a student of rudolf buccheim. he studied chloroform. trained over 60 phD pharmacologists.

known as the father of pharmacology.

1. covalent

2.electrostatic

3. hydrophobic

• strongest type
• usually irreversible
• less common than electrostatic bonds
• examples: 
• acetyl group of asprin and COX 
• DNA alkylating agents used in chemo to disrupt cell division of tumor

weaker and more common than covalent bonds. 

range from strong ionic bonds to weaker van der waals forces. 

the weakest of the 3 receptor bonds

important in interactions of highly lipid soluble drugs with lipids of cell membranes

Carvedilol

ketamine

metacholine 

the S enantiomer is a potent B-receptor blocker

the R enantiomer is 100x weaker (at blocking beta receptors)

both are equipotent as alpha-receptor-blockers

determines the group the drug is classified in

and whether that group is appropriate for a particular symptom or disease

the effect of the body on the drug

governs ADME of drugs

important in choice of administration route of a drug for a particular patient

it is an acetylcholine receptor blocker (antagonist)

it prevents access of Ach to the Ach receptor site

it stabilizes the receptor in its inactive state

it reduces effects of Ach in the body

can be overcome by increasing agonist concentration 

antagonists that bind very tightly in an irreversible way

they cant be displaced by increasing concentration of agonist.

in this kind of binding, the drugs bind to the same receptor, but don't prevent the binding of agonist. 

action of the agonist may be enhanced or inhibited. 

bind to the same receptors that full agonists do, but do not evoke as great a response 

ex: pindolol:

a partial agonist

it acts as an agonist if no full agonist is present 

it acts as an antagonist if a full agonist is present

the inactive and active receptor forms are bound in the same amounts

no changes are observed

drug will appear to be without effect

drugs that have a stronger affinity for the inactive form and reduces constitutive activity, resuting in effects that are the opposite of those produced by conventional agonists at that receptor. 

binding of a drug to an __________ will result in no chance in the function of the biologic system

pharmacokinetic importance: this type of binding effects distribution of drug within the body because it determines amount of free drug in circulation

ex: plasma albumin

1. aqueous diffusion
2. lipid diffusion
3. special carriers
4. endocytosis and exocytosis 

driven by the concentration gradient of the drug, a downhill movement

drugs bound to plasma proteins wont permeate these pores

occurs within intestinal space and cytosol, across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores

this is the most important limiting factor for drug permeation bc of the large # of lipid barriers separating body compartments. 

the lipid:aq partition coefficient of a drug determines how readily the dru gmoves btwn the aq and lipid media

occurs when substances are too large or impermeant. 

the substance is bound at cell surface receptor, engulfed by the membrane, and carried into cell by pinching of the newly formed vescicle inside the membrane. the substance is released inside the cytosol by breakdown of vesicle membrane. 

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gives the passive flux of molecules down a concentration gradient

• C1: high concentration - C2: low conc
• area: of the place accross which diffusion is occuring
• permeability coeff: mobility of the drug molecules in the medium of the diffusion path
• thickness: length of the diffusion path 

process by which extracellular signaling molecule activates a membrane receptor. 

in turn, intracellular molecules are altered. 

this creates a response. 

6.4 - 7.6

is the pH of ... 

7.5-8.0 

is the pH of ... 

1.92-2.59 

is the pH of... 

6.54-7.40 

is the pH of ... 

3.4-4.2

is the pH of ... 

