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Flashcards in Exam 1 Deck (254):
1

Explain and give example of three drug names

- Chemical name: No!

- Generic name: atorvastatin

- Trade name: Lipitor

2

Difference between pharmacology, pharmacy, toxicology

- Pharmacology: science of interaction of chemical substances with living cells, tissue and organism, so mechanisms through which drugs counteract disease

- Pharmacy: science of preparation, storage, dispensing and proper utilization of drugs

- Toxicology: science of harmful/poisonous effects of drugs and mechanism by which they produce pathology and death

3

Difference bw pharmacokinetics and pharmacodynamics

- Pharmacokinetics: PROCESSES THAT AFFECT BIOAVAILABILITY such as absorption, distribution, metabolism and elimination. What the body does to a drug.

- Pharmacodynamics: HOW A DRUG PRODUCES AN EFFECT including through receptors, transduction pathways and WHAT ARE THE EFFECTS caused by a particular drug? What the drug does to the body.

4

Difference bw rx and non-rx drugs

- Rx: sale restricted and available with rx from provider. FDA controls rx drugs. State regulates who can rx drugs.

- Non-rx: drugs for sale OTC with safety directions.

5

Who monitors OTC drugs?

- Non-rx drugs advisory committee of FDA.

6

Describe drug scheduling

- General pattern = lower schedule, less abuse potential and/or potential for psychological and physical dependence.

- Schedule 1: no medical use, high abuse potential (eg. heroin)

- Schedule 5: less abuse potential than 4, has medical use with limited dependence (eg. buprenorphine)

7

Steps to develop and market a new drug

1.) Identification of a new compound (drug combo, new target, modification of existing drug, mass screening)

2.) Experimentation: in vitro studies, animal testing to characterize drug and determine toxicity

3.) Clinical testing
a. Phase I: limits of safe dosing range (Is it safe?)

b. Phase II: Does it work? – 100-200 people

c. Phase III: Does it work? - RCT double blind 1000s

4.) Drug approval

5.) Phase IV: Post-marketing surveillance (Are there populations who aren’t responding to drug the same as general population?)
- Patent expires, generic available

8

Describe drug nomenclature classification and give examples

1.) Drug action: name based on therapeutic action, eg. antiviral
- Problem: What do these agents treat? How do they work?

2.) Molecular target: name based on molecular target (receptor, enzyme), eg. beta-blocker

3.) Drug source: name based on natural source of drug, eg. atropine from Atropa genus of plant
- Problem: name gives no indication how it works, what target is

4.) Chemical nature: name based on chemical structure/nature, eg. steroid, benzodiazepines

5.) Generic name: derived from chemical name providing an indication of the class to which a particular drug belongs (eg. statins)

9

List common receptor types that serve as drug targets. What are their functions?

1. Intracellular receptors:
- direct regulators of gene activity

2. Receptors with intrinsic enzymatic activity:
- protein and lipid kinase cascades, protein phosphatases

3. Receptors that directly associate with intracellular enzymes
- protein and lipid kinase cascades, protein phosphatases

4. Ligand-gated ion channel
- function through voltage changes?

5. 7-membrane spanning receptors (G-protein)
- signal transduction via GDP (off), GTP (on)

10

Examples of intracellular receptors

- estrogen receptor, vitamin A receptor

11

Examples of receptors with intrinsic enzymatic activity

- EGFR, IR, TGF-betaR

12

Examples of receptors that associate directly with intracellular enzymes

- IL-3 receptor, EPO receptor, leptin receptor

13

Examples of ligand-gated ion channels

- nicotinic ACh receptor

14

Examples of 7-membrane spanning receptors (G-protein)

- beta-adrenergic receptor, rhodopsin, frizzled, smo

15

Continued stimulation of a receptor causes what to happen to receptor #

- decrease in receptor # which is called downregulation

16

Continued exposure to inhibitor of a receptor causes what to happen to receptor #

- increase in receptor # which is called upregulation

17

Draw and label a ligand biding affinity curve. Explain what is meant by the graph. Provide definitions for the Bmax and Kd

- See image in SG (exam 1)

- As we increase drug concentration, the amount of receptor bound to drug increases.

- Kd = [ ] at which 50% of receptors are bound to drug and 50% are free from drug, this is affinity of ligand for receptor. Lower Kd = less drug required to bind 50% of receptor, therefore greater affinity.

- Bmax = point at which drug [ ] is sufficient to completely bind all the receptors, ie. receptor saturation.

18

How is Kd calculated?

- Example drug – receptor interaction: A + B ⇔ AB

- Rate constant for formation of AB = k(on)

- Rate constant for dissociation of AB = k(off)

- Kd = [A].[B] / [AB] or k(off)/k(on)

19

How can one use the ligand binding affinity plot to distinguish between binding affinities of drugs?

- Plot all curves on same graph
- Curve that is furthest left (ie. lowest Kd) has greatest binding affinity.

20

When designing a drug that is to compete with an endogenous ligand for a receptor, which one (drug or ligand) needs to have the lowest Kd?

- Drug should have greater affinity, therefore lowest Kd.

- If it was higher, we would have to use a higher concentration (mass action) to overcome the effect of the endogenous ligand for the receptor. This could cause deleterious effects to kidney and liver.

21

What is the difference between Bmax and Emax?

- Bmax is seen on a receptor:drug binding vs drug concentration curve. It refers to concentration where receptor is maximally saturated with drug.

- Emax is seen on a drug effect vs drug concentration curve. It refers to the concentration at which drug causes maximal effect.

22

What is the difference between efficacy and potency of a drug? How do you distinguish between potency and efficacy using a dose-response curve? Show.

- Efficacy: maximal effect a drug can induce. Determined from E max (maximal effect). Larger Emax = more efficacious.

o From graph, larger Y value = more efficacious.

- Potency: affinity/effectiveness of a drug, ie. EC50 (concentration of drug that produces a half maximal effect). Smaller EC50 = higher potency of drug.

o From graph, smaller X value = more potent

- See image on SG (exam 1)

23

Define agonist

- Drug/ligand that binds to a receptor and produces a molecular, cellular or physiological response.

24

Define antagonist

- Drug/ligand that binds to a receptor and inhibits the response produced by an agonist.

25

Define competitive antagonist. What is seen on a dose-dependent response/effect curve to map this?

- Agonist and antagonist compete for same binding site.

- Right shift in EC50 as the agonist concentration increases, Emax (maximal effect) is still attainable.

- See image on SG (exam 1)

26

Define noncompetitive antagonist. What is seen on a dose-dependent response/effect curve to map this?

- Agonist and antagonist bind to different sites. Once antagonist fits onto the receptor, changes in receptor occurs so that agonist may not be able to bind or if it does the functional capacity is decreased.

- Agonists affinity for receptor may not change in presence of antagonist, decrease in maximal effect (Emax) as concentration of agonist increases.

- See image on SG (exam 1)

27

Define partial agonist. Show on a graph

- Drug that produces a lower maximal response as compared to the agonist.

- See image in SG (exam 1)

28

From the following curve (see image in SG exam 1), which drug is most potent? Most efficacious?

- Most potent = B. It has the smallest EC50.

- Most efficacious = A, C and D, have the same Emax.

29

From the following graph (see image in SG exam 1), which curves represent dosing in of agonist against a competitive antagonist? Which represent dosing in of non-competitive antagonist?

- Competitive: B and C

- Non-competitive: D and E

30

Define ED 50, LD 50, TD 50

- ED50: median effective dose

- LD50: median lethal dose – dose that is lethal for 50% of individuals tested.

- TD50: median toxic dose

31

Define therapeutic index

- TI = TD50/ED50
- Greater the ratio (greater window between effectiveness and toxic), the safer the drug. On graph, curves should be further apart.

32

Cancer drug A produces tumor regression at cumulative dose of 100 mg/kg over a 1 month period. If cumulative doses reach 4000 mg/kg over the same time period, liver and kidney damage occurs. Cancer drug B produces tumor regression at cumulative dose of 200 mg/kg over a 1 month period. If cumulative doses reach 1000 mg/kg over the same timer period, liver and kidney damage occurs. Which drug has greater window of safety?

A: TI = TD50/ED50 = 4000 / 100 = 40

B: TI = 1000/200 = 5

A has greater window of safety and is safer.

33

Drug tolerance vs drug sensitization. What happens to the EC50?

- Tolerance: decrease in drug response following repeated administration. EC50 increases.

- Sensitization: increase in drug response following repeated administration. EC50 decreases.

34

Additive vs synergistic effects of drugs

- Additive: combination of drugs produces a response consistent with each agent’s potency

- Synergistic: combination of drugs produces a response magnified beyond the sum of either’s potency

35

List and define the processes of pharmacokinetics

- Absorption: movement of agent from administration site to circulation (blood/plasma)

- Distribution: process by which drug leaves the circulation and enters tissue perfused by blood

- Metabolism (biotransformation): reactions that convert a compound into an active or inactive metabolite

- Elimination: removal of drug from circulation and body

36

List types of routes for drug administration.

1. Enteral: using GI tract – oral, SL, buccal, rectal

2. Parenteral: non-GI – IV, IM, SC, intrathecal, epidural

3. Transdermal: through skin by patch

4. Inhalational

37

Pros and cons to oral drug administration

- Pro: greatest level of compliance, easy

- Con: GI tract is setup to break things done (acidity, enzymes), portal circulation can degrade drug

38

Pros and cons to SL/buccal drug administration

- Pro: absorption directly into venous system bypassing the liver

- Con: irritating to oral mucosa for patient

39

Pros and cons to rectal drug administration

- Pro: easy way to deliver meds to unconscious patient, partially avoid first-pass effect (1/2 drug bypasses portal circulation)

- Con: not convenient, rare to get complete absorption, irritation

40

Pros and cons to IV drug administration

- Pro: greatest availability (all dose gets into blood)

- Con: cannot recall drug

41

Pros and cons to IM drug administration

- Pro: dosing less frequent (slowly diffuses from tissue)

- Con: dependent on blood flow to tissue

42

Pros and cons to SQ drug administration

- Pro: slowly diffuses to circulation

- Con: compliance is low d/t pain, changes in tissue seen if this method is frequently used

43

Pros and cons to intrathecal and epidural drug administration

- Pro: easy access to CNS

- Con: damage / incorrect technique = significant effect

44

Pros and cons to transdermal drug administration

- Pro: avoid first pass effect from liver

- Con: skin is an affective barrier, must be lipophilic drug, condition of skin affects absorption

45

Pros and cons to inhalation drug administration

- Pro: large surface area = quick delivery of large dose

- Con: irritating to tissue, drug reaches heart first (cardiotoxicities)

46

How to determine the relative amount of drug that would be absorbed at a site given the pH of the environment and the pKa of the drug?

