Pharm Exam #1

Front 1

Pharmacodynamics

Back 1

is the study of the biologic activity that a drug has on a living system. It includes a study of the mechanisms of action of the drug and the exact processes that are affected by it.

Front 2

Pharmacokinetics

Back 2

deals with the magnitude and time course of drug effect, and it attempts to explain these aspects of drug action through a consideration of dosage and the absorption, distribution, and fate of chemicals in living systems.

Front 3

Bioavailabitity

Back 3

indicate the fractional extent to which a dose of drug reaches its site of action (how much blood is available in the blood for the receptors)

Front 4

Enteral

Back 4

oral, sublingual, rectal

Front 5

Parenteral

Back 5

o Intravenous, Subcutaneous,
o Intramuscular, Intra-Arterial, Intrathecal

Front 6

Topical

Back 6

o Transdermal, Mucous membranes, Eye, Ear

Front 7

Advantages of Oral Ingestion

Back 7

o Safest, most convenient, most economical
o Daily administrations and / or for a long period of time
o Auto-administration

Front 8

Which is safest way of administering a drug?

Back 8

Enteral --> ORALLY

Front 9

Disadvantages of Oral Ingestion

Back 9

- Disadvantages
o Limited absorption - physical characteristics
o Emesis - irritation of the GI mucosa
o Destruction - digestive enzymes or low gastric pH
o Presence of food and other drugs
o Cooperation on the part of the patient
o Metabolization - Enzymes of the intestinal flora, mucosa, or liver
o First-pass metabolism

Front 10

First-Pass Metabolism

Back 10

lose a lot in hepatic portal system BEFORE the drug is even able to find the receptor --> esp. pts. with liver problems

Front 11

Advantages of Rectal Ingestion

Back 11

o less hepatic first-pass metabolism (50% less)
o do it when patient is unconscious or vomiting

Front 12

Disadvantages of Rectal Ingestion

Back 12

o Absorption - irregular and incomplete
o Irritation of the rectal mucosa
o Diarrhea

Front 13

Which method has the FASTEST ABSORPTION?

Back 13

Parenteral - Intramuscular

Front 14

Advantages of Parental Intramuscular Absorption

Back 14

o Rapid absorption (FASTEST ABSORPTION)
o Possible Slow, constant absorption -by repository vehicles

Front 15

Disadvantages of Parental Intramuscular Absorption

Back 15

o Big volumes
o Irritations, accidents
o Paraesthesia, accidental intravenous
o Cost; Trained people

Front 16

Advantages of Parental Intervenous Absorption

Back 16

o Bioavailability - complete and rapid (100% of the drug reaches the blood !!!)
o Avoid absorption (no absorption… as you are directly placing drug into the blood)
o Drug delivery - controlled, accurate and immediate
o Big volumes; irritating solutions

Front 17

In which method is there NO ABSORPTION?

Back 17

Parental Intravenous --> you are placing it directly into the blood

Front 18

Advantages of Inhalation

Back 18

o Almost instantaneous absorption
o Avoidance of hepatic first-pass loss
o Pulmonary disease - local application

Front 19

Disadvantages of Inhalation

Back 19

o Local and systemic reactions to allergens

Front 20

Advantages of Topical Application

Back 20

o Rapid absorbance in mucosa
o Local and systemic effects

Front 21

Disadvantages of Topical Application

Back 21

o Intact skin - lipid barrier
o Dependent on the blood flow
o Unwanted systemic side effects

Front 22

The cell membrane is a bilayer of amphipathic lipids with their hydrocarbon chains oriented inward to the center of the bilayer to form a continuous _______ phase and theirs _______heads oriented outward

Back 22

hydrophobic heads inward
hydrophillic heads outward

Therefore.... in order to reach, you must cross the hydrophillic heads... but to leave the cell membrane, need to encounter hydrophobic heads

Front 23

Oil/water partition coefficient

Back 23

- drug ususally has a # that will tell you whether it is more lipophilic or hydrophilic
- “1” means there is an equal amount of hydrophilic and hydrophobic which is IDEAL so it can cross
- A HIGH coefficient means it is lipophilic  so it is harder for the drug to reach the cell membrane … HOWEVER , it is easier to cross the membrane
- Lipophilic drugs are good drugs to cross the blood-brain barrier

Front 24

Passive diffusion

Back 24

- Concentration gradient across the membrane
- Lipid-water partition coefficient of the drug
- Surface area exposed to the drug

Front 25

Active transport

Back 25

- Requirement for energy
- Movement against an electrochemical gradient
- Saturability, selectivity, and competitive inhibition by co-transported compounds

Front 26

Facilitated diffusion

Back 26

Carrier-mediated transport process in which there is no input of energy

Front 27

What form of the drug will be able to cross the barrier?

Back 27

ONLY the non-charged form

Front 28

Will an acidic drug be absorbed faster in the stomach (acidic) or intestines (basic) ?

Back 28

Stomach

**** However…. The time in the stomach will be shorter b/c NOT meant to absorb… just meant to breakdown.
Therefore…. RATE is higher in the stomach, but MORE is absorbed in the intestines, just much slower for acidic drugs

Front 29

Distribution of a Drug is Dependent Upon

Back 29

- Drug’s physicochemical properties
- Cardiac output and regional blood flow
- Capillary permeability
- Tissue volume

Front 30

Where are most basic drugs trapped?

Back 30

in the STOMACH
--> even stuff like cocaine, even if inhaled

Front 31

Plasma Proteins

Back 31

Some drugs .. For example… have like 30% bound to plasma protein (especially albumin) … so the other 70% is free in the blood
So the plasma protein can be considered a reservoir
- This binding is capacity limited because the number of binding sites is finite.
- Drugs differ tremendously in their affinity for plasma proteins; the percentage of binding of individual agents ranges from 0% to 100%.

Front 32

How would you transfer something across the blood-brain barrier?

