Chemical that has the ability to determine one or more functional changes in a living organism
Because this potential capacity to fulfill it is necessary that:
a) use an appropriate dose,
b) the drug can enter the body,
c) you have pre-existing functional activity of the organism
Drug doses that, administered under certain conditions, are able to benefit, determining therapeutically useful pharmacological actions.
POISON or TOXIC
Drug doses that, administered under certain conditions, result of damage, causing a morbid state said poisoning.
- Product complex of animal or vegetable origin, used as a drug because it has special biological activity, linked to the presence of some active ingredients.
- In the broadest sense popularized the term drug is used to refer to substances that cause addiction.
- The term science has not specifically this meaning (for example, there are drugs cardiocinetiche and purgative drugs that do not give drug addiction).
And 'the discipline that deals with the study of drug reactions of living organisms
BRANCHES OF PHARMACOLOGY
Study of the functional changes evoked by a drug and its mechanism of action
One or more functional variations determined in a living organism by well-defined doses of a chemical substance, coming in contact with the body.
Types of action
An action can be:
a) stimulating or inhibiting
b) local (or topical) or general (or systemic)
c) monophasic or biphasic
d) the direct or indirect
and) profit or junk
f) constant or inconstant
g) intensity of gradual or all-or-nothing
The dose is a very important factor in influencing the nature, intensity, duration and reversibility of the pharmacological action.
The doses can be distinguished:
a) doses pharmacologically inactive
b) pharmacologically active doses.
The pharmacologically active doses can in turn be divided into:
a) non-toxic doses (therapeutically possible)
b) toxic doses,
c) lethal doses.
The pharmacological response:
-Starts after a latency time
-Reaches a maximum
Also the time course of the response is of considerable importance in pharmacotherapy.
Mechanism of Action
The majority of drugs acts on specific receptors,
The first formulation of the concept of receptor back to Langley (1880).
The receptor is a macromolecular protein component functional organism equipped with:
a) ability to bind an endogenous molecule or a drug b) to trigger a biological response.
May be targets for drugs not only specific receptor structures, but also
1) Nucleic acids
3) Carriers for neurotransmitters
The vast majority of drugs act through receptors, but there are exceptions. For example:
1) chelating agents (EDTA)
2) Antacids gastric
3) osmotic diuretics (mannitol)
4) General anesthetics volatile
In these cases:
1) There is no need for a specific chemical structure,
2) The stereoisomers do not significantly differ in pharmacological potency,
3) Their powers are related, perhaps, to their solubility in the membrane lipids.
CLASSIFICATION FOR LOCATING CELL RECEPTORS
The receptors can be divided into:
1) Receptors and intracellular
2) Membrane Receptors
1) MEMBRANE RECEPTORS
The vast majority of receptors is localized on the protoplasmic membrane of the cell and from this transduce the message within the cell.
The membrane receptors present
a) with the ligand binding domain
b) the effector domain that triggers the response,
c) region of the transmembrane anchor.
2) INTRACELLULAR RECEPTORS
Steroids, thyroid hormones, vitamins A and D have intracellular receptors that control the synthesis of specific proteins from the nucleus.
The membrane receptors are classified into six main classes:
1) G-protein coupled receptors
2) Receptors channel
3) Receptors for growth factors
4) Receptors for cell adhesion
5) Receptors for cytokines
6)-guanylate cyclase receptors with activity
1. G-protein coupled receptors
It 's the largest family of receptors.
Are formed from a single protein chain that traverses the plasma membrane seven times.
The terminal carboxylic and 'intracellular, extracellular amino what.
The filament protein identifies three intracellular loops. The third is coupled to a G protein (capable of binding GTP and equipped with intrinsic GTPase activity) which operates the signal transduction.
The ligand can bind to various positions of the extracellular portion of the filament or transmembrane polypeptide
Activation of the receptor involves the binding of GTP to the G protein cytoplasmatic. At the same time the protein G (heterotrimer) dissociates into subunits and in that (linked covalently).
Both subunits can mediate the effects of the ligand by modulating the activity of the effector enzyme from which originate second messengers.
Gs and Gi
Gs and Gi proteins mediate stimulation or inhibition of adenylate cyclase that generates cAMP-
The cAMP was the first compound proposed as a second messenger (1957).
The cAMP has as main target PKA (cAMP-dependent protein kinase) which is activated by cAMP through liberation of its catalytic units.
The PKA induces phosphorylation of cytoplasmic proteins or translocates to the nucleus where it controls the transcription factors gene as the CREB (cAMP responding element binding protein)
Gq proteins activate the FLC (phospholipase C). The receptor activation free subunit q G protein that promotes the translocation of FLC in the membrane where cleaves the phosphatidyl-inositol bisphosphate (PIP2) of membrane rise to:
a) inositol triphosphate (IP3), and
b) diacylglycerol (DAG).
The IP3 causes the release of Ca + + from the endoplasmic reticulum and the complex of calciosomi. The concentration of calcium in the cytoplasm also increases for greater input from the membrane.
The DAG, in the presence of Ca + + activated PKC (protein kinase C), which phosphorylates numerous enzymatic proteins.
Modulate the activity of ion channels.
Gs and Go have activity on the opposite conductance of the channels of the Ca + +.
The Go in many cells as well as inhibit the channels for the Ca + +, increases the conductance of the channels for the K + (hyperpolarizing effect).
Activated K + channels denominated GIRK.
The subunit of the protein also have the ability to influence isoforms of PLC and the MAP-kinase (Mitogen activated protein kinase)
There are also monomeric G proteins, associated for example to receptors for growth factors.
These G-proteins (for example Ras and Rap1) go to activate intracellular effector systems such as MAP kinase ERK 1 and 2.
2. Receptor channel
Are formed from subunits, formed from individual polypeptide chains that cross the membrane from 2 to 6 times.
The opening of the channel causes input or output of ions inducing modification of the potential and enzymatic activities.
Are pentamers that assemble four different subunits. Each is formed by a polypeptide cha crosses the membrane 4 times. Includes the following receptors:
GABA-A and Glycine
The GABA-A receptors and those for glycine (GLY-R) are associated with ion channels that control the entry of Cl-ions
Are pentamers with two subunits 1 1 1 in the adult, 1 in the embryo.