Consider the following:
- Non-ionized forms of drugs (weak acids or weak bases) more readily cross membranes. Weak acids must be protonated and weak bases must be unprotonated.

- Weak acids are protonated in lower pH of stomach. Weak bases are unprotonated in higher pH of intestines.

- log [protonated]/[unprotonated] = pKa – pH

- When pH > pKa: H off = unprotonated

-- When pH

47

Factors that impact the distribution of a drug in the body

- Cardiovascular factors (CO, blood flow, permeability of capillaries, binding to plasma proteins)

- Tissue binding

- Drug molecular size

- Lipid solubility

48

Describe biotransformation phases. What reactions occur? What cytochromes are involved? What is the goal?

- Phase 1: generate more polar molecule, may still be active, by exposing functional group.
o Rxns = oxidation, reduction and hydrolysis

o Cytochromes = CY P-450

- Phase 2: reactions yield a more water soluble and inactivated conjugated product
o Rxns = glucoronidation, acetylation, sulfation, amidation, methylation, glutathione conjugation

o No cytochromes

49

What is the first-pass effect?

- Drug absorbed by stomach or intestine carried to liver where it is metabolized and can be inactivated prior to reaching intended target.

50

Where are drugs eliminated? What factors are important?

- Urine: primarily. Factors: GFR, binding to plasma proteins and alkalinization/acidification of urine.

- Fecal: hepatic secretion into bile into intestine or enterocyte-mediated. Factors: ?

51

Define volume of distribution. How to calculate V?

- Volume of distribution (V): space in body available to contain drug

- C = concentration of drug in blood or plasma

- V = (amount of drug in body) / (C)

52

Describe the difference between a drug with a V (volume of distribution) similar to blood volume verses a drug that has a V 100 times blood volume.

- Larger V, the greater extent to which drug distributes to extravascular tissue and therefore to target.

- Blood volume for an avg adult is ~ 5.5 L (plasma ~ 3L). Suppose we calculate V and it is close to that value. This would suggest that the majority of the drug is located within the vasculature.

- If we calculate V and it is much greater than the blood volume for an adult, then it would suggest that the majority of the drug is located in the extravascular compartments (tissue, fat). Higher V, more highly distributed extravascularly. Note: V can exceed actual body volume (it is theoretical).

53

Calculate the blood and plasma volume of a 100 kg adult

- Blood volume: 0.08 L/kg body weight = 0.08 x 100 = 8 L

- Plasma volume: 0.04 L/kg body weight = 4L

* Low yield.

54

Define clearance.

- Clearance: rate of elimination in relation to drug concentration. CL = rate of elimination / concentration of drug (C)

55

What is the difference between zero-order and first-order elimination kinetics? What is the difference between capacity-limited elimination and flow-dependent-elimination in the context of zero and first-order kinetics? Graphic representations of this.

- Zero-order: elimination process is at capacity (saturated), therefore a constant amount of drug is eliminated over a period of time independent of drug concentration. Example: 100 mg dose of drug X is eliminated at 20 mg q 2 hours. This is capacity-limited elimination.

- See image on exam 1 SG

- First-order: elimination process is not at capacity (not saturated), therefore a constant fraction (not amount) of drug is eliminated over a period of time independent of drug concentration. Example: 65 mg dose of drug X is reduced by 50% q 2 hours. This is flow-dependent elimination.

- See image on exam 1 SG

56

Drugs subject to capacity-limited elimination

- ASA, etoh and phenytoin

- Capacity-limited elimination: zero-order kinetics

57

How does one calculate the t1/2 (half-life) of a drug?

- Half-life: time it takes for [ ] of drug in plasma to decrease by 50%

- t1/2 = (0.693 x V) / CL

- V = volume of distribution

- CL = clearance of drug

- Note: equation used when drug is eliminated by first-order kinetics (reduced by constant fraction over a period of time)

58

Predict the impact of changing the volume of distribution and clearance on drug half-life.

- As V increases, half-life increases. See equation. Clinically significant = reduction of clearance of drug (in case of renal failure or insufficiency), the half-life increases.

59

After how many half-lives do we consider a drug “completely” eliminated from the body?

- 4-5 half-lives

60

What is the impact of predicting the initial plasma concentration (Cp0) using a one-compartment model and a two-compartment model?

- One-compartment model: Cp0 can be determined by extrapolating the semi-log plot of plasma concentration vs time back to the 0 time point. This is for drugs eliminated by first-order process.

- Two-compartment model: cannot extrapolate as we miss out on exponential decay in drug concentration prior to it being eliminated by first-order elimination.

61

Use the accumulation factor to predict the ratio of the steady-state concentration to the initial dose.

- AF = 1/(fraction lost in one dosing interval). This value predicts the ratio of steady-state [ ] to the dose seen following the first dose.

- Accumulation of drugs occurs if dosing interval is shorter than four half-lives.

62

If a drug is given once every 3 half-lives, what concentration will the drug accumulate to?

- AF = 1/(fraction lost in one dosing interval)

- AF = 1/0.875 = 1.143

- Drug will accumulate to a [ ] of 1.143 as much as that seen following the first dose.

63

Define bioavailability and predict the impact of clearance, hepatic blood flow and gut absorption on the bioavailability of a drug taken orally.

- Bioavailability: amount of drug that reaches the systemic circulation. If IV, 100%.

- ER = CL (liver)/Q – where ER = extraction ratio, CL = clearance, Q = hepatic blood flow

- F = f x (1 – ER) – where F = bioavailability, f = extent of gut absorption.

- - Clearance up = bioavailability down



- Gut absorption up = bioavailability up

64

Define therapeutic window.

- For a drug, there is a [ ] that will produce the desired response and a concentration that will produce adverse effects. The range between these two points = therapeutic window.

65

Define steady-state concentration. What is the impact of dosing rate and clearance have on the steady-state concentration.

- Steady-state [ ]: point during dosing of drug when elimination of a drug = bioavailability of drug.

- Css = dosing rate / CL. CL = clearance of a drug.

- If dosing rate increases, steady-state [ ] increases.

- If clearance decreases, steady-state [ ] increases.

66

Explain why it takes 4-5 half-lives to reach a steady-state concentration.

- I don’t have a clue. I can tell you that at this point, the concentration of the drug from the 1st dose has been eliminated by between 94-97%.

67

Define maintenance dose. How is it calculate? How does dosing frequency affect the peak and trough concentrations?

- Maintenance dose: dose needed to maintain steady state concentrations.

1. Dosing rate (ss) = CL x TC. TC = target concentration

2. Dosing rate (oral) = dosing rate (ss) / F oral. Use only if meds will be given PO.

3. Maintenance dose = dosing rate x dosing interval. Dosing interval = length of time the steady state needs to be maintained.

- Less often dosing occurs, greater variation between peaks and troughs. More frequent dosing keeps tighter window around steady state concentration.

68

A target plasma theophylline [ ] of 10 mg/L is desired to relieve acute bronchial asthma in a patient. Use a mean clearance of 2.8L/hr/70kg. Drug will be given IV.
a.) Calculate the dosing rate to maintain this target plasma concentration
b.) If the asthma attack is relieved and the clinician wants to maintain the target plasma concentration using an extended release oral dose (F=0.96), what is the maintenance dose required

a.) Dosing rate (ss) = CL x TC = 2.8L/hr/70kg x 10mg/L = 28 mg/hr/70kg

b.)

- Dosing rate (oral) = dosing rate (ss) / F = 28 / 0.96 = 29.17 mg/hr/70kg

- MD = dosing rate (oral) x dosing interval = 29.17 mg/hr/70kg x 12 hr = 350 mg / 70kg given every 12 hours.

69

Define loading dose. How is it calculated? Predict the impact of changing the volume and bioavailability on the loading dose. Advantages of loading dose? Disadvantages?

- Loading dose: initial dose that can be given in order to achieve the target concentration rapidly.

- Loading dose = (V x TC) / F, where V = volume of distribution, TC = target concentration and F = bioavailability

- V up = LD up

- TC up = loading dose up

- F up = loading dose down

- Advantages: time to steady state is long, drugs that have a long half-life

- Disadvantages: abrupt high concentration = toxic, drug initially concentration to blood (although calculation using entire volume), LD typically divided into multiple smaller doses

70

Accumulation of digitalis (t1/2 = 3.1 days) in a patient is gradual if only a maintenance dose is administered – takes at least 12 days. A more rapid response could be obtained (if necessary) by using a loading-dose strategy. A target concentration of 0.9 ng/ml is chosen as a target below the recommended maximum of 1.0 ng/ml. The volume of distribution for digitalis is 496L for a 70 kg adult and has a bioavailability of 0.7. Calculate the loading dose.

- LD = (V.TC) / F = (496 x 0.96)/0.7 = 638 ug = ~ 0.625 mg

- Practically to avoid toxicity, this would be given as an initial 0.25 mg dose followed by a 0.25 mg dose 6-8 hours later with careful monitoring of the patient and the final 0.125 mg dose given 12-14 hours later.

71

PSNS fibers are carried in what nerves

- CNs III (ciliary ganglion), VII (sphenopalatine and submaxillary ganglia), IX (otic ganglion) and X

- S2-4

72

What are the 2 plexuses of the ENS? Where is each located? Function?

1. Myenteric (Auerbach’s): outer, bw external longitudinal and deeper circular SM layer of the gut lining. Function = motility.

2. Submucosal (Meissner’s): inner, within the submucosa of the gut lining. Function = ion and fluid transport.

* Activation of this system = wet picture

73

T/F. ENS can function without extrinsic input.

- True. Has both dependent and independent components.

74

Exceptions to dual innervation in ANS

- Only SNS = hair follicles, sweat glands, liver, adrenals, kidney

- Salivary glands have both PSNS and SNS input with similar effects = secretion of saliva.

75

PSNS. What NT is released from the pre-ganglionic fiber? What type of receptor does it act upon? What NT is released from the post-ganglionic fiber? What type of receptor does it act upon?

- Pre-G fiber releases Ach, acts on nicotinic receptor

- Post-G fiber releases Ach, acts on muscarinic receptor

76

SNS. What NT is released from the pre-ganglionic fiber? What type of receptor does it act upon? What NT is released from the post-ganglionic fiber? What type of receptor does it act upon?

- Pre-G fiber releases Ach, acts on nicotinic receptor

a.) Post-G fiber (to sweat glands) releases Ach, acts on muscarinic receptor

b.) Post-G fiber (to all other targets except a and b) releases NE, acts on alpha and beta adrenergic receptors

c.) Post-G fiber (to renal vascular SM) releases DA, acts on D1 receptor

d.) Chromaffin cells in adrenals release Epi, NE systemically

77

Somatic nerve fibers acting on skeletal muscle release what NT? What type of receptor does this act upon?

- Ach, acts on nicotinic receptor

78

Describe homotropic interactions at the nerve terminal

- NT release acts on autoreceptor at the nerve terminal to negatively feedback on the release of NT, ie. decrease/block the release of the NT.

