anything that brings about a change in a biological system

Any agent approved by the Food and Drug Administration for the treatment or prevention of disease.

is it safe in PATIENTS with the disorder

100-200

does it WORK in patients, double blind studies

1000-6000 patients

post marketing surviellance

selling to the population at large

acute toxicity, possibly LD testing

chonic toxicity testing if drug is for long term

effect on reproduction

carcinogenisis/mutagenesis

mechanisms of toxicity

effecs of a drug on the body

(mechanism of action magnitude of effect)

receptor binding

signaling mechanism

physiological effect

effects of the body when on a drug

-absorption

-distribution

-metabolism

-excretion

lower limit set by requirement for sufficient selectivity

upper limit dictated by poor absorption nd distribution in the body

must be selective in their binding properties

receptor becomes altered or modified when bound

binding of the drug initiates a series of events that leads to the observed functional change

proteins

ion channels

enzymes

transport proteins

protiens that bind neurotransmitters or hormones

GPCR

nucear

ligand gated ion

voltaged gated ion

estrogen binds which causes the phosphorylation of endothelial nitric oxide synthase (eNOS) leading to:

increase eNOS activity

increase NO production

Increase dilation

in the ex. of epidermal growth factor receptor:

ligand binds extracellular domain which can then bind with another bound momomeric receptor to become active dimers

intracellular cytoplasmic enzyme domains then become activated and phosphorylate other substrate proteins

just the same as a tyrosine kinase but kinase activity is not intrinsic to the receptor

 the amount of drug:receptor complexes formed.

Maximum effect is achieved when all receptors are occupied.

what is affinity?

How is potency affected by affinity?

affinity is the ability of the drug to bind its receptor site

The potency of a drug is dependent on the affinity of the drug for its receptor.

Drugs with a higher affinity are usually more potent.

Kd = drug concentration required to bind 50% of the receptor sites in the system

the smaller the Kd the greater the drugs affinity --> potency = less drug needed to get a desired affect

It shifts it to the R, increasing the EC50.

it is surmountable if enough agonist is added 

YES

if a partial agonist is added with a full agonist, it will act as an antagonist to the full agonist causing a max partial agonist response rather than a full agonist response

Irreversible antagonist shifts the response curve downwards, reducing the maximal response.

The effects of an irreversible antagonist are insurmountable and cannot be overcome by adding more agonist

- Increase response : Positive modulator

chloride channel expressed on neurons that

  inhibits neuron function when activated

Catabolic actions of glucocorticoid hormones can lead to increased blood sugar

Insulin acts at the insulin receptor to decrease blood sugar levels

Clinicians sometimes administer insulin to oppose the hyperglycemic effects of elevated glucocorticoid hormones levels.

- Remove the drug from the system

When 5 receptors need to be filled to reach a max response and if the irreversable antagonists have bound 3 out of 10 receptors you can increase the drug to still reach that response, this is true even if 5 of ten are bound.  

When there are less than 5 receptors available to be bound due to irreversable antagonists, you can no longer reach a max response and your curve is further pushed to the right.

in a system with spare receptors what is the ED50 to Kd ratio?  

What does this mean?

ED50< Kd

there is more sensitivity to the agonistand maximum effect is achieved before all receptors are occupied

when there are no spare receptors

ED50 = Kd

what is drug threshold?  

How is it the inverse of spare receptors?

With a drug threshold, EC50 > Kd

drug threshold decreases the sensitivity of a system to agonist

what is tachyphylaxis?

change of responsiveness at the drug level

Decreased absorption

Decreased penetration to site of action

Increased metabolism

Increased clearance

The amount of drug that reaches the site of action is decreased

responsiveness change at the receptor level

Change in receptor

Receptor uncoupled from signaling pathway   

Total number of receptors in the system is decreased

prevents G protein from from interacting with the receptor.  Uncoupling the receptor .  The receptors can also be internalized and be degraded by lysosomes. This leads to an overall decrease in the total number of receptors.

