Pharmacology Flashcards
Pharmacokinetics
How the body impacts the drug
Absorbed into the body
Distributed throughout the body
Eliminated from the body
Standard drug dose
Based on trials in individuals with average physiological processes.
Therapeutic window
Dosage difference between minimum effective concentration for desire response and for adverse response
Physiological barriers to drugs
Lipid bilayer, cell membrane
Only small, non-polar molecules may cross
Large, polar molecules can enter through protein pore or channel., facilitated or active carrier.
Effect of charge on diffusion
Best drug absorption in the gut occurs with uncharged drugs
pH or Ion Trapping
PKa < pH drug is in charged form
PKA > pH drug is in uncharged form
Uncharged form can diffuse through the lipid bilayer in the stomach at low pH, gets trapped in the blood where the pH is higher
Blood Brain Barrier
Drugs that act on the CNS must be hydrophobic.
Intrathecal administration can also bypass BBB.
Enteral route
Oral administration, uptake through GI tract
Simple, convenient no chance of infection
Subject to 1st pass
Slow delivery
Parenteral route
Injection to tissue, muscle, or intravenous
Not subject to 1st pass or GI tract
Rapid delivery
Irreversible
Mucous membrane
Ex. Sublingual or inhalation
Rapid delivery
Not subject to 1st pass, simple and convenient
Few drugs are able to be absorbed through this route
Transdermal
Ex. Patches Simple, convenient, not subject to 1st pass Good for prolonged admin Requires highly lipophilic drug Slow delivery May irritate skin
Subcutaneous
Slow onset, can admin oil based drugs
Slow onset, small volumes only
Intramuscular
Intermediate onset, can admin oil based drugs
Can affect lab tests, intramuscular hemorrhage, painful
Intravenous
Rapid onset, controlled drug delivery
Peak related drug toxicity
Intrathecal
Bypasses BBB
Infection risk, requires highly skilled personnel to deliver
First pass metabolism
All drugs coming through the gut are subjected to the liver first via the portal system
Liver is the major site of drug metabolism, so 1st pass can reduce the amount of drug reaching the target tissue by inactivating it.
Or it could convert the drug into its active form.
Bioavailability (F)
Quantity of drug reaching systemic circulation / Quantity of drug administered
F is between 100 and 0
F of intravenous is 100% by definition
Bioequivalence
Generic drugs must have same bioavailability as their name brand counterparts
Loading dose
Initial dose admin to compensate for distribution into the body tissues. Dependent on volume of distribution (Vd)
Steady state
Therapeutic dosing of a drug maintained between peak and trough. Takes 3-5 half lives to achieve.
Maintenance dose
Maintains the steady state concentration. Subsequent doses only need to replace the amount of drug lost through metabolism.
Dependent on clearance
Clearance
(metabolism + excretion)
_______________________________
[Drug]plasma concentration
Sanctuary compartments
Tight junctions restrict drug distribution into these. CNS (BBB) and testes (BTB)
Drug distribution
Water soluble drugs reside in the blood
Fat-soluble drugs reside in the cell membranes, adipose tissue, and other fat-rich areas.
Volume of distribution (Vd)
Represents the fluid volume required to contain the total amount of absorbed drug in the body at a uniform concentration equivalent to the plasma concentration at steady state.
Amount of drug in body(mg) / Plasma drug concentration (mg/L)
This is an extrapolated volume, not an actualy volume, so Vd can exceed body volume
Vd predicts?
Whether a drug will reside in the blood or in the tissue
Small Vd is primarily vascular
Large Vd is extensively distributed to tissues, has a long duration of action
Vd of 4 L
Present mainly in vascular compartment
Ex. Heparin
Vd 10 L
Present in extracellular fluid, but unable to penetrate cells
Ex. Mannitol
Vd of 42 L
Drugs able to pass most biologic barriers and distributed in total body water
42 L is the average total body water
Vd > 42 L
Drugs are extensively stored within specific cells or tissues and are at low concentration in blood at steady state.
Ex. Chloroquine
Azithromycin
Digoxin
Tissue distribution
Rate of accumulation depends on blood flow to organ, chemistry of drug, plasma protein binding of the drug
Drug binding proteins
Albumin, most common, binds acidic drugs
Alpha 1 acid glycoprotein, binds basic drugs
Lipoproteins, binds most lipophilic drugs
Bound drugs are NOT active
Changes in concentration of plasma proteins due to disease state.
Can displace a highly protein bound drug and increase the free drug concentration. Can lead to toxicity.
Drugs known to cause displacement interaction
Warfarin
Phenytoin
Tolbutamide
Need to be monitored
Pediatric considerations for dosing
Dosed mg/kg
More total body water
Less plasma protein and body fat
Geriatric considerations for dosing
Decreased total body water
Increased fat stores
During acute illness, albumin may be decreased and alpha 1 acid may be increased.