79

Describe heterotropic interactions at the nerve terminal

- NT release from one nerve terminal acts on heteroreceptor of another nerve terminal to negatively feedback on the NT released there, ie. decrease/block the release of the NT.

80

What is withdrawal rebound hyperactivity/disuse hyperactivity? Describe mechanism. Example.

- Sustained blocking of transmission increases the sensitivity of target when blockage is removed.

- Mechanism: proliferation of receptors, loss of mechanisms for removal of NT, increased post-junctional response.

- Example: rebound HTN upon withdrawal of adrenergic blocker.

81

What is co-transmission at the nerve terminal?

- Nerve terminals release more than one NT (or modulator), each interacts with specific receptors and produces effects both pre and post-synaptically.

- Example: NPY acts (+/-) on receptors for ATP and NE at the post-synapse, but also on pre-synapse to reduce the release of ATP and NE. If used clinically, NPY endogenously becomes decreased. If patient taken off this drug, then –ve feedback lost and ATP and NE remain high.

82

Function of hemicholiniums

- Choline carrier blocker blocking cholinergic NT synthesis

83

Function of vesamicol

- Ach carrier blocker – VAT, blocking cholinergic NT storage

84

Function of botulinum toxin

- Pre-synaptic toxins against VAMPs, SNAPs – blocks cholinergic NT release

85

Function of tubocurarine (curare)

- NM blocking agent, prevents action of Ach on cholinoceptors.

86

Function of neostigmine (AChE inhibitor)

- AchE inhibitor, blocks termination of action of ACh

87

List the two types of cholinergic receptors. Describe each.

1.) Muscarinic (M1-5): G-protein serpentine (7-membrane) receptor

2.) Nicotinic: 5 subunit ion channel, alpha units bind Ach

88

Types of nicotinic receptors and effect of their activation

- Nn (adrenergic medulla): Epi and NE secretion

- Nn (autonomic ganglia): receptor on post-ganglionic fibers (SNS and PSNS), net effect depends on receptor dominance

- Nm (NM junction): twitch of skeletal muscle (mnemonic: M = muscle)

89

Describe the distribution of cholinergic and adrenergic receptors in the eye. List the function of activation of each receptor.

1. Dilator/radial muscle: alpha-1

o Alpha-1 = contraction = mydriasis

2. Constrictor/sphincter muscle: M3

o M3 = contraction = miosis, opening of canal of Schlemm

3. Ciliary muscle: M3 and beta-2

o M3 = contraction = fattening of lens for accommodation (near vision) and open canal of Schlemm

o Beta-2 = relaxation = flattening of lens

4. Ciliary body/epithelium: alpha2, beta-1, beta-2

o Alpha-2 = decrease aqueous humor production
o Beta-1 = increase aqueous humor production
o Beta-2 = increase aqueous humor production

90

Which muscarinic receptors are found in the eye and what is the effect of activating them?

- M3

- Miosis, opening canal of Schlemm – sphincter muscle

- Accommodation (for near vision), opening canal of Schlemm – ciliary muscle

91

Treatment of glaucoma with what type of drug

- M3 agonist (causes contraction of constrictor/sphincter and ciliary muscle and opens canal of Schlemm)

OR

- Alpha-2 agonist (decrease production of aqueous humor)

- Beta-antagonists (beta-1 and 2 increase production of aqueous humor)

92

Where are M2 receptors predominantly found?

- Heart

93

Where are M1 receptors predominantly found?

- Glands

94

Which muscarinic receptors are found in the heart and what is the effect of activating them?

1. SA node: decrease HR (-ve chronotropy)

2. AV node: decrease conduction velocity

3. Atrial muscle: decrease atrial contraction

4. Ventricular muscle: decrease ventricular contraction (weak effect)

95

What type of drug causes cycloplegia?

- Cycloplegia = paralysis of ciliary muscle

- Drug = M3 antagonist

96

Muscarinic receptors found in the lungs and what is the effect of activating them?

- M3

- Bronchospasm – bronchioles

- Secretion – glands

97

Muscarinic receptors found in the GI tract and what is the effect of activating them?

- M3, except glands are innervated by M1 and M3

- Increased motility and cramps – stomach

- Secretion – glands

- Contraction – intestines

98

Muscarinic receptors found in the bladder and what is the effect of activating them?

- M3

- Contraction (detrusor)

- Relaxation (trigone)

99

Muscarinic receptors found in the sphincters and what is the effect of activating them?

- M3

- Relaxation (except for LES, which contracts)

100

Muscarinic receptors found in non-GI glands and what is the effect of activating them?

- M3

- secretion (sweat, salivation, lacrimation)

101

Muscarinic receptors found in the blood vessels and what is the effect of activating them? Explain the mechanism.

- M3 in endothelium

- Dilation, relaxation

- Mechanism: Ach causes increase Ca [ ] = + NOS (nitric oxide synthase) = Arginine converted to NO. NO diffuses into SM cells. NO stimulates soluble guanylyl cyclase = GTP converted to cGMP = relaxation

102

Effect of muscarinic receptor activation on secretions in stomach.

- M1 receptors on ECL (enterochromaffin) secrete histamine, which act on H2 receptors increasing H+ concentration.

- M3 receptors activated on parietal cells = increase in H+ concentration.

103

Classify the adrenergic, cholinergic, histaminic, dopaminergic and vasopressin receptors by types of G-proteins. Also describe the downstream effect after activation of the receptor.

- Mnemonics:

o QISS, QIQ, SIQ, SQS – a1, a2, b1, b2, m1, m2, m3, d1, d2, h1, h2, v1, v2

o HAVe 1M&M – h1, a1, v1, m1, m3

o MAD2s – m2, a2, d2 = MAD is inhibitory, so Gi

1. Gq: PLC activated; PIP2 into DAG and IP3; DAG activateds PKC; IP3 increases Ca2+ concentration and activates smooth muscle

2. Gs: Adenylyl cyclase activated; ATP into cAMP; cAMP activates PKA; increase in Ca2+ concentration (heart) and inhibition of MLCK (SM)

3. Gi: inhibits adenylyl cyclase, opposite effect

104

Types of cholinomimetic drugs / cholinoceptor agonists

1. Direct-acting: bind and activate muscarinic or nicotinic cholinoceptors

2. Indirect-acting: inhibit action of AChE

105

What receptors do Ach bind?

- Muscarinic

- Nicotinic

106

Cholinoceptor agonist drug actions. Name drugs under each category

1. Direct acting: receptor agonists

a.) Muscarinic:

i.) Choline esters: Ach, methacholine, carbachol, bethanechol,

ii.) Alkaloids: muscarine, pilocarpine

b.) Nicotinic:

i.) Alkaloids: nicotine, succinylcholine

2. Indirect acting: AchE inhibitor

a.) Reversible: edrophonium, neostigmine, physostigmine, donepezil, tacrine

b.) Irreversible (organophosphates): echothiopate, malathion, parathion, sarin

107

Contraindications to direct acting cholinomimetics (agonists)

- peptic ulcers: increase H secretion

- GI tract disorders: contraction/secretion = pain. What about bethanechol?

- asthma: bronchoconstriction

108

Drug interactions of direct-acting cholinomimetics (agonists)

- any drug that is antimuscarinic will block the effects of these drugs

- quinidine (anti-arrhythmic), procainamide (anti-arrhythmic), TCA (antidepressant)

109

Chemical properties of choline esters that affect function

- Drugs: Ach, methacholine, carbachol, bethanechol

- Quaternary cationic ammonium = insoluble in lipids therefore poor GI absorption and poor CNS distribution

- Methyl on methacholine and bethanechol means longer half-life

- Amide on carbachol and bethanechol means enhanced half-life as these are insusceptible to cholinesterase

110

ACh. Drug class, physiologic effects, indication

1.) Drug class = direct-acting cholinoceptor agent, muscarinic agonist

2.) Physiologic effects

- As expected, see M receptor effects.

- Note: low dose = vasodilation = BP decrease = reflex tachy. High dose = bradycardia and decrease in FOC

- No nicotinic effect since lipid insoluble and cannot penetrate fat surrounding skeletal muscle and autonomic ganglia

3.) Indication:

- Limited d/t short half-life. Eye surgery (short-lasting miosis), provocation test in coronary angiography to diagnose coronary vasospasm

111

Methacholine (provocholine). Drug class, physiologic effects, indication, other notes

1.) Drug class = direct-acting cholinoceptor agent, muscarinic agonist

2.) Physiologic effect:

- See M receptor action, similar to ACh with longer half-life (methyl group)

- Similar to Ach, no nicotinic effect d/t lipid insolubility

3.) Indication:

- Methacholine challenge – if excessive bronchoconstriction via M3, then brochiolar hypersensitivity (asthma) diagnosis

112

Carbachol. Drug class, physiologic effects, indication, other notes

1.) Drug class = direct-acting cholinoceptor agent, muscarinic and nicotinic agonist

2.) Physiologic effect:

- Muscarinic and nicotinic receptor agonist. See M receptor action. Nicotinic: ANS ganglia, adrenal medulla and skeletal muscle

3.) Indication:

- Glaucoma

4.) Other notes:

- May induce cardiac arrest at high doses

113

Bethanechol (urecholine). Drug class, physiologic effects, indication, other notes

1.) Drug class = direct-acting cholinoceptor agent, muscarinic agonist

2.) Physiologic effect:

- Predominantly on M3 receptors. Mnemonic: B for bowel (GI) and bladder (GU).

- Weak/minimal M2 (cardiac) effects

3.) Indication:

- Gastric atony (post-vagotomy, increases LES tone)

- Gastric emptying abnormalities (eg. Ileus), gastroparesis, GERD

- Urinary retention (w/o obstruction NB!)

114

Muscarine. Drug class, physiologic effects, indication, other notes

1.) Drug class = direct-acting cholinoceptor agent, muscarinic agonist

2.) Physiologic effect:

- 100x more potent than ACh. Like ACh, no nicotinic activity. Not broken down by ACh. See M receptor effects.

3.) Indication:

- Not indicated, poison from Amanita muscaria (aka fly agaric) mushroom.

4.) Other notes:

- Poisoning: excess activation of all M receptors = WET clinical picture. Symptoms generally subside within 2 hours. Can lead to cardiac and respiratory failure.

115

Pilocarpine (isopto carpine, salagen). Drug class, physiologic effects, indication, other notes

1.) Drug class = direct-acting cholinoceptor agent, muscarinic agonist

2.) Physiologic effect:

- Opthalmic M3 effects predominate with topical application. Poor systemic absorption. Salivary secretion.

- Mnemonic: You cry, sweat and drool on your Pilow

3.) Indication:

- Glaucoma (rx of choice) – open and closed

- Xerostomia (dry mouth) – oral rx

- Test autonomic state if you suspect PSNS dysfunction, hypersensitivity to drug.