Back 32

- Most common way of transport in CNS is via transporters
- Higher the lipophilic… higher the chance to reach the CNS
- Meningeal and encephalic inflammation increase permeability

Front 33

Placental Transfer of Drugs

Back 33

lipid-soluble drugs pass thru the placenta

--> but fetus exposed to ALL drugs taken by mother

Front 34

What types of compounds are most easily removed from the body ?

Back 34

- Polar compounds will not be reabsorbed…. Will exit the body

- Lipid soluble NEED to be metabolized or will go back

Front 35

A major factor influencing the reabsorption of weak electrolytes from renal tubular fluid is:

Back 35

the pH
--> Depending on the rate of H+ secretion, the urinary pH may vary from 4.5 to 8.0.

Front 36

Weak acids such as aspirin and phenobarbital are reabsorbed more effectively under _________; the reverse is true for weak bases such as amphetamine and ephedrine.

Back 36

acidic conditions

Front 37

A common strategy in the face of aspirin toxicity is....

Back 37

A common strategy in the face of aspirin toxicity is to promote salicylate elimination through alkalization of the urine by the systemic administration of sodium bicarbonate.

Front 38

Where do we want the drug.. intracellular or extracellular?

Back 38

Intracellular b/c we wanna absorb the drug

Front 39

When we want to eliminate… where do we want the drug?

Back 39

Extracellular  so it can go off in the urine

Front 40

Where are acidic drugs eliminated?

Back 40

In the BASIC urine

Front 41

Biliary Excretion

Back 41

AKA "fecal" excretion

-Substances excreted in the feces
-Un-absorbed orally ingested drugs
-Drug metabolites excreted in the bile
-Drug metabolites secreted directly into the intestinal tract and non-reabsorbed
-Substances with high molecular weight (higher than 500)

Front 42

Enterohepatic recycling

Back 42

Reabsorption of molecules excreted through the bile can occur, such as with the laxative phenolphthalein.
Such enterohepatic recycling can prolong the duration of action and may continue ad infinitum until the system is interrupted (e.g., by metabolism, curtailment of bile flow, or ingestion of a drug chelator).

Front 43

First-pass metabolism

Back 43

The first-pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. It is the fraction of lost drug during the process of absorption which is generally related to the liver and gut wall.

Notable drugs that experience a significant first-pass effect are imipramine, morphine, propranolol, buprenorphine, diazepam, midazolam, demerol, cimetidine, and lidocaine.

Front 44

Which type of drug receptor is irreversible?

Back 44

Covalent

Front 45

Affinity

Back 45

Degree of attraction between the drug and its receptor

Front 46

Potency

Back 46

Amount of drug (mg) needed to produce an effect

--> Potency is usually a matter of little importance because a drug that is very potent regarding its desirable effects is often equally potent regarding undesirable effects. In the intact animal (or patient), potency is influenced by the drug's ability to reach the receptor (determined by the rate of absorption and the patterns of distribution and elimination) in addition to the agent's intrinsic activity and receptor affinity.

Front 47

Intrinsic Activity

Back 47

The ability to produce an effect (once the drug is bound to its receptor)

-Has nothing to do with affinity
-Basically… whether or not there is any effect when bound to the receptor
(i.e. Beta Blockers  has no intrinsic activity)

Front 48

Examples of Cytoplasmic 2nd Messengers

Back 48

cyclic AMP, cyclic GMP, cyclic ADP-ribose, Ca2+, inositol phosphates, diacylglycerol, nitric oxide.

Front 49

Cytoplasmic 2nd Messengers

Back 49

- Enzyme or transport protein that creates, moves, or degrades a small metabolite or ion
- They can diffuse in the proximity of their binding sites and convey information to a variety of targets, which can respond simultaneously to the output of a single receptor binding a single agonist molecule

Front 50

G-Proteins

Back 50

G proteins are heterotrimers consisting of α, β, and γ subunits. After receptor activation, guanosine diphosphate attached to the α subunit is replaced by guanosine triphosphate, and the heterotrimer splits into the α monomer and βγ dimer.

Many, but not all, of the observed cellular actions are caused by the α

Front 51

Agonists

Back 51

Bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds

Front 52

Antagonists

Back 52

Bind to receptors without regulatory effect, but their binding blocks the binding of the endogenous agonist


(Antagonist is NOT THE OPPOSITE  but rather, blocks)

Front 53

Partial Agonists

Back 53

Partly effective as agonists, no matter the amount employed

Front 54

Inverse Agonists

Back 54

Stabilize the receptor in its inactive conformation
(Clinically….. There really are no such Inverse Agonists)

Front 55

Receptor Occupancy Theory

Back 55

- There is a certain # of receptors that need to be bound for a certain effect

- Clark attempted in the 1920s to quantify drug effects through application of the law of mass action. Out of his efforts and the contributions of others emerged the occupation theory of drug action.
T- he occupation theory holds that the magnitude of a pharmacologic response elicited by a drug that reversibly combines with its receptor is directly proportional to the number (or fraction) of receptors occupied by the drug.

Front 56

EC50

Back 56

concentration of drug that produces 50% of the maximal response

Front 57

competitive antagonists

Back 57

- Drugs that bind reversibly to a receptor at the same site as the agonist but have an intrinsic activity of zero (no receptor activation; a = 0) are competitive antagonists.
- By making receptors less available for agonist binding, a competitive antagonist depresses the response to a given dose or concentration of agonist.
-The result is a parallel shift to the right of the agonist dose-response curve.
- The most important aspect of this type of inhibition is that it is completely surmountable by a sufficiently high dose of agonist.
- As in enzymology, the presence of a competitive antagonist produces an apparent reduction in the affinity of an agonist for its receptor.

Front 58

Non-competitive agonists

Back 58

- The noncompetitive blockade is insurmountable in that the ceiling effect of an agonist can never be reattained, regardless of the dose administered.
- A noncompetitive antagonist may decrease the effective number of receptors by irreversibly binding to the receptor site or binding with such affinity that the agonist cannot successfully compete with it for binding.
- The result is a downward displacement of the agonist log dose-response curve.

