Pharmacology

Front 1

Name relevant pharmacology legislation

Back 1

Pure Food and Drug Act - 1906
---Guidelines for drug labeling

Food, Drug and Cosmetic Act - 1938
---requires demonstration of safety and FDA approval for new drugs

Kefauver-Harris Drug Amendments - 1962
---Required demonstration of safety AND efficacy for new drugs. Outlined Investigation of New Drug as well.

Front 2

Partial agonist

Back 2

Agonist activity when by itself, antagonist activity when associated with natural ligand.

Front 3

Describe tradition process of drug design

Back 3

1.) Disease State
2.) Endogenous Ligand
3.) Receptor and Biological
4.) Response
5.) Drug Candidate

Front 4

Describe reverse pharmacology process of drug design

Back 4

1.) Orphan Receptor
2.) Endogenous Active Products
3.) Biological Response
4.) Disease State
5.) Drug Candidate

Front 5

Describe each phase of the clinical trials

Back 5

Phase 1 - lasts a couple of months, tests 20-200 patients, primarily for safety
Phase 2 - Can last up to two years and monitors short term safety and efficacy in several hundred patients
Phase 3 - Takes more than 4 years and monitors safety, dosage and efficacy in several hundred to several thousand people.

Front 6

Describe a within-patient trial vs a between-patient trial

Back 6

Within patients will test both drugs on the same individual and compare effects. Between patient trials test 2 different drugs on 2 different people and compares results between those two groups.

Front 7

What affects drug permeability?

Back 7

Drug Related: Lipid solubility of drug, pKa of drug and size of drug

Non-Drug related: pH of medium

Front 8

Partition Coefficient

Back 8

related to lipid solubility. larger lipid solubility means higher partition coefficient

Front 9

Where does the most drug absorption take place in the GI tract?

Back 9

The first part of the small intestine(duodenum)

Front 10

What kind of distribution do most drugs have?

Back 10

Non-uniform distribution in the body.

Front 11

Hippocrates

Back 11

Father of medicine. Freed medicine from mysticism and philosophy and made it reliant upon rational therapy.

Front 12

Galen

Back 12

Practiced in Rome and started polypharmacy mixing drugs with opium called "galenicals". Wrote a lot of books and created the theory of the 4 humors, blood, yellow bile, black bile and phlegm which persisted for 1000 years.

Front 13

Paracelsus

Back 13

Philippus Theophrastus Bombastus von Hohenheim. Called grandfather of pharmacology and first noted "dose effect" saying everything is poison, it is only the dose that makes a poison.

Front 14

Rudolph Bucheim

Back 14

Made the first laboratory in Estonia devoted to studying pharmacology. Trained Schmiedeberg

Front 15

Oswald Schmiedeberg

Back 15

taught pretty much everybody out of his lab in Germany about pharmacology

Front 16

John Jacob Abel

Back 16

Isolated epinephrine from adrenal gland and insulin from the pancreas. He developed three scientific journals and was the first chair of pharmacology at the University of Michigan before he went off to Johns Hopkins

Front 17

What reactions classify as phase 1 drug metabolism? Phase 2?

Back 17

Phase 1: Oxidation, Hydroxylation, Reduction, Hydrolysis
Ex: Oxidation by P450
Phase 2: Conjugation(this process is synthetic)
Ex: Conjugation by glucuronidation

All phase 2 reactions involve an enzyme transferase(methyltransferase, acetyltransferase, sulfotransferase, etc.)

Front 18

Where do the P450 and glucuronidation reactions occur?

Back 18

P450 and Glucuronidase takes place in the Smooth ER of the liver

Front 19

What is the most important cytochrome P450?
Secondarily important?

Back 19

The most important is Cyp3A4(50% of all drugs metabolized), Cyp2D6(25%), Cyp2C9 and Cyp2C19(15%), Cyp1A2(5%)

Front 20

Explain pharmacologic relevance of Polymorphism, Induction and Inhibition

Back 20

Polymorphism can lead to altered activity_increase or decrease) of P450 system.(relevant in Cyp2D5 and Cyp2C9) leading to unexpected results when administering drug. Ex: Codeine is normally metabolized to morphine. Some people cannot metabolize codeine.

