General principles of pharmacology د.غادة عبد الرحمن طاقة \2015\ Lecture 1

PHARMACOLOGY : is the science dealing with interactions between chemicals (drugs ) and living systems. Drug: It is an active chemical substance that interact with living system to produce response medicine is used for diagnosis , prevention , treatment and cure of disease .

Routes of Drug Delivery Parenteral (IV) Inhaled Oral Transdermal Parenteral (SC, IM) Topical Rectal

Routes of drug administration are divided into: local and systemic administration. Local route Can be used only for localized areas (so high concentration are attained at the desired site without exposing all of the body. Systemic rout : Drug is indented to be absorbed into blood stream and distributed all over the body through circulation.

Factors that effect on choice of route of drug administration : 1-physical and chemical properties of drug 2-site of desired action 3-rate and extent of absorption of drug 4- effect of digestive juice and first pass metabolism 5-rapidity of response 6-accuracy of dose required 7-condition of the patient

Systemic routes 1-oral: safe and more convenient 2- sublingual or buccal: are placed under the tongue , only lipid soluble and non irritating drugs can be administer , absorption in minutes in sublingual. 3-rectal suppositories or retention enema for systemic effects. 4- cutanuous for highly lipid soluble drugs applied over the skin for slow absorption. 5- inhalation for volatile liquids and gases 6-nasal through mucous membrane of the nose 7- parenteral by injection : take the drug directly into tissue fluids or blood it include: SC , IM , IV , ID

DRUG- BODY INTERACTION study of drug divided into : 1. Pharmacokinitics 2. Pharmacodynamic

Dose Administered Absorption Distribution Metabolism Tissue Circulation Kidneys/ Liver Elimination Dynamics Kinetics Drug at Effect Site Efficacy Adverse Events

1- Pharmacokinetic phase Describes how the body works on drugs (refers to what the body does to a drug,) pharmacokinetic properties determine: A- the speed of onset of drug action, B- the intensity of the drug’s effect, C- and the duration of drug action

consists of four major processes; pharmacokinetic : consists of four major processes; Absorption: drug absorption from the site of administration permits entry of the therapeutic agent (either directly or indirectly) into plasma. Distribution: the drug may then reversibly leave the bloodstream and distribute into the interstitial and intra cellular fluids. Metabolism: the drug may be biotransformed by metabolism by the liver, or other tissues. Elimination: the drug and its metabolites are eliminated from the body in urine, bile, or feces.

PHARMACOKINETICS Factors effect on pharmacokinetic : -route of administration - dose - onset -peak time -duration -frequency of administration

What Happens After Drug Administration? Drug at site of administration 1. Absorption Drug in plasma 2. Distribution Drug/metabolites in tissues 3. Metabolism 4. Elimination Drug/metabolites in urine, feces, bile

Note : All kinetic process involve transport of drug across biological membrane which are bilayer of phospholipids and cholesterol molecules AbsorptionIs transfer of a drug from its site of administration to bloodstream . The rate and efficiency of absorption depend on the rout of administration . 1- passive diffusion : the drug moves from a region of high concentration to lower concentration. And not involve carrier . the majority of drugs gain access to the body by this mechanism . Lipid soluble drugs readily move across most biological membrane whereas water – soluble drugs penetrate the cell membrane through aqueous channels or pores .

2-Active transport : Its capable of moving drugs against a concentration gradient ( from low concentration drug to higher concentration ) The drug need specific carrier proteins to cross membrane . Is energy – dependent (ATP). 3- Endocytosis and exocytosis for large size the cell membrane eg vit B12 (Endocytosis). (exocytosis ) :certain neurotransmitter eg norepinephrine

Factors Affecting Drug Absorption 1. Transport active vs. passive 2. pH 3. Physical factors: include blood flow surface area contact time ATP ADP + Pi A- BH+

FACTORS AFFECT DRUG ABSORPTION 2. PH Drug are either weak acid or weak base Weak acid HA H+ + A- Weak base BH+ B+H+

pH of the medication The pH of the tissues at the site of administration and the dissociation constant (pKa) of the drug will determine the amount of the drug present in the ionized state ( water soluble ). This amount will determine the easy with which the drug will penetrate or travel through the tissues.

