Basic Principles Flashcards
Arranged according to decreasing order of strength:
Covalent bonds, Electrostatic bonds, Hydrophobic bonding
Covalent bonds, Electrostatic bonds, Hydrophobic bonding
Covalent bonds-not reversible
Actions of a drug on the body
Pharmacodynamics
It is the most important limiting factor for permeation.
Important for the diffusion of weak acid and weak base
Lipid diffusion - concentration only not charged
Heparin activates anti-thrombin III, monitor: aPTT - cannot cross the placenta. Antidote?
Protamine sulfate
Aqueous solubility is ___ proportional to electrostatic charge - ionization, polarity
Directly proportional - increased aqueous solubility = increased clearance
Aqueous diffusion-passive movement of non-protein bound drugs through small water-filled pores. Affected by what?
Drug concentration and charge
Law that predicts the rate of movement of molecules across the barrier. Absorption is faster in organs with larger SA and with thinner membranes
Fick’s law of Diffusion
Weak acid: what form is more water soluble and undergoes better clearance?
Unprotonated (A-) form - while protonated (HA) form is more lipid soluble and more likely to cross membrane
Excretion of weak acid maybe accelerated by alkalinizing the urine using what?
Bicarbonate
pH determines the fraction of drug molecules charged versus uncharged predicted using what equation?
Henderson - Hasselbach equation
Actions of the body on the drug - concerned absorption, distribution, metabolism and elimination
Pharmacokinetics
Substance that brings a change in biologic function through its chemical action
Drugs
Transfer of a drug from site of administration to the bloodstream
Absorption
Three factors affecting the drug absorption
- Route of administration
- Blood flow
- Concentration
Most common route of drug administration.
Oral route - absorption is slow and less complete
drug administration bypasses the first-pass effect, except? Intravenous, Subcutaneous, buccal or rectal
Rectal /suppository route - partial avoidance not complete
Slowest route of drug administration
Topical route - for local effect , absorption varies with the area of application and drug formulation
Drug distribution depends on major factors
Size of organ
Blood flow
Solubility
Binding
True/False: bound drugs can cross membranes and exert their effect.
False - bound drugs CANNOT cross membrane
Movement of drug molecules into and within biologic environment
Permeation
Refers to chemical alteration of the drug
Drug metabolism
Weak base: what form is more lipid soluble and more likely to cross biological membranes?
Unprotonated (B) form
For acute inflammation what type of topical agents were used?
Drying agents - tinctures, wet dressing and lotions
Acidic drugs are bound to albumin while basic drugs are bound to ____
Orosomucoid
Three metabolic fates that a drug may undergo:
- Temination of drug action
- Drug activation
- Elimination without metabolism
Refers to termination if drug action
Drug elimination
Determines the duration of drug action
- Dose administered
2. Rate of elimination following the last dose
Refers to characteristic half-life of elimination, most common type of elimination
First-Order Elimination - rate if elimination is proportionate to the concentration, decreases exponentially over time
Refers to constant rate of elimination regardless of concentration
Zero - Order Elimination - concentration decreases linearly over time
Drugs that display zero order kinetics
Warfarin, heparin, aspirin, tolbutamide, phenytoin, ethanol, theophylline - WHAT PET
Specific molecules with which drugs interact to produce changes in the function of the system, most are proteins
Receptors
Causes downward shift of the DRC, not overcome by adding more agonist
Non-competitive or Irreversible antagonists
Drug reversibly leaves the bloodstream and enters the target organ
Distribution
Sigmoid curve, response of a particular receptor-effector system measured against increasing drug concentrations
Graded Dose-Response curve
Do not provoke a biological response by themselves, blocks drug response in the presence of an agonist
Antagonist
____ and ____ are derived from dose-response curve
Efficacy (Emax) and potency (EC50)
Interact directly with the drug being antagonized to remove it or prevent it from reaching its target
Chemical antagonists
Refers to concentration required to bind 50% of the receptors
Kd - the smaller the Kd, the greater the affinity of a drug for its receptor
Concentration of a drug wherein half of the maximal effect is achieved
EC50 - potency
Not governed by Fick’s law of Diffusion and is capacity-limited
Transport by special carriers - availability of carriers
Capable of fully activating the effector system when it binds to the receptor
Full agonists - sufficiently high concentrations result in all the receptors achieving the activated state
Binds to a different receptor, producing an effect opposite to that produced by the drug it is antagonizing
Physiologic antagonist
It shifts DRCs to the right (increased ED50) but same maximal effect is reached
Competitive/Reversible antagonist - effects overcome by adding more agonist
Refers to rapidly diminishing responsiveness after administration of a drug
Tachyphylaxis
Drugs that display tachyphylaxis
Metoclopromide, ephedrine, dobutamine, LSD, calcitonin, nitroglycerin, nicotine, hydralazine, desmopressin
Refers continuous activation may lead to depletion of essential substrates
Tolerance
One that is infrequently observed in most patients, not predictable
Idiosyncratic drug response
Concentration of a drug at the receptor site
Effective drug concentration
Purely pharmacokinetic parameter with no direct physical equivalent
Volume of distribution - can be altered by liver and kidney disease
If low Vd = distribute in blood, then medium Vd means?
