Pharmacodynamics

Question 1

Pharmacodynamics

Answer 1

study of biochemical and physiological effects of drugs and their mechanisms of action

Question 2

Pharmacokinectics

Answer 2

deals with the absorption, distribution and metabolism and excretion of drugs.

Question 3

Clinical pharmacology

Answer 3

study of the use of drugs in the prevention and treatment of disease

Question 4

Pharmacotherapy

Answer 4

use of drugs to treat disease

Question 5

drugs that act on DNA instead of proteins

Answer 5

anti tumor, anti microbial, mutagenic and carcinogenic agents.

Question 6

functions of ion channels

Answer 6

neurotransmission, cardiac conduction, muscle contraction and secretion.

Question 7

voltae gated ion channels

Answer 7

conductance is regulated by changes in the membrane potential.

example- local anesthetics, block voltage gated sodium channels preventing propagation of pain perception.

Question 8

Ligand gated ion channels

Answer 8

the conductance is controlled by ligand binding to the channel. The ligand can be either an extracellula mediator (neurotransmitter ACH, GABA, aspartate, glutamate ) or intracellular mediator ( Ca, cAMP, cGMP

examples, benzodiazepines, bind to GABAa receptor in neuronal membranes. This normally functions as a chloride ion channel and is activated by inhibitory GABA. when you use GABAa it will enhance the opening of the channel, hyperpolarizing the neuron.

Question 9

examples of G Protein linked receptors

Answer 9

Albuterol- Beta 2 aganoist for astham
Propranolol- Beta antagonist used for hypertension
Bethanechol, muscarinc agonist used for atonic bladder
Ipratropium, muscarinc antagonist used for asthma

Question 10

Alpha subunit characteristics

Answer 10

has bound GDP, when hormone binds it undergoes a conformational change dissociates fromt eh Beta gama subunit by exchanging GDP for GTP. can diffuse along the membrane and interact with targets located on teh plasma membrane. The time it remains dissociated from Beta and gama subunits and available to act depends on when the Alpha subunit uses its GTPase actived to hydrolye GTP to GDP which shuts down the unit.

Question 11

Targets of G protein subunits

Answer 11

Ion channels- don’t involve second messenger

Membrane bound enzymes- leads to production of sedcond messengers

Question 12

Gs protein effectors

Answer 12

activates adenylyl cyclase

Question 13

Gi protein

Answer 13

inhibits adenylyl cyclase
opens K+ channels
Closes Ca+ channels

Question 14

Gq protein

Answer 14

Activates Phospholipase C

Question 15

Phospholipase C catalyzes formation of

Answer 15

IP3 and DAG

Question 16

Adenylyl cyclase catalyzes the formation of

Answer 16

cAMP

Question 17

cAMP

Answer 17

Mediates

• -mobilzation of stored energy by breaking down carbs in liver and TAG in fat through Beta 2 and Beta 3 adrenoreceptors
• -Increases rate and contraction force of heart muscle- mediated by Beta 1 adrenoreceptors
• -relaxes smooth muscle- mediated by Beta 2 adrenoreptors.

Activates protein Kinase A which phosphorylates other proteins
activity depends on which substrates of kinase expressed n different cells

Action terminated by Phosphatases and is degraded to 5 AMP by phosphodiesterases(PDE)

Question 18

IP3 Inositol-1,4,5- Triphosphate

Answer 18

membrane bound enzyme,
Phospholipase C-Beta hydrolyzes Phosphatidylinositol-4,5 bisphosphate (PIP2) into diacylglycerol (DAG) and IP3

triggers the release of Calcium from ER, Elevated Calcium promotes binding of calmodulin which regulates enzymes like calcium dependent protein kinases.

pharmacologically important cellular responses-

• smooth muscle contraction
• increased force of contraction in cardiac muscle
• secretion of exocrine glands
• neurotransmitter release from neurons
• Hormone release

Termination is caused by dephosphorylation of IP3.