The two subunits have binding sites for acetylcholine.
The nicotinic receptors are ion channels that control the entry of ions Na +, Ca + + and K +.
Are tetramers. Each subunit consists of a polypeptide that crosses the membrane 4 times.
Includes receptors for excitatory amino acids:
Receptors for the kainate
Includes receptors for cAMP and cGMP.
These are channels for the Ca + + or K +.
Are tetramers, in which each unit has 6 transmembrane regions
Ionotropic receptors for ATP (P2X).
They have seven subunits, each with 2 transmembrane regions.
3. Receptors for growth factors
Are receptors for insulin, erythropoietin and growth factors (FGF, Fibroblast Growth Factor; EGF, Epidermal Growth Factor; HGF, Hepatocyte Growth Factor).
These are receptors involved in neoplasia: in many cases of cancer will have constitutive activation of receptors for EGF and HGF
Some growth factors (NGF, nerve growth factor, BDNF, Brain Derived Neurotrophic Factor) have neuroprotective activity.
Consist of a single polypeptide sequence.
The activation process passes to a dimerization of the receptor that can take place in various ways (the receptor for insulin is already dimer, erythropoietin binds two different receptor structures aggregating them, various growth factors determine dimerization of individual entities receptor).
Most of these receptors possesses tyrosine kinase activity and therefore catalyzes the transfer of phosphate groups from ATP to tyrosine residues on target proteins.
The dimerization allows the phosphorylation of the second receptor, generating anchoring sites for intracellular transducers. These can be proteins with enzymatic activity or can regulate the activity of other proteins.
4. Receptors for cell adhesion
The cell adhesion receptors (CAM) are multifunctional proteins that control not only cell adhesion, but also proliferation, differentiation, and motility.
There are 3 families of receptors CAM:
a. IgCAM (have regions of immunoglobulin-like domains)
b. integrins (bonds form both cell-cell and cell-extracellular matrix that bonds). Are dimers of 1 subunit and 1 . Examples are the integrin receptors IIb and IIIa on the platelet membrane.
c. cadherins (the extracellular domain has 5 sequences, interacts with the intracellular actin cytoskeleton)
The signal transduction is provided by protein kinases such as FAK (Focal adhesion kinase), the MAP kinase and other mechanisms activated by protein G.
5. Receptors for cytokines
The receptors for various cytokines have common characteristics:
- Polypeptide chain that crosses once the membrane
- Linked to the cytokine receptor dimerizes
- Then binds a cytoplasmic subunit which activates protein kinase (JAK)
- Determines the phosphorylation activation of gene transcription factors (STAT).
6. Guanylate cyclase activity with receptor-
The only hitherto known endogenous ligand is represented by atrial natriuretic peptide.
These receptors have a single amino acid chain that passes through the membrane.
The cytoplasmic guanylate-cyclase activity has and produces cGMP.
This produces activation of PKG (a serine-treonino-kinase)
1. The steroid receptors are cytoplasmic.
Once the steroid binds to this receptor is activated by detachment of inhibitory proteins (heat shock proteins), dimerizes and translocates to the nucleus where it interacts with HRE (hormonal responsive element) that control gene transcription.
2. The receptors for thyroid hormones, retinoids, vitamin A and D are nuclear.
3. Also the receptor for the NO can be considered intracellular.
In this case the receptor must be identified in the guanylate-cyclase intracellular.
This then activates PKG.
ADJUSTMENT OF RECEIVERS
The receptors may be subject to functional changes.
The number of receptors can undergo:
a. desensitization or
These phenomena may be due to:
a. change in the number of receptors (up-regulation after prolonged treatment with antagonists, or down-regulation after prolonged treatment with agonists)
b. change in receptor affinity
c. variation in the efficiency of transduction mechanisms.
For example, the adrenergic receptor is desensitizzato for phosphorylation by PKA or -ARK (adrenergic receptor kinase). Once phosphorylated receptor binds to -arrestin. Thus linked loses the ability to interact with the G protein and is internalized.
Examples of pathologies related to a lack of receptors are:
a) The familial hypercholesterolaemia (lack LDL receptors sull'epatocita)
b) The nephrogenic diabetes insipidus (lack of antidiuretic hormone receptors in the kidney)
Some diseases are caused by autoimmune processes, the body produces antibodies against its own receptors.
b) Myasthenia gravis
Various theories have been proposed to explain how the combination drug-receptor active drug response.
1) THEORY OF EMPLOYMENT
According to this theory the pharmacological response would be proportional to the number of receptors occupied then to the formation of the drug-receptor complex (Clark 1933).
But this theory does not explain why the dose-response curve obtained in functional tests do not always coincide with the curve deduced from binding studies.
In binding studies assessing the interaction between a ligand and a radioactive preparation containing the receptor. These studies provide information on:
-Affinity of the drug to the receptor and
-Receptor density in a preparation
a) In 1956, Stephenson introduced the concept of "receptor reserve". This concept has been supported by the work of Furchgott, which showed that a high percentage of inactivating receptors could be obtained the maximum response.
b) If the system is activated by stimulation of the receptor involves a cascade of events with signal amplification, the answer may be less related to the number of receptors occupied.
2) THEORY OF 'INTRINSIC
The effect of a drug is proportional to the formation of the drug-receptor complex, multiplied by the factor (intrinsic activity).
In 1954 Ariens introduced the concepts of affinity and intrinsic activity
Measure the drug's ability to bind to the receptor. If a drug has affinity for a receptor does not mean that it is able to activate it.
The affinity of the drug determines the "power" of the same, that is the range of doses in which it acts
Measure the drug's ability to evoke the functional response. The intrinsic activity determines the maximum effect of the drug
E 'a drug with affinity and intrinsic activity.
Full-L'agonista is a drug that can evoke a maximal response ( = 1)
-L'agonista partial binds to the receptor, but it evokes a response less than full agonist.
-L'agonista inverse binds to the receptor and evokes an effect, but this is opposite to the normal of the agonist.