5.0-8.0

is the pH of ... 

hint: has the biggest range out of all the compartments we need to know 

mediate the actions of endogenous chemical signals 

ex: NTs, autacoids and hormones

an antineoplastic drug that binds to & inhibits the Dihydrosfolate reductace (Dhfr) enzyme receptor

this stops DNA production because folate is needed to make thymine. 

supresses tumor growth

involved in the transport of ions or other molecules 

ex: Na/K ATPase is the membrane receptor for cardioactive digitalis glycosides

a structural protein that is the receptor for colchicine, an antiinflammatory agent. 

structural proteins maintain cellular integrety 

hyperbolic curve

relates drug concentration and its effect

resembles the mass action law 

characterizes the receptor's affinity for binding the drug in a RECIPROCAL fashion 

the conc of agonist when 50% of the receptors are bound/occupied

B-adrenoceptors in myocardial cells of the heart. 

we know these are spare receptors because the max response to catecholamines can still be elicited when 90% of the receptors are occupied by a quasi irreversible antagonist

a type of antagonist 

it reduces receptor activity below basal levels observed in the absence of a bound ligand 

reversible/competitive antagonists

&

Irreversible/nonsurmountable  antagonists

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ratio of the concentration of agonist required to produce a given effect in the presence of a fixedconcentration of competitive agonist and the agonist concentration required to produce the same effect in the absense of agonist

Schild's Equation

The concentration (C') of an agonist required to produce a given effect in the presence of a fixed concentration ([I]) of competitive antagonist is compared to  the agonist concentration (C) required to produce the same effect in the absence of the antagonist. The ratio of these two agonist concentrations (dose ratio) is related to the dissociation constant (K_i) of the antagonist

a measure of the potency of the drug and tightly the drug binds to the receptor

the larger the difference, the tighter it binds and the harder to compete it out

1. concentration of agonist required to produce a given effect in the presence of a fixed concentration of competitive agonist

2. the agonist concentration required to produce the same effect in the absence of agonist 

used to treat pheochromocytoma 

it is an irreversible alpha adrenoceptor antagonist, used to control hypertension caused by catecholamines released from pheochromocytoma (tumor of the adrenal medulla)

the tumor releases a lot of E or NE at random times, which spikes BP. 

administration of phenoxybenzamine inhibits the receptors irreversibly so the blockade will be maintained even when the tumor releases large amounts of chatecholamine. 

antagonism that doesnt involve interactions of drugs at a receptor

the antagonist takes the drug away from the receptor

ex: protamine 

antagonism that does not involve drug-receptor interaction. 

this antagonism takes advantage of endogenous regulatory pathways mediated by different receptors. 

ex: glucocorticoids increase blood sugar, opposed by insulin

abnormally slow heartbeatcaused by increased release of Ach from vagus nerve endings (ie after a heart attack)

two different approaches to treat: 

• isoproterenol 
• aropine 

a B-adrenoceptor agonist that increases heart rate by mimicking sympathetic stimulation of the heart (the opposite effect of a heart attack)

this can be ore dangerous than using a receptor-specific antagonist (atropine)

undergoes phase 2 before 1

slow acetylators are prone to toxicity of this drug

this process is known as:

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what happens to receptors after they are internalized? Internilization : 

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two things can happen: 

1. : unbinding of ligand and receptor recycling (happenns really quick in matter of seconds) (desensitization)

2.  destroying and down regulation

Know difference between down regulation and desensitization (transient)

Down regulation is longer bcgotta go thru transcription process to make new receptors 

cAMP

Ca++

Phosphoinositides

Quantal dose-effect plots.

Shaded boxes (and the accompanying bell-shaped curves) indicate the frequency distribution of doses of drug required to produce a specified effect; that is, the percentage of animals that required a particular dose to exhibit the effect. The open boxes (and the corresponding colored curves) indicate the cumulative frequency distribution of responses, which are lognormally distributed

theophyline

caffeine

methylxanthines 

ketamine

metacholine

carvedilol

intracellular enzyme stimulated by Nitric oxide once NO crosses the membrane 

• once NO diffuses into the cell, it binds to the enzyme, takes the G, and turns it from a linear GTP to a cyclic produc (CGMP)

an inhibitory constraint that usually keeps the receptor in the cytoplasm. it prevents the drug from entering the nucleus and messing around

in the absence of hormone, the receptor is bound to this protein. binding of the steroid glucocorticoid to the normal receptor triggers release of hsp90. this allows the activated receptor to initiate transcription of target genes in the nucleus. 

these hormones produce effects after a lag period of 30 minutes to several hours, which is the time taken for the synthesis of new proteins. 

ex: wont immediately relieve symptoms of acute bronchial asthma

the effects can last for hours or days after the conc has reached zero due to slow turnover of enzymes and proteins. 