116

Prescription of choice to treat glaucoma

- Pilocarpine (isopto carpine, salagen)

117

Nicotine. Drug class, physiologic effects, indication, other notes

1.) Drug class = direct-acting cholinoceptor agent, nicotinic agonist

2.) Physiologic effect:

- Nm receptor activation: SkM contraction, fasciculations, spasm, depolarizing blockage (too much activation, effect blocked)

- Nn receptor activation: increased HR, peripheral vasoconstriction, increased gut motility and secretion, increased RR (carotid bodies), nausea and vomiting (medullary emetic)

3.) Indication:

- Smoking cessation

118

Symptoms of cholinesterase inhibitors. What is the medical mgmt of this (include antidote)?

- Mnemonic = DUMBBELSS

- D: Diarrhea

- U: Urination

- M: Miosis

- B: Bronchiolar constriction

- B: Bradycardia

- E: Excitement of CNS (convulsion, coma)

- L: Lacrimation

- S: Sweating

- S: Salivation

- Management: symptomatic, airway, CV support, atropine (muscarinic receptor antagonist) + pralidoxime aka 2-PAM (if given early, regenerates AChE by breaking bond between drug and AChE)

119

Edrophonium. Drug class, physiologic effects, indication, other notes

1.) Drug class = indirect-acting cholinoceptor agent, cholinesterase inhibitor

2.) Physiologic effect:

- Cholinesterase inhibitor

3.) Indication:

- Historically used to diagnose myasthenia gravis (differentiates this from cholinergic crisis – how? Cholinergic crisis is a result of too much ACh (d/t defect in AchE enzyme), therefore when the drug is added, symptoms won’t improve.

4.) Other notes:

- short-acting

120

Neostigmine. Drug class, physiologic effects, indication, other notes

1.) Drug class = indirect-acting cholinoceptor agent, cholinesterase inhibitor

2.) Physiologic effect:

- Cholinesterase inhibitor

3.) Indication:

- Ileus, urinary retention (non-obstructive), myasthenia, reversal of non-depolarizing NM blockers, abdominal distention

4.) Other notes:

- no CNS entry (Mnemonic = neo, no CNS), intermediate-acting

121

Pyridostigmine. Drug class, physiologic effects, indication, other notes

1.) Drug class = indirect-acting cholinoceptor agent, cholinesterase inhibitor

2.) Physiologic effect:

- Cholinesterase inhibitor

3.) Indication:

- Ileus, urinary retention, myasthenia (mnemonic = rid of gm = rid of mg = rid of myasthenia gravis), reversal of non-depolarizing NM blockers

4.) Other notes:

- no CNS entry, intermediate-acting

122

Physostigmine. Drug class, physiologic effects, indication, other notes

1.) Drug class = indirect-acting cholinoceptor agent, cholinesterase inhibitor

2.) Physiologic effect:

- Cholinesterase inhibitor

3.) Indication:

- Glaucoma, antidote to atropine overdose (mnemonic: physostigmine phyxes atropine overdose)

4.) Other notes:

- Enters CNS, intermediate-acting

123

Donepezil (Aricept). Drug class, physiologic effects, indication, other notes

1.) Drug class = indirect-acting cholinoceptor agent, cholinesterase inhibitor

2.) Physiologic effect:

- Cholinesterase inhibitor

3.) Indication:

- Alzheimer’s dz

4.) Other notes:

- Enters CNS (lipid-soluble)

124

Tacrine. Drug class, physiologic effects, indication, other notes

1.) Drug class = indirect-acting cholinoceptor agent, cholinesterase inhibitor

2.) Physiologic effect:

- Cholinesterase inhibitor

3.) Indication:

- Alzheimer's dz

4.) Other notes:

- Enters CNS (lipid-soluble)

125

Echothiophosphate. Drug class, physiologic effects, indication, other notes

1.) Drug class = indirect-acting cholinoceptor agent, cholinesterase inhibitor

2.) Physiologic effect:

- Cholinesterase inhibitor

3.) Indication:

- Glaucoma

4.) Other notes:

- Lipid-soluble organophosphates

126

Irreversible AChE inhibitors

- Organophosphates insecticides : malathion, parathione

- Nerve gas: sarin

- Organophosphates: Echothiophosphate (can be used clinically for glaucoma tx, but there are better meds)

127

Cholinoceptor antagonist drug actions. Name drugs under each category

1. Muscarinic receptor antagonists

a.) Atropine, ipratropium, benztropine

2. Nicotinic receptor antagonists (Nn and Nm)

a.) Hexamethonium, mecamylamine – these are not used clinically anymore d/t toxicities

3. Neuromuscular antagonists (Nm)

a.) Non-depolarizing: D-tubocurarine

b.) Polarizing: succinylcholine

128

Atropine. Drug class, physiologic effects, indication, other notes

1.) Drug class = muscarinic receptor antagonist

2.) Physiologic effect:

- Competes with Ach at M (any) receptors. Reverse M receptor activation to find function. In order of increasing doses: decreased secretions, mydriasis/cycloplegia, hyperthermia, tachy, sedation, urinary retention/constipation, behavioral excitation and hallucinations.

3.) Indication:

- Antispasmodic, antisecretory, mgmt. of AchE inhibitor overdose, antidiarrheal, ophthalmology, prevent vagal rxn in some procedures

4.) Other notes:

- Note: no effect on BP when given alone

- Use physostigmine to tx acute intoxication

129

Ipratropium (atrovent). Drug class, physiologic effects, indication, other notes

1.) Drug class = muscarinic receptor antagonist

2.) Physiologic effect:

- Mainly acts on M3 in bronchial SM and glands when inhaled. Decreases bronchoconstriction and bronchial secretions

3.) Indication:

- Chronic obstructive lung dz, asthma

- Mnemonic: I pray I can breathe soon!

4.) Other notes:

- No CNS absorption

130

Benztropine (Cogentin). Drug class, physiologic effects, indication, other notes

1.) Drug class = muscarinic receptor antagonist

2.) Physiologic effect:

- Acts on M receptors in brain to re-establish DA:Cholinergic balance

3.) Indication:

- PD (Mnemonic: Park my Benz)

- Decrease GU/GI secretions, decrease motility, increase HR

4.) Other notes:

- CNS absorption

131

Ganglion blocking agent names. Function? Effect?

- Names: hexamethonium, mecamylamine

- Function: reduce predominant ANS tone, prevent baroreceptor reflex changes in HR

Effect: (effector: system disabled, effect)

- Arterioles: SNS, vasodilation, HoTN

- Veins: SNS, vasodilation, decreased venous return, decrease CO

- Heart: PSNS, tachycardia

- Iris: PSNS, mydriasis

- Ciliary muscle: PSNS, cycloplegia

- GI tract: PSNS, decreased tone and motility = constipation

- Bladder: PSNS, urinary retention

- Salivary glands: PSNS, xerostomia

- Sweat glands: SNS, anhidrosis

132

D-tubocurarine. Drug class, physiologic effects, indication, other notes

1.) Drug class = non-depolarizing NM antagonist

2.) Physiologic effect:

- Prevent opening of Nm ACh receptor channel, compete with ACh and block pre-junctional Na channels from releasing ACh

- Paralytic

3.) Indication:

- This is prototype non-depolarizing NM antagonist. Curare is found on poisoned arrows.

133

Succinylcholine (anectine). Drug class, physiologic effects, indication, side effects

1.) Drug class = depolarizing NM antagonist

2.) Physiologic effect:

- Phase 1: binds to Nm = depolarization, persistent depolarization = paralysis, augmented by AChE inhibitors

- Phase 2: end plate repolarizes, but not easily depolarized again (desensitized)

- Paralytic

3.) Indication:

- Tracheal intubation, decrease NM transmission during anesthesia, control of ventilation, treatment of convulsions (doesn’t tx neurologic processes involved during convulsions)

4.) Side effects:

- - HoTN (d/t histamine release, give with antihistamine)

- Hyperkalemia

- Increased intraocular pressure

- Increased gastric pressure

- Myalgias

134

Describe synthesis of NE, DA and Epi. What is the substrate required for the synthesis? Rate-limiting enzyme?

- Tyrosine

- RLS: Tyrosine hydroxylase

- Tyrosine = Dopa = Dopamine = NE = Epinephrine

- Note: Tyrosine to tyramine to octopamine to NE

135

What are the catecholamines?

- DA, Epi and NE

136

Effect of fermented cheeses and meats on catecholamine synthesis?

- Tyramine is found in these products. Tyramine to octopamine to NE via side pathway in catecholamine synthesis pathway.

137

Function of metyrosine

- Blocks tyrosine hydroxylase preventing the beginning of the catecholamine synthesis pathway.

138

Function of reserpine

- Blocks VMAT (vesicular monoamine transport) that takes DA into the storage vesicles where NE and EPI synthesized

139

Function of bretylium

- Blocks exocytosis (via VAMPS, SNAPs) of catecholamine-containing vesicle at the pre-synaptic nerve terminal.

140

Function of cocaine and TCA

- Blocks the NET1 transport preventing reuptake of catecholamine (NE) from the nerve synapse.

141

Describe the termination of adrenergic transmission

1.) Diffuses: metabolized by COMT (catechol-O-methyl transferase in liver)

2.) Autoreceptor binds ligand causing decrease in release

3.) Re-uptake via NET1, metabolization by MAO (mitochondrial monoamine oxidase)

142

Factors that determine adrenoceptor responses

1.) Receptor specificity

2.) Receptor density

3.) NET presence

4.) Receptor regulation

143

Receptors responsible for the main source of arteriole resistance?

- alpha-1. Increases TPR, DBP and afterload

144

Alpha 1 receptor. Location and response when activated?

- Radial (dilator) muscle of eye: contraction (mydriasis)

- Arterioles (skin and viscera): contraction

- Veins: contraction (increase venous return and pre-load)

- Bladder trigone/sphincter: contraction

- Vas deferens: ejaculation

- Liver: increase glycogenolysis

- Kidney: decrease renin

145

Alpha 2 receptor. Location and response when activated?

- Prejunctional nerve terminal: decrease NT release and NE synthesis

- Platelets: aggregation

- Pancreas: decrease insulin secretion

146

Beta 1 receptor. Location and response when activated?

Beta 2 receptor. Location and response when activated?

Beta 1:
- SA node: increase HR (chronotropy)

- AV node: increase conduction velocity (dromotropy)

- A and V muscle: increase FOC, conduction, CO and o2 consumption

- His: increase automaticity and conduction velocity

- Kidney: increase renin release

Beta 2:
- Blood vessels (all): vasodilation

- Uterus: relaxation

- Ciliary muscle: relaxation, flattening of lens

- Bronchioles: dilation

- SkM: increase glycogenolysis, increase contractility

- Liver: increase glycogenolysis

- Pancreas: increase insulin secretion

147

D1 receptor. Location and response when activated?

