug pKa, important in determining the ionization state, will influence significantly transport - ratios of lipid-to-aqueous-soluble forms for weak acids and bases described by the Henderson-Hasselbalch equation:
pKd = pH + lg HA A-
+ pKd = pH + lgBH B
uncharged form: lipid-soluble charged form: aqueous-soluble, relatively lipid-insoluble (does not pass biological membranes easily)
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Acids HA Bases H+ + B
25000
pKa = 6
pKa = 7
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Ionized form
AHA HA
Non-ionized form
Conclusion: Acidic drugs are best absorbed from acidic environments Basic drugs are best absorbed from basic environments Ion-trapping! Placenta, stomach, milk, kidney
Sav Ers Ampicillin Szalicilsav Acetilszalicilsav Fenilbutazon Szulfadiazin Hidralazin Fenobarbitl Fenitoin Brsav Aszkorbinsav
pK 2,5 3,0 3,5 4,5 6,5 7,1 7,4 8,3 9,2 11,5
Bzis Terbutalin Atropin Efedrin Kinin Lidokain Kodein Rezerpin Papaverin Diazepam Koffein
pK 10,1 9,7 9,6 8,4 7,9 7,9 6,6 6,4 3,2 0,8 Morfin 99,999 99,99 99,9 99 90 50
gyenge
Nagyon gyenge pH 3 4 5 6 7 8
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Special Carriers: Peptides, amino acids, glucose are examples of molecules then enter cells through special carrier mechanisms. Active transport describes an energy requiring process which is saturable, meaning that transport is probably against the concentration gradient and involves a finite number of carriers, hence the process must be saturable when all carrier sites are filled. Facilitated diffusion, while not requiring "energy" is also saturable (limited number of carrier sites) Saturable (unlike passive diffusion) because of limited number of carrier sites--once those sites are filled, transport rates cannot be increased. A property of carrier systems is that process is subject to inhibition by other small molecules.
Endocytosis and exocytosis: Entry into cells by very large substances (e.g., iron vitamin B12 -- each complexed with its binding protein -- movement across intestinal wall into the blood) Neurotransmitter system examples for exocytosis: Following neuronal electrical activation of nerve endings, two steps may be initiated: - Storage vesicles containing neurotransmitter fuse with cell membranes followed by - release or diffusion of contents into the extracellular region.
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Types of endocytosis
Pinocytosis
phagocytosis
Routes of administration
Enteral
Oral cavity(?) stomach small intestine large intestine rectum
Parenteral
sublinqual nose lungs skin eyes injections: i.v.; i. m. s.c.; i.c. i.a.; i.p. i.card.
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Per os - oral cavity (?) - stomach: pH = 1 2 - small intestine: pH = 5-6 1. duodenum: short for the absorption, ~15-20 cm 2. jejunum: 1.1 m long 3. ileum: 1.5 m long -large intestine: important in diarrhoea, - rectum: Absorption into superior hemorrhoidal veins then enters the portal venous system then to the liver (possible first pass effect) and finally into the systemic circulation. Low rectal administration of drug may allow the drug to enter the systemic circulation without passing through the liver. Generally unpredictable pharmacological responses for the above reasons. Rectal mucosal irritation possible.
Oral Administration: Most convenient, most economical Disadvantages: emesis (drug irritation of the gastrointestinal mucosa) digestive enzymes/gastric acidity destroys the drug unreliable or inconsistent absorption due to food or other drug effects metabolism of the drug by gastrointestinal flora Factors determining rate of drug effect onset: Primary factor: Rate & absorption extent by GI tract Absorption Site: mainly small intestine because of large surface area Drug ionization state: nonionized (lipid-soluble) forms favor absorption weak acids may be highly ionized in the alkaline intestinal pH (not favoring absorption) but this effect is counterbalanced by the large surface-area effect drugs which are weak acids are readily absorbed in the stomach
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First-Pass Effect Drugs absorbed from the GI tract passes through the portal venous system then through the liver and finally into the systemic circulation when drugs interact with receptors in target tissues.