E 'a drug with affinity, but not of intrinsic activity.
3) THEORY OF FREQUENCY OF INTERACTION
It 'been proposed by Paton at the beginning of the 60s. Each time that the drug occupies for a short time the receptor would transmit a "quantum of excitation".
This serves to explain the fact that certain drugs give first a peak response which then stabilizes at lower values.
4) Theory of the ternary complex
E 'was proposed by De Lean in 1980.
According to this theory, the receptor is present on the membrane as
-Free receptor (R)
-Receptor linked to the drug (FR)
-Receptor bound to the protein G (RG)
-Receptor bound to the drug and the protein G (FRG)
Agonists stabilize the shape FRG
5) allosteric THEORY OR 2 UNITED
This theory was proposed by Leff in 1995.
The drug will shift the balance between the activated state (R *) and inactivated (R) of the receptor.
The full-agonist would bind to R *, the inverse agonist would have more affinity for R, the antagonist would bind to both.
The responses to a drug may be:
1) PROGRESSIVE ANSWERS.
Are those responses that increase progressively with increasing dose. A discussion of quantitative response means describe the intensity as a function of dose of drug.
2) ANSWERS NOT MEASURABLE CONTINUOUS
These responses can be described by a vote (score) or a stage (internship). Responses of this type are pain, ulcers, certain behavioral effects.
3) RESPONSES QUANTUM
Responses are all-or-nothing (death, convulsions, vomiting, abortion, but also gradual response of a given intensity).
For these responses, the quantitative discussion is concerned with describing the frequency with which they occur.
For this type of response we measure the intensity of evoked and describe the dose-response relationships.
More common is the graphic representation on a logarithmic scale which corresponds to a sigmoid.
This graphical representation has the advantage of a "nearly linear" in the range between 20% and 80% of the maximum response.
The representation of Lineweaver-Burk uses reciprocal values both in ordered that the abscissa (1/effetto; 1/dose). It allows to have a graphical representation linear, but has the disadvantage of requiring the calculation of the reciprocal values.
A linearization of the sigmoid can be obtained by resorting to Probits.
The Probit indicates the probability of deviation from the observation made, measured in units of deviation type.
Refers to the fact that for any given experimental exists a certain probability that it is reproduced in a subsequent experiment, but there is also a certain possibility of deviation from the data observed.
The paper calibrated in probits the ordinate has the units small in the vicinity of 50% maximum effect and are gradually growing closer to the ends of the sigmoid.
The paper probit ranges from 1 to 99% maximum effect.
Measurement of KD
For [R] = [FR], that is, when the amount of free receptors is equal to that of the receptors linked to the drug, KD will be equal to [F].
Michaelis-Menten equation this condition corresponds to an effect equal to 50% maximum effect.
So, by measuring the concentration of drug that evokes an effect equal to 50% maximum effect, we have a measure of KD.
In pharmacological literature is commonly used the pD2 to express the affinity of an agonist for the receptor.
pD2 = colog KD
In the case of responses of the type "all or nothing", expresses the relation between dose and frequency of the response in the population.
Is obtained by constructing a histogram that shows on the ordinate the frequency of the response in a certain dose range.
(The frequency that is reported is that additional, ie the events which are observed in more than those measured in intervals of lower dose).
The Gauss curve is an integral curve where the cumulative frequency of the response is obtained by measuring the AUC (area under the curves) corresponding to the dose in question.
If the ordinate shows the cumulative frequencies for each dose, then we obtain a sigmoid (curve Trevan).
VARIABLE CHARACTERISTICS OF DOSE-EFFECT CURVE
E 'given by the position of the dose-effect curve on the abscissa.
In vitro is closely related to the affinity of the drug to the receptor.
In vivo depends on many other factors: absorption, distribution and elimination.
The power is relatively important for the clinical use of a drug.
2. Maximum effectiveness.
E 'given maximum effect produced by the drug.
Depends on the intrinsic activity of the drug, and the properties of the receptor-effector system.
In vivo is also linked to the ability to reach certain levels of bioavailability.
E 'given by the slope of the dose-effect curve.
Depends on the number of receptors that is necessary to take to get the answer.
The slope of the curve is of great importance in therapeutic field, because it defines the handling of the drug.
Is defined by two quantum variables:
1) the lethal dose 50 (the dose which causes the death of 50% of the experimental animals) and
2) the effective dose 50 (ie, the dose which causes the effect of the desired intensity in 50% of treated subjects).
The therapeutic index or margin of safety is the ratio LD50 / ED50.
If the therapeutic index is high and has an important margin of safety.
If the therapeutic index is equal to one the drug can not be used for systemic use because the DE50 coincide with the LD50.
The therapeutic index influences the mode of use of the drug:
a. topical or systemic
b. Use strictly in the hospital or not
Drug that interacts with the receptor or with the components of the effector mechanism without activating them. Therefore inhibits the response of the agonist.
Can be removed by increasing the concentration of agonist. You can have competitive antagonism:
a) the antagonist binds reversibly to the same receptor site of the agonist, or
b) are present "receptor reserve" even in the presence of irreversible antagonists, or anyway not competitive because they bind to site different from that of the agonist.
The affinity of the antagonist is expressed by the displacement of [A50] of the agonist (ie the concentration of the agonist that evokes 50% of the response) in the presence of a concentration of antagonist (indicated as B).
In the literature is reported the pA2 as a measure of affinity of the antagonist:
pA2 = - log [B] + log ([A 50B] - 1)
The pA2 is expressed as the concentration of B which is double the A50B compared to A50 without B.
You can not remove the blocking action with higher doses of agonist. Is observed when:
a) the antagonist irreversibly block the receptor
b) the antagonist blocks a step in signal transduction
c) the antagonist acts on a different site from the receptor, but that affects the receptor-agonist binding.
VARIABILITY 'BIOLOGICAL RESPONSE
Variability factors inherent to the patient:
a. Genetic factors
Genetic factors may alter the pharmacokinetic characteristics, but also the pharmacodynamic properties of a drug.
Pharmacogenetics is the discipline that studies the structure of an individual gene in determining its response to the drug.
