Introduction Basic principles of pharmacology Prof. Suheil Zmeili, MD; PhD Faculty of Medicine Department of Pharmacology University of Jordan
IntroductionBasic principles of pharmacology
Prof. Suheil Zmeili, MD; PhDFaculty of Medicine
Department of PharmacologyUniversity of Jordan
** Pharmacology Pharmakon = Drug; Logos = Science** Drug- A chemical substance that is primarily used
to reverse a pathophysiological defect =disease
- A chemical substance that is mainly used totreat, control, prevent, or diagnose aspecific disease
** Drug discoveryThe first step usually starts with an idea =a hypothesisWhat helps?Previous experience and availability of old drugs;
existence of plants of clinical benefits; chemicalidentification of endogenous substances e.g.hormones; availability of new preparatorytechniques ... etc
** Drug discovery Cont..- Animal studies = toxicity studies- In vitro studies, acid = antacid ...** Pharmaceutical processIt involves making a drug in a suitable dosage
form
** Administration (Routes) = Systemic orlocal
** Systemic administration :- Oral (tablets, syrups, suspensions...),- Prenteral route = Subcutaneous S.C
(solution), intramuscular I.M (solution)intravenous = I.V (solution)
- Buccal (tablets) sublingual (tablets) rectal(suppositories)
- Transdermal (patches)- Inhalational (sprays)
** Topical = local administration- Liquid forms (sprays, lotions, solutions =
ear or ophthalmic drops, mouth washes, S.Cinfiltration e.g. local anesthetics...)
- Semisolid forms (creams, ointments...)- Solid forms (suppositories, pessaries =
vaginal tablet...)
** Pharmacokinetic processIt is the study of what the body does to a drugIt includes the processes:- Absorption- Distribution- Metabolism- Excretion = elimination
** Pharmacodynamic processIt is the study of what a drug does to the body It includes the processes:- Pharmacological effects- Therapeutic effects- Mechanisms of drug actions- Side effects = adverse reactions = unwanted
or untoward effects = toxic effects
** PhrmacogeneticsIndividual variations in responding to drugs** Major objectives:Giving the patient the minimal possible dose
capable of producing the desired effect orrelieving the signs and symptoms of aspecific disease without producing side ortoxic effects
** Branches of pharmacology usually answerall of the following questions:
- How much of a drug to give? Dose- How frequent a drug should be given?
Related to the biological half-life (t1/2)- When to give it? Before or after meals; at
bed time, PRN...- How to give it? administration ... etc
Chemical nature of drugs:- Neutral ... Steroids- Acidic ... Aspirin, Barbiturates- Basic ... Morphine; AlkaloidsDrug sources:- NaturalPlants (atropine, digoxin), animals (insulin),
human (growth hormone)
- Semisynthetic (human insulin)- Synthetic (agonists; antagonists)Drug nomenclature:- Chemical name e.g. acetyl salicylic acid- Generic name; nonproprietary; approved
name... Aspirin (most widely used inpharmacology)
- Official name... Aspirin BP; Aspirin USP- Trade name; Proprietary; brand name
Remine®; Bufferin®…
Drug absorptionPassage of drug from route of administration
to circulationBioavailability:The fraction of the given dose that gets into
bloodThe bioavailability of an I.V given drug is
100%
Protein binding: Represents:- A reservoir to the drug- A mean by which drug reaches its site of
action- A major site of drug-drug interactionsStrongly bound drugs to blood proteins
remain longer in blood, have longer t1/2 &DOA
** The free form of the drug, is the formwhich is active and crosses membranes
Sites of drug absorption:- Oral mucosa (buccal; sublingual tab.)- Stomach (aspirin)- Intestine (iron; vit. B12)- major site- Lungs (general anesthetics)- Rectum- Skin
Factors affecting absorption:- Drug size- Lipid solubility (major factor)Lipid/water partition coefficient- Degree of ionization or environmental pH:pH = pKa + log [A-]/[HA]pH = pKb + log [BOH]/[B+]
Cont. factors affecting absorption:Polar = ionized = water soluble = active formNonpolar = unionized = lipid soluble =
crosses membranes- Concentration of drug- Surface area of absorption- Blood circulation to absorbing area- Route of administration (I.V the fastest)
Enterohepatic circulationBioequivalency:A comparison between 2 drugs- Chemically similar- Similar bioavailability- Biologically similar- Therapeutically similar
Drug distributionPassage of drugs from blood to different
tissues (site of action)70 Kg man 60% H2O ≈ 42 litersPlasma extracellular fluid intracellular
fluid[F] [F] [F]2.8 L 10.5 L 28.7 L
Apparent volume of distribution (AVD):
The volume in which a given drug distributesin different body compartments
AVD = Dose (mg)/C0 (mg/L)
C0 = Concentration of drug in blood at timezero
Highly lipid soluble drugs e.g. digoxin, have avery high Vd (500 liters)
Drugs which are lipid insoluble e.g.neuromuscular blockers, remain in theblood, and have a low Vd
Very very high Vd indicates extensive tissuebinding
Factors affecting drug distribution:- Compartmental selectivity- Protein binding ( Major factor)- Natural barriers BBB Placenta Mammary glands
Mechanisms of drug transfer across membranes:- Simple diffusionCrossing through water pores of membranes, no
energy or carrier required, from high to lowconcentration, drugs with low M.W (must be lipidsoluble and concentration gradient is the drivingforce)
D
- Passive diffusion (major mechanism) Crossing through cells or the lipid bilayer, no
energy or carrier required, from high to lowconcentration
D D D
The only requirement for passive diffusion isthat the drug should be lipid soluble
- Facilitated diffusionRequires a carrier, no energy required, from
high to low concentration- Active transportRequires energy ± carrier, could be from low
to high concentration- Endocytosisis Phagocytosis (solid particles) Pinocytosis (fluid particles)
Drug metabolismA change in the chemical structure of the
drug, or addition of a hydrophilic groups toan initially lipophilic drug until it becomessufficiently ionic so as to be easily filteredand excreted by the kidneys
It has nothing to do with the benefit or harmof the drug
Drug metabolism involves 2 major pathways:- Pathway I = Oxidation reduction reactionsAlso known as mixed function oxidase system
and cytochrome P450 system (CYP system)- Pathway II = Conjugation reactions Metylation Acetylation Glucuronide formation
Characteristics of an ideal metabolite:- Water soluble- Pharmacologically inactive- Not to be toxicSites of drug metabolism:- Liver (major site)- Intestine- Lungs; brain; kidney; plasma...etc
Factors affecting drug metabolism:- Genetic factors and species differences
(major factor)- Drug-drug interactions- Age (paracetamol vs chloramphenicol)- General health of patients and nutritional
status- Dose and frequency of administration
Drug excretion = eliminationA process by which a drug or it’s metabolites
are eliminated from the bodyMajor sites:- Kidney (most drugs)- LiverKidney function !!!!!