Induction can cause an increase in the enzyme production in response to drug administeration resulting in a form of tolerance. Can also lead to build up if given drug is a "prodrug" that is converted into an active drug
Special Note: Cyp2D6 is the only P450 enzyme that cannot be induced.

Inhibition is when a drug inhibits the P450 system and can lead to overdoses when drug accumulates. Ex: Drug A inhibits the enzyme that metabolizes Drug B causes an accumulation of Drug B

Front 21

Autocatalytic Inactivation

Back 21

A reaction with a substrate causes production of free radicals that irreversibly damage enzyme. De novo synthesis of enzyme must occur to replace destroyed enzymes.
Ex: Chloramphenicol

Front 22

Reversible Inhibition

Back 22

Ketoconazole

Front 23

Metabolic Intermediate Complexation

Back 23

P450 converts an original non inhibitory molecule into an inhibitor that binds to create an intermediate complex that is non functional. Ex: Erythromycin

Front 24

Propananol

Back 24

Important Beta adrenergic receptor antagonish(beta blocker) it is largely metabolized by first pass because it is converted into an active metabolite.

Front 25

Relevance of Nitroglycerin to drug metabolism

Back 25

99% metabolized first pass so it is administered under the tongue so it reaches systemic circulation before it hits the liver.

Front 26

Acetaminophen toxicity is caused by?

Back 26

Glucuronidation enzyme saturation and depletion of glutathione(antioxidant) and consequent metabolic activity of P450 pathway that makes toxic metabolites.

Front 27

What Phase II reactions are NON-microsomal?

Back 27

All of them EXCEPT glucuronidation.

Front 28

What metabolic processes are inducible?

Back 28

P450 and glucuronidation. Essentially the microsomal reactions.

Front 29

Describe the kidneys function in drug metabolism are and where each occurs.

Back 29

1.) Glomerular filtration occurs at the glomerulus
2.) Proximal tubule has active secretion
3.) Distal tubule has passive reabsorption

Front 30

Factors affecting drug disposition in populations

Back 30

Children have a higher water content which can affect the distribution of water soluble drugs. Elderly in contrast have higher lipid content and affects their distribution of fat-soluble drugs.

Infants can have altered absorption

Excretion and oxidative/glucuronidation reactions follow bell curve for infants-children-adults.

Front 31

Pharmacokinetic Tolerance vs Pharmacodynamic Tolerance

Back 31

Pharmacokinetic Tolerance: Occurs when rate of elimination is increased or rate of absorption is decreased.
Ex: Induction of a Cyp450 by barbiturates


Pharmacodynamic Tolerance: occurs when there is reduction in normal reactivity of the receptor or coupling factors.
Ex: Desensitization - Beta-ark phosphorylates G-protein receptor causing beta-arrestin to bind effectively making the receptor unresponsive to ligand binding. Over time arrestin releases and the receptor is dephosphorylated.

Front 32

What are effects of Succinylcholine. Describe metabolism of this drug.

Back 32

muscle relaxant. Metabolized by pseudocholinesterase. People who have atypical pseudocholinesterase do not metabolize succinylcholine very well causing persistent apnea and paralysis. In addition, some people have overactive plasma cholinesterase in which case you would have to increase dosage.

Front 33

Acetylation Polymorphism

Back 33

Isoniazid is metabolized by acetylation and is used to treat tuburculosis. Isoniazid metabolism is bimodal in the population with fast and slow acetylators.

Slow acetylators show peripheral neuropathy. To treat this you give Pyroxidine(Pyridoxal Phosphate).

Notable drug-drug interaction based on genetics is demonstrated by INH toxicity with phenytoin. INH inhibits phenytoin metabolism and creates a toxic build up. This is not due to INH accumulation because that is treated with the pyroxidine, rather is a result of the INH inhibition of phenytoin metabolism.