In particular, the pharmacogenetic studies.
-Genetically controlled variations of the enzymes involved in drug metabolism
-Simple diagnostic methods to identify individuals "abnormal" before administering the drug
If there are alleles for a gene locus variants (which encode different molecular isoforms of the same protein) at a rate equal to or greater than 1% is called "genetic polymorphism"
Most of the polymorphisms are due to genetic mutations that involve a single nucleotide.
If is reduced the expression of an enzyme that metabolizes drugs (for example, the CYP2D6) the subject becomes poor metaboliser of many drugs, such as -blockers, tricyclic antidepressants, antiarrhythmics.
Some individuals show an atypical cholinesterase, so do not separate well succinylcholine (neuromuscular blocking agent (risk of prolonged apnea)
In the newborn, a different response to drugs may be due to different systems development metabolizing enzyme, a lower drug-binding protein and low renal clearance.
In the elderly patient is observed reduction in renal clearance and hepatic impairment. Reactions to CNS active drugs tend to be magnified.
The CYP3A4 activity is higher in women than in man; CYP3A4 influence many drugs
May increase the metabolic clearance rate of many drugs, and decrease renal clearance of other drugs.
For drugs in pregnancy serious dangers to the fetus coumarin anticoagulants, ACE inhibitors, anti-cancer, valproic acid, etc..
and. Body weight
The differences in body weight require dose adjustment in proportion to weight.
In subjects with relevant panel adipose storage possibilities of drugs in adipose tissue.
In obese subjects you may want to refer to body surface area rather than weight.
The simultaneous intake of foods can reduce the absorption of drugs, but tends to increase the absorption of lipophilic drugs.
The intake of grapefruit juice inhibits the CYP3A4 enzyme influencing the metabolism of many drugs
Foods high in tyramine can cause a hypertensive crisis while taking MAO inhibitors.
Foods rich in vitamin K reduces the effect of anticoagulants.
Amino acids long-chain reduce the absorption of levodopa.
g. Pathological states
Pathological conditions may alter the metabolism or excretion of drugs (liver and kidney)
Chronic pancreatitis reduces the alkaline intestinal secretions, reducing the breakdown of oral pharmaceutical forms.
Certain actions of drugs occur only in pathological conditions (antipyretic effect of NSAIDs).
h. Low Compliance
Incomplete observance of the prescription by the patient (non-recruitment, incorrect doses, etc)
g. At rest or fatigue
Changing insulin requirements in diabetic
i. Environmental factors
The different temperature affects enzyme activity, affects the release of hormones (see vasopressin), influence the neurotoxicity of MDMA.
l. Placebo Effect
Effect linked to psychological conditioning and psychosomatic influences.
VARIABILITY 'BIOLOGICAL RESPONSE
Variability factors inherent to the drug:
a. Pharmaceutical Form
b. Route of administration
c. Physical and chemical characteristics
and. Regimen (dose, interval of intake, treatment duration)
QUANTITATIVE ABNORMAL RESPONSES
Even individuals of the same age, race, weight, sex, etc. may show significant difference in individual sensitivity to drugs.
As a result, data are expressed as averages, around which are "missing" individual data.
Commonly spoken responses medium-normal when they are in the range = + 20% above the average. Beyond this limit, we have:
Consists enhances drug response in terms of intensity and / or duration.
Consists of a reduced pharmacological response in terms of intensity and / or duration
Tolerance, Addiction, Habit, mithridatism, acquired resistance
These terms are used, essentially as synonyms, to indicate a hyporeactivity not congenital, but consequent to repeated exposure to the drug.
The tolerance may be due to:
1. Reduced absorption of the drug. For example ferrous salts in the treatment of anemia hypochromic
2. Altered drug metabolism
-Increased rate of metabolism
-Production of P-glycoprotein which transports the drug (eg. anticancer) out of the cell
3. Receptor or modifications of the mechanisms of signal transduction at the cellular level
-Phosphorylation of receptors channels which reduces their ability to open the channel
-Phosphorylation of receptors coupled to G proteins (with reduction of affinity for agonist and reduced ability to transduce the signal).
- Tolerance to a drug results in tolerance to chemically similar compounds with similar pharmacological action. Examples: Penicillins and cephalosporins, various CNS depressants.
Tolerance develops rapidly after repeated administration of drug and close.
Can 'depend on:
1. desensitization of the receptor
2. depletion of mediator substances with indirect action.
INTERACTIONS BETWEEN DRUGS
Often used in the concomitant administration of multiple drugs.
1. Associations impromptu: Several medications administered.
2. Or medicinal products which present a mixture of drugs
Purposes of the associations:
1. Combining the most active drugs in the same condition you can reduce the dosage of each mitigating their effects
2. Is associated with a drug primary action useful in therapy, with another drug that reduces side effects.
3. Multiple diseases may require more than one medicine at the same time.
Drawbacks and dangers:
1. E 'easier the onset of iatrogenic diseases, which increases in a geometric way with the number of drugs administered.
2. Possibility of interactions between various drugs with modification of their effect.
Drug interactions may be due to altered drug response, as well as the appearance of adverse reactions to drugs.
There are three types of drug interactions:
1) drug interactions
Are due to chemical or physical-chemical interaction between drugs.
An example of drug-drug interaction is the interaction between protamine (basic protein) and heparin (mucopolysaccharide acid).
Pharmaceutical interactions occur when a drug alters the pH of the solution and therefore the solubility of another, making it fall. These interactions are very common when mixing compounds in solutions for intravenous infusion.
2) Pharmacokinetic interactions
Occur when a medication change the plasma levels of another drug.
Pharmacokinetic interactions may be due to:
a) interactions at the level of absorption.
-Tetracyclines are not absorbed if they are chelated by ions Ca, Al, Mg, Fe. Attention to milk and cheese and antacids.
-Quinolones are not absorbed if chelates from Al and Mg content in antacids
-Cholestyramine may seize a number of drugs in the gut (anticoagulants, digoxin)
-Drugs that slow gastric emptying (antimuscarinic) slow, and may in some cases reduce the absorption of drugs taken orally
b) drug-protein interactions in the binding
Consist in the fact that a drug can be moved from the drug-protein binding to the work of another drug.