Front 59

Allosteric Antagonist

Back 59

Drug produces effect by binding a site on the receptor distinct from that of the primary agonist and thereby changing the affinity of the receptor for the agonist

--> resembles non-competitive antagonism

Front 60

Action of drugs not mediated by receptors

Back 60

- Agents that are chemically reactive (i.e. antacids)
- Agents that act according to non-pharmacological colligative properties (Cholesterol-binding agents - orally)
- Drugs that are structural analogs of normal biological chemicals - incorporated into cellular components and thereby alter their function
(analogs of pyrimidines and purines)

Front 61

In humans, the ______ represents the major pathway for drug excretion.

Back 61

kidney

Front 62

xenobiotics

Back 62

Usually: lipophilic chemicals that in the absence of metabolism would not be efficiently eliminated

(environmental pollution, food additives, cosmetic products, agrochemicals, processed foods and drugs)

Front 63

Most drugs are metabolized in the

Back 63

liver

Front 64

The most common way to metabolize a drug is

Back 64

during distribution

Front 65

Metabolism during absorption....

Back 65

One of the most important things that can occur during oral administration is the first-pass effect
--> BEFORE being distributed, the drug is metabolized
This means we will have LESS of the drug reaching the blood… and the receptors (DECREASE IN BIOAVAILABILITY)
--> Therefore, must take MORE of the drug to get same effect

Front 66

What methods don't really undergo 1st pass metabolism?

Back 66

sublingual & rectal routes

Front 67

For hepatic metabolism... most of the reactions are caused by _____ ...... and the reaction types are mostly ______

Back 67

enzymes / oxidation

Front 68

Hepatocyte

Back 68

extensive network of smooth endoplasmic reticulum that catalyzes the metabolism of a variety of endogenous chemicals

Front 69

Phase 1 of metabolism is responsible for

Back 69

inactivation of the drug
(does LITTLE to affect the water solubility o the drug)

--> cytochrome P450 is the most important enzyme in phase 1

Front 70

Phase 2 of metabolism is responsible for

Back 70

increase water solubility & mol. weight --> drugs get eliminated more easily

facilitate the elimination of drugs and the inactivation of the electrophilic and potentially toxic metabolites produced by oxidation

Front 71

What is the most important enzyme in phase 1

Back 71

cytochrome P450 (catalyzes oxidation of the drug to be eliminated)

Front 72

oxidation results in compounds that are:

Back 72

- more polar
- relatively more hydrophilic
- LESS LIKELY to penetrate cells and bind to tissue elements

Front 73

common things that affect cytochrome p450

Back 73

- Grapefruit juice inhibits cytochrome P450  so unable to metabolize the drug

- char-grilled meat INDUCES  so the drug works better and is better able to metabolize

Front 74

CYP34A

Back 74

- CYP34A is responsible for 28% of the liver… but is responsible for the metabolism of ~ 60% of the drugs

Front 75

reduction reactions

Back 75

- limited to molecules with nitro or carbonyl groups or azo linkages.
- most reductions appear to result primarily from the action of enteric bacteria
- when reduction occurs at one site in a molecule, oxidation usually takes place elsewhere, and the final product is more polar despite the initial addition on hydrogen atoms

Front 76

hydrolysis reactions

Back 76

occasionally depends on microsomal enzymes
(not too important)

Front 77

Dehalogenation rxns

Back 77

compounds such as: chlorophenothane and some volatile general anesthetics (halothane, sevoflurane) - dehalogenated by microsomal enzymes
may result in the formation of potentially toxic metabolites
(not too important)

Front 78

Glucuronide conjugation

Back 78

- only phase 2 reaction catalyzed by microsomal enzymes (glucuronosyltransferases)
- the conjugate is usually excreted by active secretion, into the bile or urine
- is a quantitatively significant metabolic pathway for many drugs and their metabolites
--> morphine: primary mode of metabolism
(- Since phase 2, responsible for making drugs MORE hydro-soluble so it will NOT be reabsorbed)

Front 79

difference between 1st pass metabolism and enterohepatic cycle

Back 79

1st pass metabolism  in the beginning when you LOSE drug (happens during absorption)

Enterohepatic cycle  at the end.. You actually GAIN drug (happens during metabolism)

**enterohepatic cycle is the reason why you can only take birth control once a day

Front 80

factors that might interfere with the metabolism

Back 80

- liver condition
- enzymatic inhibition/induction
- genetic factors
- age
- pathology
- cardiac insufficiency
- diet and environmental factors

Front 81

Cardiac insufficiency

Back 81

decrease the cardiac flow --> therefore decrease the liver clearance

If you have less blood, or the blood is moving slower ---> would take longer for the drug to reach the liver and be metabolized (which means you have too much active drug)

Front 82

Prodrugs

Back 82

Drugs that become active after metabolism

may change:
- Effect
- Toxicity
- Pharmacokinetics – absorption, distribution

Front 83

Clearance

Back 83

body’s efficiency in eliminating drug

Amount of drug removed by the kidney per unit of time
CL = rate of elimination / concentration of drug

Front 84

Volume of distribution

Back 84

apparent space in the body available to contain the drug

**If drug has a high volume of distribution… this means that that the drug might be very liposoluble and would be found in the fat, NOT in the blood

Front 85

Elimination half-life

Back 85

rate of removal of drug from the body

Front 86

Bioavailability

Back 86

fraction of drug absorbed as such into the systemic circulation

Front 87

If drug has a high volume of distribution… this means that that the drug might be very _____and would be found in the ______

Back 87

If drug has a high volume of distribution… this means that that the drug might be very liposoluble and would be found in the fat, NOT in the blood

Front 88

Volume of distribution may vary widely depending on:

Back 88

- The relative degrees of binding to high-affinity receptor sites
- Tissue proteins
- The partition coefficient of the drug in fat
- Accumulation in poorly perfused tissues

Front 89

If you have a drug that has a very high MW or bound to a plasma protein, most of the drug would be in the blood  volume of distribution would be ____

Back 89

LOW

Front 90

One-compartment model

Back 90

Body - single homogeneous compartment
- Does not describe the entire time course of the plasma concentration
- Sufficient to apply to most clinical situations for most drugs
(Its almost like the body is just the blood)

Front 91

Multi-compartment model

Back 91

- For many drugs, the simple single-compartment model does not adequately describe the early time course of plasma concentration.
- Large discrepancies are particularly likely to be observed when a relatively lipophilic drug is given intravenously, as in the use of CNS depressants for conscious sedation.
- In that situation, the assumption that the body acts as a single compartment does not hold, and one or more additional drug reservoirs must be postulated.

