Basics Flashcards
pKa and acid strength
pKa-a measure of the strength of an acid, defined as the negative logarithm of the acid dissociation contact Ka
A lower pKa value indicates a stronger acid meaning the acid fully dissociates in water
Pharmacokinetics
The study of what the body does to a drug
4 steps
Absorption-entry of the drug into the plasma from the site of administration
Distribution-the reversible transfer of a drug from the bloodstream to interstitial and intercellular fluid
Metabolism- biotransformation of the drug mainly by the liver
Elimination- removal of the drug and its metabolites from the body via urine, feces, bile
Routes of drug administration
Enteral (oral, SL, buccal)
Oral most common convenient and economical, some drugs maybe be inactive by low gastric pH
SL/buccal- provides rapid absorption bypassing harsh GI environment and avoiding first pass metabolism
Parenteral injectable
IV- direct introduction into systemic circulation offers most control and rapid onset
IM, SQ, intradermal-different levels of absorption and onset times irreversible route
Others-
Inhalation/nasal- rapid delivery to lungs useful for respiratory conditions
Intrathecal/intraventricular- direct delivery to the CNS when a rapid or local effect is needed
Topical- local effect at site
Transdermal- systemic effects via skin patches, absorption may vary
Rectal- minimized liver metabolism avoids GI destructors useful when oral admin not possible
Drug absorption
Mechanism- passive diffusion, facilitated diffusion, active transport, endocytosis, exocytosis
Facts that affect absorption
pH-drugs pass through membranes more readying if uncharged
Blood flow- higher blood flow areas have more absorption
Surface area- greater surface area enhances absorption
Contact time- prolonged contact time at site increased absorption
Bioavailability
The rate and extent to which a drug reaches systemic circulation.
Measured by comparing plasma levels after different routes of administration
Factors that increase bioavailability
-first pass metabolism- drugs metabolized in the liver or gut before reaching systemic circulation have reduced bioavailability
-drug solubility- drugs need to be both lipophilic and hydrophilic for optimal absorption
-chemical stability- some drugs are unusable In the GI tract or degraded by enzymes
Drug distribution
The reversible movement of a drug from the blood stream to tissue
Factors
-blood flow-high blood flow leads to rapid distribution (Brain, liver)
-capillary permeability- varies by tissue, BBB restricts entry
-plasma protein binding-drugs bound to proteins like albumin are sequestered in the blood stream
-Liphophilicy- lipophilic drugs easily cross cell membranes enhancing distribution into tissue
Volume of distribution-indicates how a drug is distributed in the body compartments, calculated amount of drug in body derived by plasma concentration at time zero
Kinetics
First order - a constant fraction of the drug is metabolized per unit of time
Zero order- metabolism rate is constant regardless of drug concentration occurs when enzymes are saturated
Phases of metabolism
Phase 1-converts lipophilic drugs into more polar molecule often involving the cytochrome P450 system
Phase 2-conjugation reaction that increases the drugs water solubility facilitating excretion
Phase 1 metabolism
Invokes the modification of drugs through oxidation, reduction and hydrolysis reaction often involving the cytochrome P450 enzyme system (CYP450) this phase is crucial for converting lipophilic drugs into more polar compounds that can be excreted by the body
Common CYP450 inhibitors
Certain drugs and natural substances can inhibit the CYP450 enzymes, potentially leading to increased drug levels and adverse effects
Inhibiting drugs
-cimetidine
-estrogens
-macrolide antibiotics
-azole antifungals
-fluoroquinolones
-isoniazid
-amiodarone
-sulfas
-ritonavir
-some SSRI fluoxetine, paroxetine
Natural inhibitors
-grapefruit juice
-licorice
-black tea
-chamomile tea
-milk thistle
-cloves
-ginger
-kava kava
-alcohol injection
Inhibitor adverse outcomes
Cimetidine and warfarin-increased risk of hemorrhaging
Erythromycin and glyburide-hypoglycemia
Erythromycin and lovastatin-myalgia
Ketoconazole and cyclosporine-increased immune suppression
SSRI (Prozac, Paxil) and dextromorphan-CNS depression
Grapefruit and statins- increased GI side effects and myalgia
Phase 1 metabolism not involving CYP450
Some metabolic reactions in phase 1 do not involve the CYP450 system
Amine oxidation (catecholamines, histamines)
Alcohol dehydrogenation
Esterases (ASA in liver)
Hydrolysis
Phase 2 metabolism
Involves conjugation reactions where the drug or its phase 1 metabolites are coupled with an endogenous solution (glucuronic acid, sulfuric acid, acetic acid, amino acids) these reactions are highly polar water soluble compounds that can be easily excreted by the kidney or bile
Glucuronidation is the most common and significant conjugation reaction the resulting drug conjugates are excreted by the kidneys or the bile
Factors affecting drug metabolism
Age- younger and older population have slower metabolism
Pregnancy- can alter metabolism
Health status/disease- conditions like liver or kidney disease can significantly impact metabolism
Environment- exposure to chemicals or pollutants
Lifestyle-diet, exercise and substance use alcohol, tobacco
Genetics- variations in DNA can alter enzyme activity
Drug clearance by kidneys
Drug elimination primarily occurs through the kidneys for effective excretion drugs must be polar enough. Renal compromise like in CKD, can leads to drug accumulation and adverse effects
Process in renal clearance
GFR-lipid solubility and pH do not affect drug passage into filtrate, GFR and protein binding of drug are critical factors
Proximal tubular secretions-active transport system in the proximal tubule remove drugs from the body
Distal tubular reabsorption-uncharged drugs can be reabsorbed into circulation unless ionized by pH manipulation (alkalizing urine for weak acid drugs)
Excretion by other routes
Bike, lungs, breast milk
Total body clearance and drug half life
Total body clearance-the sum of all clearance processes from metabolizing and eliminating organs
Half life - time required for the plasma concentration of a drug to reduce by half it determines how frequently a drug needs to be dosed