- Renal, mesenteric and coronary vasculature: vasodilation. In kidney: increase GFR, RBF and Na excretion

148

How can you tell if someone has overdosed on a drug by looking at their eyes? What type of drug?

- Check if pupil is pin-point or dilated. If mydriasis seen (dilated) it could be d/t M3 antagonist (such as atropine) or alpha-1 agonist.

- M3 activation = miosis and accommodation.

- Alpha-1 activation = mydriasis without accommodation.

- Shine penlight. If pupils constrict, alpha-1 receptor agonist used. If no response from pupils, M3 antagonist has been used.

149

Atropine overdose mnemonic

- Hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter.

- Belladonna atropa: has beautiful eyes and makes you hot (without sweating), mad and have blinded vision.

150

Describe reflex responses upon changes to TPR

- Increase TPR (d/t increase alpha-1 activation) = reflex bradycardia. Alpha-1 agonist = reflex brady.

- Decrease TPR (d/t decrease alpha-1 activation) = reflex tachycardia. Alpha-1 antagonist = reflex tachy.

151

Explain why an alpha-1 antagonist can be dangerous for use in a patient with ischemic heart disease who presents to ED with HTN and chest pain. What is the solution to this? What is the preferred drug in cases of heart failure then?

- Alpha 1 antagonist will cause a decrease in BP, but reflex tachy will set in and increase the HR worsening the ischemia. You can prevent this by using a small dose of beta-1 receptor antagonist to prevent increase in HR.

- Use dobutamine (non-selectie adrenergic agonist). Increases FOC without too much of an increase in HR. Inotropic effect is greater than chronotropic effect.

- Agent of choice for pt with HTN and ischemic disease = beta receptor antagonists. These decrease BP and decrease myocardial o2 consumption.

152

RAAS system

- Low BP = low renal blood flow = increase renin production = increase angiotensin = increase TPR + increase aldosterone = increase blood volume = increase CO = increase BP

153

Adrenergic agonist classes, mechanism and names

1.) Direct-acting (receptor acting)
a.) Selective: phenylephrine (a1), clonidine (a2), metaproterenol (b2), terbutaline (b2), albuterol (b2), ritodrine (b2), fenoldopam (D1)

b.) Non-selective: isoproterenol (b1 and 2), dobutamine (b1, a1, b2), epinephrine (a1, a2, beta1, beta2), NE (a1, a2, b1), dopamine (d1, d2, a1)

2.) Mix-acting (acts on receptor and increases release of NE from vesicles) ephedrine (a1, a2, b1, b2 and releasing agent)

3.) Indirect-acting (act on release of NT)
a.) Releasing agent: amphetamine, tyramine
b.) Uptake inhibitor: cocaine
c.) MAO/COMT inhibitors: pargyline, entacopone

154

How do you maintain selectivity of a drug?

- Low dose. If high enough, selectivity is lost.

155

Which drugs have responses that are not reduced by prior tx with reserpine or guanethidine?

- Direct-acting (selective and non-selective) adrenergic agonists.

156

Which drugs have responses that are potentiated by cocaine, reserpine and guanethidine?

- Direct-acting (selective and non-selective) adrenergic agonists.

157

Which drugs have responses that are reduced by prior treatment with reserpine or guanethidine?

- Ephedrine

158

Which drugs have responses that are abolished by prior treatment with reserpine or guanethidine?

- Amphetamine or guanethidine

159

Phenylephrine (neo-synephrine). Drug class, physiologic effects, indication, other notes

1.) Drug class = alpha-1 selective adrenergic receptor agonist

2.) Physiologic effect:

- Activates alpha-1 receptors on vascular SM = increase in BP and TPR. Can activate beta receptors at high dose.

3.) Indication:

- Anti-hypotensive, paroxysmal atrial tachy, nasal decongestant, mydriatic (responsive to penlight)

160

Clonidine (catapres). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = alpha-2 selective adrenergic receptor agonist

2.) Physiologic effect:

- Activate central alpha-2 receptors = decrease central SNS outflow = decrease BP

- Decrease aqueous humor production = decrease intraocular pressure

3.) Indication:

- Systemic HTN (clonidine and alpha-methyldopa)

- Glaucoma (apraclonidine, brimonidine)

4.) Adverse effects:

- Xerostomia, sedation, HoTN

161

Metaproterenol (metaprel). Drug class, physiologic effects, indication, other notes

1.) Drug class = beta-2 selective adrenergic receptor agonist

2.) Physiologic effect:

- Beta-2 receptor agonist

3.) Indication:

- Long-term tx of obstructive airway dz (asthma) and acute bronchospasm

4.) Other notes:

- Resistant to methylation by COMT

- Less specificity than albuterol or terbutaline and can activate beta-1 causing cardiac effects. Not best for indications above.

162

COMT methylation? What is it?

- Deactivation of catecholamines via methylation

163

Terbutaline (bricanyl). Drug class, physiologic effects, indication, other notes

1.) Drug class = beta-2 selective adrenergic receptor agonist

2.) Physiologic effect:

- Beta-2 receptor agonist

3.) Indication:

- Long-term tx of obstructive airway dz (asthma), acute bronchospasm and emergency tx of status epilepticus via IV

4.) Other notes:

- Not a substrate for COMT methylation.

164

Albuterol (ventolin, salbutamol). Drug class, physiologic effects, indication, other notes

1.) Drug class = beta-2 selective adrenergic receptor agonist

2.) Physiologic effect:

- Beta-2 receptor agonist

3.) Indication:

- Acute bronchospasm

4.) Other notes:

- Delays preterm labor

165

Ritodrine (yutopar). Drug class, physiologic effects, indication, other notes

1.) Drug class = beta-2 selective adrenergic receptor agonist

2.) Physiologic effect:

- Beta-2 receptor agonist

3.) Indication:

- Uterine relaxant: arrest premature labor, prolong pregnancy

166

Adverse effects of beta-2 selective adrenergic agonists

- Excessive activation of beta-receptors = tachy (higher risk in CAD or arrhythmia patients and adverse CV effects if MAOI used), increase plasma glucose/lactate and FFAs, decrease plasma K (esp if taking digoxin and diuretics).

- Adverse effects less likely with inhalation therapy compared to IV or oral.

167

John Smith is taking MAOIs for the past 6 months since Pocahontas left him. He has a history of depression and well-controlled asthma with a rescue inhaler. Late one night he is rushed to the emergency department with complaints of chest pain. His HR is 210 and his blood work shows hyperglycemia and a lactic acidosis. After speaking to Mr. Smith, he states that he tried to overdose using his rescue inhaler. Explain why the patient had this adverse effect.

- Patient is on MAOIs and the plasma concentration of his beta-2 agonist (albuterol rescue inhaler) built up loosing selectivity and excessively activating beta receptors. This resulted in tachycardia, hyperglycemia and a lactic acidosis.

168

Fenoldopam (corlopam). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = D1 selective adrenergic receptor agonist

2.) Physiologic effect:

- D1 agonist, some stimulation of a2. Effets = renal, mesenteric, peripheral and coronary vasodilation. Renal blood flow maintained and natriuresis promoted.

3.) Indication:

- Hypertensive crisis

4.) Adverse effect

- HoTN

169

Isoproterenol (isuprel). Drug class, physiologic effects, indication, other notes

1.) Drug class = non-selective beta (1 and 2) adrenergic receptor agonist

2.) Physiologic effect:

- Powerful beta receptor agonist with no alpha receptor effect. CV effect: decrease TPR, increase HR, increase FOC, bronchodilation.

3.) Indication:

- Bradycardia, AV block, Torsades de pointes

170

Dobutamine (dobutrex). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = non-selective (b1, a1, b2) adrenergic receptor agonist

2.) Physiologic effect:

- Mainly acts on b1. Also with alpha 1 and b2. No effect on release of NE from SNS endings.

- CV effect: increase FOC, HR. TPR unaffected (a1 and b2 balance)

3.) Indication:

- Short term tx of cardiac failure (post-cardiac surgery, CHF, MI)

4.) Adverse effects:

- Excessive increase in BP and HR

- Increased ventricular response rate in pts with afib (too much re-entry of foci to AV and down to ventricles)

- Ventricular ectopic activity

- Increase size of MI (if dose high and HR up to high)

171

Epinephrine. Drug class, physiologic effects (IV vs SQ), indication (and contraindication), adverse effects

1.) Drug class = non-selective (a1, a2, b1, b2) adrenergic receptor agonist

2.) Physiologic effect:

- Potent alpha and beta receptor stimulant with complex effects (see below).

a. Main site of action = smaller arterioles and precap sphincters. Cutaneous BF decrease, skeletal muscle BF increase, unchanged cerebral BF, renal BF down (renin up), pulmonary blood flow up, coronary blood flow up)

b. Cardiac: HR up, decreased systole and diastole time, FOC up, lusitropy (myocardial relaxation) up, increase o2 consumption, increase automaticity

c. Smooth muscle: vascular SM most affected, GI relaxes

- Small IV doses: b1 = increase pulse pressure, increase HR, increase SV and increase CO. b2 = decrease TPR. Overall MAP lowered

- Moderate IV doses: same as above + a1 response = increase TPR, increase BP. Overall MAP remains the same.

- Large IV doses: a1 response greater than b1 and b2 = increase TPR and BP predominates.

- SubQ: slow absorption = vasoconstriction

3.) Indication:

- Cardiac arrest, hypersensitivity rxns (incl. anaphylaxis), local anesthetic, post-extubation croup, viral group
- Note contraindication in those with non-selective beta-blockers

4.) Adverse effects:

- Throbbing HA, tremor, palpitations, cerebral hemorrhage (large dose rapid IV), cardiac arrhythmias, angina in CAD pt

172

What is the epinephrine reversal phenomenon?

- Epi activates both alpha and beta receptors. If you block either before you use epi, then effect on remaining receptors is much more pronounced.

- If alpha antagonist used, Epi induced vasodilation predominates = drop in TPR = drop in MAP

- If beta antagonist used, Epi induced vasoconstriction predominates = increase in TPR = increase in MAP

- Example:
a.) Phentolamine alone (alpha-1 antagonist): decreases MAP, reflex tachy follows

b.) Epi alone (non-selective adrenergic agonist): increase MAP, increase in HR

c.) Phentolamine first then epi: vasodilation (unopposed beta stimulation) = drop in MAP!!, reflex tachy.

173

Norepinephrine. Drug class, physiologic effects, indication, adverse effects

1.) Drug class = non-selective (a1, a2, b1) adrenergic receptor agonist

2.) Physiologic effect:

- Stimulates a1, a2 and b1. Little action on b2. Effects = increase MAP (DBP, DBP and PP increase), increase coronary flow (dilation), = or down CO, increase in TPR (no beta-2), decrease renal BF, decrease splanchnic and hepatic BF.