Endogenous drug processing enzymes
Cytochrome P450
Alcohol dehydrogenase
Monoamine oxidase
Phases of metabolism reactions
Phase I: Redox reactions
Phase II: Conjugation/Hydrolysis reactions
Aim is to reduce lipid solubility
Phase 1 Reactions: Redox
Purpose is to add or uncover polar moiety yield more polar, water-soluble metabolites for renal elimination.
Phase 2 Reactions: conjugation/hydrolysis
Purpose is to increase polarity by adding more soluble moiety to yield very polar, inactive metabolites
Enhances drugs solubility to be excreted into urine or bile
Three types of conjugation reactions
Glucuronidation, acetylation, sulfation
Deficiency of UDP-glucuronyl transferase in infants causes jaundice
Cytochrome P450
Heme protein mono-oxegenase
Smooth ER of hepatocytes
Metabolizes hydrophobic drugs
Important CYP for drug metabolism
3A4 2D6 2C19 2C9 2E1 1A2
Pharmacogenomics
Study the effects of genetic variability on drug metabolism
Rapid metabolizers
More enzyme present and increase drug metabolism (induction)
Poor metabolizers
less functional enzyme present and decreased drug metabolism (inhibition)
Example of CYP Inhibitors
Statins and Grapefruit
Acetaminophen and Disulfram
Clozapine and Quinolones
Examples of CYP inducers
Statins and St. John’s Wort
Acetaminophen and Ethanol
Clozapine and Tobacco
Drug elimination rate through the kidneys depends on ____
Drug filtered
Drug reabsorbed
Drug secreted
First order kinetics
Constant fraction eliminated
Elimination is proportional to drug
Exponential decay
Most drugs (~95%)
Zero Order Kinetics
Constant amount eliminated
Elimination saturates at higher
Linear decay
Alcohol, aspirin, warfarin, theophylline
Half life (t1/2) =
The amount of time over which the drug concentration in the plasma decreases to one half of its original value
Half life equation for First order kinetics
T1/2 = 0.693 x Vd / Clearance
0.693 = Ln 2
Pharmacodynamics
What the drug does to the body
Biochemical and physiological mechanisms of drug actions and relate to molecular interactions between body constituents.
Based on drug receptor interactions in order to determine efficacy potency, and toxicity.
Efficacy
Difference in Emax when effective dose is the same
Ex. Morphine is more efficacious than aspirin
Potency
Dose amount related to effective dose
Ex. Morphine is more potent than Merperidine
LD50
Lethal dose 50, median dose at which population dies from the drug. Also sometimes refers to adverse effects instead of lethality
Therapeutic index
Difference between ED50 and LD50
Relative safety
Therapeutic index compared to alcohol, which is 10.
Ligand
Agonist or antagonist chemical that binds to a receptor
Receptor
Target/site of drug action
Affinity
Propensity (attraction) of a drug to bind with a receptor
Selectivity
Specific affinity for certain receptors vs other receptors
Drug-Receptor interactions
[L]+[R] = [LR]
Agonist
A chemical that binds to a receptor and activates the receptor to produce a biological response
Antagonist
Blocks the action of the agonist at the same receptor
Pharmacological agonist
Mimics the actions of endogenous neurotransmitters
High affinity binding and good specificity
Pharmacological antagonist
Block actions of neurotransmitter at same site
Competitive antagonist
Reduce potency of agonists but haver no effect on overall efficacy. Effect is able to be overcome by increasing concentration of agonst
Noncompetitive antagonist
Reduce agonist efficacy and their effects are not overcome by increasing agonist concentration
Partial agonists
Act at the same site as the full agonist, but with lower maximal efficacy
Inverse agonist
Causes an action opposite to that of the agonist at the same receptor
Physiological antagonists
Activate physiological responses that oppose agonist mediated physiological responses
Receptor types
Enzyme
Ligand-gated ion channel
G protein-coupled receptor
Transcription factor
Enzyme
Receptor is linked to a kinase which leads to series of phosphorylation reactions
Ligand-gated ion channel
Ligands bind to receptor which causes channel to open allowing ions to pass in/out of cell
G protein coupled receptor
Receptor is linked to a family of G proteins which then cause a biological response through secondary messenger systems like cAMP
transcription factor
Receptor is intracellular and activation/inhibition affects gene transcription so biological response takes longer to occur.
Specificity
Ability of a drug to produce its action at a specific site.
Alterations to a drugs chemical structure may influence potency.
Many drugs have multiple sites of action, resulting in side effects.
Sensitivity (up-regulation)
The presence of an antagonist causes increased cellular build up of receptors. Removal of antagonist produces increased physiological response to agonist due to increased receptor count
Tolerance (down-regulation)
Long term exposure to an agonist reduces receptor population (or responsiveness) thus reducing physiological response
Additive
effect of substance X and substance Y together is equal to the sum of their individual effects
Synergistic
Effect of substance X and Y together is greater than the sum of their individual effects.
Tachyphylaxis
Broad term related to decreased drug response by many potential mechanisms.
Acute decrease in response to a drug after initial/repeated administration.