Question 19

DAG

Answer 19

congined to membrane where it along with Calcium activates Protien kinase C(PKC which cuases phosphyrlation)

Dag is terminated by being phosphorylated to phosphatidic acid which is converted back to phospholipids or it is deacylated to give aracidonic acid

Question 20

Tyrosine Kinases(ligand regulated transmembrane enzyme)

Answer 20

includes insulin receptor, EFGR (epidermal growth factor receotpr, PDGFR (platelet derived Growth Factor) and NGFR (nerve growth factor

the binding of molecules to the receptor causes two receptor molecules to come together in the plasma membrane forming a dimer. Contact activates their kinase and one phosphorylates the other. This triggers a signaling complex on the receptor tails where the phosphorylated tyrosines serve as binding sites for several proteins which are activated by it. these proteins lead to activation of signal transduction pathways such as MAP kinase which regulate gene expression

Can lead to gain of function mutations
imatinib is an example and treats chronic myelogenous leukemia

Question 21

Cytokine receptors

Answer 21

Group of peptide ligands, include growth hormone, prolactin, erythropoeietin and interferons
the protein tyrosine kinase activity is not an intrinsic receptor molecule , the intracellular domain binds to an intracellular tyrosone kinase from the JAK family

they dimerize upon binding to an activating ligand leading to activation of the bound JAK which then phosphorylate tyrosine residues on the receptor.

Also phosphorylate STAT that dimerize and translocate to the nucleus to regulate genes.

Question 22

Intracellular receptors

Answer 22

these are gene regulatory enzymes or structural proteins

Question 23

Gene regulatory proteins

Answer 23

receptors for steroid, vitamin D and Thyroid hormones. they are gene regulatory. they stimulate transcription of genes by binding to DNA sequences called response elements.

Question 24

Steroids hormones, vitamin D and thyroid hormones diffuse

Answer 24

across the plasma membrane of target cells and bind to receptors called the steroid super family. they are transcription factors that have binding sites for hormones and for DNa. binding of hormone causes conformational change allowing it to bind to regulatory DNA sequences and affect the transcription of target genes.

these have a lag period of 30 minutes to several hours because you have to synthesize new proteins

effects can persist for hours to days because of the slow turnover of most enzymes and proteins. this means effects of hormone will decrease slowly.

Question 25

enzymes

Answer 25

common cytosolic target, most drugs will inhibit the enzyme.

example Statins- competitive inhib for HMG coA reductase which causes lower synthesis of cholesterol, up regulation of LDL receptors and increased clearance of LDL in blood

Question 26

structural proteins,

Answer 26

important targets for anti-neoplastic drugs. Tubulin is a protein that is targeted by Vinca alkaloids and prevent the polymerization of this molecule into micro tubules.

Question 27

Extraceulluar enzymes

Answer 27

active site is located on the outside of the plasma membrane. ACE is an example.

Question 28

Transporters

Answer 28

Membrane transporters are targets for drugs. many psychiatric drugs are used here.

Selectie serotonin re-uptake inhibitors SSRI like fluoxetine or sertraline are part of this. they block serotonin transporter.

Question 29

actions of drugs not mediated by binding to receptors.

Answer 29

• antacids neutralize a acid
  mesma- reacts with acroleine which is a reactive metabolite of cyclophosphamide which can cause hemorrhagic cystitis
  -mannitol increases osmolarity in body fluids, can promote, diuresis, cathariss, expansion of circulating volume in vascular compartment or cerebral edema.
  -cholestryamine, colestipol, colesevelam bind to bile acids in the lumen and prevent re-absorption. used to treat hyeprlipidemia
  -dimercarpol chelate heavy metals
• structural analogs to pyrimidines and purines

Question 30

graded dose response

Answer 30

effect of doses on an individual. usually increase in direct proportion to dose. can reach a point where no further in crease in response is achieve.

plot using concentration and effect and it causes a hyperbolic curve with the equation E=(Emax x C)/ (C+EC50)

E is effect observed at concentration C
E max is maximal response
EC 50 is concentration of drug that produces 50% max effect.

Question 31

drug bound receptors relationship with concentration

Answer 31

B= (Bmax x C)/(C+Kd)

Bmax is total concentration of receptor sites
Kd is equilibrium dissociation constant- concentration of free drug when half of receptors are occupied.- describes affinity. Kd low = high affinity.

Question 32

Spare receptors.

Answer 32

EC50 is usually lower than Kd because of spare receptors. this means there is signal amplification for each receptor it may activate several proteins which activate several other molecules.

