PHARMACOLOGY
DVM Sylvia Arrau BarraPharmacological Sciences
Doctor
• IT HAS ACCOMPANIED THE MAN FROM THE DAWN OF ITS EVOLUTION
DIFFERENT CULTURES HAVE DEVELOPED FROM DIFFERENT ORIGINS TREATMENT BASED ON OBSERVATIONS OF NATURE:
EGYPTIANSHINDUSINCASMAYAASIAN CULTURES
HIGH CURRENT DEVELOPMENT
Human beings origin . Ebers Papyrus1500 b.C
Teophrasthus(370-286 b.C.)
Dioscórides(100 a.C.)
Classifies medical fieldFor substances, 1st botanical
Galen (200 a.C.)
Describes multiple
substances
EGYPT
GRACEOne of the greatest pioneer of natural medicine
and homeopathy
GRACE
GRACE
Ebers Papyrus, that really it is acompilation of medicaltextbooks that are dated at1550 years b. C, and it is one ofthe oldest collection in the artof healing, documents containsoriginal 700 formulas, in honorof the German Ebers thatadquired it in 1873.
Among Neolithic peoples, preparing allkinds of potions and poisons is welldocumented, also supposedly healingsubstances
Midle AgeMixtures that “cures everething”
More than 100 compounds.TRIACA o TEHRIACA
Avicena (900 a 1037 a.C.)
Basic preparations of somemedications
Leonard Fuchs (XVI)
First book of medicinal herbs
Paul Ehrlich (1854 to 1915)
“Chemotherapy”
Penicillin discovery
Fleming (1881 to 1955)
MULTIDISCIPLINARY INTEGRATION OF MANY OTHER SCIENCES:
Toxicology
Physiology
Physiopathology
Statistics
Pathology
Chemistry
Biochemistry
Others
Common root with human pharmacology
DRUGS USED TO TREAT DISEASES
Correlated effect and Pathophysiology
Ever quantify risk / benefit drug use
Establishes guidelines and rational schemes
Treatment dosages
Currently Clinical Pharmacology
Science that studies the origin and physicochemical properties ofchemical substances, which are introduced from outside the body:
They are xenobiotic….and are….
o ABSORBED
o DISTRIBUTED
o BIOTRANSFORMED
o EXCRETED
Especially studies the pharmacokinetics and pharmacodynamics ofdrugs, thanks to its pharmacological action
Shows physiological changes (effects) in living systems, which aregenerally used for therapeutic purposes.
Chemical ofany source, which is
able to interact with aliving organism.
NO MEDICINAL USES OF CHEMICALS
DetergentsPesticidesDyesIndustrial wasteCorrosion thinnersNatural food ingredients
• Neurotransmitters
• Neuropeptides
• Hormones
• Nucleotides
• Gases and Co
ENDOGENOUS DRUGS
DRUG
Drug that contributes to the proper functioning of
organism.
Drug used in the prevention, diagnosis or treatment
disease.
TOXIC= POISON
Drug with unwanted effects
DRUGS:Drug = medication. Accurate translation.
Drugs = Substance impaired consciousness. Dependence.
State drug used to modify mood or behaviorPotential drug abuse or addiction.
Branch of pharmacology that studies the adverse or toxic effects of different substances (drugs or not) acting on organic systems producing undesirable effects and indicates how they treat them.
Toxic is any inorganic substance that causes damage to our organs or cells.
Biological poison toxin is synthesized by plants or animals.
VEGETAL DRUG
Budleja globosaChilean plant, many ethno
pharmacology uses
Plant parts used as curatives (leaves, flowers, roots, bark, seeds, resin).Contains active ingredients.It is the plant or plant parts used raw with a medicinal purpose or pharmacist
Pharmacological effects.Tree maticoBudleja globosa. Active ingredients:
healing; antibacterials;antiinflammatory and others.
Green plant drug in capsulesMorphineCodeineThebaine
Drugs vegetable seeds:Strychnine neurological toxic,opisthotonus and deathBut also drugs
CLASSIFICATION OF DRUGS:
NATURAL DRUG: PHYTODRUG, MEDICINAL HERBAL.
DRUG ALLOPATHIC: SEMI SYNTHETIC OR SEMISYNTHESIS.