Front 34

Glucose 6 Phosphate Dehydrogenase Deficiency

Back 34

Glucose 6 Phosphate dehydrogenase is responsible for converting NADP to NADPH in the red blood cell. Takes glutathione(oxidized) and reduces it.
Oxidized glutathione causes hemolysis if it accumulates.
G6PD deficiency is generally not a problem unless you are taking medication or are on a diet that causes build up of oxidizants.

Front 35

Tetracycline Antibiotics are inhibited by what?

Back 35

Will have reduced absorption if taken with various alkali earth metals(Al, Ca, Mg, Fe, Bi, Zn) because it forms poorly soluble chelates
Ex: Milk with drug

Front 36

Digitalis with cholinergic drugs

Back 36

Cholinergic drugs decrease stomach motility thereby decreasing absorption of digitalis

Front 37

What is probenecid used for?

Back 37

Probenecid is used to inhibit active secretion of a drug in the kidney. It was used in World War I to increase efficacy and conserve penicillin.

Front 38

What drugs have the most drug-drug interactions?

Back 38

Anticoagulants have the most. Anti-diabetics and MAOIs have the second most.

Front 39

What do barbiturates do to drug metabolism?

Back 39

They induce p450 increasing the enzyme activity.

Front 40

What does phenobarbitol do to plasma levels of other drugs?

Back 40

It reduces efficacy of anti-coagulants.

Front 41

What is the equation for half life?

Back 41

t(half life) = 0.7/Ke(elimination rate constant)

Front 42

Name different ways a drug can affect enzymes without adversely affecting normal human processes.

Back 42

1.) A drug influences an enzyme we don't have/use that bacteria/fungi do use.
2.) Drugs that target enzymes with different species specificity.
3.) "counterfeit incorporation" where you put in a drug that gets used as a substrate where the reaction produces a product that creates the desired therapeutic effect.
4.) Inhibitors of enzyme activity in specialized cells occur in many drugs affecting neurotransmitters.

Front 43

What is the definition of the therapeutic index?

Back 43

LD50/ED50

Front 44

What is the definition of the margin of error in the context of pharmacology?

Back 44

LD1/ED99

Front 45

Potency vs Efficacy

Back 45

Potency measures ED50 while Efficacy measures Emax.

Front 46

Name the 4 characteristics of receptors.

Back 46

Affinity, Specificity, Intrinsic Activity, Saturability

Front 47

Name the different G proteins and their actions

Back 47

Gi - inhibits adenyl cyclase, activates K+ channels

Gs - Activates adenyl cyclase, activates Ca channels

Gq - Activates phospholipase C

Front 48

Activates adenyl cyclase, activates Ca channels

Back 48

Gs

Front 49

inhibits adenyl cyclase, activates K+ channels

Back 49

Gi

Front 50

Activates phospholipase C

Back 50

Gq

Front 51

Describe the various types of membrane receptors and the time scale of their action when affected by a drug.

Back 51

Ionotropic - milliseconds),

Metabotropic(G-protein Receptors - seconds

Kinase Linked Receptors - minutes

Receptors linked to gene transcriptions(nuclear receptors) - hours

Front 52

Why is PLA2 important?

Back 52

PLA2 is a g-protein second messenger that maked arachadonic acid which can then lead to the creation of prostoglandins and leukotrienes.

Front 53

Occupance Theory

Back 53

The more receptors bound, the more effect seen

Front 54

Spare Receptor Theory

Back 54

There is a higher effect mediated by drugs when not all receptors are bound.

Front 55

Rate Theory

Back 55

The rate of binding is relevant to drug effect. very few drugs respond this way.

Front 56

Name an important organ that generally does not have dual innervation.

Back 56

Arterioles generally only have sympathetic innervation

Front 57

Name an important organ that does the same thing when stimulated by either the sympathetic or parasympathetic system.

Back 57

Salivary Glands

Front 58

Name an organ that has a different effect when innervated by either the sympathetic or parasympathetic system.but has the same effect

Back 58

The pupillary muscles are both told to contract by both systems but the sympathetic control radial muscle which make the pupil dilate while the parasympathetic controls the muscle going around the pupil which make it contract.

Front 59

What is an important exception to the general rule that post ganglionic sympathetic nerves secrete norepinephrine?