 --> our body is actually a multi-compartment system

Front 92

HALF-LIFE

Back 92

Time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%

** Halflife is dependent on clearance
If you have a pt. who has a disease that increases clearance ...half-life will be lower

Front 93

MEC

Back 93

minimal effective concentration for the desired result

Front 94

- Oral administration ____________ bioavailability of the drug

Back 94

decreases

Front 95

Steady State

Back 95

- Attained after approximately four half-lives
- Time to steady state independent on the dosage(constant dose).

- Steady state occurs when the amount of drug administered (in a given time period) is equal to the amount of drug eliminated in that same period.
-At steady state the plasma concentrations of the drug (Css p) at any time during any dosing interval, as well as the peak and trough, are similar.

Front 96

Time to steady state is _____ of the dosage(constant dose).

Back 96

independent

Front 97

Loading dose

Back 97

- You don’t increase the dose in every dose… JUST the beginning, and then you give maintenance dose
- When you give a loading dose  reach steady state MUCH FASTER

Front 98

If the you give the same amount of drug to a patient who is deficient in plasma proteins in the drug, will :

Back 98

have much more free drug in the blood b/c not enough plasma proteins to bind to

Front 99

Hypoalbuminemia

Back 99

Less drug binding to albumen (plasma protein)  will increase amount of free drug !!!
(Reduce the extent of binding of acidic and neutral drugs)

Front 100

Phenytoin

Back 100

- anticonvulsant drug
- more than 90% bound to plasma protein

Front 101

How would you adjust to Hypoalbuminemia?

Back 101

1) Adjust the dose (Lower dose)
2) Shorter dosing intervals

Therapeutic plasma levels

Front 102

Adverse Effects of Impaired Hepatic Clearance of Drugs

Back 102

- decrease the metabolism of some drugs (Less blood going to the liver = less metabolism)
- increase the oral bioavailability of drugs
- marked increase - drugs that normally have high first-pass hepatic clearance

**First pass effect--> you will lose some of the drug b/c will be metabolized by the liver
So if out of the original 100, the liver normally takes out 30, so you would have 70 in the blood… if the liver isnt functioning properly, and only takes out 20, you would have 80 remaining in the blood

Front 103

How does liver disfunction relate to first pass effect?

Back 103

First pass effect --> you will lose some of the drug b/c will be metabolized by the liver
- So if out of the original 100, the liver normally takes out 30, so you would have 70 in the blood… if the liver isnt functioning properly, and only takes out 20, you would have 80 remaining in the blood

Therefore, if drugs have high first-pass hepatic clearance, you probably need to modify / stop them

Front 104

How can you see how much the liver is metabolizing?

Back 104

- There is NO quantitative way to see how much the liver is metabolizing
- So what you have to do… is titrate the dose.. Start small and increase and see if a pt responds (usually thru IV not oral)  ideally measure plasma concentration in hospital

Front 105

Adverse Effects of impaired renal clearance of drugs

Back 105

elevated levels of drug

- Renal system is responsible for most elimination of drug via urine
- If not eliminated, still have drugs in body, some may be active some inactive…
- One way to monitor this is amount of creatinine in the urine --> compare with normal value

Front 106

Drugs to be considered for pt. with Impaired HEPATIC Clearance of Drugs

Back 106

- morphine
- meperidine
- midazolam
- nifedipine

Front 107

Drugs to be considered for pt. with Impaired RENAL Clearance of Drugs

Back 107

- Vancomycin
- Aminoglycoside antibiotics
- Digoxin

Front 108

What should be employed when renal clearance of a drug is diminished

Back 108

- DECREASE the dose
- INCREASE the interval between doses

Front 109

how would you estimate glomerular filtration rate ?

Back 109

- Iothalamate clearance method
- Creatinine clearance

Front 110

Optimal therapeutic decisions

Back 110

Based on the evaluation of the individual patient in concert with assessment of the evidence for efficacy and safety of the treatment under consideration

Front 111

Total body water for infants are __%, adults are__%

Back 111

Total body water for infants are 80%, adults are 50-60%

Front 112

Gastric pH of newborn

Back 112

Gastric pH = 7-8 at birth and then falls to < 3 during the first 1-2 h of life

Front 113

hepatic enzymes in children

Back 113

Hepatic enzymes don’t work very well in children  don’t even HAVE cytochrome P450

Front 114

young kidney

Back 114

- Young kidney is less competent to excrete drugs

Front 115

Pharmacokinetic changes in the elderly population

Back 115

Results from changes in body composition and the function of drug-eliminating organ.

Front 116

changes in the elderly

Back 116

- Clearance of many drugs - reduced
- Renal function - decline - 50% of that in young adults
- Hepatic blood flow and drug metabolism - reduced
- Elimination half-lives of drugs - increased (Elimination for half lives is increased because takes much longer for drug to leave the body)

Front 117

receptor sensitivity in the eldery

Back 117

- Physiological changes and loss of homeostatic resilience - increased sensitivity to unwanted effects of drugs
- More illnesses
- Consume a disproportionate share of prescription and over-the-counter drugs + age-related changes = serious adverse effects and drug interactions.

Front 118

malformation of the unborn child

Back 118

1st trimester

Front 119

functional disturbances in growth and maturation (when in development of unborn child?)