Quantal doses give an all or none effect

graded increases doses give a incremental increase in effect

ED50 = effective dose at which 50% of subjects respond               a drug with a high potency has a low ED50

dose toxic effect

=   _________________

dose therapeutic effect                                                                

The higher the TI, the safer the drug

If TI ≤ 2.0, the drug is considered to have a narrow therapeutic index (NTI) What are 4 drugs in use with a NTI?

Lithium - bipolar disorder

Warfarin - prevents blood clots

Digoxin – congestive heart failure

Theophylline- respiratory diseases such as asthma

Index used for estimation of drug dosage

Defined range of drug concentration at which the desired effect occurs within the safety range.

Below the therapeutic window there is little effect and above the toxicity is greater than the desired effect

Typically the range is between ED50 and TD50

what is the calculation for Kd?

What is it for EC50?

Kd= 1/affinity

EC50 = 1/potency

absorption

distribution

metabolism

excretion

bioavailability is a measure of the drug available to the systemic circulation over time after administration.  How is it measured?

AUC_oral

=________

AUC _iv

 what is pKa?

pKa is the pH value at which [protonated]=[nonprotonated]

For weak acids, if pH is low (< pKa), lots of H+ are around, which drives A− toward HA and absorption is favored.

For weak bases, if pH is low (< pKa), lots of H+ are around, which will drive B toward BH+ and

absorption is disfavored

1. Different tissues have different blood perfusion rates;

2. For the same tissue, different drugs have different partition ratio;

3. For the same drug, different tissues have different partition ratio.

4. Blood flow can dictate how fast a drug saturates a tissue.

5. Partition ratio Kp determines the maximum amount of distribution at a tissue 

  Kp = Ctissue/Cvenous-blood (at equilibrium)

what is the PK concept of volume of distribution (Vd)?

how is it calculated?

  Vd: The volume of fluid in which a drug would need to be dissolved (homogenously) in order to have the same concentration in that volume as it does in plasma.

Vd= amount of drug in body/plasma [drug]

functionalization:

oxidation

reduction

hydrolysis

The products of phase I functionalization are conjugated, commonly with endogenous molecules like glucuronic acid.  The reason for this is to make a hydrophilic compound that can be excreted. 

No

some such as 5FU become active.  This is known as bioactivation 

when a drug becomes a toxin due to metabolism

This is the case for acetominophen being metabolized to NAPQI.  Sulfhydryl groups can be attacked by NAPQI.  Large amounts can lead to liver damage when it nucleophilicaly attacks proteins

CYP2C9 - metabolizes weakly acidic drugs

CYP2D6 - metabolizes weakly basic drugs

CYP3A4 - metabolizes practically everything else

what is the main function of cytochrom P450 enzymes? 

Where are they found?

Catalyzing oxidative metabolism reactions (Phase I)

found in the liver sitting on the ER membrane of hepatocytes

 An increase in the steady-state concentration of enzyme following exposure to an appropriate stimulus

ex. for someone who drinks a lot of alcohol, they will have raised CYP levels for dealing with OH reduction

  Chemicals |  drugs | xenobiotics

·  Diet | Nutritional factors

·  Biological rhythms (stress/pregnancy)

(1) Increased rate of transcription/gene expression of P450s

(2) Decreased rate of degradation of P450 protein products

(3) Increased rate of translation of P450 protein products

Loss or decrease of the drug-metabolizing enzymatic activity following exposure to stimuli

ex: GFJ induces CYP3A4 protein degradation

urine

bile

feces

expired air

sweat

saliva

milk 

tears

what does the bile system typically excrete?

what are 2 examples?

highly polar organic anions and cations (and some neutral molecules) with molecular weights greater than 300-500

ex: Glucuronate and sulfate derivatives of steroids

Intestinal glucuronidases and sulfatases can convert drug metabolites back to the free drug.

