1) General Principles Flashcards
Pharmacology definition
- Science of chemicals that are utilized to prevent, diagnose, and treat disease
Drug definition
- Small molecule (MW 100-1000) with particular shape that when introduced into the body will alter physiology
3 major drug modes of action
- Interfere with physiological ligands that bind to receptors
- Inhibit normal body enzymes
- Replace something that is missing in the body
Pharmacodynamics
- Deals with receptors, interactions, antagonists, efficacy, and toxicology
- Effect of the drug on the body
Pharmacokinetics
- Study of the time course of a drug and its metabolites in the body following administration
- Effect of the body on the drug
Three parameters of kinetics
- Absorption (permeation)
- Distribution (metabolism)
- Elimination (clearance)
Duration of action
- For many Rx, inversely proportional to the rate at which the Rx is metabolically inactivated
- More rapidly inactivated = shorter DOA
Dosage regimens
- Designed on the basis of DOA alone and does not take into consideration age, weight, renal/hepatic function, polypharmacy, etc.
Absorption (permeation)
- Process of drug movement from the site of application to the systemic circulation
Routes of administration
- Enteral (GI tract: buccal, rectal)
- Parenteral (injection IA, IV, IM, subcut, intrathecal)
- Other (percutaneous, inhalation, intranasal)
Factors which affect absorption from the GI tract
- Physical state and solubility
- pKa of the drug and pH of the gut
- Lipid solubility
- Destruction of drug by stomach acid pH
- Blood flow/surface area
- Transit time
- Binding to food
Unionized form of drug
- More lipid soluble
- Pass readily across membranes
Ionized form of drug
- Generally more water soluble
Drug binding to food
- Best to take on an empty stomach (one hour before or two hours after eating)
Ion trapping
- Precipitation of a drug by gastric acid
To increase absorption rate after injection
- Give IV > IM > sub q
- IV is direct to blood
- IM has increased blood flow and surface area
To decrease absorption rate after injection
- Inject the basis along with insoluble salt or in an oil base
- Inject the basis along with a vasoconstrictor to decrease blood flow to the area (and thus decrease absorption and metabolism)
Examples of skin (transdermal) absorption
- Nitroglycerine
- Estrogen
- Clonidine
- Scopolamine
Examples of lung absoprtion
- Gaseous anesthetics
- Aerosols or volatilization “free basing” (nicotine, TCH)
Examples of nasal absorption
- Decongestants
- Calcitonin
- Cocaine
Bioavailability
- Rate at which and extent to which the active drug or its metabolite enters the general circulation
Biological barriers
- GI mucosa
- Blood brain barrier
- Placental barrier
Transport mechanisms across BBB
- Passive diffusion
- Facilitated diffusion
- Active transport
- Pinocytosis
Passive diffusion
- Transport across the CM in which the driving force is the concentration gradient of the solute
Fick’s Law of Diffusion
Flux = [(C1 - C2) x area x permeability coefficient] / thickness
Factors affecting diffusion
- Lipid solubility
- Degree of ionization
- Molecular size
- Absorptive surface
Lipid solubility example
- Thiopental rapid acting due to high lipid solubility vs barium sulfate (poorly lipid soluble) in normal body pH
Henderson Hasselbach
- Relates the ratio of pronated form of a Rx to the unprotonated form to the pKa (of the Rx) and pH of the surrounding medium
Degree of ionization
- Non-ionized are more lipid soluble
- Ex: NSAIDS in the pH of the stomach are non-ionized, thus more lipid soluble, thus more completely absorbed, thus more GI toxicity
Facilitated diffusion
- Drug molecules driven across a cell membrane with a concentration gradient with assistance of a special “carrier component” due to the drugs low lipid solubility, or large molecular size
Plasma membrane receptors
- Polypeptides on the surface of target tissues
- Triggered by the molecule to permit uptake of glucose and amino acids and regulate metabolism of glycogen and triglycerides
Active transport
- Allows a drug to move intra-cellularly against a concentration gradient
- Requires energy
- Must have a chemical structure similar to normal body constituents
Factors that affect distribuiton
- Blood flow
- Plasma binding
- Membrane permeation
- Tissue solubility
Volume of distribution
- V = dose (mg) / plasma concentration (mg/l)
- Related to clearance (CL)
Biotransformation
- Chemical alteration of drugs in the body
- Creates a more water soluble substance for excretion
- Often ↓ the activity of the drug (but not always)
Nonsynthetic reactions (phase I mixed function oxidases)
- All drugs: microsomal enzyme system of liver (endoplasm reticulum cytochrome P-450)
Common cytochrome P450 pathways
- 1A2
- 2C9, 2C19, 2D6
- 3A4
Types of phase I mixed function oxidases
- Aromatic hydroxylation (heparin)
- N-dealkylation (benzopiazepines)
- Desulfuration (thiopental)
- Alkyl oxidation (narcotics)
- Deamination (amphetamines)
- Sulfoxidation (cimetadine; phenothiazines)
- Epoxidation
Oxidations (mitochondria)
- Xanthine oxidase
- Monoamine oxidase (MAO)
- Alcohol or aldehyde dehydrogenase
Reduction (anaerobic)
- Microsomal enzyme system of liver
Types of reduction reactions
- Nitro (–NO2) creates the amine (eg. chloramphenicol; dantrolene)
- Organic nitrates are reduced to nitrites
- Azo groups (-N=N-) are hydrolyzed to form two primary amines
Hydrolysis
- Microsomal enzyme system of the liver, plasma, cytoplasm, etc.
- Esterases, amidases, and peptidases
Phase II metabolism
- Conjugation synthesis
- Conjugation reactions