3.) Indication:

- Tx of low BP

4.) Adverse effects:

- Similar to Epi, but greater elevation of BP: Throbbing HA, tremor, palpitations, cerebral hemorrhage (large dose rapid IV), cardiac arrhythmias, angina in CAD pt

174

Dopamine. Drug class, physiologic effects, indication (+ precautions and contraindications), adverse effects

1.) Drug class = non-selective (d1, d2, b1, a1) adrenergic receptor agonist

2.) Physiologic effect:

- Dose dependent effects.

- Low dose: D1, D2 receptor effect only, therefore no cardiac effect
a.) Pre-synaptic D2: decrease Ne, decrease alpha stimulation of vascular SM

b.) D1 (renal, mesenteric, coronary receptors): vasodilation, increase GFR, increase Na filtered = Na diuresis

c.) D1 (renal tubular cell): decrease Na reabsorption = Na diuresis

- Moderate dose:
a.) Beta1: NE induced tachycardia

b.) Increase SBP and PP, increase MAP, TPR equal

- High dose:
a.) Alpha1: general vasoconstriction

3.) Indication:

- Severe CHF, particularly in pts with oliguria and low/nml peripheral vascular resistance.

- Cardiogenic and septic shock. Cardiac and renal function improvement may be seen in severely ill patients with chronic heart dz or renal failure.

- Precaution: hypovolemia must be corrected before use (esp for alpha-1 effect).

- Contraindication: MAOI and TCA use.

4.) Adverse effects:

- Extravasation of DA into tissue d/t poor infusion technique can lead to ischemic necrosis and sloughing.

- Tachy, angina pain, HA, arrhythmias, HTN

175

Ephedrine. Drug class, physiologic effects, indication, other notes

1.) Drug class = mixed acting (a1, a2, b1, b2 + releasing agent) adrenergic receptor agonist

2.) Physiologic effect:

- Mild CNS stimulant. Acts on receptors and on release of NE from vesicles.

3.) Indication:

- Pseudoephrine (enantiomer) = decongestant.

4.) Adverse effects:

- High bioavailability, relatively long duration of action

176

Amphetamine. Drug class, physiologic effects, indication, adverse effects

1.) Drug class = indirect-acting sympathomimetic amine

2.) Physiologic effect:

- Transported by NET1 (structurally similar). Displaces NE and NE release becomes exocytosis independent.

- CNS effect = release of amines from storage sites in nerve terminals, stimulates the medullary respiratory center, stimulates cortex and reticular activating system = prevent fatigue, delays need for sleep.

- CV effect = activates peripheral alpha and beta, increase SBP and DBP, increase HR.

- Increase bladder sphincter contraction

3.) Indication:

- Obesity (decreases food intake), enuresis (involuntary urination), incontinence

4.) Adverse effects:

- May cause arrhythmias

177

Tyramine. Drug class, physiologic effects, indication, adverse effects

1.) Drug class = indirect-acting sympathomimetic amine

2.) Physiologic effect:

- Used to synthesize NE and Epi via alternative pathway. Destroyed by MAO in the gut wall and liver.

3.) Indication:

- None

4.) Adverse effects:

- Ingestion of tyramin-rich foods (fermented cheese and cured meats + chocolate) = sudden rise in BP.

178

Alpha adrenoceptor antagonists. Type and name.

1.) a1 >>> a2: prazosin, terazosin, doxazosin

2.) a1 > a2: phenoxybenzamine

3.) a1 = a2: phentolamine

4.) a2 > a1: yohimbine, rauwoscine, torazoline

179

General effects of alpha-receptor antagonissts

- Decrease BP, orthostatic HoTN

- Tachycardia reflex (transient, adaptation goes away typically)

- Reverses pressor effects of alpha, beta agonists

- Miosis (radial muscle a1)

- Nasal stuffiness

- Decrease resistance to urine flow (sphincter open)

180

Therapeutic uses of alpha-receptor antagonists

- Pheochromocytoma

- HTN emergencies

- Chronic HTN

- Peripheral vascular dz

- Urinary obstruction

- Erectile dysfunction

181

Phenoxybenzamine (dibenzyline). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = alpha (a1 > a2) receptor antagonist

2.) Physiologic effect:

- Irreversible a1 and a2 blockage (long duration). Also blocks H1, ach and 5-HT receptors. Lower BP, tachy reflex.

3.) Indication:

- Pheochromocytoma, high catecholamine states

4.) Adverse effects:

- Half-life > 1 day. Orthostatic HoTN, tachy, myocardial ischemia

182

Prazosin (minipress). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = alpha (a1 >>> a2) receptor antagonist. Note: other drugs = doxazosin and terazosin.

2.) Physiologic effect:

- a1 selective drug: relaxes arterial, venous and prostate SM. Lower BP, reflex tachy.

3.) Indication:

- HTN, BPH

4.) Adverse effects:

- Orthostatic HoTN with tachy esp with first dose.

183

Tamsulosin (Flomax). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = alpha (a1a) receptor antagonist

2.) Physiologic effect:

- a1a selective antagonist, may relax prostatic SM more than vascular SM

3.) Indication:

- Prostate hyperplasia

4.) Adverse effects:

- Orthostatic HoTN (less common)

184

Yohimbine. Drug class, physiologic effects, indication, adverse effects

1.) Drug class = alpha (a2 > a1) receptor antagonist

2.) Physiologic effect:

- Blocks a2 = increase in central SNS activity = increase in NE release. Raise BP and HR

3.) Indication:

- Male ED, HoTN

4.) Adverse effects:

- Anxiety, excess pressor effect if NET1 blocked (eg. cocaine)

185

Labetalol. Drug class, physiologic effects, indication, adverse effects

1.) Drug class = mixed adrenergic (b > a1) receptor antagonist (third generation)

2.) Physiologic effect:

- Beta blocked > a1 blocked. Vasodilatory = lowers BP with limited HR increase.

3.) Indication:

- HTN

4.) Adverse effects:

- Less tachycardia with lowering of BP (no compensation?)

186

Beta adrenoceptor antagonists. Type and names.

1.) 1st generation: non-selective: b1 = b2: propranolol, nadolol, timolol, pindolol.

2.) 2nd generation: selective: b1 >>> b2: AMEBA mnemonic = atenolol, metoprolol, esmolol, betaxolol, acebutolol

3.) 3rd generation (mixed alpha-beta antagonists): vasodilatory: b1=b2 >= a1>a2: labetalol, carvedilol

187

Drugs that possess ISA (intrinsic sympathomimetic activity)? What does this mean?

- Pindalol and acebutalol = beta-blockers. In addition to inhibiting the receptors (beta-blockers), they also stimulate the receptors.

188

General effect of beta-receptor antagonists

- CV effects: decrease FOC, decrease HR = decrease BP in HTN patients. No effects on normotensive individual. Decrease myocardial o2 consumption. Decrease renin release.

- Respiratory effects: b2 blockage = increase airway resistance.

- Eye: decrease aqueous humor production = decrease in IOP

- Metabolic: inhibits lipolysis, may decrease glucagon release, increase VLDL, decrease HDL

189

Adverse effects of beta receptor antagonists

- Fatigue

- Worsening peripheral vasculature dz (beta-2 blocking)

- Worsening bronchospasm

- Decreases sexual functions.

- Increased incidence of DM

- Masking symptoms of hypoglycemia (NB!!!) – hypoglycemia symptoms = HR, palpitations via neural control of SNS. Now with agonists, HR and palpitations not present. Sweating still remains.

190

Indications for beta receptor antagonists

- HTN

- Ischemic heart dz

- Cardiac arrhythmias

- Heart failure: ANS response to chronic low BP = reflex in SNS outflow and therefore catecholamines up = increase in renin. After a while, beta-1 receptors are downregulated because of chronic activation. If low dose selective beta-1 antagonist used to block existing receptors from effects of high concentrations of circulating catecholamines. Not enough to severely block receptors, just to protect them.

- Glaucoma

- Hyperthyroidism (symptomatic tx for tachy)

- Neurologic dz (migraines, anxiety)

191

Patient has history of asthma and was recently placed on a beta-2 antagonist for newly diagnosed HTN. Patient returns to the clinic for a checkup 6 weeks later and it is noted that the HTN is not improved. Second year resident sees the patient and reports his findings back to the attending recommending increasing the dose. Does the attending agree with the residents decision? Why or why not?

- No. No beta blocker is free of beta-2 blocking effect. This patient is asthmatic. Blocking beta-2 will result in increased airway resistant leading to asthma attack.

192

Important properties to consider when choosing beta-blockers
In order for consideration

- Cardioselectivity (don’t use non-specific in COPD group)

- ISA: intrinsic sympathomimetic activity (in addition to effect as blocking agent, they can also stimulate receptor).

- Lipid solubility (Lipid metabolism by liver. Older patients have decreased liver function. Also be careful in liver failure patient.)

193

Adverse effects of beta-receptor antagonists

- Fatigue

- Worsening peripheral vasculature dz (beta-2 blocking)

- Worsening bronchospasm

- Decreases sexual functions.

- Increased incidence of DM

- Masking symptoms of hypoglycemia (NB!!!) – hypoglycemia symptoms = HR, palpitations via neural control of SNS. Now with agonists, HR and palpitations not present. Sweating still remains.

194

Cell responsible for release of HCl. Function?

- Parietal cell

- Function of HCl: protein digestion, sterilization, nutrient absorption

195

Cell responsible for release of pepsinogen. Function?

- Chief cell

- Function of pepsinogen: protein digestion

196

Cell responsible for release of mucus and bicarb. Function?

- Superficial epithelial cell of stomach

- Function of mucus, bicarb: gastroprotection

197

Cell responsible for release of histamine. Function?

- ECL cell

- Function of histamine: promote HCl secretion

198

Cell responsible for release of gastrin. Function?

- G cell

- Function of gastrin: promote HCl secretion

199

Function of Ach in stomach?

- promote mucus, bicarb and HCl secretion

200

Cell responsible for release of somatostatin. Function?

- D cell

- Function of somatostatin: suppress HCl secretion

201

Substances that suppress HCl secretion

- Somatostatin and PGE2

202

Describe how HCl secretion is regulated in the stomach

- Ach binds = Ca2+ up = proton pump activation (neuronal pathway). Note ach can bind (directly) to parietal cells or onto ECl stimulating histamine release (indirect).