Intestinal bacteria can facilitate this process

dA/dT = −KAⁿ

when n = 0

this means that A (amount of drug) has a decreasing LINEAR relationship with t at any given time.

The rate of drug elimination is constant

Zero order kinetics suggests that

the elimination process is saturated

when n = 1

The amount of drug decreases exponentially as time goes

The rate of drug elimination (dA/dt) is proportional to the (remaining) amount of drug

If drug elimination has first-order kinetics, how long does it take to have 95% of the drug to be removed after a single dose?

0 = 100

1 = 50

2= 25

3 = 12.5

4 = 6.25

5 = 3.125

rate of elimination:

zero = constant, 1st = dependent on A

limination rate constant:

zero = mg/hr, 1st = hr

half life (t1/2):

zero = n/a, 1st = constant

relationship between A and T

zero = linear, 1st = exponential

Measure plasma drug concentration Cplasma (Cp).

What is Cp equal to? 

Amount plasma/volume plasma

is the amount of the drug in the plasma equal to the amount of the drug in the body?     

A = A0e−Kt

volume of distribution =

Vd = amount of drug in the body/ plasma drug concentration

a measure of the efficiency of irreversible removal of a drug by an eliminating organ

CL = rate of elimination/plasma [drug]

CL is a constant for first-order kinetics

CL is dependent on the drug and the condition of the eliminating organ

if excretion > creatinine clearance = active secretion

if excretion < creatinine clearance = reabsorption or plasma protein bound

CL = (dA/dt)/Cp = −KA / (A/Vd) = − KVd ß ml min−1

so CL can be considered as a fraction of Vd that

gets “cleared” in unit of time.   

        Since t½ = 0.693 / K  &   CL= K Vd

  CL = 0.693Vd / t½      or  t½ = 0.693Vd / CL

what does  t½ = 0.693Vd / CL

 mean?

what does CL = 0.693Vd / t½      

 mean?

4−5 half-lives are required to achieve a steady state level.

3−4 half-lives are adequate to achieve an effect indistinguishable to the steady state effect

Dosing ratess = CL X Css

meaning that in a steady state the dosing rate must be equal to the rate of elimination

to rapidly achieve therapeutic concentration

Loading dose = Vd X Ctarget

 (Cp=A / Vd)

what are the differences in dosing rate between:

IV

intermintent

Oral

Iv: dosing rate = infusion rate

intermittent: dosing rate =

maintenance dose/dose interval

Oral dose: dosing ratess= dosing rateoralx bioavailability

choline acetyl transferase

takes choline and Acetyl CoA and makes Ach

A cleaves a protein on the nerve terminal

B cleaves a protein on the synaptic vessicle

Persistent muscle spasms

Poststroke spasticity

Treatment of hyperhidrosis

Healing of anal fissure

Migraine headaches

Neurogenic detrusor overactivity

Elimination of facial wrinkles

the Tx of Alzheimers (counter act the effect of the loss of cholinergic neurons)

Tacrine- first drug  approved for treatment of Alzheimer’s; many actions in addition to AChE inhibition; high incidence of liver toxicity

Donepezil- more specific for inhibition of AChE; delays progression of symptoms; side effects- diarrhea, etc.-  expected based on cholinergic stimulation

myasthenia gravis is an autoimmune disease that forms Abs against the nAchR decreasing # and function at the NMJ.  What are tx options?

What should be given concurrently?