Extensive hepatic metabolism/extraction result in minimal drug delivery to the systemic circulation for certain agents. Drugs with large first pass effect exhibit significant differences in pharmacological effects comparing oral vs. IV administration
Parenteral Administration Ensures active drug absorption subcutaneously intramuscular injection: more rapid/predictable than oral administration route only route of administration acceptable for: uncooperative patients unconscious patients Factors the determine rate of systemic absorption: absorbing capillary membrane surface area drug solubility in interstitial fluid aqueous channels (vascular endothelium) promote high diffusion rates of drugs, independent of their lipid solubility Advantages of IV administration rapid/precise blood drug levels obtained (e.g., no first-pass effect) Irritant drugs: more comfortably administered (blood vessels relatively insensitive); drug rapidly diluted (particularly if administered into large forearm vein)
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Types of injections
Intravenous injection: rapid therapeutic response, nearly instant absorption, most dangerous Intravenous infusion (iv drip): plasma levels can be easily controlled Intramuscular injection: slower response, larger amounts can be injected, depends on perfusion quality Subcutaneous injection: aqueous solutions absorbed quickly (e.g. insulin), depends on perfusion quality
Transdermal: easy to use convenient for certain applications (e.g. nicotine patch)
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Bioavilability
AUCi.v. = 1 Bioavailability: AUCp.o./AUCi.v.
bioequivalent
transzportlt vagy metabolizlt mennyisg transzportlt vagy metabolizlt mennyisg
bioinequivalent
transzportlt vagy metabolizlt mennyisg
dzis
dzis
dzis
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Distribution
After absorption, the drug is distributed via plasma to organs and the site of action. The rate and extent depends upon: blood flow to each organ (more blood flow = more drug distributed) organs with high blood flow: lungs, kidney, liver, heart, brain systems with low blood flow: skeletal muscle, bone, adipose tissue binding of drugs to plasma proteins and tissue components permeability of tissue membranes. For lipophilic drugs, tissue membrane presents little barrier. Tissue uptake will continue until equilibrium is established between tissue and blood.
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Distribution
Compounds distribute differentially within body. Plasma protein binding may limit distribution Lipophillic compounds may accumulate in fatty tissues Liver, kidneys and other excretory organs often show high concentrations of compounds. Concentrations in brain are often very different from plasma concentrations - BBB Distribution can be studied using 14C-labeled compounds
Protein Binding
Human Serum Albumin
Most drugs: bound to some extent to plasma proteins Major plasma proteins important for drug binding include: albumin lipoproteins 1 -acidic glycoprotein Extent of protein binding important for drug distribution since only unbound fraction may diffuse across biological membranes Volume of distribution (Vd): inversely proportional to protein binding Drug clearance: influenced by protein binding since only the unbound drug fraction may reach and serve as substrate for drug metabolizing enzymes
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Small changes in fraction of drug bound significantly influences free plasma concentration for highly plasma protein bound drugs, e.g. warfarin, propranolol, phenytoin, diazepam For example: a drug that is 98% protein-bound --following a decrease to 96% protein-bound results then a twofold increase in plasma drug concentration Characteristics of drug-protein binding Extent of protein binding: parallels drug lipid solubility Drug-plasma albumin binding -- often nonselective many drugs with similar chemical/physical properties may compete for the same protein-binding sites Renal failure: may decrease drug bound fraction (may not require changes in plasma albumin or other plasma protein concentration; suggesting elaboration of a metabolic factor from the kidney that competes with drug-plasma protein binding sites)
Tissue binding-accumulation
Many drugs accumulatein tissues at higher concentrations than dose in the extracellular fluids. Tissue binding usually occurs with cellular constituents: proteins phospholipides nuclear proteins Reversible Bound drugs serve as a reservoire: fat lipid-soluble drugs Physical solution low blood flow sudden reduction of weight bone tetracyclines, heavy metals adsorption, incorporation slow release! local destruction, radioactive drugs
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Placental barrier
lipid solubility plasma binding Ionization
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Metabolism
Drug metabolism can occur in every tissue (e.g. gut, lung and kidney). However, the major drug metabolizing enzymes (DMEs) are expressed at the highest levels in the liver, which thus serves as the major organ of metabolic clearance
Drug metabolism serves to control the exposure of a potentially harmful substance. Usually via oxidation of a lipophilic xenobiotic, DMEs increase the polarity and aqueous solubility thus facilitating its elimination from the body.
Absorption I. phase Drug modified metabolite Drug ineffective metabolite Drug conjugation metabolism II. phase conjugation conjugation elimination
Lipophilic
hydrophilic
DMEs also help to regulate endogenous function (e.g. cytochrome P450s are involved in steroid and fatty-acid metabolism; and the glucuronosyl-S-transferase, UGT1A1, is involved in the clearance of bilirubin)
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DMEs broadly classified into two types of reactions: Phase I Metabolism: Introduces or reveals functional groups (usually polar) to help drug excretion. Three types of phase I metabolism will be discussed: oxidative reductive hydrolytic Phase II Metabolism: Attaches a solubilizing group to the drug (or to a Phase I metabolite). Examples of groups that are commonly attached: glucuronide - glutathione sulfate - acetate glycine/glutamine (amino acids) - methyl Others
Drug Metabolism: Phase I A. Oxidations Most oxidations are catalyzed by the cytochrome P450 enzyme superfamily which is located primarily in the liver. This family of enzymes catalyzes a fairly small set of reactions that act on essentially infinite possibilities of chemical compounds. When P450 enzymes is exposed to CO they have a strong UV-VIS absorption at 450 nm (hence the name). The enzymes are conjugated to heme and the mechanism of oxidation is fairly well understood now.