The interactions of this type have considerable relevance when the binding protein drug is very high.
Object-drug interaction are anticoagulants, oral hypoglycemic agents, phenytoin, methotrexate, sulfa drugs, salicylates.
c) interactions affecting the metabolism
-They can be a result of induction or inhibition of metabolising enzymes. Particular importance is the induction or inhibition of CYP enzymes, particularly the 3A4 that metabolizes approximately 50% of the drugs.
Of hepatic microsomal enzyme-inducing drugs are phenytoin, phenobarbital, carbamazepine, rifampicin, dexamethasone,
-They can be a result of enzyme inhibition. Inhibitors of metabolising enzymes are the drugs antiMAO, chloramphenicol, cimetidine, various antibiotics.
-L'allopurinolo inhibits xanthine oxidase which metabolizes also mercaptopurine. You can have toxic manifestations of mercaptopurine.
d) interactions in the excretion
-Probenecid reduces the renal excretion of penicillin.
-NSAIDs reduce excretion of methotrexate
3) Pharmacodynamic interactions
Are linked to interaction of the effects of two or more drugs.
We can have direct interaction, well predictable.
-Acetylcholine and atropine,
-Sympathomimetics and their antagonists
-Morphine and naloxone.
-Summation of the effect of drugs depressants (alcohol, benzodiazepines, antidepressants, anti-epileptics).
-We can have interactions as a result of side effects of drugs.
Examples of such interactions:
-Tricyclic antidepressants, and antimuscarinic
-Diuretics that eliminate K + and cardiac glycosides
a) are potentially enormous number
b) However, not all interactions are clinically relevant,
c) are worrying especially for drugs with narrow therapeutic index,
d) The pharmacist must consider not only the interactions between OTC pharmaceuticals but also between SOP and drugs prescribed by doctors.
e) attention to the interactions between drugs and dietary supplements (containing St. John's wort, ginko biloba or ginseng) or drug-drug interactions and food (grapefruit juice)
e) whether there is an interaction between two medications can be used in texts such as Martindale, Drug Interactions (Stockley) Manuals interactions (eg Medical Letter), etc, or computer programs such as Micromedex.
ABNORMAL RESPONSES QUALITATIVELY
- There is talk of idiosyncrasy when drug response is abnormal both quantitatively and qualitatively.
The idiosyncrasy has the following characteristics:
a. And 'congenital and therefore appears from the first administration of the drug
b. The reaction to the drug is dose-dependent
c. Can provide diverse and unpredictable events
d. Is not transmissible by humoral immunity.
and. For drugs that cause it are not necessary antigenic properties
- How are the idiosyncratic responses:
1. Non-appearance of pharmacological effect:
Non-response to insulin or 2 adrenergic agonist for receptor alterations
Non-response to mercaptopurine and azatiprina to lack the enzyme hypoxanthine-guanine-phosphoribosyl-transferase (HGPRT)
Youth-in pernicious anemia Vitamin B12 is not absorbed by congenital deficiency of intrinsic factor of Castle.
2. Occurrence of toxic effects:
-Aplastic anemia by chloramphenicol (inhibition of DNA in the bone marrow in patients with poor synthesis of the same)
-Hemolytic anemia from sulfa drugs, acetaminophen, aspirin. The idiosyncrasy is due in this case to a deficiency in red blood cell glucose-6-phosphate dehydrogenase (G6PD), which is important to maintain the levels of reduced glutathione in the red blood cells.
Exalted-effect of succinylcholine (breathing problems) to impaired (reduced) affinity cholinesterase drug
-The polymorphism of CYP2D6 cause abnormal reactions to antiarrhythmic drugs, antidepressants, antidiabetic.
-Alteration of the characteristics of the iron transporter protein (ferritin) results in accumulation of iron in tissue level.
It 'an abnormal reaction that occurs after a previous exposure to the drug, which led to the awareness of the subject drug.
The farmacoallergia has the following characteristics:
1. Requires a previous drug intake (is acquired)
2. Evokes responses dose-independent
3. Manifests itself in a rather uniform (regardless of the type of drug taken)
4. Drugs that cause it have antigenic properties
3. It can be transmitted through the humoral
- The drugs may have the characteristic of acting as haptens, that is to have antigenic determinants acts to antibody recognition.
- Bound to plasma proteins or tissue acquire immunogenicity.
- After a previous administration of the drug that gave rise to the antibody response (IgM, IgG, IgA, IgE), a subsequent administration may result in allergic reactions of various kinds:
1. Type I due to IgE antibodies bound to cells basophils and mast cells that react with the antigen. The antigen-antibody reaction is followed by the release of histamine, leukotrienes, prostaglandins with edema, bronchospasm, vasodilatation, anaphylactic shock.
Is the frequent occurrence of this type of farmacoallergia to penicillins or cephalosporins (7-8% of cases), local anesthetics, insulin, aspirin. Attention to the second cycle of treatment with the drug.
Treatment of allergic manifestation:
-Epinephrine (1:1000 solution subcutaneously; 0.5-1 ml in adults, 0.015 ml / kg in children). The administration may be repeated every 10 min.
- 2 adrenergic agonist
-Intravenous dopamine for severe hypotension
2. Type II, the antibody (IgG, IgM) binds to the antigen fixed to the cell surface. Reactions are cytotoxic, as
-Hemolytic anemia penicillins or -methyldopa.
-Thrombocytopenia sulfonamides and chlorothiazide
-Acute interstitial nephropathy tetracycline
Treatment: corticosteroids and transfusions as required.
3. Type III Immune complex deposition, aggregated antigen-antibody (IgG) of vessels and organs with inflammation and functional impairment:
a. serum sickness
b. hypersensitivity pneumonitis
c. vasculitis, etc.
