Midterm - Pharmacodynamics & Pharmacokinetics Flashcards
NAPRA I drugs
- Prescription needed for sale by Pharmacist
- Includes prescription drugs (Pr), narcotics (N), controlled substances (C1, C2, C3), and targeted substances (TS)
- eg. Fentanyl patch
NAPRA II drugs
- Prescription not required
- Must be dispensed by pharmacist (ie. behind the counter)
- eg. insulin
NAPRA III drugs
- Client may obtain at pharmacy without need of pharmacist
- eg. ranitidine (Zantac)
Unscheduled drugs
- Client may obtain at retail stores as well as pharmacy
- eg. naproxen (Aleve)
Pharmacodynamics vs pharmacokinetics
Dynamics = drug’s actions on body
Kinetics = body’s actions on drug
Signal transduction pathway
- aka receptor-effector coupling mechanism
- consists of the receptor, its cellular target, and any intermediary molecules
Drug affinity
- Favourability of a drug-receptor binding interaction
- Sum total of forces imparts high affinity of the drug for receptor
What drugs are MORE selective for their receptors?
Drugs that bind through multiple weak bonds to their receptors (if a drug has a super strong bond, it can likely bond to lots of things and will be less selective)
Strength of bonds from greatest to least
Covalent (uncommon, irreversible) > ionic > hydrogen > Van Der Waals (common, reversible)
Enantiomer
- Same atomic structure but arranged spatially different (optical isomer)
- produce different effects
Racemic mixture
50:50 mix of both enantiomers
Cell-type distribution
The more restricted the cell-type distribution of the receptor targeted by a drug, the more selective the drug is likely to be
eg. restriction of H2 receptors in the
stomach means Ranitidine has limited effects on body beyond the stomach
Effector domain purpose
Message propagation = conformational change in receptor that is transduced intracellularly to effect downstream molecules to cause a response (activate, enhance, diminish, terminate)
Ligand activated (gated) channels
- found in the CNS
- binding of molecules induces a conformational change that opens the pore
- eg. nicotinic acetylcholine receptor
Types of ligand activated (gated) channels
- Excitatory (ACh or glutamate)
- Inhibitory (glycine or GABA)
Voltage-activated channels
- Initiate action potentials in the
axons of nerves and muscle cells - activated channel depolarizes the membrane to attract positive ions through open pore
- refractory period = “reset”
Sulfonylurea receptor
- aka SUR1
- Regulates ATP-dependent K+ channel in pancreatic β-cells
G-protein coupled receptors
- aka GPCRs
- sensory perception, nerve activity, etc.
- target of over half of all non-antibiotic
drugs
G-protein activation
1) Agonist binding
2) GTP-GDP exchange
3) G-protein activation
(terminated by GTP hydrolysis)
β-adrenergic receptor group
- group of G-proteins
- eg. epinephrine and norepinephrine (both are catecholamines that increase second messenger cAMP)
Transmembrane receptors with an intracellular linked enzymatic domain
- single membrane spanning
- add/remove phosphate groups from specific aa’s
Types of transmembrane receptors with an intracellular linked enzymatic domain
- Receptor Tyrosine Kinases
- Tyrosine Kinase-Associated Receptors (receptors have no intrinsic enzymatic activity, but dimerization allows for binding of an intracellular tyrosine kinase)
Nuclear hormone receptors
“lag on, lag off”
Nitric oxide (NO)
- binds N-terminal of soluble GC and enhances activation of cGMP (vasodilation)
Dissociation constant
- aka Kd
- most important for impacting the chance of binding (drives affinity)
- ligand concentration where 50% of receptors are bound by ligand (lower Kd = higher affinity)
[LR]/Ro
Fraction of all available receptors that are ligand bound
Types of D-R relationships:
- Graded = D-R of individual
- Quantal = D-R of population
Efficacy
Maximal response produced by the drug at that receptor
Potency
- drug concentration which elicits 50% of the maximal response
- considers both affinity and efficacy
Therapeutic Index
- Gives an estimate of relative safety margin of drug
- considers both toxic and effective doses
Effect of competitive ANTagonists
- increase Kd for agonist = decrease affinity = decreases potency
- no effect on efficacy since they can be outcompeted with higher doses
Non-competitive ANTagonists
irreversible binding can not be “washed out” or outcompeted by the agonist