Back 119

after 1st trimester

Front 120

problems during birth

Back 120

will affect the neonate (newly born child)

Front 121

Parts of the Central Nervous System

Back 121

- brain
- spinal cord

Front 122

Parts of the Peripheral Nervous System

Back 122

- Somatic Nervous System
- Autonomic Nervous System
- Sympathetic
- Parasympathetic
- Enteric

Front 123

main function of the autonomic nervous system

Back 123

Maintenance and control of an stable internal environment (homeostasis), as an answer for fluctuations in the internal conditions and variations induced by external stimulations.

Front 124

sympathetic activation of the heart

Back 124

increase the heart rate, contractility and conduction velocity

Front 125

sympathetic activation of the lung

Back 125

increase respiratory frequency

Front 126

sympathetic activation of blood vessels

Back 126

skin and mucosa = constriction
Skeletal muscles = dilation

Front 127

sympathetic activation of the eyes

Back 127

- Pupil dilation (mydriasis);
- relaxation of the ciliary muscle for far vision

Front 128

mydriasis

Back 128

Pupil dilation

Front 129

sympathetic activation of the adrenal medulla

Back 129

secretion of Epinephrine and Norepinephrine

Front 130

miosis

Back 130

pupil constriction

Front 131

parasympathetic activation of the eyes

Back 131

- Pupil constriction (miosis)
- Lens accommodation to a short focal distance

Front 132

parasympathetic activation of blood vessels

Back 132

- Vasoconstriction of the leg muscles
- Vasodilatation of the viscera (internal organs)

Front 133

Pre-ganglionic neuron

Back 133

- cell body in brain or spinal cord
- axon is myelinated type B fiber that extends to autonomic ganglion

Front 134

Post-ganglionic neuron

Back 134

- cell body lies outside the CNS in an autonomic ganglion
- axon is unmyelinated type C fiber that terminates in a visceral effector

Front 135

Sympathetic Fibers

Back 135

- pre-ganglionic fiber is SHORT / post is LONG
- Some fibers go from the spinal cord to the adrenal medulla, activating it and causing a discharge of epinephrine into the blood

Front 136

Parasympathetic Fibers

Back 136

- Preganglionic fiber is long
- Post ganglionic is shorter (because already close to target organs)

Front 137

where would you find acetylcholine ? (symp or para?)

Back 137

BOTH

In Sympathetic… Ach is usually pre-ganglionic
In Parasympathetic, ONLY have Acetylcholine

Front 138

where would you find norepinephrine? (symp or para?)

Back 138

Norepinephrine ONLY in sympathetic

Front 139

in stressful situations, what neurotransmitter is released?

Back 139

norepinephrine (which is present ONLY in sympathetic response)

Front 140

cholinergic vs. adrenergic neurons

Back 140

Classified as either cholinergic or adrenergic neurons based upon the neurotransmitter released

Adrenegic --> adrenaline (NE)
Choligernic --> Acetylcholine

Front 141

adrenergic receptors

Back 141

a class of G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline).

(G- proteins need 2nd messengers, so we need less drug molecules binding to those receptors to actually have many cell responses)

Front 142

The main types of adrenergic receptors are:

Back 142

alpha and beta receptors

Alpha1 and Beta1 receptors produce excitation
Alpha2 and Beta2 receptors cause inhibition
Beta3 receptors (brown fat) increase thermogenesis

Front 143

compare the effects triggered by adrenergic neurons compared to those triggered by cholinergic neurons

Back 143

Effects triggered by adrenergic neurons typically are longer lasting than those triggered by cholinergic neurons..

Front 144

Alpha1 and Beta1 receptors produce _______

Back 144

Alpha1 and Beta1 receptors produce excitation
Alpha2 and Beta2 receptors cause inhibition
Beta3 receptors (brown fat) increase thermogenesis

Front 145

Alpha2 and Beta2 receptors cause __________

Back 145

Alpha1 and Beta1 receptors produce excitation
Alpha2 and Beta2 receptors cause inhibition
Beta3 receptors (brown fat) increase thermogenesis

Front 146

Beta3 receptors increase ___________

Back 146

Alpha1 and Beta1 receptors produce excitation
Alpha2 and Beta2 receptors cause inhibition
Beta3 receptors (brown fat) increase thermogenesis

Front 147

What is the MOST IMPORTANT way to stop the effect of NE that’s in the synaptic cleft

Back 147

MOST IMPORTANT way to stop the effect of NE that’s in the synaptic cleft is through RE-UPTAKE

- NE will go back to the neuron, where it may be stored in vesicles again or destroyed by mono-amino oxidase (MAO), which is an intra-neuronal enzyme that destroys NE
- NE in the synaptic cleft can also go thru uptake by the effector organ and go into cells or blood; can be destroyed by an enzyme called catechol-O-methyl transferase (COMT)…It is widely distributed in many tissues and is the principal extraneuronal enzyme involved with the metabolic inactivation of norepinephrine.

Front 148

MAO

Back 148

During re-uptake, NE will go back to the neuron, where it may be stored in vesicles again or destroyed by mono-amino oxidase (MAO), which is an intra-neuronal enzyme that destroys NE

Front 149

COMT

Back 149

One method of reuptake is...NE in the synaptic cleft can also go thru uptake by the effector organ and go into cells or blood; can be destroyed by an enzyme called catechol-O-methyl transferase (COMT)…It is widely distributed in many tissues and is the principal extraneuronal enzyme involved with the metabolic inactivation of norepinephrine.