Treatment: corticosteroids and symptomatic interventions
4. Type IV, cell mediated reactions due to T lymphocytes and the macrophages, even in the absence of antibodies.
When the cell is in contact with the sensitized antigen is generated inflammation with activation of T lymphocytes sensitized that produce lymphokines. We have:
5. Pseudoallergic reactions
Mimic the symptoms of allergic reactions, but are not due to immunological mechanisms
-Imbalance of arachidonic acid metabolism toward the lipoxygenase after NSAIDs, with consequent bronchospasm
-Degranulating action live on mast cells and basophils
The term "iatrogenic" means generated by the care.
In pharmacology we deal with iatrogenic disease, caused by the drugs.
Reasons why medication iatrogenic damage:
1) Interactions between drugs.
2) Use of drugs in conditions in which they are not indicated. Dangers of self!
3) spectrum of action of the drug which also includes side effects, toxic.
4) Hyperactivity individual drug.
5) Idiosyncrasy and farmacoallergia.
6) Errors in the dispensation of drugs
Conditions that facilitate the appearance of iatrogenic diseases:
1) Co-administration of multiple drugs.
When you take only 1 or 2 drugs the percentage of iatrogenic diseases is very low (1%).
The percentage increases exponentially with the number of drugs.
If we take 18-20 medications at the same time has very high probability of iatrogenic disease.
2) Use of drugs for a long time
3) Use of new drugs have not been adequately studied.
The iatrogenic diseases can not be deleted because ':
a) insufficient knowledge about drugs,
b) spectrum of action of drugs, usually large
c) different reactivity individual
d) continuous introduction of new drugs on the market (although not innovative)
However, errors in dispensing medications can and should be eliminated (the role of the pharmacist):
-Control of the pharmacist on the administration of drugs by nurse
-Dispensing unit dose
-Technological support to the dispensation ("smart carts")
Responsible for iatrogenic diseases:
b) Sick same, for its autoterapie,
c) Pharmaceutical industry
The pharmacokinetics studies the movement of a drug within a living organism.
The four basic steps in the pharmacokinetics are:
Metabolism and excretion contribute to the elimination of both drug
TRANSFER OF DRUGS THROUGH MEMBRANES
The passage of a drug through the membrane can occur by different mechanisms.
1) Passive Diffusion
It 's the most frequently used mechanism.
-It happens second gradient of concentration and thanks to its solubility in lipids of the membrane.
-It does not require energy consumption.
-E 'influenced by the pH, since the drugs are mostly weak electrolytes with the undissociated form in equilibrium with the undissociated form.
-E 'influenced by the electrochemical gradient for the absorption of ionized molecules.
Small molecules and soluble in H2O pass through pores (size approximately 4 A °) especially due to osmotic.
2) active transport mediated by carriers
It has the following features:
-Is against electrochemical gradient and concentration,
-Is saturable and selective
-Is inhibited by congeners.
It 'important in neuronal membranes of hepatocytes and renal tubular cells (eg sodium pump).
3) facilitated diffusion
-E 'mediated by carriers, but it's the second electrochemical gradient and the concentration gradient.
-Opera without wasting energy.
-Dramatically accelerates the rate of diffusion.
-Important for polar substances (choline).
4) pinocytosis and phagocytosis
Fluid and solid particles incorporated by the cell membranes.
Little quantitative importance.
5) Mass flow through pores intercellular
Important for diffusion through capillary endothelium.
It 's the transition from the seat of administration of the drug to the bloodstream.
The absorption of a drug depends on:
1. Intrinsic characteristics of the drug
-Dissociation constant (pKa)
-Partition coefficient water / lipid
2. Dosage form used
3. Anatomo-physiological characteristics of the absorbing surface.
-Damaged surfaces absorb more
Routes of administration of drugs
They can be divided into natural
It 's the way most frequently used
Comfort, safety, economy
-Requires patient cooperation
Irregular-absorption in the presence of food
-Delete to presystemic first pass metabolism (both hepatic and intestinal)
-Incompatible with emesis
-Risk of destruction of the drug in the stomach (proteins, peptides, compounds that can be destroyed by gastric acidity)
Good absorption for soluble molecules (nitroglycerin, estrogen).
The venous blood from the oral cavity flows in the superior vena cava, for which the drug is protected from the hepatic metabolism of the passage.
Absorption is generally irregular and incomplete.
Is not well defined the amount of the absorbed drug that reaches the liver and the one that goes directly to the vena cava.
-Use in vomiting or unconscious patient.
-Acceptable in children.
The absorption is somewhat irregular
Are absorbed gas or solutions of drugs in aerosol.
-Absorption very fast,
-It avoided the hepatic metabolism of the passage.
-Bad handling of the methods of administration
-Poor control of the dose,
-Irritation of the pulmonary epithelium.
Other natural ways
In addition dermal, medications can be absorbed by application
-Urethra and bladder
Bypasses the factors limiting the absorption, resulting in an immediate bioavailability of the drug.
precision, immediacy, possible administration of irritants.
sterility, cost, experienced staff, problems with frequent repetitions.
You can not use oily solutions or suspensions.
Intramuscular and subcutaneous
The absorption takes place mostly by diffusion second gradient from the site of injection plasma.
Large molecules such as proteins reach the circulation via the lymphatics.
The intramuscular route ensures faster absorption compared to subcutaneous.
absorption constant, and that can be prolonged in time (suspensions, pellets)
Avoid irritants (pain and necrosis). Disadvantages injection.
Used to administer antineoplastic agents or diagnostic agents to them straight in a "centrifugal".
Inject drugs in the spinal subarachnoid space.
E 'used for spinal anesthesia or treating acute infections of the CNS.
E 'used especially for drugs that do not cross the blood-brain barrier.
Has the disadvantage of enhancing the possible neurotoxicity of drugs. Requires personnel with specific experience.
Initial distribution of basic circulatory
Stage I = Distribution in highly perfused organs: heart, liver, kidney, brain
Stage II = Increased drug delivery to the muscles, organs, skin and adipose tissue.
Subsequent distribution of biochemical basis
Bond with cellular constituents, accumulation in sites of deposit from which the drug is then gradually transferred.
Distribution in the CNS
The endothelium of the capillaries in the CNS lack intercellular pores. Although glial cells pericapillari reduce exchanges between blood and CNS.