DRUG SYNTHESIS: HIGH TECHNOLOGY AND INVESTMENT
THE VAST MAJORITY OF CURRENT DRUGS ARE SEMISYNTHETIC
SUMMARY STEPS OF DEVELOPMENT DRUG
Folk Medicine (information between generations)
Isolation and Purification active compounds
Determination of the NMR chemical structure (Structural Elucidation)
Relationship between structure and activity (QSAR)
Preclinical and Clinical Research
Drug trade: Security Studies-Efficiency and Quality
They can SPEND OVER 10 YEARS
ACTIVE PART OF COMPLEX HAVING AN EFFECT PHARMACOLOGICAL METHODS ARE EXTRACTED BY CHEMICAL EXTRACTION, IDENTIFICATION AND STANDARDIZATION
DOSES AND EFFECT PLASMATIC CONCENTRATIONAmount of drug administredto a patient at one time
PHARMACOKINETICS FARMACODYNAMICD/R
A.D.M.E L.A.D.M.E.
D: DrugR: ReceptorL:Release of the drug from the vehicule
BIOPHASE
It is the Middle surrounding the cell membrane, thatis where ocurred the Drug Receptor binding in theDigestive, occurs in the mucosa Absorption:
waterLipidsProteins (enzymes, mucus, food)Hydrogen ions (H + pH)Chemical compounds (Sales, drugs)Microorganisms
BIOLOGICAL STEP THROUGH BARRIERSIN FACT ... ..INTO THE BLOOD
It is the passage of the drug from the site of administration to the systemic circulation through at least one membraneWhat routes of administration lack this process?
ABSORTION
o Factors determining the absorptionDrug dependentPharmaceutical formMolecular sizeLiposolubilityMolecular stateDependent organismAbsorption areaIrrigationPresence of enzymes
o Pathological conditions
The pKa of a drug is the pH at which a drug has half of itsdissociated or ionized molecules and half undissociated
molecules.
Therefore weak acids are well absorbed in the stomach,where the pH is acidic, and the bases are best absorbed inthe intestine where the pH is alkaline.
ABSORPTION THROUGH MEMBRANES
EVERY time the pH of the medium is less than pk drug, the unndissociated fraction of the acids and ionized
forms of the bases predominates,the opposite occurs when the pH is greater than pk
HA A- + H + (HA) + (A)
PLASMA pH = 7.4
GASTRIC JUICE pH = 1.4
HA A- + H +
WEAK ACID (pK 4.4) HA A- + H +
NONNIONIZED DRUG
IONIZED DRUG
LIPID BARRIER MUCOSA
UNNIONIZED DRUG
LIPOSOLUBLE
DISSOCIATED, IONIZED DRUG
NON LIPOSOLUBLE
WEAK BASE
ESTOMACH
1. Degree of lipid solubility2. Molecular Size3. Degree of ionization
1. A> Liposolubility> diffusibility2. Small soluble molecules passaquaporin channels2. Large water-soluble moleculesdiffuse but little3. A lower greater is the degree of ionization Liposolubility.
LIPOSOLUBILITY DEGREE AND CAPACITY OF CROSSING MEMBRANES
SIMPLE DIFFUSIONDriving force passive absorption of a drug, is the concentration gradient across a membrane, separating two compartments, (drug moves from an area of high concentration, to one of low concentration, until equilibrium is reached between the two sides.
FILTRATIONPassive process by which drugs cross the plasma membranes, (biological barriers) when passing by so-called functional pores, which is necessary for certain molecular size.
Ósmosis: movimiento del agua a través de membranas
Osmosis depends on the relativeconcentration of solutemolecules on both sides of the
membrane.
The presence or absence of cellwalls influence, as cells respondto osmotic environmentalfluctuations.
AQUAPORIN CHANNELS
LITTLE LIPOSOLUBE MOLECULES
ACTIVE TRANSPORTATIONProcess involving specific protein carrier (carrier) and shows saturation kinetics, always against a concentration gradient.
FACILITATED DIFFUSIONTransport system also requires a carrier molecule, without requiring energy, always in favor of a concentration gradient.
PASSIVE MECHANISMS
PINOCYTOSISIs a type of endocytosis, used for absorption of macromolecules in solution generally be internalized into the cell.
Ausencia de transporteLarge molecules such as proteins, polypeptides, ornucleic acids polisaccharydes do not pass by diffusionthrough membranes.
Must be broken, in their monomeric components, i.e.amino acids, sugars or nucleotides, to pass throughthe membranes.