- Gastrin acts on ECL cells (indirect) = release of histamine = activation of Gs = increase cAMP = proton pump activation (endocrine pathway)

- Gastrin binds (direct) = increase Ca2+ = proton pump activation (paracrine pathway)

- PGE2 = activation of Gi = decrease cAMP = proton pump inhibition (paracrine)

203

Role of prostaglandins in stomach

- Increase mucus and bicarb secretion

- Suppress HCl secretion

- Increase gastric blood flow

- NSAIDs prevent this: therefore high acid with less neutralization/protection = ulcers

204

Causes of ulcers

- Most common in US = NSAID use, H. pylori infection

- Other = increase in parietal cells, high serum gastrin (Zollinger-Ellison gastrinoma), rapid gastric emptying, decreased mucosal bicarb secretion, GERD

205

Symptoms of ulcer

- Abdominal pain, nausea, vomiting (incl. hematemesis), bloody/tarry stool, dyspepsia, weight loss, fatigue

206

Drug classes (and drug names) that protect stomach from acid

1.) Antacids: sodium bicarb (alka-seltzer), calcium carbonate (tums), mag hydroxide, aluminum hydroxide (milk of magnesia = mag and al hydroxide)

2.) H2 receptor antagonists: cimetidine (tagemet), ranitidine (zantac), nizatidine (axid), famotidine (Pepcid)

3.) PPIs (proton-pump inhibitors): omeprazole (Prilosec), lansoprazole (prevacid), rabeprazole (aciphex), esomeprazole (nexium), pantoprazole (protonix)

4.) Mucosal protective agents: sucralfate (Carafate), misoprostol (cytotec), bismuth subsalicylate (pepto-bismol)

207

Sodium bicarb (alka-seltzer). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = antacid

2.) Physiologic effect:

- Neutralization of gastric acid. Base + acid = salt + water

3.) Indication:

- GERD, peptic ulcers, dyspepsia

4.) Adverse effects:

- Common with antacids: reduced drug bioavailability, enteric infection
- Metabolic alkalosis, excessive NaCl absorption, gas/bloating

5.) Other notes:

- Equally efficacious as H2-receptor antagonists

- Fast rate of reactivity, short duration of action (1-2 hours)

208

Calcium carbonate (tums). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = antacid

2.) Physiologic effect:

- Neutralization of gastric acid. Base + acid = salt + water

3.) Indication:

- GERD, peptic ulcers, dyspepsia

4.) Adverse effects:

- Common with antacids: reduced drug bioavailability, enteric infection
- Acid rebound (as pH goes up, feedback mechanism prevents it from going to high by increasing amount of acid produced), gas/bloating, hypercalcemia, hypophosphatemia (rare)

5.) Other notes:

- Equally efficacious as H2-receptor antagonists

- Moderate rate of reactivity, short duration of action (1-2 hours)

209

Mag hydroxide (milk of magnesia). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = antacid

2.) Physiologic effect:

- Neutralization of gastric acid. Base + acid = salt + water

3.) Indication:

- GERD, peptic ulcers, dyspepsia

4.) Adverse effects:

- Common with antacids: reduced drug bioavailability, enteric infection
- Osmotic diarrhea, hypermagnesemia (large doses over long period)

5.) Other notes:

- Equally efficacious as H2-receptor antagonists

- Slow rate of reactivity, short duration of action (1-2 hours)

210

Aluminum hydroxide. Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = antacid

2.) Physiologic effect:

- Neutralization of gastric acid. Base + acid = salt + water

3.) Indication:

- GERD, peptic ulcers, dyspepsia

4.) Adverse effects:

- Common with antacids: reduced drug bioavailability, enteric infection
- Constipation, aluminum toxicity (impaired renal function), hypophosphatemia, bone resorption, hypercalcemia

5.) Other notes:

- Equally efficacious as H2-receptor antagonists

- Slow rate of reactivity, short duration of action (1-2 hours)

211

Antacids are note to be equally efficacious as H2-receptor antagonists. What is the clinical downside to using these?

- Must take them very often. Duration of action is only 1-2 hours. Difficult to have patients be compliant on these agents.

- Common adverse effects = reduced drug bioavailability and enteric infection

212

Cimetidine (tagemet). Drug class, physiologic effects, indication, adverse effects, other notes, what other drugs are in this class?

1.) Drug class = H2-receptor antagonist

2.) Physiologic effect:

- Competitive inhibitor of H2 receptors = decrease in HCl secretion. Partially decreases gastrin and muscarinic-induced HCl secretion. Note: all indirect ways of HCl secretion are suppressed here.

3.) Indication:

- GERD, peptic ulcers, dyspepsia, gastritis

4.) Adverse effects:

- Common with this class: headache, diarrhea, fatigue, constipation, infection, drug kinetics, brady (IV), hypotension (IV)

- Cimetidine specific: CNS effects (confusion, hallucinations, agitation), endocrine (inhibition of androgen receptors, inhibition of estradiol metabolism, increase prolactin), inhibition of hepatic CYP metabolism (prevent drug metabolism)

5.) Other notes:

- Equally efficacious as antacids, given less frequently

6.) Other drugs: ranitidine (zantac), nizatidine (axid), famotidine (Pepcid)

213

Omeprazole (prilosece). Drug class, physiologic effects, indication, adverse effects, other notes, what other drugs are in this class?

1.) Drug class = PPI (proton-pump inhibitor)

2.) Physiologic effect:

- Drug is acid-labile and absorbed by GI. Concentrates at site of action = apical surface of parietal cell, concentrates at site of action, activated by low pH and irreversibly binds and inhibits K/H atpase pump. New pump required to have action.

3.) Indication:

- GERD, peptic ulcers, dyspepsia, gastritis, hypersecretory diseases, NSAID-associted ulcers, H. pylori-associated ulcers.

4.) Adverse effects:

- Common with this class (safe drug): decreased drug bioavailability, diarrhea, HA, abdominal pain.

- Other effects: decreased nutrient absorption (B12, Fe, Ca, Zn), enteric/respiratory infection.

5.) Other notes:

- Most efficacious inhibitor of acid secretion. Takes 3-4 days to reach max effect (give antacid or H2 antagonist when first rx this drug). Duration of action = 24 hours.

6.) Other drugs: lansoprazole (prevacid), rabeprazole (aciphex), esomeprazole (nexium), pantoprazole (protonix)

214

Sucralfate (carafate). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = mucosal protective agent

2.) Physiologic effect:

- Adhere to ulcer and create a physical barrier, potentially stimulates mucus secretion through PGs

3.) Indication:

- Prevent stress-related bleeding when you don’t want to suppress acid secretion

4.) Adverse effects:

- Common adverse effects: constipation (gel-like), impaired drug absorption

- Other effects: caution with renal insufficient patient (aluminum contents)

5.) Other notes:

- Duration of action: 6 hours

215

Bismuth Subsalicylate (pepto-bismol). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = mucosal protective agent

2.) Physiologic effect:

- Adhere to ulcer and create a physical barrier, potentially stimulates mucus secretion through PGs. Inhibits intestinal PG synthesis. Also bind bacterial toxins.

3.) Indication:

- H.pylori-associated ulcers, travelers and non-specific diarrhea, dyspepsia

4.) Adverse effects:

- Common adverse effects: blackening of stool and tongue

- Other effects: high dose salicylate toxicity (abdominal pain, dizziness, hallucinations etc.)

5.) Other notes:

- Duration of action: 6 hours

- Effect of this in stomach is reversed to effect in intestines as seen above.

216

Misoprostol (cytotec). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = mucosal protective agent (prostaglandin analogue)

2.) Physiologic effect:

- PG analogue: stimulate mucus/bicarb secretion, suppress HCl secretion, increase gastric blood flow

3.) Indication:

- NSAID-associated ulcers

4.) Adverse effects:

- Common adverse effects: diarrhea and cramping (d/t SM contraction)

- Other effects: abortificent (stimulates uterine muscle, don’t use in pregnant patients)

5.) Other notes:

- Duration of action: 6 hours

217

Treatment strategy for H.pylori-associated gastric ulcers

- 1st line triple therapy = PPI + clarithromycin + amoxicillin or metronidazole (if pen allergy)

- Can add bismuth subsalicylate (pepto-bismol) for quadruple therapy

218

Therapeutic receptor targets on GI smooth muscle

1. Motilin receptor: promotes motility in upper GI tract (stomach and duodenum), effect disappears distally

2. D2 receptor: pre-synaptic receptors that effect release of Ach. Stimulation of receptor = decrease Ach = decrease motility. Vice versa. Also pre-synpatic receptors for release of 5HT.

3. Ach binds M3 = promotion of SM contraction

4. Serotonin receptor 4 = promote and inhibit neuronal firing to regulate gut motility.

219

Prokinetic drugs. Type, name, use and adverse effect

- D2 antagonist: metoclopramide (reglan) for GERD, impaired gastric emptying, dyspepsia and antiemetic. Adverse effect = CNS (restlessness, drowsy, insomnia, anxiety), altered motor function (Parkinsonian symptoms)

- M3 agonist: bethanechol (urecholine) for GERD and gastroparesis. Adverse effect = see cholinergic side effects.

- AchE inhibitor: neostigmine (prostigmin) for non-obstructive urinary retention and abdominal distention. Adverse effect = see cholinergic side effects.

- Erythromycin: motilin receptor agonist for gastroparesis. Adverse effect = erythromycin side effects = diarrhea.

220

Laxatives. Drug class and name

1.) Bulk-forming: methylcellulose (Citrucel)

2.) Stool softeners: glycerin (colace)

3.) Osmotic: lactulose (enulose), polytethylene glycol (PEG)

4.) Stimulant: senna (ex-lax)

5.) Serotonin partial agonist: tegaserod (zelnorm)

6.) PG derivative (chloride channel activator): lubiprostone (amitiza)

7.) Mu-opioid receptor antagonists: methylnaltrexone (relistor), alvimopan (entereg)

221

Methlycellulose (citrucel). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = bulk-forming laxative

2.) Physiologic effect:

- Fiber resistant to digestion. Fiber retains water in GI, stimulates peristalsis via bulk.

3.) Indication:

- Constipation, minimize straining, prior to surgical / endoscopic GI procedure

4.) Adverse effects:

- Gas/bloating

5.) Other notes:

- Route = oral (with lots of water!!!)

222

Glycerin (Colace). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = stool-softening laxative / surfactant

2.) Physiologic effect:

- Not quite well understood. Possibly through mixing, softening and coating of stool

3.) Indication:

- Constipation, minimize straining, prior to surgical / endoscopic GI procedure

4.) Adverse effects:

- Nutrient malabsorption

5.) Other notes:

- Route = oral or rectal.

223

Lactulose (enulose). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = osmotic laxative

2.) Physiologic effect:

- Non-absorbable sugar/salt that induces changes in osmotic pressure

3.) Indication:

- Constipation, minimize straining, prior to surgical / endoscopic GI procedure

4.) Adverse effects:

- Gas, electrolyte flux

5.) Other notes:

- Route = oral or rectal.

