Pharmacodynamics Flashcards
Most drugs produce their affect by binding what?
Protein molecules. Important exception is DNA
Pharmacodynamics vs pharmacokinetics
pharmacodynamics=how the drug affects us
pharmacokinetics=how the drug moves about us/how we affect the drug
Major types of drug receptors
Ion Channels G protein-linked receptors Ligand-regulated transmembrane enzymes Cytokine receptors Intracellular receptors: enzymes, transcription factors, structural proteins Extracellular enzymes Transporters
Ion channels as receptors
*2 types
voltage-gated ion channels: depends on action potentials
ligand-gated ion channels: controlled by ligands
Ex: local anaesthetics block voltage gated., benzodiazepines bind to GABAa receptor and opens it for Cl to pass. This hyperpolarizes the cell
G Protein-linked receptor
*60% of drugs bind to this type of receptor
G Proteins: Alpha, Beta, gamma
*remember alpha has GDP is inactive, GTP makes it active
Alpha is a GTPase
Gs activates AC -> cAMP ->PKA ->phosphorylates proteins
Gq activate PLC-> IP3 and DAG ->IP3: releases Ca from ER DAG: activaes PKC which phosphorylates proteins
Gi inhibits AC
Ligand regulated transmembrane enzyme aka Receptor Tyrosine Kinase
*know an inhibitory drug
binding of 2 molecules causes the receptor to come together in plasma membrane forming a dimer. the tails P eachother which will activate the MAP kinase cascade leading to gene expression regulation.
TKR important for cell growth and differentiation
*imatinib
Cytokine Receptors
respond to growht hormone, prolacton, erythropoietin and interferons
Similar to Tyrosine kinase but it isn’t intrinsic to the receptor. It binds to Tyrosine kinase from JAK family
*cytokine receptors dimerize, activate JAK which will P tyrosine residues on receptor. JAK also P STAT proteins. STAT dimerize and move to nucleus to regulate gene expression
Intracellular Receptors
Generally are gene regulatory proteins, enzymes, structural proteins
Receptors for steroid hormones, vit d, thyroid hormones. They must diffuse across membrane first
*all these hormones have a lag phase of about 30min to hours before effect is seen.
*the effect also can persist for hours to days after plasma concentration is zero (due to slow enzyme turnover)
Enzymes: mostly inhibited by drugs. Statins competatively inhibit HMG CoA reductase to decrease cholesterol
Structural Proteins: tubulin is important target for anticancer drugs. Vinca alkaloids bind to tubulin to arrest the cell in metaphase. Cell will die
Extracellular Enzymes
Example: Angiotensin converting enzyme.
Ace inhibitors target this to prevent conversion to angiotensin2. This will lower blood pressure
Transporters
SSRI like fluoxetine or sertraline block Serotonin transporter
Actions of drugs not mediated by binding to receptors
Antacids: neutralize gastric acid
Mesma: reacts with acroleine which is a metabolite of cyclophosphamide and prevents hemorrhagic cystitis
Mannitol: increases osmolarity to reduce cerebral edema
Cholestyramine, Colestipol, colesevelam: bind to bile acid to prevent reabsorption. Treats hyperlipidemia
Dimercaprol: chelates heavy metals
Structural analogues of pyrimidines and purines and can be incorporated into nucleic acids and alter their function
Graded vs Quantal dose-response relationships
Graded: shows effect of various doses of a drug on INDIVIDUAL/indicates maximal efficacy of a drug
Quantal: shows effect of various doses of drug on POPULATION of individuals/indicates potential variability of responsiveness
BOTH: provide info on potency and selectivity of drugs
Graded Dose response relationship equations for effectiveness and binding to receptors
E=(Emax * C)/(C+EC50)
B=(Bmax * C)/(C+Kd)
C=concentration of drug (on x Axis)
E or B on Y axis
Kd=concentration of free drug when 50% of receptors are bound
*if Kd is low there is high binding efficiency
Spare Receptors and signal amplification
EC50 vs ED50
If EC50 is less than Kd then there are spare receptors
Spare receptors means there is signal amplification. Ex Ligand Gated channels
EC50=concentration in vitro
ED50=doses give to intact animal or patient
Efficacy vs Potency
Efficacy: maximal effect a drug can produce Up and Down Shift
Potency: concentration of drug to elicit 50% effect R and L shift
Low Kd=more Potent
*Efficacy if more important than potency
Reversible vs irreversible competative antagonism
Reversible: right shift of the graph. can be displaced if the drug concentration is high enough. (makes it less potent, decreased affinity, increased Kd)
Irreversible: dissociates very slowly or not at all from receptor. this is NOT surmountable. This decreases drug effectiveness. (covalent bond)
*irreversible antagonist drugs:phenoxybenzamine, aspirin, omeprazole, MAO inhibitors
Noncompetitive Antagonism
also called allosteric antagonism. Binds to a different site than agonist. This is also insurmountable and decreases the Emax
Ex: ketamine:dissociative anesthetic at NMDA receptor
Non receptor antagonism
* 2 types and describe them
Functional antagonism: 1) indirect: any drug that binds to a molecule withni the pathway to stop the phyysiological effect
2) phyysical antagonism: one agonist opposes another agonist using a different receptor. Ex: Epiniphrine and Histamine (think of epipen for allergic reaction)
Chemical antagonism:A drug that chemically reacts with an agonsit to form a product that can’t bind to its receptor. Ex: protamine can act on heparin to inhibit it
Partial Agonist and Inverse Agonists
Partial agonists can only cause a submaximal response. Decreased Emax even if all receptors are activated. Can act as a competitive antagonist in the presence of full agonist.
Inverse Agonist: reverse the baseline activity of receptor. Ex: famotidine, losartan, metoprolol and risperidone
Drug selectivity
- assessed by weighing beneficial effects and adverse effects.
- measured by comparing Kd and ED50 for different effects of a drug
- *a drug is selective if there is a 10 fold difference b/w binding affinity for beneficial effects and adverse effects
- 10 fold means little adverse effect
- 100 fold means no adverse effect
Desensitization and Tachyphylaxis
Tolerance
Refractoriness
Drug Resistance
- synonymous terms for effect of a drug diminishing over time when given continuously or repeatedly. Occurs over MINUTES
- more gradual decrease in responsiveness DAY or WEEKS
- loss of therapeutic efficacy
- Loss of effectiveness of antimicrobial/antitumor drugs
Causes for Desensitization
- Change in receptors: especially G protein coupled receptors due to P
- Loss of receptors: due to endoctosis
- Exhaustion of mediators: drugs like amphetamines release the stores of NE and they become depleted
- Increased metabolic Degradation of the Drug: tolerance to drugs like barbituates and ethanol, occurs b/c repeated administration produces lower plasma concentration
- Physiological adaptation: there is a homeostatic response countering the effect of the drug
Quantal Dose effect curves
shows the fraction of the population that respondsto a given dose of drug as a function of the drug dose. The curve is an expression of the pharmacodynamic variability in the population
ED50
TD50
LD50
Therapeutic Index vs Therapeutic Window
TI=TD50/ED50 or LD50/ED50 the bigger the index the better
*never truly known for humans
TW=more relevant to human safety. Is the dosage range between the minimum effective therapeutic concentration and the minimum toxic concentration.