DO NOT PASS
ONCE THE BIOLOGICAL BARRIERS TRANSFERR OCCURS:
Drug release: Inside the body by a vehicle
VEHICLE: A chemical substance that transports and can also act as an excipient
The active ingredient is released according to the route of administration
DRUG VEHICLE
AMOUNT OF DRUG THAT ENTERS THE BODY
THROUGH AN EMPIRICAL SETTING ???: LONG DELAY IN OBTAINING THE DESIRED EFFECT, DANGER OF INTOXICATION
1. SETTING THE DOSE RESPONSE BY CLINICAL OBSERVING EFFECTS on the patient and also through monitoring of plasma levels of DrugsTO WIDE THERAPEUTIC MARGIN DRUGS
2. PHARMACOKINETICS ADMEAccording to input speeds (absorption) and output (Distribution + Delete) from the bloodTO NARROW THERAPEUTIC MARGIN DRUGS
NEED PHARMACOKINETICS INFORMATION
PLASMATIC CURVE LEVELS AND A UNIQUE DOSE
a.-ABSORPTION PREDOMINANTLY follows first order kinetics, this means that the rate of absorption depends on the amount of drug administered. At this stage the speed of entry of the drug into the blood is greater than the output.
b.- COMBINATION OF ABSORPTION, DISTRIBUTION AND DISPOSAL input speed is equal to the output speed of the drug. Coincides with the maximum effectiveness of the drug. Then there are drug distribution. When the curve starts to decline, it means the elimination begins.
c.-ELIMINATION PREDOMINANTLY elimination follows first order kinetics.
a
b
c
IN THIS CURVE OF PLASMA LEVELS WE WILL BE APPRECIATE OTHER IMPORTANT PARAMETERS:
MINIMUM EFFECTIVE CONCENTRATION OR THERAPEUTIC (CME) that from which the pharmacological effect starts.
MINIMUM TOXIC CONCENTRATION (CMT) that from which starts a toxic effect.
LATENCY PERIOD (PL): time from the time of administration until the pharmacological effect starts.
INTENSITY OF EFFECT (IE) is often related to that achieved by plasma drug concentration. Depends therefore on the height of the curve; higher, greater effect.
DURATION OF ACTION OR EFFECT (TE): elapsed between the time the CME and the time drops below this concentration while is reached.
ABSORTION DISTRIBUTION
METABOLISM
ELIMINATION
(GUT AND STOMACH)
DIGESTIVE MUCOSA
RENAL
PORTAL CIRCULATION
LIVER
ROUTES OF ADMINISTRATION OF MEDICATIONS :
ONLY LOCAL EFFECT: TOPICALSYSTEMIC DRUG ADMINISTRATION (ABSORPTION SPEED):
OralSub-cutaneousintramuscularendovenosoVia Intraosseousintradermalintrathecalsub Duraltransdermal ¿Intravascular or Extravascular
Tarjet tissuePlasmaticconcentrationand circulation
¿WHAT ARE THE DIFFERENCES BETWEEN THEM?
IF THE ENTIRE DOSE IS AVAILABLE TO PRODUCE THE DESIRED PHARMACOLOGICAL EFFECT, IS THEN SAID THAT THE DRUG IS BIOAVAILABLE.
VIA THE E.V. OR I.A.. DRUG BIOAVAILABILITY IS 100% OR THE ENTIRE DRUG.
ABSOLUTE BIOAVAILABILITY
EV ENDOVENOUS
IA INTRARTERIAL
Enteral: oral, sub-lingual (oral), rectal
Parenteral: iv, im, sc, id, it, etc.
Area: skin, lungs ?, for systemic or local effects?...it depends on the molecular size
Inhalation: local or systemic effect?
Vaginal (usually local)
Eye: (usually local)
MODIFY DRUG ABSORPTION FACTORS
OWN DRUG
CONCENTRATION OR DOSE
LIPOSOLUBILITY
DISSOCIATION CONSTANT
PHARMACEUTICAL FORM
SOLIDS•CAPSULES•PILLS OF TABLETS
LIQUIDS
•SYRUPS•SOLUTIONS•SUSPENSIONS
JOINING FORCES BETWEEN DRUGS AND PROTEINS
DRUG - PLASMA PROTEIN DRUG INTERACTION
COVALENT BONDS (RARE)
IONIC BOND
LINK DIPOLE DIPOLE
HYDROGEN BONDS
VAN DER WAALS BONDS
COMBINATION WITH SULFHYDRYL GROUPS
PLASMA PROTEIN INVOLVED IN THE UNION A PLASMATIC PROTEIN ARE:
ALBUMIN
THE α - ACID GLYCOPROTEIN
LIPOPROTEINS
PH DEPENDENT DRUG
RARELY GLOBULIN
FIRST PASS EFFECT –EXTRACTION RATE
HOW TO EVALUATE FIRST PASS EFFECT?