Lipid soluble Water soluble

Drugs pass through ,membrane more easy if it is uncharged (not ionized) i.e ((HA) for acid ) and ((B) for base) while charged (ionized ) can not passes the ratio between charged and uncharged is determined by PH at site of absorption and by the strength of acid and base i.e (pka) Pka : is the Negative logarithm of acidic dissociation constant of the weak electrolytes . The lower pka of drug the stronger the acid ,conversely the higher pka the stronger the base

e.g. in case of infection low PH (acidic tissue) cause less effect of L.A (weak base). i:e the PH > pKa ( more drug in ionized form) e.g. acidic drug (aspirin) unionized at acid gastric PH and absorbed from stomach. Ion Trapping: Is to accelerate excretion of drug out of body (prevent absorption from tubules) by adjusting the urine PH . Thus the weak acid are usually excreted faster in alkaline urine while weak base excreted faster in acidic urine

2.PHYSICAL FACTOR A-Blood flow to the absorption site Blood flow to intestine is much greater than stomach thus absorption from intestine is favored over that from the stomach . B-Total surface area The intestine has a surface rich in microvilli thus the absorption of drug across the intestine is more efficient C-Contact time at absorption surface If drug moves through the GI tract very quickly, as in sever diarrhea ,it is not well absorb . Conversely , anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug.

BIOAVAILABIITY Definition: Fraction of a drug that reaches systemic circulation after a particular route of administration . eg if 100mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged , the bioavailability is 0.7 or 70 %

Bioavailability=AUC ORAL *100/ AUC injection Injected Dose Serum Concentration Oral Dose Time

BIOAVAILABIITY : Affected by: 1- 1st pass metabolism (First-pass hepatic metabolism ) (eg: Lidocaine) 2- Solubility : very hydrophilic (water soluble ) drugs are poorly absorbed because of their inability to cross the lipid cell membranes. i:e highly lipid soluble drugs easily cross cell membrane 3- Instability (eg: Penicillin G, insulin ) Instable in oral administration 4-nature of drug formation

1- 1st pass metabolism (eg: Lidocaine,) It mean: When a drug is absorbed across the GIT , it enters the portal circulation before entering the systemic. If the drug is rapidly metabolized by the liver , the amount of unchanged drug that reach to the circulation is decrease . such as propranolol or lidocaine undergo significant biotransformation during passage through the liver . [Note: First-pass metabolism by the intestine or liver limits the efficacy of many drugs when taken orally. For example, more than 90 % of nitroglycerin is cleared during a single passage through the liver, which is the primary reason why this agent is administered via the sublingual route].

First Pass Metabolism Occurs Primarily in the Liver and Gut

Factors that Affect on Distribution: II. Drug distribution Is the process by which a drug reversibly leave the blood stream and enter the interstitium and or the cells of the tissues. Factors that Affect on Distribution: 1- Blood flow in : brain, liver, kidney is grater than the skeletal muscle .

2- Capillary permeability The basement membrane in liver allows drug to exchange While in the brain , the capillary structure is continuous and there are no slit junction called blood brain barrier . Endothelial cells in liver capillary Endothelial cells in brain capillary Glial cell

Drugs enter to brain must pass through the endothelial cells of the capillaries of the CNS or by active transported. Lipid soluble drugs readily penetrate into the CNS while ionized or polar drugs generally fail to enter of the CNS. 3- Drug structure: hydrophobic drugs (lipid soluble) , no net charge , readily move across most biologic membrane . By contrast hydrophilic (water soluble) drugs + or – charge , do not readily penetrate cell membrane , therefore , must go through the slit junction

4-Binding to proteins (role of albumin) Drugs bind differentially to albumin Reversible binding to plasma proteins sequesters drugs in non diffusible form and slows their transfer out of the vascular compartment. Binding is relatively nonselective as to chemical structure. Drug X warfarin

Plasma albumin: (Plasma albumin): is the major drug binding protein and may act as a drug reservoir, the concentration of the free drug decreases due to elimination by metabolism or excretion , the bound drug dissociates from protein this maintains the free drug concentration as a constant fraction of the total drug in plasma . Albumin Drug X warfarin

Bound drug are pharmacologically inactive only the free ,unbound drug can act on target site in the tissue , elicit biological response , and then elimination . Binding capacity of albumin the binding of drugs to albumin is reversible and may show low capacity (one drug molecule per single albumin molecule ) or high capacity( number of drug molecule binding to a single albumin molecule)

The drug with high affinity for albumin can be divided into 2 class Class I: dose od drug less than available binding sites (e.g: most drugs) eg warfarin Class II: dose of drug greater than binding sites (e.g: sulfonamide antibiotic ) The problem: one drug may out-compete the other for the available binding site (warfarin+ sulfonamide) leading to bleeding due to increase concentration of warfarin . Albumin Drug X warfarin

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