Question 33

In Vitro experiments vs whole animal

Answer 33

in vitro you plot concentrations and you get EC 50 in whole animal you use doses and get ED50

Question 34

Efficacy

Answer 34

maximal efficacy is the maximal effect a drug can produce. it is determined mainly by the nature of the receptor and its associated effector system.

measure of the intrinsic ability of a drug to produce an effect
useful for thearuapeutic purpsoes.

Question 35

Potency.

Answer 35

Left to right position of the dose curve. indicates magnitude of the effects for a given dose. it refers to the concentration of a drug required to produce 80% of that drug’s maximal affect.

it depends on Kd( affinity) and it’s efficiency of drug receptor interaction.

determines the dose of the drug needed.

low potency is important only if the drug is needed in large amounts

Question 36

Clinical effectiviness

Answer 36

doesn’t depend on potency but maximal efficacy.

Question 37

reversible competitive antagonism

Answer 37

binds to agonist binding site and is reversible

causes a right shift on the concentration effect curve.

Question 38

Irreversible competitive antagonism.

Answer 38

Irreversible occurs when the antagonist dissociates very slowly or not at all form the receptor with the result that no change in the antagonist occupancy takes place when agonist is applied. a receptor can no longer respond to agonist so Emax is reduced.

it is insurmountable. they usually posses a reactive groups which form covalent bonds.

Phenoxybenzaime is an irreversible alpha adrenoreceptor blocker used to treat pheochromocytoma

aspirin, omeprazole and MAO inhibitors are also inhibtors.

Question 39

Noncompetitive antagonism

Answer 39

is insurmountable and decreases Emax, Ketamine a dissociated anesthetic antagonizes an NMDA receptor.

Question 40

functional antagonism

Answer 40

Indirect- binds to intermediate macromolecule in the pathway that links the receptor to the physiological effect- drugs that inhibit protein kinase A

Physiological- one agonist opposes another through a different receptor- histamine and epinephrine.

Question 41

Chemical antagonism

Answer 41

reacts chemically with an agonist to form a product taht cannot activate a receptor- protamine a postively chaarged drug is used to counteract the effects of the negatively charged heparin.

Question 42

partial agonists

Answer 42

can only produce a submaximal response. at full receptr occupancy. even if all receptors are occupied you can’t produce an emax. can act as a competitive antagonist in the presence of the full agonist by competing with the full agonist for receptor occupancy.

can be used to buffer a response.

Question 43

Inverse agonists

Answer 43

reverse the constitutive basal activity of a receptor.
in systesm that are not constitutively active, the inverse agonists behave like competitive antagonists.

-examples- famotidine, losartan, metorpolol, risperidone.

Question 44

Drug selectivity.

Answer 44

assesed by separatin effects into beneficial effects versus adverse effects.

compare binding affinities of a drug to a different recpetor or by comparing EC50s or ED50s for different effects of a drug.

10 fold increase between binding affinity for first target and second target is required for a drug to be selective.

100 fold difference means no detectable occupancy of second target.

Question 45

change in receptors leading to desentization

Answer 45

activation of ion channel receptors can do it.

most Gprotein coupled receptors show it. involves receptor phosphorylation which interferes with its ability to activate the cascade even though it can still bind to the molecule. usually only a few minutes to develop and recovers at a similar rate when agonist is removed.

Question 46

Loss of receptors leading to desentization

Answer 46

prolonged exposre leads to gradual decrease in number of receptors expressed on the cell surface as a result of endocytosis.

Question 47

Exhaustion of mediators

Answer 47

amphetamine release norepi and other amines show tachyphylaxis becasue the releasable stores become depleted.

Question 48

physiological adaptiation

Answer 48

decrease of a drugs effect may occur becasue it is nullified by homeostatic response. blood pressure loering effect of thizide diuretics limited because of gradual activation of renin angiotensin system.

Question 49

Quantal dose effect.

Answer 49

is a graded or all or nothing response that plots the fraction of the population that repsonds to a given dose of drug as a fucntion of the drug dose. relationships show the concentrations of a drug that produce a fiven effect in the population.

Question 50

Theapeutic index.

Answer 50

TI = TD50/Ed50 or LD50/ED 50

Question 51

Therapeutic window

Answer 51

more clinically relevant index of safety is the dosage range between the minimum effective threapeutic concentration and the minimum toxic concentration.