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Other 26%
CYP1A2 13%
CYP3A 30% CYP2E1 7% CYP2D6 2% Shimada et al., JPET: 1994 CYP2C 18%
CYP2C9 13.6%
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Human Cytochromes P450 and their Relative Contribution to Hepatic CYP3A Drug Metabolism 40-50% 60% of drugs are metabolized primarily by CYPs
CYP2C19 4% CYP2A6 2%
CYP2C9 10%
CYP1A2 CYP2E1 6% 5%
CYP2D6 30%
substrate
Product(s)
CH3
R
R HC
CH2 OH
R1 CH O
R
H2N
CH CH R1
HOHN
R R R
R
CH3
NH CH3 S CH3
CH3 NH2 S R1
S P O R2 O R3
O
S R1
O R3 R2
+ NH3
CCl4
[CCl3.]
O P R1 O
CHCl3
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Product(s)
R CHO + NH3 CH3CHO + CH3COOH
H3C
CH2 OH
Reduction:
Reaction type Azoreduction Nitroreduction karbonil reduction Substrate R N = N R1 R NO2
R C O R1
Hydrolysis:
esthers
R C O
O R1
C O
OH
R1
OH
amides
R CONH2
R COOH + NH3
Substrates
Inhibitors
Disulfiram
Inducers
Rifampin Secobarbital
Prednisone Rifampin
None identified
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GST-A GST-P UGTs GST-T GST-M NAT2 NAT1 others HMT: histamine methyltransferase; TPMT: thiopurine methyltransferase; COMT: catechol O-methyltransferase; UGT: Uridine Glucuronosyl-S-Transferases; ST: Sulfotransferase; GST: Glutathione-S-Transferases
Sulpho transferase Methyl transferase Acetyl transferase Acil-CoA-amino acid transferase Glutathione-Stransferase
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Excretion in Feces
Excretion in Urine
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Elimination: exretion
Kidneys = primary site Mechanisms dependent upon: I. Passive glomerular filtration: small molecules (<15000) unbound drugs only II. Active tubular transport: weak acides and bases pl.: penicillin, Chlorotiaside, salicilates, histamine Partial reabsorption: passive diffusion, active transportation, pH, pK, changing urin pH Renal disease Slows excretion Prolongs effects
Bile:
Passive diffusion and active transport Biliary excretion is usually the major route of elimination of compounds with a molecular weight of more than 400500 Da. Many compounds that are eliminated in bile as glucuronide conjugates are hydrolysed in the small intestine by bacterial flora that secrete the enzyme glucuronidase. After hydrolysis the unchanged drug is reabsorbed, metabolized and re-excreted as a glucuronide conjugate: enterohepatic recycling
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Other routes: I. Exhaled air II. Sweat III. Saliva IV. Breast milk V. Hair
I.
II. Non-ionized, lipid soluble drugs, passive diffusion III. In the mouth saliva is swallowed-same c as in the plasma IV. More acidic than plasma-basics concentrated, acides less V. Forensic importance
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Pediatric Patients Higher proportion of water Lower plasma protein levels More available drug Immature liver/kidneys Liver often metabolizes more slowly Kidneys may excrete more slowly
Geriatric patients Chronic disease states Decreased plasma protein binding Slower metabolism Slower excretion Dietary deficiencies Use of multiple medications Lack of compliance
Drug-Drug Interactions Drug interaction: when one drug affects the pharmacological response of a second drug given at the same time. may be due to: pharmacodynamic and pharmacokinetic effects Consequences of drug interactions: increased drug effects; decreased drug effects; desired consequences; adverse or undesired effects Adverse effects: Interaction results impede absorption competition for the same plasma protein-binding sites one drug may affect metabolism of another by either enzyme induction or enzyme inhibition one drug may change the renal excretion rate of the other.
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Fzis II.:
Fzis III.:
Literature: CORINA IONESCU and MINO R. CAIRA: Drug Metabolism Current Concepts Alfred Goodman Gilman: The pharmacological basis of therapeutics
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