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.