Methods of excretion:- Filtration- Tubular secretion Probenecid PenicillinThe rate of excretion is measured by a
specific constant known as Ke
Ke = Clearance (ml/min)/AVD (ml)Ke unit: min-1 = 1/min
Ke = 0.693/t1/2 (min)
t1/2 = o.693 × AVD/clearance
Steady state level (chronic administration) PlateauBloodConc.
TimeReached after 5 t1/2 livesLoading dose
Terms:- Indication:Clinical uses of drugs- Contraindications:Situations when not to use drugs- Drug tolerance:↓ response after repeated doses e.g. drugs of
addiction
- Tachyphylaxis:Rapidly developing tolerance- Drug interactions:The effect of one drug on another. Takes
many forms:↑ or ↓ absorption; ↑ or ↓ protein binding; ↑ or
↓ metabolism; ↑ or ↓ excretion; ↑ or ↓toxicity; ↑ or ↓ binding toreceptors… etc
** Rule: one drug is better than two; twodrugs are better than three…etc
- Side effects and drug toxicity:Unwanted, untoward, undesirable, adverse
reactions to a given drug- Idiosynchracy:Abnormal genetically reaction to a given drug
PharmacodynamicsMeans mechanism of action (MOA)Drugs could either act through receptor or
non-receptor mechanisms- Non-receptor mechanisms:Acid-antacids; laxatives; heparin-protamine
sulfate…etc
Binding of D to R requires that:- Both D and R should be close enough to
each others- The R has to be complementary in it’s
chemical structure to the D- Binding of the D to the R should be
reversible
Binding forces between D & R:- Van der Waals:The weakest bond N…..NThe commonest bond between the D & RClose approximation between the D & R is
requiredThe R chemical structure should be
complementary to the D
- Hydrogen bond:Stronger than Van der WaalsReversibleOccurs when a hydrogen connects 2 oxygens
or 2 nitrogens -O H……O= -N H……N=
- Ionic bond:Stronger than hydrogen bondReversibleOccurs between ions of different charges
- Na+….. Cl-
- Covalent bond:Irreversible bondThe least common bond between the D & its
receptorThe strongest bond; energy is required to
break it downOccurs when the D and the R share a pair of
electrons
- Vmax:Maximum response. Also known as efficacy orintrinsic activity. It is important in
pharmacology- ED50:The dose which produces 50% of response- LD50:The dose which produces death in 50% of
animals
Death is considered the most severe sideeffect to any drug
- Therapeutic index (TI):A measure of the safety of drugs
TI = LD50/ED50
The larger the TI the more safe is the drug
- Potency:A term used whenever we compare the
activity of two drugs producing the sameeffect
Defined as the dose of one drug necessary toproduce a specific response as compared toa second drug producing the same effect
- Affinity:The ability of a drug to form a stable complex
with the receptor
Types of drug-receptor interactions:1. Drug agonism:Agonist:A drug that interacts with a specific receptor
and produces a responseAddition: Applies whenever two drugs
producing similar response given togetherresult in a final response equals to the sumof the response of each drug (1+1=2)
Synergism: Applies whenever two drugsproducing similar response given togetherresult in a final response greater than thesum of the response of individual drugs(1+1=3 or 5…)
Potentiation: Applies when one drugproducing no response given with anotherproducing a specific response results in anincrease in the final response of the seconddrug (0+1=2 or 5…)
2. Drug antagonism:A pure antagonist is a drug which binds a
specific receptor producing no effect orresponse , but if given with an agonist itreverses the effect of the agonist
Antagonism may take many forms:a. Physiologic antagonism:Sympathetic vs parasympathetic
b. Antagonism by neutralization:Applies whenever two drugs given together
form an inactive complexc. Pharmacologic antagonism: 2 major types1. Competitive antagonism Ag. Ant. Ag. Ant.
Characteristics of competitive antagonism:- Both agonist and antagonist compete
directly for the same receptor or even site- It is reversible- ED50 of agonist ↑ in presence of antagonist- No change in total # of receptors- Dose-response curves are shifted to the right
Characteristics of noncompetitive antagonism:- Both agonist and antagonist act on different
sites of a given receptor or even differentreceptors
- It is irreversible- Results in no change in the ED50 of agonist- Total # of receptors ↓- Results in downward shift in the Dose-
response curves