AChE Inhibitors- increase [ACh] at the NMJ- improves efficiency of NM transmission (neostigmine, pyridostigmine)

  Also: use a muscarinic receptor antagonist (e.g., atropine) to counter effects of increased ACh at muscarinic synapses

sweat glands

adrenal medulla

mAchR increases K+ permeamiability slowing rate of diastolic depolarization

Ach decreases the rate of the atrial action potential

(decreases Ca entry & force of contraction)

relaxation of the ciliary muscles decreasing curvature of the lens

opposite effect for PSNS

No

  -Airway epithelial cells

  -Vascular endothelial cells

  -Keratinocytes

  -T-cells

  -Urothelial cells

  -Placenta

  -Various human cancer cell lines and tumors

acetylcholine

carbachol 

bethanecol

methacholine

causes release of NO which diffuses to SM where it activates cGMP which lowers cell [Ca]

also causes release of endothelial derived hyperpolarizing factor.  EDHF is a c type naturietic peptide that activates K+ channels causing hyperpolarization of SM causing relaxation of small diameter vessels

release of H₂S causes smooth muscle relaxation

1. CNS- Low doses of atropine may act preferentially in the CNS to increase parasympathetic outflow

2. Presynaptic effect- Low doses of atropine may act preferentially on presynapticmAChR on parasympathetic terminals, resulting in increased ACh release onto the heart

Block mAChR on heart-

Block effects of ACh, increases HR

1. 4° antagonists not lipid soluble (tertiary more soluble):

  -don’t act on CNS after systemic administration

  -more poorly absorbed from the GI tract

2. 4° antagonists may block nAChR at:

  -NMJ, interfere with respiration

  -autonomic ganglia, can cause hypotension

where are H1 receptor subtypes found?  

What type of receptor is H1?

smooth muscle

endothelium

brain

Gq

what type of histamine subtype receptor is H2?

Where is it found?

gastric mucosa, heart, mast cells, brain

Gs

brain, myenteric plexus

Gi

immune cells

Gi

anaphylaxis

lower blood pressure

H1, H2 both lead to vasodilation

H2 in SA node increases HR and increases spontaneous action potential

it has all subtypes but H4

Drinking, temperature regulation, appetite

increase bronchoconstriction

increase GI contraction

is an H1 agonist

H1 stimulation in inner ear -> vasodilation -> ­ vascular permeability -> ­ increases endolymphatic drainage

between 1st generation and 2nd gen.

1st generation antagonists cause sedative effects

most are OTC and safe

rapidly absorbed (1-2h) with a wide range of duration (2-24h)

readily penetrate CNS

have mild to marked sedative effects

ethanolamines are a 1st generation antihistamine.

 What are 3 commonly used ones?

high amount of sedation involved

1st gen antihistamine

hydroxyine

used for motion sickness and anxiety

non OTC

a 1st gen anti histamine

active drug is pyrilamine 

moderate sedation

MIDOL

PROMETHAZINE

1st gen anti histamine

1. vagus nerve increases Ach to M3 receptor activating Gq increasing calcium which increases H+ pump

2. In the antrum, g cells are stimulated to release gastrin which binds to CCK2 receptors and CCKB receptors which stimulate Gs causing an increasein Ca and a release of H+

3. ECL cells release histamine onto H2 receptors of parietal cells causing them to stimulate Gs receptors which increase cAMP and increase H/K pump activity

vagus nerves increase antrum Ach which increase GRP

This leads to increase in gastrin and a decrease in somatostatin which indirectly causes an increase in gastrin

increased levels of gastrin and Ach lead ECL cells to increase histamine release

increased acid in the antrum leads to activation of D cells to release somatostatin which binds to the ST2 receptor (Gi) on g cells lowering cAMP levels & gastrin release

The ST2 receptor is also on ECL cells causing a decreased release of histamine

these actions lower the acid in the fundus

heart burn

acid regurgitation

sore throat

causes a lower anti-reflux barrier and esophageal sphincter function

Carbonates: NaHCO3, CaCO3

proton pump inhibitors

irreversible inhibition of action at H/K pump

omeprazole (prilosec)

pantoprazole (protium)

serum t 1/2 = 0.5 - 2 hours•minimal side effects (<5% patients)

bismuth

sucralfate

prostaglandin analogs

 Adverse Effects: diarrhea, abdominal pain

hydrolysis of lipids, chylomicrons - VLDL, into capillaries

upon hydrolysis, TGs are removed

TGs are removed and become IDLs.  IDLs can either go to the liver or give up more TGs and become LDLs.