PROCESS IN WHICH THE
DRUG IS
CARRIED ALONG DIFFERENT
BODY TISSUES, TAKING
INTO ACCOUNT THE
CARDIOVASCULAR
SYSTEM AND
HEMODYNAMICS.
capillary permeability
Structure of the drug
Protein binding
plasma
physiological barriers
Irrigation degree of organ
BRAIN BLOOD BARRIER
PLACENTAL BARRIER OCULAR BARRIER
IN FACT…. ONCE THE FIRST AMOUNT OF DRUG ENTERS THE BODY, ALL PROCESSES OCCURS SIMULTANEOUSLY:
ABSORPTION}
PP UNION
DISTRIBUTION
METABOLISM
Drug concentration in certain tissues
Production of active and inactive metabolites
Excretion of active and inactive metabolites
Drug excretion as such
KINETICS OF DISTRIBUTION AND DISPOSAL
Kinetics of First Order or Order one (1)
Zero order kinetics (0)
What is in the Distribution?
What does the excretion?
Disappearance rate (removal) of the drug is constant.
Constant amounts of drug per unit time removed
Is independent of its concentration in plasma
BUT ALSO MAY OCCUR WHEN,,,SATURATION LIVER ENZYMES.
ONE COMPARTIMENT MODEL
The body can be represented as "one box"
FOR EXAMPLE THE BLOODSTREAM
In order to demonstrate the changes in drug concentration
TO PREDICT DRUG RESPONSE
XO=FIRST DOSIS;X1=PLASMATIC CONCENTRACIÓN;K=ELIMINATION CONSTANT
;E=ELIMINATION;=Cpl=PLASMATIC CONCENTRATION;V1=INITIAL SPEED.
ONE COMPARTIMENT MODEL
THE DRUG ENTERS THE BLOOD REACHING INSTANTLY
THE DRUG DISTRIBUTION IS IN BALANCE SO FAST ALL AROUND THE ORGANISM THAT CAN NOT BE MEASURED
BY THE WAY, YOU MAY CONSIDER THAT THE BALANCE OF DISTRIBUTION, IS AN INSTANT PROCESS AND ONLY THE PROCESS OF ELIMINATION COULD BE MEASURED.
ONE COMPARTIMENT MODEL
ASSUMING A KINETIC 1ST ORDER HYPOTHETICAL MODEL
Concentrations rapidly reach equilibrium blood / tissue
The change in plasma concentration reflects changes in
tissues
Elimination Rate of a compound is just proportional to
their concentrations in a given moment
Removal rate is high when dosage is high to the point
XO=FIRST DOSIS;X1=PLASMATIC CENTRAL CONCENTRATION;X2=PERYPHERAL CONCENTRATION; K=ELIMINATION CONSTANTS=K1-2 = SPEED SPEED DISTRIBUTION FROM
CENTRAL TO PERYPHERAL; K2-1 = SPEED SPEED DISTRIBUTION FROM PERIPHERAL TO CENTRAL
;K1-0=SPEED OF EXCRETION;E=ELIM;INATION;=Cpl=PLASMATIC CONCENTRATION;V1=SPEED 1. V2 =SPEED 2
MAIN PHARMACOKINETIC PARAMETERS
BIOAVAILABILITY (F):Fraction of administered drug that reaches the systemic circulation as unchanged.
VOLUME OF DISTRIBUTION (VD):Fictitious volume occupied by the drug in the body.
LIFE MEDIA (T1 / 2):The time necessary to fall plasmatic concentration at half
CLEARANCE OR CLEARANCE:Plasma volume is purged of drug per unit of time.
BIOAVAILABILITY (F%)
For your calculation other kinetic parameter which is the area under the curve (AUC) which allows estimating patient exposure to the drug (%) is used:
It is expressed as percentage relative to plasma levels obtained after intravenous administration of same dose:
DISTRIBUTION VOLUME
IT IS A KINETIC PARAMETERNOT A REAL VOLUME
Lets relate the amount in the body with the same concentration
IT IS A SPACE OF DILUTION
It can be defined as the volume that should have the body to balance the amount present was at the same concentration as in the blood.
DISTRIBUTION VOLUME
APPARENT VOLUME DISTRIBUTION OF A DRUG IS:VOLUME THAT WOULD HAVE BEEN DISSOLVED DOSE OF A
DRUG ADMINISTERED TO ACHIEVE EQUAL TO THE PLASMA CONCENTRATION REACHED IN THE REST OF THE BODY
THIS APPARENT VOLUME REALY IS REALATED WITH REAL ONE, IT DEPENDS ON UNION DEGREE OF DRUG TO PLASMA PROTEIN UNION AND THE DISTRIBUTION VOLUME ALSO
DRUG AMOUNT-DOSE
Vd. = ————————————
PLASMATIC CONCENTRATION
DISPOSAL
It is an irreversible process
INCLUDES PROCESSES:
Metabolism and Excretion
Metabolism or biotransformation: It is influenced by irrigation Liver, Hepato cellular intrinsic activity, Fraction Drug Free.
Excretion renal perfusion, Fraction Free Drug, Devices of Transportation.