Front 150

receptors for epinephrine

Back 150

alpha-1
alpha2
beta-1
beta-2

Epi drug will cause BOTH constriction in the skin/mucosa AND relaxation in the skeletal muscles

Front 151

receptors for norepinephrine

Back 151

alpha-1
alpha-2
beta-1

NE will ONLY cause constriction of the skin/mucosa (NO EFFECT ON RELAXATION OF SKELETAL MUSCLES)

Front 152

alpha-1 receptor

Back 152

constricts the skin & mucosa

Front 153

beta-2 receptor

Back 153

dilates skeletal muscles

Front 154

effects of epi vs. NE

Back 154

NE does NOT bind to beta-2

- Epi drug will cause BOTH constriction in the skin/mucosa AND relaxation in the skeletal muscles
- NE will ONLY cause constriction of the skin/mucosa (NO EFFECT ON RELAXATION OF SKELETAL MUSCLES)

Front 155

Back 155

Front 156

Effects of Epinephrine

Back 156

Epinephrine affects alpha and beta receptors

- stimulate heart (B-1)
- relax lung (B-2)
- constrict skin & muscosa vessels (A-1 & A-2)
- Relax skeletal muscles (B-2 & A-1)

Front 157

Effects of Norepinephrine

Back 157

norepinephrine affects alpha and beta-1 reeptors

- stimulate heart (B-1)
- NO EFFECT on lung (B-2)
- constrict skin & muscosa vessels (A-1 & A-2)
- CONSTRICT skeletal muscles (B-2 & A-1)

Front 158

Effects of Isopre

Back 158

isopre affect beta receptors

- stimulate heart (B-1)
- relax lung (B-2)
- NO EFFECT on skin & muscosa vessels (A-1 & A-2)
- Relax skeletal muscles (B-2 & A-1)

Front 159

Muscarinic receptors

Back 159

- acetylcholine receptors that form G protein-receptor complexes in the cell membranes of certain neurons and other cells.
- They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system.

Front 160

Cholinergic neurons release

Back 160

Cholinergic neurons release acetylcholine

- all pre-ganglionic neurons
- all parasympathetic post-ganglionic neurons
- few sympathetic post-ganglionic neurons (to most sweat glands)

(Excitation or inhibition depending upon receptor subtype and organ involved)

Front 161

compare uptake of andergenic vs. muscarinic/nicotinic receptors

Back 161

adrenergic receptors have reuptake

nicotinic/muscarinic DO NOT (or very little)

Front 162

Acetylcholine crosses the junctional cleft and attaches _______to the postjunctional receptor, which exists in close proximity to a highly specific enzyme, ___________. Acetylcholine becomes bound to the enzyme at two primary sites and is hydrolyzed to _____ and ______ at such a rapid rate that the nerve can respond to another stimulus milliseconds later.

Back 162

Acetylcholine crosses the junctional cleft and attaches reversibly to the postjunctional receptor, which exists in close proximity to a highly specific enzyme, acetylcholinesterase (AChE). Acetylcholine becomes bound to the enzyme at two primary sites and is hydrolyzed to choline and acetate at such a rapid rate that the nerve can respond to another stimulus milliseconds later.

(Acetylcholine is also removed from the junctional cleft by the simple process of diffusion.)

Front 163

Even in the total absence of AChE activity, the action of acetylcholine can be terminated quickly by pseudocholinesterase, a nonspecific plasma enzyme also known as ___________, which is found in many tissues, including blood.

Back 163

butyrocholinesterase

Front 164

butyrocholinesterase

Back 164

Even in the total absence of AChE activity, the action of acetylcholine can be terminated quickly by pseudocholinesterase, a nonspecific plasma enzyme also known as butyrocholinesterase, which is found in many tissues, including blood.

Front 165

muscarinic receptors

Back 165

Front 166

nicotinic receptors

Back 166

- Form ligand-gated ion channels
- Do not operate with a second messenger
- Forms a pentameric structure consisting of homomeric a and b subunits.
- In humans, eight a and three b subunits have been cloned.

Front 167

Nicotinic receptors usually cause contraction of the ________ and secretion of ___________.

Back 167

Nicotinic receptors usually cause contraction of the skeletal muscles and secretion of catecholamines (Epi or NE) in the adrenal medulla

Front 168

Back 168

Front 169

Sympathomimetics

Back 169

Sympathomimetics = mimics the sympathetic response

Front 170

Sympatholytics

Back 170

Sympatholytics = antagonists; will have an opposite effect of the sympathetic response

Front 171

Parasympathomimetics

Back 171

Parasympathomimetics = mimic the parasympathetic response

Front 172

Parasympatholytics

Back 172

Parasympatholytics = antagonists; have opposite effects of the parasympathetic response

Front 173

Dominance by the sympathetic system is caused by ____________

Back 173

Dominance by the sympathetic system is caused by physical or emotional stress --

“E situations”
- emergency
- embarrassment
- excitement
- exercise

Front 174

flight or fight response

Back 174

- dilation of pupils
- increase of heart rate, force of contraction & BP
- decrease in blood flow to nonessential organs
- increase in blood flow to skeletal & cardiac muscle
- airways dilate & respiratory rate increases
- blood glucose level increase

Front 175

why are sympathetic responses long-lasting?

Back 175

Long lasting due to lingering of NE in synaptic gap and release of norepinephrine by the adrenal gland

Front 176

rest-and-digest

Back 176

parasympathetic responses

- Mechanisms that help conserve and restore body energy during times of rest
- Normally dominate over sympathetic impulses

Front 177

SLUDD type responses & 3 decreases

Back 177

associated with parasympatheric responses

salivation, lacrimation, urination, digestion & defecation

3 “decreases” =
1) decreased HR
2) diameter of airways
3) diameter of pupil

Front 178

muscarinic receptors --> nerves

Back 178

receptor = M1, M2

response = DECREASE ganglionic transmission

Front 179

muscarinic receptors --> Heart

Back 179

receptor: M2, M3

Response: vasodilation
< cardiac rate
< rate of conduction in the specialized tissues of the SA and AV nodes
< force of cardiac contraction

Front 180

muscarinic receptors --> Smooth Muscles

Back 180

Receptors: M2, M3

Response: > GIT tone & motility
> amplitude of contraction
> secretory activity
Detrusor - contraction
> voiding pressure
> ureter peristalsis

Front 181

muscarinic receptors --> Glands

Back 181

Receptors: M1, M3

Responses: INCREASE secretions

Front 182

muscarinic receptors --> CNS

Back 182

Receptors: M1, M2, M3. M4, M5

Response: > cognitive function
> seizure activity
< dopamine release
M4 and M5 - facilitate dopamine release

Front 183

nicotonic receptors --> skeletal muscular junction

Back 183

Receptor: Nm

Membrane Response: skeletal muscle contraction

Agonists: Ach, Nicotine, Succinychloline

Front 184

nicotonic receptors --> autonomic ganglia/ adrenal medulla

Back 184

Receptor: Nn

Membrane Response: firming of the post-ganglion neuron
- secretion of catecholamines

Agonists: ACh, nicotine, epibatidine

Front 185

Adrenergic Agonists

Back 185

Drugs that mimic or enhance the actions of norepinephrine or epinephrine in adrenergic neurotransmission

Effect - usually similar to the sympathetic nervous system stimulation

Front 186

What are the possible fates of norepinephrine by ending the synapse?