• polypeptides with an extracellular hormone binding domain and a cytoplasmic enzyme domain. the two domains are connected by a hydrophobic segment of the polypeptide that crosses the lipid membrane 
• they mediate the first steps in signaling by insulin, epidermal growth factor, platelet derived growth factor and atrial natriuretic peptide
• when a hormone binds to extracellular domain it results ina change in receptor conformation that causes the receptor molecules to bind to one another noncovalently
• the protein tyr kinase domains are brought together
• the tyr residues in both cytoplasmic domainsbecome phosphorylated by each other forming dimers-autophosphorylation. 
• this activates enzymatic activity and catalyzes phosphorylation of substrate proteins

limits the intensity and duration of epidermal growth factor and other agonists of RTKs. 

ligand binding induces endocytosis of receptos from the cell surface, followed by degradation of those receptors and their bound ligands 

When receptor degradation occurs faster than synthesis of receptors, the total number of cell surface receptors is reduced

as a result that cell's responsiveness to ligand is diminished

once EGF binds to RTK it unergoes rapid endocytosis, and is trafficked to lysosomes. 

________________ is the process where the receptors in the vescicles are brought back to the cell surface rather than being degraded. 

the number of receptors doesn't change, they are just in the process of being recycled. 

a regulator of blood bolume and vascular tone. 

it acts on a transmembrane receptor whose IC domain, a guanylyl cyclase, generates cGMP. 

they become active in their dimeric form 

it binds when blood pressure is high 

receptors that have sytoplasmic domains with serine/threonine kinase activity. they are transmembrane enzymes. 

ex: TGF-B

serene-threonine kinases that signal thru the SMAD family of proteins

regulates growth and proliferation of cells, blocks growth of many cell types. 

there are type 1 and 2 subunits

these receptors respond to peptide ligands that include growth hormones, erythropoietin, interferons, and other regulators of growth and regulation. 

once the receptors are activated by ligand they form a dimer

the cytoplasmic domain has no enzymatic activity with itself so it associates with JAK which bind noncovalently 

when kinase receptors are activated and form a dimer, it associates with __________ noncovalently. 

it becomes active and phosphorylates tyr residues on the receptor, which bind STATs

the bound STATs are also phosphorylated by ______

• recruited when tyrosine is phosphorylated, and then it binds to the tyr residues on the receptor
• once bound it becomes phosphorylated by JAK.
• the phosphorylated _____ then dissociate from cytoplasmic side of receptor and form a dimer with eachother
• ______ dimer then travels to nucleus where it regulates gene transcription 

natural ligands of ligand-gated channels

(synaptic transmitters)

• acetylcholine
• serotonin
• GABA
• excitatory amino acids
• glycine
• asp
• glu

a pentamer made up of 4 diff polypeptide subunits (2 alpha 1 beta 1 gamma 1 delta)

example of a ligand gated transmembrane ion channel that can be induced toopen by ligand binding. 