Therefore, the distribution in the CNS is a function of the lipid solubility of the drug.
The active transport operates in some cases.
Meningeal inflammation and brain increase the permeability of the blood-brain barrier.
The lipid soluble drugs pass very well. Possible effect of drugs on the fetus.
Sites of deposit
Beginning require higher amount of drug is observed because the therapeutic effect.
May prolong the effects of the drug, gradually ceded in free form
It 'a storage site for fat-soluble substances. The deposit is relatively stable due to the low blood flow.
Albumin and 1-acid glycoprotein can adsorb a percentage of the drug in plasma
The drug-binding protein reduces:
-The concentration of drug in the site of action
-The biotransformation of the drug.
The fraction of drug bound depends on:
-Concentration of the drug
-Number of binding sites
-Affinity for the binding sites
The binding of drugs to plasma proteins is rather non-selective (acidic substance bind to albumin, bases the 1-glycoprotein) for which wide range of competing drugs for this bond (possibility of pharmacokinetic interactions)
The binding capacity of plasma proteins is lower in the fetus and neonate than in adults.
Sites for storage cell
The storage cell may be due to bond formation with cellular components. For example tetracyclines bind the bones and lead
The pharmacologically active substances used metabolic pathways for endogenous compounds, thanks to a certain structural analogy with these.
I am especially interested in the biotransformation fat-soluble substances, which can then more easily access to intracellular sites
Consequences of biotransformation:
• Inactivation of the drug.
• Formation of the active metabolite.
For example the paracetamol is more active of phenacetin.
The L-Dopa inactive (prodrug) generates active dopamine
• Formation of the active metabolite with different activities.
Typically biotransformed products are more water soluble and therefore more easily removed in the kidney.
The biotransformation are influenced by
-Age (infants and the elderly have lower amounts of enzymes)
-Sex (estrogen influence oxidative processes, progesterone inhibits glucuroconjugation).
State-feeding (the biotransformations are reduced in the case of malnutrition)
-Liver disease (reduce biotransformation)
Seat of biotransformation
The enzymes biotrasformanti are contained mainly in the liver. Are rich in the kidney, muscles and lungs.
At the cellular level the biotransformations occur to a considerable extent in the microsomal fraction of the endoplasmic reticulum. And 'the smooth portion of the lattice, consisting of lipoproteins
Microsomal enzymes are responsible for the oxidation of lipophilic substances. Have low selectivity towards the substrate.
In addition to the microsomal enzymes can have biotransformations by:
-Cytoplasmic enzymes, oxidation of water-soluble substances.
-Mitochondrial enzymes. For example, monoamine oxidase (MAO) responsible for the oxidative deamination of biogenic amines and several drugs.
-Plasma enzymes (esterases)
Classification of biotransformation
Phase I reaction
Involve alterations of the molecule of the drug, without addition of further molecular species. Include:
The redox reactions are catalyzed by the microsomal cytochrome P 450 (CYP450)
Have been identified 12 families of CYP450 isoenzymes in humans. The most important in quantitative terms are:
1. CYP3A4 (metabolizes approximately 50% of the drugs!)
The kit of cytochromes is under genetic control, so there may be large differences in metabolic capacity between different subjects.
For this the system of CYP is the subject of careful study by pharmacogenetics.
If you knew the subject matter the amount of enzyme that metabolizes the drug administered, may prevent many adverse reactions to drugs!!
Induction or enzyme inhibition
Drugs and foods can act as inducers of CYP enzyme induction (ie increase its production).
Are enzyme inducers phenobarbital and rifampicin.
Rifampicin increases CYP3A4, 1A2, 2C9, 2C19
Some compounds instead are enzyme inhibitors as bind to CYP in an irreversible way, impeding the activities. For example:
Some macrolides inhibit CYP3A4
Fluoroquinolones inhibit CYP1A2
Grapefruit juice contains coumarin derivatives and bioflavonoids, which inhibit CYP3A4.
The enzyme induction leads to a faster metabolism of all those compounds metabolized by CYP-induced, reduced their pharmacological activity
The enzyme inhibition results in a slower metabolism and thus tends to enhance the response to pharmacological compounds metabolised by the enzyme inhibited.
Both the induction that the enzyme inhibition can be due to interactions between drugs or between drugs and food, potentially of clinical relevance
Phase II reactions
Consist of synthesis reactions. Include:
-Amino acids (glycine, cysteine, glutamine, serine, lysine)
The residue to be transferred to the drug must be activated with energy ties (with intervention usually ATP or UTP).
The transfer reaction is catalyzed by transferase localized not only in the microsomal.
The glicuronoconiugazioni synthesis reactions are more common. The glucuronic acid is originated for catabolism of glycogen.
Following the glucuroconjugation the drug loses its activity in general, also the products that arise are water soluble and therefore eliminated by excretion.
The glucuronides excreted in the intestine may be split regenerating the parent drug that can be reabsorbed (enterohepatic recycling)
Involves extrusion of drugs from the body
1) Renal excretion
The kidney eliminates especially water-soluble substances.
The elimination involves three different processes:
-Glomerular filtration rate,
-Active tubular secretion,
-Passive tubular reabsorption.
The acidification (with NH4Cl) or alkalisation (with NaHCO3) urine influence the passive reabsorption, respectively for the basic and acidic substance)
2) Biliary excretion and fecal
For the most active transport of glucuronides or circulated according to a concentration gradient.
Substances in the faeces are disposed of in various juices flowing into the gastrointestinal tract
3) excretion through sweat, saliva, tears
Minor quantitative saliva and tears.
The mechanism of elimination is passive diffusion.
4) Excretion in milk
The milk is more acidic than plasma so concentrated bases. It 'important for the effects on the nursing infant.
5) Excretion pulmonary
Important for gaseous and volatile.
Kinetics of first-order
The elimination rate may be correlated to the concentration of drug in plasma (The order kinetics):
V = k C1
In other words, the unit of time is eliminated a constant fraction of the drug, not a constant quantity.