Back 186

1) negative feedback given to the neuron, which tells body to stop the release of NE into the synaptic cleft
2) re-uptake to the neuron.. where it will be destroyed by MAO ... or restored in vesicles
3) taken up by effector organ and COMT breaks down NE

Front 187

Sympathomimetics are much related to ______

Back 187

Sympathomimetics are much related to BP, heart and lungs (main uses for the drug)

Front 188

main actions of aympathomimetics

Back 188

- Stimulates a / b receptors
- Increases the NE release with or without direct stimulation

Front 189

alpha 1 drugs

Back 189

- Eyes – mydriasis, or if blocked, can cause miosis
- BV – skin and mucosal BV. Drug binding causes constriction
- Bladder – changes the muscle and sphincters

Front 190

alpha 2 drugs

Back 190

- Causes relaxation/dilation of vessels
- Found in presynaptic terminals to inhibit NE pre-neuronally
- Found in effector organs, then causes dilation of vessels

Front 191

what are the main receptors for skin and mucosa?

Back 191

alpha-1

Front 192

beta 1 drugs

Back 192

Primarily in the heart (stimulates)

Front 193

Beta-2

Back 193

- Mostly in the lung and cause broncodialtion / relaxation
- lDilation of skeletal muscle vessels

Front 194

classification of adrenergic agonists

Back 194

- receptor affinity
- receptor localization
- mechanism of action

Front 195

classifying mechanism of action of adrenergic agonists

Back 195

Direct-acting --> directly binds to receptor
Indirect-acting --> no binding but somehow increases the endogenous E or NE
Mix-acting --> does both, binds to receptor and releases NE

Front 196

chart of classifying adrenergic agonists

Back 196

Front 197

direct-acting adrenergic agonists

Back 197

Drugs acting directly on the adrenergic receptors (agonists)
response: similar to the sympathetic stimulation
(SAME EFFECT AS THE ENDOGENOUS COMPOUND IN THE BODY)

Front 198

We use a direct-acting adrenergic agonist as an anesthetic in dentistry... what do we want from that?

Back 198

We want to decrease the absorption of lidocaine (You want to work with the longer period of time)

Front 199

What are the IMPORTANT direct-action adrenergic agonist drugs?

Back 199

P.E.N.I.L.

Propranolol --> beta-1 & beta-2
Epinephrine --> alpha-1, alpha-2, beta-1, beta-2
Norepinephrine --> alpha-1, alpha-2, beta-1
Isoprenaline --> beta-1 & beta-2
Levonordefrin --> alpha-1 alpha-2, beta-1

Front 200

vascular effects of norepinephrine

Back 200

Local injection: vasoconstriction
Intravascular injection: Constriction of ALL vessels

Increases - peripheral resistance

Increases BP - in physiological doses
Baroreflex - slows the heart.

Front 201

vascular effects of a local injection of epinephrine

Back 201

vasoconstriction

Front 202

vascular effects of a local injection of norepinephrine

Back 202

vasoconstriction

Front 203

Intravascular injection of norepinephrine

Back 203

Constriction of ALL vessels

Front 204

Intravascular injection of epinephrine

Back 204

DEPENDS ON THE DOSE !!!

Low dose of EP
- Decrease BP
- more B-2 receptors active → decrease in BP
High dose EP
- similar to NE effect:
- Increase in the BP

Front 205

vascular effects of epinephrine

Back 205

Local injection: vasoconstriction
Intravascular injection: Epi - mixed effects - DOSE

Decreases - skin, mucosa, and kidneys blood flow rate

In therapeutic doses - it doesn’t affect the brain blood flow rate
Increases - Lung blood pressure
Increases - coronary blood flow rate
Skeletal muscles - vasodilation
slightly decreases - Blood Pressure (BP) and tachycardia

Front 206

high vs. low doses of epinephrine

Back 206

high dose --> ENHANCE the blood pressure
- Direct stimulation - myocardium
- Increase the cardiac frequency
- Vasoconstriction

low dose --> DECREASE the blood pressure
- Stimulation of beta 2 receptors from the skeletal muscle vessels - dilation

Front 207

- In dentistry, what do we use with local anesthetic?

Back 207

a vasoconstrictor
--> this will help to keep the anesthetic localized

- Increase duration – slower absorption
- Decrease toxicity - slower absorption, and will be metabolized and eliminated
- Decrease bleeding – vasoconstrictor thus causes hemostasis

Front 208

stress will increase endogenous levels of

Back 208

epinephrine and noepinephrine

Front 209

Systolic blood pressure results from ________

Back 209

the cardiac stimulation by beta 1
(the heart)

Front 210

Diastolic blood pressure results from _____

Back 210

the vessels resistance by alpha 1 and beta 2
(blood vessels)

Front 211

pharmacological effect of epi & NE on the heart

Back 211

- Direct excitation - beta 1 receptors in the myocardium, and of cells of the pacemaker and conducting tissues.
- Cardiac systole is shorter and more powerful, cardiac output is enhanced, and the work of the heart and its oxygen consumption are markedly increased.
- Cardiac efficiency is lessened.