Back 59

The eccrine sweat glands that control thermoregulation. They respond to acetylcholine. As a result to affect the sweat glands you would use a cholinergic drug which is generally seen as a parasympathetic drug but in this important exception acts as a sympathetic drug.
However, stress-induced sweat glands(apocrine) are normal and controlled by adrenergic receptors and norepinephrine.

Front 60

What organ receives single innervation without a post ganglionic nerve?

Back 60

Adrenal gland via sympathetic system.

Front 61

What is the pharmacologic relevance to the fact that most blood vessels have adrenergic receptors?

Back 61

While the vessels may have muscarinic receptors(parasympathetic) they do not have parasympathetic innervation. This means if you stimulate the parasympathetic system you will not get a response, however, if you give muscarinic drugs then you will get a "parasympathetic" response.

Front 62

What organ receives single innervation and responds to dopamine?

Back 62

The juxtaglomerular cells in the kidneys. It receives single innervation via the sympathetic system and responds to epinephrine as well as dopamine.

Front 63

Name the effectors of the Enteric nervous system.

Back 63

1.) Smooth muscle cells
2.) Secretory Epithelium
3.) Endocrine cells
4.) Vasculature
5.) Immune cells

Front 64

Name the layers of the lumen in the gastrointestinal tract.

Back 64

from inside to outside:
lumen, mucosa, circular muscle, longitudinal muscle, serosa

Front 65

In a given cross section of the GI tract, where is the myenteric plexus?

Back 65

between the longitudinal and circular muscle layers

Front 66

What does the Area Postrema do?

Back 66

Senses plasma electrolytes, hormones and chemicals in the CSF.

Front 67

What does the Nucleus Tractus Solitarius do?

Back 67

Its like a central processing station for the brain that takes general visceral afferent input and sends it out to the relevant nuclei in the brain.

Front 68

What is important about NPY?

Back 68

Neuropeptide Y is a contransmitter together with norepinephrine and together with ATP in post-ganglionic sympathetic nerves.

Front 69

What is important about VIP?

Back 69

Vasoactive intestinal peptide is a contransmitter together with ATP with acetylcholine in post ganglionic parasympathetic nerves

Front 70

With regards to the eye muscle, what ganglion is sympathetic? parasympathetic?

Back 70

Superior Cervical Ganglion is sympathetic and the Ciliary ganglion is parasympathetic.

Front 71

What type of receptors dilates/contracts the pupillary muscles?

Back 71

alpha 1 andrenergic and M3 cholinergic

Front 72

What is the word that means pupilary dilation? contraction?

Back 72

dilation = mydriasis
contraction = miosis

Front 73

When do you need to know the difference between M2 and M3 cholinergic receptors?

Back 73

The heart definitively has an M2 cholinergic receptor. M3 is predominantly present in the eye and works through phospholipase C.

Front 74

Describe the lens when it is normal.

Back 74

The ciliary muscle is relaxed and the suspensory ligaments are under tension. The lens is flattened and the focus is on distant objects.

Front 75

Describe the lens when it is in accommodation. Which system causes acommodation?

Back 75

The ciliary muscle contracts, reduced tension on suspensory ligaments, the lens becomes round and the focus is on near objects. This is done by the parasympathetic system.

Front 76

Name relevant vocabulary for heart conduction, contracility and increasing heart rate/

Back 76

increase heart rate = chronotropic
contractility = inotropic
conduction = dronotropic

Front 77

What receptors are most prominent in heart?

Back 77

The adrenergic receptors are almost all Beta 1 while the muscarinic receptors are almost all M2.

Front 78

Where is the parasympathetic innervation in the heart important? not important?

Back 78

It is important in the SA node, AV node and atria. It is not as important in the ventricles and the HIS Purkinje system.

Front 79

What is the principle receptor that causes contraction in the blood vessels?

Back 79

alpha 1 adrenergic.

Front 80

What is important about skeletal muscle blood vessels?

Back 80

It has innervation from both alpha 1 and beta 2 adrenergic receptors. Beta 2 dilates vessels in fight or flight.

Front 81

What is the biggest difference between norepinephrine and epinephrine?

