pharmacology 1

Effects on respiration, cardiovascular system

Genotoxicity

Evaluated in vitro

Cell based systems for genotoxicity

Assessed in animals in Acute and chronic studies

they have reverse ralationship.

if the amount of drug in blood decrease the valume distribution of drug will increase.

- Drugs with high plasma protein binding

- patient’s age

- gender

- body composition

- disease state

V = amount of drug in body / C

C= concentration of duge in blood

- Include protein binding

- Fluid volume filtered in the glomerulus

- Disease states may also impact renal clearance

- the science of drugs including their origin, composition, pharmacokinetics, therapeutic use, and toxicology

- the properties and reactions of drugs especially with relation to their therapeutic value

-The study of the interaction between chemicals and living systems

Biomolecules (e.g., DNA, enzymes, receptors)

-Organelles (e.g., mitochondria, nucleus, ribosomes)

-Cells (e.g., b cells, neurons, hepatocytes)

-Tissue (e.g., smooth muscle, renal tissue)

-Organs (e.g., kidney, liver, heart, brain)-

-Organ systems (e.g., cardiovascular and nervous systems)

-Organism (e.g., man, parasite)

-Society Most complex

- Medicine and health

- Pharmaceutical industry

- Social interactions

Molecular pharmacology

Biochemical pharmacology

Cardiovascular pharmacology

Neuropharmacology

Behavioral pharmacology

Psychopharmacology

Endocrine pharmacology

Immunopharmacology

toxicology

ADME and Pharmacokinetics

Integrative pharmacology

Clinical pharmacology

Pharmacoepidemiology

Pharmacogenomics

- Absorption

- Distribution

- Metabolism

- Elimination

- Binding and activity at therapeutic target

- Toxicity

- Stomach

- skin

- vein

Physicochemical properties of the drug

    o Molecular size and shape

    o Degree of ionization

    o Lipid solubility

Membranes

    o Most drugs must cross the lipid bilayer of cell membranes to reach the site of

      action nProtein binding

    o Serum and tissues

state of ionization

        Charged forms do not cross readily

        Uncharged forms penetrate membranes

- pKa of drug

- pH at which half of drug is in ionized form

- pH on either side of membrane

Henderson-Hasselbach Equation

When the pH is lower than the pKa, the protonated form will predominate

When the pH is higher than the pKa, the unprotonated form will predominate

Fractional extent to which a dose of drug reaches the systemic circulation Depends on: Rute of administration ,Absorption (impact of pH and pKa),Metabolism and/or excretion oFor some routes

Calculated as F= [(AUC)PO . dose IV] / [(AUC)IV.dosePO]

Oral ingestion, Sublingual

Subcutaneous injection

Intravenous injection

Intramuscular injection

Transdermal

Intranasal

Inhalation

Rectal

Subcutaneous injection

Intravenous injection

Intramuscular injection

Absorption: variable, must cross intestinal mucosa

Easiest route of administration and usually safe

Subject to metabolism andPatient compliance

In oral absoption, Designed for slow, uniform absorption of drug for 8 hours or longer, Reduce frequency of administration ,Potentially improving compliance, More uniform blood levels, Eliminating peaks à decreased side effects oEliminating troughs à maintain therapeutic response

- Interpatient variability in systemic drug concentrations

- Dosage form may fail

- Dose dumping with increased toxicity due to large amount of drug released

- May occur with increased stomach acidity or administration with high-fat meal

- it is for drug which have short half life less than 4 hr

Absorption from oral mucosa

Venous drainage through superior vena cava

Protects drugs from rapid hepatic first-pass metabolism

Useful with more lipid soluble drugs (e.g., nitroglycerin)

- Route of administration

- Absorption (impact of pH and pKa)

- Metabolism and/or excretion

- Subject to metabolism

-  Patient compliance

Weak acids absorbed from stomach (pH 1 to 2) rather than from upper intestine (pH 3 to 6)

Absorption of weak acids does occur in the small intestine due to high surface area

- Slow

- Uniform absorption of drug for 8 hours or longer

- Reduce frequency of administration

- Potentially improving compliance

- More uniform blood levels

- Eliminating peaks à decreased side effects

- Eliminating troughs à maintain therapeutic response

Direct application to skin

Hydration can improve permeability

May be irregular and incomplete but it is Useful when oral ingestion is precluded and good for Patient unconscious or vomiting