Distribute in extracellular space or body of water
While high Vd - distribute in tissues
Most important pharmacokinetic parameter to be considered in defining a rational steady state during dosage regimen
Clearance - depends on the drug and the condition of the organ of elimination
Condition in which average total amount of drug in the body does not change over multiple dosing intervals
Steady state - input rate=elimination rate
Constant for drugs following first-order kinetics
Half-life
Fraction of the administered dose that reaches the systemic circulation
Bioavailability
Plan for drug administration over a time period
Dosage regimen
Equal to rate of elimination at steady state, important to maintain concentration above minimum therapeutic level
Maintenance dose - Vd is not involved in calculating MD
Large Vd for a therapeutic concentration be achieved rapidly
Loading dose
Refers to the safe range between minimum therapeutic conc and the minimum toxic concentration of a drug
Therapeutic window
Equation to calculate for patient’s creatinine clearance
Cockroft-Gault equation
Clearance = [(140-age)xweight(kg)]/[72xserum creatinine(mg/dL)]
Multiplied by 0.85 in females
Metabolism: what phase converts the parent drug to more polar or more reactive product by unmasking or inserting a polar functional group
Phase I reactions - example: oxidation, reduction, deamination, hydrolysis
Mixed-function oxidases, high conc in smooth endoplasmic reticulum of liver
CYP450
Metabolism: at what phase involve conjugation of subgroups to -OH, -NH2 and -SH functions on the drug molecule
Phase 2 reaction - glucuronate, acetate
Most important organ for drug metabolism
Liver
CYP450 inducers
Ethanol, barbiturates, phenytoin, rifampicin, griseofulvin, carbamazepine, st. Johns wort and smoking
CYP450 inhibitors
Isoniazid, sulfonamides, cimetidine, ketoconazole, erythromycin, grapefruit juice, ritonavir, amiodarone, quinidine and valproic acid
Administration of single doses of the agent up to the lethal level in at least 2species
Acute toxicity
Required for most agents, esp intended for chronic use
Subacute/Chronic toxicity
FDA drug category: safe for both pregnant human and animal studies
Class A
FDA drug category: positive evidence of human fetal risk, but benefit from use in pregnant women maybe acceptable despite the risk
Class D
Teratogen: Fetal renal damage
ACE inhibitors
SE: antiepileptic drugs
Neural tube defect
Causes fetal hydantoin syndrome
Phenytoin
Cause neonatal hypoglycemia
Oral hypoglycemic agents
Teratogen causes vaginal clear cell adenoCA
Diethylstilbestrol / DES
Teratogenic effect of alcohol
Fetal alcohol syndrome
Teratogen causes Ebstein’s anomaly
Lithium
Teratogen causes craniofacial malformation
Isotretinoin
Teratogen causes congenital hypothyroidism
Iodide
Teratogen causes Mobius sequence
Misoprostol
Preclinical data collected up to the time of submission and detailed proposal for clinical trials
Investigational new drug (IND)
Produces less than the full effect, act as inhibitor in the presence of an agonist
Partial agonist
Teratogen causes tooth discoloration
Tetracycline
Teratogenic effect of Sulfonamides
Kernicterus
Penicillamine teratogenic effect
Cutis laxa
Topical preparation used for chronic inflammation
Lubricating agents - creams, ointments
Thalidomide teratogenic effect
Phocomelia
Teratogenic effect of warfarin at 1st tri
Chondrodysplasia
Refer to drug for a rare disease
Orphan drug
Standard in vitro test for mutagenicity, loss of this dependence signals mutation
Ames test - uses Salmonella
Teratogenic effect of Streptomycin
Ototoxicity
Teratogenic effect of smoking
IUGR
Phase: careful evaluation of dose-response relationship and pharmacokinetics among normal human (25-50)
Phase 1 trial
Postmarketing surveillance phase
Phase 4 trial
Teratogenic effect of warfarin at 2nd trimester
CNS malformations
Teratogenic effect of warfarin 3rd trimester
Bleeding diathesis
Refer to two related drugs showing comparable bioavailability and similar times to achieve peak blood concentrations
Bioequivalence
Phase: explore further the spectrum of beneficial actions of the new drug. Large design involving many patients (1000-5000)
Phase 3 trial
Request for approval of general marketing of new agent for prescription uses
New drug application (NDA)
Evaluation of drug to moderate number of patients (100-300)
Phase 2 trial
Warfarin inhibits vitamin K dependent factors synthesis, antidote would be Vitamin K, FFP. What will you monitor in the patient?
PT/INR - can cross the placenta
Maximal effect achievable with increasing concentration of a drug
Emax or efficacy
Excretion of weak base maybe accelerated by acidifying the urine using what?
Ammonium chloride
Preferred route for drugs that has unpleasant taste and for patients who are vomiting
Rectal or suppository route