A first-order kinetics is generally seen when deleting
1. not made via a saturable (carrier or metabolising enzyme)
2. there is a saturable system, but the drug is used in low doses that do not saturate (typically therapeutic doses of medication)
When the system saturable (enzyme or carrier) is saturated, the rate of elimination is constant and not dependent on the plasma concentration of the drug (zero-order kinetics).
V = k C °
In the zero-order kinetics you delete a constant amount (not a constant fraction of drug)
The clearance is a measure of elimination
Is defined as = rate of elimination
conc. plasma drug
Eliminin speed. = Mg / min
Plasm concentration. = Mg / ml
From the relationship between these quantities is has ml / min
According to this report, the clearance can also be defined as the volume of plasma from which the drug is completely removed per unit time.
The clearance has the advantage of being fairly constant over time. This is due to the fact that the removal of drugs (at therapeutic doses) generally follows a first order kinetics.
Therefore, the decrease in the plasma concentration of the drug decreases the rate of elimination, and the ratio above (which defines the clearance) tends to be constant.
The clearance on the part of an organ is equal to the product of Q (blood flow) to the value
Ca (arterial concentration of the drug) -
Cv (venous concentration) divided by Ca
Organ CL = Q Ca - Cv
The CL organ has big changes in pathological condition (liver and kidney).
If the drug is eliminated effectively by a body, the clearance of the drug is primarily governed by the bloodstream.
However, if the elimination of a drug from an organ is small, then there will be much influenced by the blood flow, but the intrinsic clearance.
If the medication is 'eliminated by more' organs,
clearance by means of various organs is additive.
Systemic CL = CL renal + CL + liver ....
When the drug is administered repeatedly we are interested to establish a steady state for plasma levels of the drug.
This can be achieved by administering repeated quantities of drug according to the following formula:
Vel. of somm.farm = CL x Css
CL = clearance
Css = steady state concentration
VOLUME OF DISTRIBUTION
Volume is also called apparent.
It does not refer to a volume physiological, but indicates the volume of liquid that would be necessary to contain all the drug (in the body) to the concentration of the plasma.
V = amount of drug in 'body
Provides a measure of how the drug is present in the plasma.
The volume of distribution can also be 1000 liters!
It is an abstract value, because a person of 70 kg has 3 liters of plasma.
If the volume of distribution is 1000 liters means that the drug is localized electively out of the bloodstream
The volume of distribution depends on:
-Degree of ionization of the drug,
-Plasma protein binding,
-Distribution in lipids,
-Binding to other tissues,
If the drug is rapidly distributed in the tissues, may treat the body as a single compartment (kinetic unicompartmental).
If the distribution is slow kinetics will bi
It 'also known as the half-life or half-life.
Indicates the time interval in which the plasma concentration of drug in the body is reduced by 50%.
The half-life depends on the clearance and volume of distribution, according to the following relationship:
T 1/2 = 0.693 V
The half-life gives information on:
-Duration of action of the drug.
-Time required to reach steady state.
-Time required for elimination of the drug
The goal of a therapy prolonged in time is in general to achieve a concentration of drug in plasma stationary.
This objective is searched using multiple doses of drug to periods of time such as to wait for the complete elimination of the dose previously administered.
If the elimination kinetics is first order the evolution of the plasma concentration will be a branch of the hyperbola and will lead to a plateau after 4-5 times the T1 / 2.
Example of construction of graph relating all'andamemto plasma concentration of a drug in case of T1 / 2 of 24 hours, kinetics of first order and administration every 24 hours (1 day)
If the T1 / 2 is too long in relation to the therapeutic needs, use is made of an initial dose of saturation (or attack) equal to
Vd x C
(Where C is the desired plasma concentration)
1. The time required to reach the plateau depends only on the T1 / 2.
2. The level of drug concentration at steady-state depends on
-T1 / 2 and
3. The amplitude of the oscillation between maximum plasma concentration and the minimum dosing interval is directly proportional and inversely proportional to T1 / 2.
If the elimination kinetics is zero order and we continue to administer the drug before it has been completely eliminated, the performance of the plasma concentration of the drug will be a straight line.
1) Level target
Desired steady state concentration of the drug.
2) Maintenance Dose
Dose suitable to maintain the steady state. Its size can be calculated from the target concentration and the clearance.
DOSE mant. Target Conc CL = x
and correcting for the availability of the drug
3) Dose of attack
Dose or number of doses used to 'initiation of therapy to rapidly achieve the target concentration.
Dangers related to the dose of attack.
4) Range interdose
Serves to control fluctuations of drug concentration.
5) Individualization of dosage
Serves to take account of variation in a particular patient by mean pharmacokinetic parameters.
6) Therapeutic Drug Monitoring
Used to verify the achievement and maintenance of the target level.
Therapeutic drug monitoring is recommended for long therapies, drugs with a narrow therapeutic and where there is strong inter-individual variability in the response:
Amount of drug that reaches the active site of his 'action, or a biological fluid from which the drug can access the site' s action.
The concept of bioavailability is implicit in the assessment of trends over time of the amount of drug.
The absolute bioavailability is expressed by the area under the concentration-time curve.
The AUC after a single dose = Dose____
We can express the bioavailability (F) in a relative sense as systemic availability of the drug obtained for any route of administration (eg oral), compared to the intravenous route of administration
The bioavailability depends on:
1) absorption of the drug
This is influenced by a multitude of factors such as:
route of administration, processes of biotransformation in which the drug must match before the 'absorption, pathological factors that may influence the absorption.
2) drug-protein bond.
The drug bound to plasma proteins is not bioavailable.
3) Elimination of the drug.
All the factors that modify the 'elimination of the drug, influence the bioavailability.
4) Characteristics of the pharmaceutical preparation.
Disgregabilità of tablets, size of the drug particles, crystalline form.
Bioequivalence or BIOAVAILABILITY 'RELATED
There refers to various pharmaceutical forms happy the same active ingredient, or different formulations of the same pharmaceutical form.
There is talk of preparations bioequivalent if they give rise to no significant differences in terms of
-Cmax (maximum concentration in plasma) and
-Tmax (time after which you reach Cmax)
Prepared bioequivalent assumes that they must be therapeutically equivalent.
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