Back 81

Norepinephrine is very poor in activating Beta 2 receptors. In contrast epinephrine is good at activating both Alpha 1 and beta 2 receptors

Front 82

What happens when you increase cGMP in a blood vessel? cAMP?

Back 82

You get relaxation of the blood vessel.

Front 83

describe the action of alpha 1 and beta 2 receptors.

Back 83

alpha 1 receptors are almost always excitatory. Beta 2 receptors are almost always inhibitory.
In smooth muscle the beta 2 receptor is inhibitory and causes relaxation.
However, Beta 1 receptors in heart are excitatory and increase contractile force, etc.

Front 84

What receptors are present in the lung? What do they do?

Back 84

The sympathetic receptors are beta 2 which cause bronchodilation and mast cell inhibition. There is also some alpha 1 receptors which have parasympathetic-like effects. The parasympathetic receptors are M2 and M3 which stimulate mast cell secretion and bronchoconstriction

Front 85

Why is it a conundrum that sympathetic input results in bronchodilation? What is a theory solving this conundrum?

Back 85

It is strange that sympathetic input causes bronchodilation because the lungs have beta 2 receptors and norepinephrine is not a good agonist for beta 2. A possible theory is that norepinephrine inhibits the release of acetylcholine by the parasympathetic system thereby inhibiting its action of bronchoconstriction while simulatenously the beta 2 receptor is stimulated by epinephrine flowing in the circulation.

Front 86

Why does both alpha and beta receptors in the stomach and intestine cause a decrease in motility and tone?

Back 86

Because it the alpha receptor works similarly to the lung innervation hypothesis. The alpha receptor is on the postganglionic parasympathetic neuron and serves to inhibit the release of acetylcholine decreasing excitatory input. The beta receptor, meanwhile, is naturally an inhibitor.

Front 87

What receptors do the stomach have/

Back 87

alpha 1, alpha 2, beta 1, beta 2, M3

Front 88

What receptor causes release of renin?

Back 88

a beta receptor.

Notably, there is no parasympathetic innervation of the juxtaglomerular cells that secrete renin.

Front 89

What receptors are on the uterus? what do they do?

Back 89

There are mostly sympathetic receptors, both alpha and beta. Beta relaxes uterus and alpha starts pregnant contractions. Beta agonists can be used to prevent early labor.

Front 90

How many subunits is acetylcholine composed of?

Back 90

5. It is a pentamer

Front 91

How many times does the G protein cross the membrane?

Back 91

7 times

Front 92

M1, M3 and M5 have what type of G- protein? What are the downstream effects?

Back 92

These muscarinic receptors have Gq proteins that activate Phospholipace C and increase intracellular Ca. They may also activate PLA and lead to synthesis of leukotrienes and prostoglandins

Front 93

M2 and M4 have what type of G-protein? What are the downstream effects?

Back 93

These muscarinic receptors have Gi proteins that lead to the inhibition of adenyl cyclase leading to decreased cAMP as well as the activation of potassium channels. They also inhibit Calcium channel and cause inhibition and hyperpolarization.

Front 94

What type of receptor is atropine sensitive?

Back 94

Post-ganglionic muscarinic and Ganglionic Muscarinic

Front 95

What type of receptor is hexamehtonium sensitive?

Back 95

Ganglionic Nicotine I receptors

Front 96

What type of receptor is Curare sensitive?

Back 96

Neuromuscular Nicotinic II

Front 97

What is needed for Ach synthesis?
Where does each component come from?

Back 97

Choline acetyl transferase from the soma, acetyl-coA from miyochondria and choline from plasma transporters.

Front 98

What two sites does Ach bind to acetylcholinesterase?

Back 98

An anionic site and an ester site

Front 99

What is the rate limiting step of the synthesis of nerepinephrine?

Back 99

The first step utilizing tyrosine hydroxylase.

Front 100

alpha 1 receptors are?

Back 100

g protein coupled receptors that activate phospholipase C

Front 101

Beta 1, beta 2 and alpha 2 receptors are?

Back 101

g proetin coupled receptors that either activate(beta 1 and beta 2) or inhibit(alpha 2) adenyl cyclase.