- decrease efficacy (sometimes potency too)
Types of non-receptor ANTagonists
- Chemical = renders agonist inactive
- Physiologic = binds different receptor and produces opposite effect
Allosteric modulators
Indirectly influence the effects of an agonist at its receptor (alters Kd or conformational change)
Types of passive transport
- passive diffusion = unbound drug carried through cell membrane by bulk flow of water
- paracellular transport = passage of molecules through intercellular gaps
Passive flux formula
Flux = [concentration gradient (aka C1 - C2) x area x partition coefficient] / membrane thickness
Partition coefficient
- solubility of drug
- greater coefficient = faster diffusion
Un-ionized species vs ionized species
- Unionized = more lipid soluble, more readily diffuse cell membranes
- Ionized = less lipid soluble, less able to diffuse through cell membranes
pKa
pH at which 50% of drug is ionized and 50% is unionized
Ionized form of an acid
Deprotonated (negatively charged)
Ionized form of a base
Protonated (positively charged)
Henderson-Hasselbalch equation
log([protonated]/[deprotonated]) = pKa - pH
Ion trapping
- Drug accumulates on side of cell membrane where ionization is highest
- Basic drugs accumulate in acid fluids
- Acidic drugs accumulate in basic fluids
What determines the degree of ionization of a drug?
pH on either side of the cell membrane
Weak acid formula
HA = A- + H+
Weak base formula
BH+ = B + H+
Carrier-mediated transport
Large, insoluble molecules (can’t passively diffuse)
Types of carrier-mediated transport
- Active transporters (requires ATP to move molecules against concentration or electrical gradient)
- Facilitated transporters (no energy required, moves large/lipid insoluble molecules DOWN the electrical gradient)
Pharmacokinetic processes
- Absorption
- Distribution
- Metabolism
- Excretion
Absorption
- into systemic circulation from site of administration (to get to target site)
- slower rate of absorption = drug sticks around in body longer
What administration methods do not require absorption?
Intravenous, intrathecal (into spine), topical
Dissolution
- liberation of active pharmaceutical ingredient
- required for absorption to occur
What keeps the concentration gradient in favour of drug absorption?
regional or local blood flow (continuously takes drug away)
Enteric coated formulations
- protect against destruction by gastric juices
- eg. Acetylsalicyclic acid (aspirin)
Long-acting insulins
- addition of proteins or changes in formulation pH (slows dissolution)
- eg. adding protamine or zinc
Controlled release formulations
eg. Paroxetine
Bioavailability
Fraction (%) of administered dose that reaches the systemic circulation unchanged
Precipitation of drug
- local reaction at site of injection
- drug is now unavailable and not absorbed in the time frame you want
Reverse transport protein
- P-glycoprotein throws drug back out across epithelial barrier (can’t be absorbed by GI tract now)
First pass
Liver metabolizing enzymes can inactivate/destroy drug before it gets out into systemic circulation
Oral administration
- aka per os (PO)
- risk of first pass elimination
Types of oral transmucosal administration
- Sublingual (under tongue)
- Buccal (between gum and cheek)
Rectal administration
Used for patients with GI issues (motility, nausea)
Bypassing the first pass effect
- sublingual methods = venous
drainage to superior vena cava - rectal methods = ~50% of drug will bypass
- parenteral methods (SC, IM, IV, topical, transdermal)
Subcutaneous injection
- Into tissues lying below the skin (not into muscle or vein)
- easier to administer than IV, but absorbs slower than IM and can be erratic
Intramuscular injection
- Into muscle
- Absorption is typically rapid for drugs in aqueous solution; oily suspensions will form depot
Intravenous injection
- Into vein
- good for rapid emergency administration of large volumes, full bioavailability
Topical administration
- drug is locally administered, but may end up systemic
Transdermal administration
- applied to skin (absorbed into systemic circulation)
- can control release and prolong action, but takes a long time to reach levels
Distribution
- drug must reach target site in adequate concentrations to be effective
- achieved by systemic circulation and lymphatics
Why might a drug remain in the vascular space (blood)?