Factors influencing the Drug Response
Prescribed dose
Administered dose
Concentration at site of action
Drug effects
Dose dependent toxicities
Pharmacological toxicity
Pathological toxicity
Genotoxicity
Dose independent toxicities
Allergic reactions
Idiosyncratic toxicities
Extreme sensitivity
Extreme insensitivity
Drug Effect Cp
Dictates therapeutic vs toxic effect
Severity also depends on length of exposure
Drugs with narrow therapeutic indexes
Warfarin Anti-arrhythmics Anti-covulsants Digoxin Lithium Carbonate Oral hypoglycemics Theophylline Amphotericin B
Margin of Safety MOS
LD1/ED99
Therapeutic Index TI
LD50/ED50
TD1
Toxic threshold
Hepatotoxicity
Jaundice Elevated serum levels of hepatic enzymes ALT AST ALP
Nephrotoxicity
Reduced creatinine in urine
Edema
Hypersensitivity
Rash
IgE levels
On target effects
Overdose
Right receptor wrong tissue
Effects of chronic inhibition/activation
Off-target effects
Due to interaction with unintended receptor.
Ex. Propranolol, for hypertension, can worsen asthma
Pathological toxicity
Body’s ability to metabolize or inactivate damaging toxicants is overwhelmed
-Necrosis
Off-target bile salt export protein (BSEP) inhibition
BSEP normally transports bile salts from the hepatocytes into the biliary duct. When BSEP is inhibited the bile salts accumulate in the hepatocytes.
Can cause intrahepatic cholestasis- life threatening.
Biotransformation
Therapeutic drugs can undergo this and turn into toxicants.
Ex. Acetaminophen is metabolized into toxic NAPQ, which is usually conjugated with GSH into a nontoxic product. Excessive Acetaminophen intake can lead to depletion of GSH, and hepatotoxicity
Genotoxicity
Results from damage to DNA
Ex. Chemotherapeutic agents, ionizing radiation, environmental toxins
Long term causes cancer
Absorption factors affecting apparent dose
Slower motility: elder drug, drug slow motility
Altered Gastric pH: Effect depends on drugs pKa and whether it is a weak acid or base.
Hypoproteinemia: reduced plasma protein binding can increase free drug. Can be caused by malnutrition, liver disease, nephrotic syndrome, sepsis
Reduced elimination
Affects apparent dose
Renal clearance depends on adequate blood flow, drugs can block the blood filtration or increase accumulation of toxicants
Alterations of urine pH can be used to enhance
Impaired hepatic function
Metabolic factor affecting apparent dose
Impaired blood flow through liver—> reduced metabolism
blockade of transporters
Reduced expression or inhibition of metabolic enzymes
Inhibition of metabolizing enzymes can increase apparent dose. Ex. Grapefruit juice.
Increased expression of metabolic enzymes decreases apparent dose. Ex. Rifampin, St. John’s Wort.
Clinical settings where Drug-Drug interactions are likely
Low TI
# of drugs taken concurrently (esp >10)
Compromised renal, hepatic, pulmonary function
Immunodeficiency syndrome
Behavioral/psychiatric disorders, esp drug abuse
Steps to prevent Drug-Drug interactions
Document ALL drugs patient is taking Minimize # of drugs being taken Extreme caution with low TI drugs Critically ill or compromised organ function Adverse DI’s in differentials
Type I Hypersensitivity
Anaphylaxis
IgE antibodies on mast cells bind to an allergen or bind to hapten complex. Mast cells degranulate.
Vasodilation, edema, and inflammation occur.
Ex. Penicillin
Occurs almost immediately.
Type I Hypersensitivity
Red Man syndrome
Rare, occurs with intravenous drug administration
Anaphylactoid mechanism
Flushing, erythema, pruritus of upper body, neck and face
Ex. Vancomycin, rifampin
Type II Cytolytic Reactions
Antibody dependent cytotoxic hypersensitivity
Auto immune response
Drug binds to RBC, IgE or IgM recognize drug cell complex. Cells are lysed—> complement
Ex. Penicillin induced hemolytic anemia
Type III Arthus reactions
Serum sickness
Soluble antigens are complexed by IgG or IgM and deposited in the vasculature endothelium
Tissue undergoes necrosis
Ex. Antivenins.
Type IV Delayed hypersensitivity reactions
Inflammation resulting from sensitized T cells encountering familiar antigen.
Ex. contact dermatitis
Repeated exposure can trigger cytokine storm
Stevens-Johnson Syndrome
Toxic epidermal necrolysis
Rare Type IV reaction
Blistering, skin loss, multiorgan damage
Stevens johnson = 10% of body surface
Toxic epidermal = >30%
Idiosyncratic effects
Abnormal reactivity to a chemical peculiar to a given individual
Extreme sensitivity or insensitivity
G6PD deficiency
Common in people of mediterranean descent
Red blood cells cannot protect against oxidative damage from treatment with antimalarial primaquine, or in foods high in vicine and convicine.