LDLs are high in cholesterol, low in TGs

cholesterol = <200

LDL <130

TG < 120

HDL = > 40 for men > 50 for woemen

abnormal amounts of lipids/cholesterol in the blood

these could be hyper or hypo

Primary causes :

 low growth and development

high LDL

 high chylomicrons, VLDL

HMG CoA reductase inhibitors

Structural analogs of HMG-CoA

liver produces less cholesterol

hepatocytes increase LDL receptor synthesis

more receptors means more LDL/VLDL bound and turned into bile salts

lower TG synthesis and increase ApoB degredation

decrease VLDL secretion

lower HDL breakdown

stimulates increased production of proteins involved in Free fatty acid breakdown

less LDL and VLDL and more HDL

prevent bile reabsorbtion and lower plasma cholesterol

isoproterenol

NE

epi

dopamine

80% Epi

20% NE

what is the rate limiting step for the conversion of Epi to NE?

What is the enzyme that does this?

the conversion of tyrosine to DOPA

tyrosine hydroxylase

relaxation of smooth muscles

(some B2 are in heart)

what are the orders of potency for alpha receptors between Epi, NE, and Iso?

for beta receptors?

A:  EPI > NE > ISO

B: ISO > EPI > NE

mediates stimulation of adenylylcyclase

        (ß-AdR)

mediates inhibition of adenylylcyclase; activates

         potassium channels in heart

        (M2, M4mAChR; a2-AdR)

activate certain forms of phospholipase C

        (M1, M3, M5mAChR; a1-AdR)

regulate the activity of GPCRs by phosphorylating their intracellular domains.  They can up or down regulate the activity.  

Upon phosphorylation of serine or threonine residues binding sites are made for arrestins which prevent the reassociation of the G proteins with their receptors, thereby preventing reactivation of the signaling pathway

Beta 1 levels go down and Gi go up

B2 receptors at low volume cause vasodilation and lower TPR

A1 cause vasoconstriction and increase TPR

Causes relaxation of intestinal and bronchial smooth muscle

Cardiac stimulation

Treatment of anaphylatic shock

Slows absorption of local anesthetics

in the heart it causes are "stronger" heart beat by increasing contractility, but lowers heart rate

in the vasculature it stimulates alpha1 receptors and causes vasodilation which increases TPR

(1) vasodilatory dopamine (D1)  receptors   in renal, mesenteric, and coronary vascular beds             

(2) beta receptors in heart (greater effect on

contractile force than rate)

(3) stimulates NE release from nerve  

    terminals (contributes to cardiac effects)

(4) high doses can activate vascular a1 receptors

high TPR, high BP

Low HR

One isomer is ß1 agonist and alpha1 agonist

Other isomer is ß1 agonist (and apparently weak a1 antagonist) Increases contractile force, little effect on heart rate or TPR

Used to increase cardiac output (e.g., CHF)

Why does dobutamine have little effect on HR and TPR?

  1. Human atria: 40- 50% ß1; human ventricle: 70-85%ß1

  2. Little ß2- mediated vasodilation, so no reflex          tachycardia

3. alpha1 agonist activity may also contribute to direct         stimulation of ventricles and lack of vasodilation

D1 agonist

IV used in rapid vasodilation for emergency hypertension

-Blocks  a1-AdR in vasculature- cause vasodilation

-Doesn’t block  a2-AdR on sympathetic nerve terminals-

   therefore- less NE released on heart than if a2-AdR  were blocked

   therefore- less tachycardia than if a2-AdR  were blocked

-Used in the treatment of hypertension

-Also used in the treatment of BPH (benign prostatic hyperplasia)