If it is highly protein bound
Why does the first pass effect occur?
Vessel-rich (aka perfuse) tissues receive the greatest cardiac output and thus distribution of drug
- eg. liver, kidney, brain, heart
Tissue perfusion
Vessel-rich tissues are more perfuse but have lower capacities than other areas like muscle
Non-target binding of a drug
- Plasma protein binding = drugs bound to plasma protein (eg. albumin) cannot diffuse from the vascular space into tissues
- Tissue binding = accumulate in tissues by binding cellular proteins or phospholipids
Volume of distribution
- aka Vd
- extent to which a drug partitions between blood and tissue compartments
Volume of distribution formula
Vd = amount of drug in body / plasma drug concentration
Total body water
- 66% intracellular
- 33% extracellular (25% interstitial, 7-8% intravascular)
Drug elimination methods
- Excretion (cleared from body unchanged)
- Biotransformation (aka metabolism, converted to metabolites)
First-order elimination
A constant fraction (%) of drug is eliminated per unit time
Clearance
The apparent complete removal of drug from a certain volume of plasma per unit time per unit body weight
Extraction ratio
Extent to which an organ contributes to drug clearance
Enteroheptic recirculation
Reabsorption of excreted drug into small intestine to re-enter systemic circulation
Active drug secretion
From proximal convoluted tubule into urine
Reabsorption of drug
- from urine back into blood (in distal convoluted tubule OR passive reabsorption of unionized drug)
Inactive “prodrugs”
- activated by metabolism
- eg. Ramipril (Altace) = converted to active metabolite by hepatic metabolism
Catalysis of biotransformation reactions
- performed by cellular enzymes that are located in hepatocytes
- in cytoplasm and smooth ER
Phases of drug metabolism
1) Phase I reactions (oxidation/reduction/hydrolysis reactions) = drug converted to polar metabolite, then excreted or enters:
2) Phase II reactions (conjugation reactions) = dietary component binds to product to become a more polar, excretable product
Cytochrome P-450
- aka CYP
- group of enzymes used for Phase I reactions
- found in smooth ER
Goal of Phase I reactions
Introduce or unmask functional groups
What does Phase II require?
Metabolite must have an acceptor for the hydrophilic conjugate moiety
Types of Phase II reactions
- Glucuronic acid conjugation
- Sulphate conjugation
- Acetylation
- Glutathione conjugation
Sulphate conjugation
Phenols and alcohols conjugated to sulphate (SO4)
Acetylation
Occurs in drugs with -NH2 group conjugated to COCH3
Glucuronic acid conjugation
Conjugation to glucuronic acid
Glutathione conjugation
Epoxides & arene oxides conjugated to glutathione (GSH)
Key parameters of drug disposition (PK) and dosage regimens
- Bioavailability (%F)
- Volume of distribution (Vd)
- Clearance
- Elimination half-life
Amount of drug eliminated after 4 half-lives
93.75%
(4-5 half-lives is when a drug is clinically eliminated)
Minimum effective concentration
- point where adverse effects begin OR where desired effects begin
- maximum dose you would want to administer OR minimum
- multiple small doses above MEC for desired can help avoid MEC for adverse
Elimination half life
Is a hybrid constant = depends on volume distribution and clearance
Loading dose
Initial higher dose of drug to reach therapeutic levels faster
Factors affecting drug elimination half-life
- aging = decreases (less distribution)
- obesity = increases (more distribution)
- pathologic fluid = increases (drug can distribute farther through this fluid)
- cytochrome P-450 = decreases (more metabolism)
- organ failure = increases (less clearance)
Pharmaceutical interactions: in vitro
- Before the drug is absorbed by the patient
- Affects total dose available for absorption
Pharmacokinetic interactions
- causes most drug interactions of clinical significance
- interactions during absorption, distribution, metabolism, excretion
Induction of P450 enzymes
- increased gene transcription = increased expression of enzyme
- increased metabolism of the inducing drug means reduced half-life
Inhibition of P450 enzymes
- enzyme directly inhibited by affecting drug
- inhibition effects on other co-administered drugs means decreased dose is required