50% of the drugs will bypass the liver and (some elimination via lung)

a disadvantage is Irritation of rectal mucosa

Allow for absorption by simple diffusion from drug depot to plasma

Intravenous

SubcutaneousI

Intramuscular

Intraarterial

Intrathecal

- Circumvented by direct injection of drug

- Immediate effects

- Useful in emergencies

- Titration or adjustment of doses possible

- Not subject to first pass metabolism in the liver oLimitations

- Adverse effects – once injected, no going back

- Slow injections usually required

Prompt from aqueous solution

Slow from depot formulations

Useful for poorly soluble suspensions and depot formulations

Not subject to first pass metabolism in the liver oLimitations

Not suitable for large volumes

Potential pain or necrosis at injection site

Extent to which drugs reach potential target sites in the body

Depends on cardiac output, blood flow, capillary permeability, tissue volume, First phase – well-perfused organs (rain, lungs, liver, kidney), Second phase (Muscle, viscera, fat)

Determined by partitioning of drug between bloodstream and tissues

Lipid solubility and pH gradients important for weak acids and weak bases

pH gradient usually has small small effecto because tissue pH is almost the same with blood pH

Protein binding in plasma and tissue (has most effective one for distribution)

limit their availability to pass through glomures for filtration

limit drug availability to to cross the membrain. only unbounded drug can pass through memberain.

Some drugs accumulate in tissues by active transport or binding to tissue proteins and Act as reservoir of bound drug that prolongs activity in the tissue  and May also produce local toxicity .

Lipid soluble drugs may be stored in body fat and because Fat has relatively low blood flow and drugs such as thiopental can remain in body fat for several hours

prolongs activity in the tissue

produce local toxicity

synthetic analog of pyrophosphate

its a med for osteoporosis that can stay in bone by binding to bone and slow release can treat the patients.

lipid solubile drug

no charge

small size drugs

there are some drugs with charge go into the brain because of active transport

key amino acid can pass by active transport

free drugs go through rapid equilibration in renal tubular secretion

biotransformation of free drugs occur faster.

- tight junction in endothelial cells

- astrocytes outside the endothelial cells

- microglia also they are outside the endothelial cells of brain

they all help to limit drugs access into brain

A similar barrier exists at the choroid plexus with epithelial cells separating blood from the CSF

- Tight junctions

- Efflux transporters

Drugs also leave CNS via the arachnoid villi

Drugs can cross the placenta causing potential problems for the developing fetus - Lipid solubility

- plasma binding

- ionization important determinants of drug transfer across placenta

Fetal plasma pH slightly lower (7.0 to 7.2) than mother’s plasma (pH 7.4)

urine

feces

unchanged (water soluble)

following metabolism(lipid soluble generally require metabolism)

Glomerular filtration

Active tubular secretion

Passive tubular reabsorption

glomerular filtration rate

extent of plasma binding of the drug, because only unbounded drug is filtered by glomerular

active secretion of proximal and active reabsobtion of distal tubular

    in active secretion of proximal there are to transporter exist, one of  them which is p-gp and MRP2 which secrete anion to the tubular.

the other transporter is ABC which secrete organic cation to the tubular.

passive reabsoption proximal and distal tubular

in passive reabsoption of proximal and distal tubular the water reabsobed to the blood, also the unionized weak acid and  base reabsorb to the blood depend to pH

Drugs can be given orally to bind substances excreted from bile to limit reabsorption.

example: Ezetimibe reduces intestinal reabsorption of cholesterol

orally-administered

unabsorbed drugs and/or metabolites

Lungs Primarily for volatile anesthetics (gases)

Sweat

Saliva

Tears

Significant route Breast milk – minor route for mother, important route for neonate

Chemical modification of drug molecule and increase water solubility of lipophilic drugs and prevents reabsorption and improve elimination. it may be active or inactive.

Liver microsomal enzymes

- Cytochrome P450

- Oxidases

- Glucuronidation

- to increase water solubility of lipophilic drugs

- prevents reabsorption

- improves elimination

Phase I  and phase 2

phase 1: functionalization reactions which is Introduce or expose functional groups (e.g., hydrolysis) whichResult in both active and inactive compounds

may convert prodrugs into pharmacologically active compounds

Example, ACE inhibitors

Enalapril à Enalaprilat through esterases

Net result is water-soluble compounds that can be easily excreted into urine