Front 212

baroreceptors

Back 212

Once you have a change in the BP or heart rate --> baroreflex --> Slows down the heart (after E / NE acts)

Front 213

blood pressure in response to giving a bolus injection of EPI or NE:

Back 213

- High dose administration of EPI → BP increases because it is binding to a1 and b1 causing the constriction of the vessels
- the resulting high blood pressure is decreased via the baroreflex

Front 214

blood pressure in response to epi in low doses

Back 214

- B2 action occurs and there is a slight decrease in BP
- Baroreflex recognizes this and INCREASES HR

Front 215

blood pressure in response to norepinephrine

Back 215

- no action on B2 so there is no decrease in BP, thus we just see an INCREASE in BP and then baroreflex will bring it back down (red circled portion in Epi)

Front 216

vasoconstrictor in the blood can cause:

Back 216

- Slight decrease in BP if we administer the drug slowly
- Slow administration = low dose = no absorption
---> Safe for a hypertensive or cardiac diseased pt even if accidently administered into the blood

Front 217

effects of epi on GIT and bladder

Back 217

- Relaxation - smooth muscles
- Reduction - Tone and the frequency and amplitude of spontaneous contractions
- Contraction - sphincters
- In vitro contraction of the uterus / Close to the due day - relaxation
- Relaxation - bladder detrusor and contraction - bladder sphincter

--> retention of materials inside

Front 218

effects of epi on metabolism

Back 218

- Increase glucose level via glycogenolysis
- Inhibit insulin secretion → more glucose available
- Cells in the brain do not require insulin (I assume she means GLUTs and etc. to transport glucose via insulin receptors)
--> Can just directly transfer glucose to the inside of the cells

Front 219

Isoproterenol

Back 219

adrenergenic agonist --> beta agonist

- Increases heart rate, force of contraction, and cardiac output with no reflex vagal activation (direct beta 1 effects)
- Vasodilation in skeletal muscle, resulting in decreased diastolic BP and decreased TPR (beta 2 effects)

Uses:
- Torsades de points (heart disease)
- Cardiac arrest of complete heart block
- Asthma or COPD

Front 220

Dobutamine

Back 220

adrenergenic agonist --> beta-1 agonist

- Increase contractility and heart rate

Uses:
- Severe congestive heart failure

**this is good b/c no changes in the lungs or anywhere else except for in the heart

Front 221

Albuterol

Back 221

andrenergic agonist --> beta-2 agonist

Uses:
- Bronchodilator
- long-term treatment of obstructive airway diseases, asthma, and for the treatment of acute bronchospasm

Front 222

Penylephrine

Back 222

andrenergic agonist --> alpha- agonist

- Marked arterial vasoconstriction during intravenous infusion.
- May activate b-receptors - at much higher concentrations.
- Neo-Synephrine

Uses:
- restore blood pressure during spinal or general anesthesia, in hypotensive emergencies, or after overdose of an antihypertensive medication
- nasal decongestant

Front 223

Clonidine

Back 223

andrenergic agonist --> alpha-2 agonist

- Capacity to lower blood pressure - activation of alpha 2 receptors in the cardiovascular control centers of the CNS
- Changes in blood pressure and heart rate - post-synaptic a2 receptors in many blood vessels
- Transient vasoconstriction - followed by a more prolonged hypotensive response = decreased sympathetic outflow from the CNS

Uses:
- Hypertension, antidepressive

Front 224

what is important about clonidine

Back 224

Therapeutic effects, but dangerous as A2 is found in the preneuronal membrane
- A2 agonist, hence, the effect is inhibition of more release of Epi
Do NOT bind to other organs receptors → inhibits release of NE (although NE levels not high)
- Anti-adrenergic

Front 225

what are indirect acting adrenergic agonists

Back 225

Drugs that do not bind to the receptor but increase NE in the synapse

Front 226

indirect acting adrenergic agonists

Back 226

- Stimulation of the mediator synthesis and release (amphetamine)
- Inhibition of the mediator uptake (cocaine)
- Inhibition of the mediator inactivation (MAO Inhibitors)

***Non - selective thus have lots of side effects but we have been using these for so long that in some patients, body finds homeostasis with these drugs

Front 227

amphetamine

Back 227

an indirect acting adrenergic agonist

Stimulation of the mediator synthesis and release of norepinephrine

Uses:
- Attention deficit hyperactivity disorder (amphetamine)
- Drug abuse

Tolerance:
- Readily develops to the CNS stimulant effects, appetite suppression and mood elevation

Front 228

cocaine

Back 228

an indirect acting adrenergic agonist
--> stimulates release of NE

- Prevents reuptake and no therapeutic effect whatsoever
- Inhibition of the mediator uptake and thereby prolong the effect of the adrenalines

Front 229

MAO inhibitor

Back 229

indirect acting adrenergic agonist
--> increases amount of NE

- Inhibition of the mediator inactivation
- MAO = Enzyme to breakdown NE, prolonged effect achieved by inhibiting MAO
Anti-depressant drugs

Front 230

what is the most important example of a mixed-acting adrenergic agonist?

Back 230

ephedrine

Front 231

mixed-acting adrenergic agonists

Back 231

Two different mechanisms

- Directly in the receptor (a and b agonist)
- Releases mediators in the synapses

Ex. Ephedrine

Front 232

Back 232

- Amphetamine and MAO inhibitors Increases the release of NE
- Drugs inhibit reuptake of EPI such as cocaine
- No selectivity
- Work in the CNS and ANS as well as every single organ
- Therefore, it does have some therapeutic uses, but the patients need to be monitored closely due to this non-selectivity

Front 233

Back 233

- ephedrine
- increased release of NE in synapse

Front 234

Adverse Reactions of Adrenergic Drugs

Back 234

- Dose related: too large dose, accidental intravascular injection, impaired uptake of the drug, heightened sensitivity or number of adrenergic receptors, preexisting cardiovascular disease
- Patients with history of uncontrolled hyperthyroidism, hypertension, or angina pectoris --> susceptible to cardiac disturbances
- local tissue necrosis

Front 235

Why is it important for us as dentists to give vasoconstrictors with local anesthetics?

Back 235

By adding vasoconstrictors, you can almost double the duration of the LA, and do NOT need to administer a higher dose

--> helps to prevent LA toxicity