• opened by Ach
• allows Na+ to flow down its conc gradient into cells, producing a depolarization
• in the absence of ligand, the receptor is closed and sodium ion cant pass through
• immediate pharmacological effects
• calcium acts as a second messanger after being released & it triggers transduction cascades

released when Ach binds to ligand gated channel or it can be released from a change in cell potential (electrical charge across the membrane)

it acts as a second messanger and triggers cell transduction cascades 

an effector enzyme activated by G protein 

when activated it increases intracellular second messangers

involves binding and hydrolysis of GTP

G protein is associated with GDP when GPCR is not activated by ligand. when it is activated, GDP is released and GTP takes its place on the binding site of the G protein. the activated G protein leavs receptor and regulates teh acivity of an effector enzyme or ion channel. 

signal is terminated by hydrolysis of gtp then effector goes back to unstimulated state. 

type of G protein

effector is increased adenylyl cyclase activity, and increased cAMP

how to remember: S for Speed, speed is sortof synonomous with increased and the opposite of slow (Gi)

G protein that decreases adenylyl cyclase activity and decreases cAMP

it openss cardiac K+ channels to slow 

how to remember: I is close to J in the alphabet (HIJK), and Gi opens K+ channels

opposite of Gs

ligand binding activates Gs-GTP as well as BARK (B-adrenergic receptor kinase) which phosphorylates the sytoplasmic tail of GPCR on ser/thre residues. B-arr then binds to tail, resulting in diminished ability of receptor to interact with G protein. 

result is reduced response of agonist. 

when agonist is removed, phosphatases cleave phosphates form the tail, and BARK activity is decreased so the receptor is ready to respond to agonist. 

in other words, it has reset itself 

desensitized b receptors can be resensitized. internalized receptors return to plasma membranes

down regulated receptors are degraded in lysosomes so they decrease cellular responsiveness. this has a slower onset and prolonged effect. 

• cAMP 
• Ca2+
• phosphoinositides
• cGMP 

• beta adrenergic amines
• glucagon
• histamine
• serotonin
• other horones 

• means cAMP kinase is activated, therefore more substrates are phosphorylated
• more glucose is released
• insulin is needed to store sugar in cells 

1. hydrolysis of GTP so adenyl cyclase is inactivated and no more cAMP is made
2. conversion of cAMP to linear AMP through cyclic nucleotide phosphodiesterase
3. dephosphorylation of substrate generated by cAMP kinase 

caffeine, theophylline, methylxanthine.

in the presence of either of these, cAMP responses continue so cAMP levels stay high.  since cAMP kinase is dependent on cAMP it stays as well 

terminates cAMP signalling in cells by converting it into linear AMP 

can be inhibited by caffeine, theophylline, and methylxanthines  (competitive inhibitors)

• Alpha-adrenergic amines
• muscarinic Ach
• opoids
• serotonin
• GABA receptors 

• cAMP kinase activity is decreased
• less substrates are phosphorylated
• more glycogen is in the body resulting in glucagon release and possibly hyperglycemia 

• muscarinic ach
• bombesin
• serotonin receptors
• platelet activating factor 

a membrane enzyme stimulated by Gq that splits a phosphoipid component of the plasma membrane into 2 second messengers :

1. DAG: stays in membrane and activates protein kinase C
2. IPE : water soluble, diffuses thru cytoplasm to trigger release of ca2+ by binding to ligand gated calcium channels in the membranes of the Er

a second messenger that triggers release of Ca2+ by binding to ligand-gated calcium channels in the membranes of the ER

it is water soluble so it diffuses thru cytoplasm

it is activated by phospholipase C (which is activated by Gq)

activated by binding of Ca2+

it regulates activities of other enzymes including protein kinases. 

• causes relaxation of vascular smooth muscle

show efects on a continuous scale and the intensity of the effect is proportional to the dose. you can measure the response at any point on the curve. indicates the maximal efficacy of a drug

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measure of the effect produced by the drug

has to do with ability of drug to reach receptors, not on its potency 

alpha blocker

acts on receptors in vascular smooth muscle to reduce blod pressure. depending on plasma concentration may cause postural hypotension, which is a sudden drop in bp when standing. 

sudden drop in bp when standing

can be  a result of taking prazosin

alpha 2 adreno receptor 

what tissue?

presynaptic adrenergic nerve terminals 

what adrenoceptor?

alpha 1 adrenoceptor

what tissues