224

Senna (ex-lax). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = stimulant laxative

2.) Physiologic effect:

- not well understood: stimulation of ENS, inducing a leaky mucosa, inhibiting sodium uptake by gut

3.) Indication:

- Constipation, minimize straining, prior to surgical / endoscopic GI procedure

4.) Adverse effects:

- GI irritation

5.) Other notes:

- Route = oral or rectal.
- Senna = anthraquinone derivative (as aloe)

225

Tegaserod (zelnorm). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = serotonin agonist (not available for general use)

2.) Physiologic effect:

- Activation of 5HT4 receptor (pre-synaptic) promote NT (eg. Ach) release and motility. Also decrease in sensory neuron firing to block pain.

3.) Indication:

- Chronic idiopathic constipation (IBS-constipation)

4.) Adverse effects:

- GI and CV (MI and stroke)

5.) Other notes:

- 10% absorbed, therefore adverse effects

226

Lubiprostone (amitiza). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = PG derivative (chloride channel activator)

2.) Physiologic effect:

- Chloride channel (CIC2) activator. Increase concentration of Cl in gut = water and Na accumulation = stool softening and motility stimulated.

3.) Indication:

- Chronic constipation

4.) Adverse effects:

- Nausea, vomiting, diarrhea

5.) Other notes:

- Poor absorption

227

Lubiprostone (amitiza). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = PG derivative (chloride channel activator)

2.) Physiologic effect:

- Chloride channel (CIC2) activator. Increase concentration of Cl in gut = water and Na accumulation = stool softening and motility stimulated.

3.) Indication:

- Chronic constipation

4.) Adverse effects:

- Nausea, vomiting, diarrhea

5.) Other notes:

- Poor absorption

228

Methylnaltrexone (relistor). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = mu-opioid receptor antagonist

2.) Physiologic effect:

- Mu-opioid receptor activation = constipation resulting from delayed intestinal motility. These drugs block this.

3.) Indication:

- Opioid-induced constipation during palliative care

4.) Adverse effects:

- Abdominal pain, flatulence, nausea, diarrhea

5.) Other notes:

- Poor CNS penetration

229

Alvimopan (entereg). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = mu-opioid receptor antagonist

2.) Physiologic effect:

- Mu-opioid receptor activation = constipation resulting from delayed intestinal motility. These drugs block this.

3.) Indication:

- Post-op ileus in hospitalized patients with bowel resection

4.) Adverse effects:

- GI (abdominal pain, flatulence, nausea, diarrhea)
- MI (only use this drug for 7 days)

5.) Other notes:

- Poor CNS penetration

230

Treatment strategies for diarrhea

- Infection: antimicrobials

- Inflammation: anti-inflammatory agents

- Osmotic diarrhea: avoid lactose

- Secreting tumors: hormonal therapy

231

Antidiarrheal drugs. Types and names

- Opioid agonist: loperamide (Imodium), diphenoxylate (lomotil)

- PG synthesis inhibitor: bismuth subsalicylate (pepto-bismol)

- Bile acid/salt binder: cholestyramine (prevalite)

- Somatostatin receptor agonist: octreotide (sandostatin)

232

Loperamide (Imodium). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = opioid agonist

2.) Physiologic effect:

- Opioids alter GI SM by decreasing peristalsis, increasing segmentation, increasing anal sphincter tone, decrease perception of GI distention (and pain therefore).

3.) Indication:

- Diarrhea (IBS)

4.) Adverse effects:

- Constipation (very safe)

5.) Other notes:

- Poor CNS penetration

233

Diphenoxylate (lomotil). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = opioid agonist

2.) Physiologic effect:

- Opioids alter GI SM by decreasing peristalsis, increasing segmentation, increasing anal sphincter tone, decrease perception of GI distention (and pain therefore).

3.) Indication:

- Diarrhea

4.) Adverse effects:

- CNS effects, atropine effects

5.) Other notes:

- Greater CNS penetration in comparison to loperamide, but less than bona fide opioids. Combined with atropine to deter someone from taking for opioid stimulation. Also atropine causes cholinergic antagonist effect that are beneficial in treating the diarrhea too

234

Cholestyramine (prevalite) Drug class, physiologic effects, indication, adverse effects

1.) Drug class = bile acid and salt binder

2.) Physiologic effect:

- Binds bile salts causing them to be excreted in feces

3.) Indication:

- Impaired bile-salt absorption mediated diarrhea

4.) Adverse effects:

- Bloating, flatus, constipation, fecal impaction, impaired fat absorption

235

Octreotide (sandostatin). Drug class, physiologic effects, indication, adverse effects, other notes

1.) Drug class = somatostatin receptor agonist

2.) Physiologic effect:

- Agonist on somatostatin receptor. Somatostatin blocks acid secretion, increases fluid absorption, decreases SM contraction, decreases bile flow, inhibits GB contraction and inhibits Sphincter of Oddi relaxation

3.) Indication:

- Severe secretory diarrhea

4.) Adverse effects:

- Impaired pancreatic secretion, decreased GI motility (nausea, pain), decreased GB contraction, glucose homeostasis

5.) Other notes:

- Administer IV or SC

236

Vestibular receptors involved in the emetic response

- H1 and M1

237

Antiemetic agents. Type and name

1.) Direct
a. Ondansetron (Zofran): 5HT3 antagonist
b. Scopolamine (transderm scop): M1 antagonist
c. Metoclopramide (octamide): D2 antagonist
d. Dimenhydrinate (Dramamine): H1 antagonist
e. Aprepitant (emend): NK1 antagonist
f. Prochloperazine (compro): M1, D2 and H1 antagonist

2.) Indirect
a. Lorazepam (Ativan): GABA agonist
b. Nabilone (cesamet): cannabinoid agonist
c. Dexamethasone: glucocorticoid agonist

238

Ondansetron (Zofran). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = 5HT3 antagonist

2.) Physiologic effect:

- 5HT3 antagonist

3.) Indication:

- Chemotherapy, postoperative, postradiation - antiemetic

4.) Adverse effects:

- HA, dizziness, constipation, prolonged QT

239

Scopolamine (transderm scop). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = M1 antagonist

2.) Physiologic effect:

- M1 antagonist

3.) Indication:

- Motion sickness (anti-emetic)

4.) Adverse effects:

- Antimuscarinic effects

240

Metoclopramide (octamide, reglan). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = D2 antagonist

2.) Physiologic effect:

- D2 antagonist

3.) Indication:

- Chemo and radiation therapy induced nausea and vomiting, GERD, impaired gastric emptying, dyspepsia

4.) Adverse effects:

- CNS (restlessness, drowsy, insomnia, anxiety), altered motor function/extra-pyramidal (Parkinsonian symptoms).

241

Dimenhydrinate (Dramamine). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = H1 antagonist

2.) Physiologic effect:

- H1 antagonist

3.) Indication:

- Motion sickness (anti-emetic)

4.) Adverse effects:

- Drowsiness

242

Aprepitant (emend). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = NK1 antagonist

2.) Physiologic effect:

- NK1 antagonist (NK1 receptor for substance P)

3.) Indication:

- Chemotherapy antiemetic

4.) Adverse effects:

- Fatigue, dizziness, diarrhea, CYP34A interactions (check drug-drug interactions)

243

Prochloperazine (compro). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = M1, D2, H1 antagonist

2.) Physiologic effect:

- M1, D2, H1 antagonist

3.) Indication:

- Severe nausea and vomiting

4.) Adverse effects:

- Extrapyramidal, drowsiness, anticholinergic

244

Lorazepam (Ativan). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = GABA agonist

2.) Physiologic effect:

- GABA agonist

3.) Indication:

- Anxiety, chemotherapy (antiemetic)

4.) Adverse effects:

- Drowsiness

245

Nabilone (cesamet). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = Cannabinoid agonist

2.) Physiologic effect:

- Cannibinoid agonist

3.) Indication:

- Chemotherapy antiemetic

4.) Adverse effects:

- Dysphoria, sedation, increased appetite

246

Dexamethasone. Drug class, physiologic effects, indication, adverse effects

1.) Drug class = Glucocorticoid agonist

2.) Physiologic effect:

- Glucocorticoid agonist

3.) Indication:

- Post-op, chemotherapy antiemetic, increase effectiveness of 5HT antagonists

4.) Adverse effects:

- Weight gain, water retention, other corticosteroid effects

247

Pathophysiological differences between IBS and IBD

- IBS: idiopathic chronic relapsing disorder characterized by abdominal pain, bloating, distension, cramp in association with diarrhea, constipation or both.

- IBD: refers to Crohn’s and Ulcerative colitis. Crohn’s = idiopathic inflammatory disorder affecting any part of GI tract. UC = chronic inflammatory disease causing ulcerations of colonic mucosa (typically distally).

248

Role of serotonin and their receptors in regulating motility and sensation of pain in GI tract.

- 5HT4 activation = NT release in ENS resulting in motility

- 5HT4 activation = decrease firing of extrinsic sensory neurons to CNS (to block pain)

- 5HT3 blocking = block visceral pain, motility and secretions

249

IBS treatments. Names, types and mechanism of drugs

- Tegaserod (Zelnorm): 5HT4 partial agonist – treats IBS-constipation

- Alosteron (Lotrenex): 5HT3 antagonist – treats IBS-diarrhea only in women

250

Alosetron (lotrenex). Drug class, physiologic effects, indication, adverse effects

1.) Drug class = 5HT3 antagonist

2.) Physiologic effect:

- Blocking pre-synaptic 5HT3 receptor = decrease in Ach, therefore block visceral pain detection and also motility and secretion resulting from ach activation

3.) Indication:

- IBS-diarrhea predominant (in women only)

4.) Adverse effects:

- Constipation, fatal ischemic colitis

251

IBD treatments. Names, types and mechanism of drugs.

1. Aminosalicylates (ASA): inhibition of cox (PG decreases), interfere with inflammatory cytokine production, inhibit NF-kB signaling
- Names: sulfasalazine, balsazide, olsalazine, mesalamine-pentasa, mesalamine-asacol, mesalamine-rowasa and canasa

2. Glucocorticoids: suppress many inflammatory processes

- Names: prednisone, prednisolone, hydrocortisone, budesonide

3. Antimetabolites: inhibit immune cell proliferation

- Names: 6-mercaptomurine, azathioprine, methotrexate

4. Anti-TNF-alpha: inhibition of TNF-alpha mediated immune response

- Names: infliximab

252

First line agent for mild-moderate IBD

- Sulfasalazine (aminosalicylate): inhibit cox, interfere with inflammatory cytokine production and inhibit NF-kB

- Mesalamine (aminosalicylate): same as above

253

Agent for moderate to severe IBD

- Prednisone (glucocorticoid): suppresses many inflammatory processes

- Infliximab (anti-TNF alpha): inhibits TNF-alpha mediated immune response

254

Agent to maintain remission of IBD

- Azathioprine (antimetabolite): inhibits immune cell proliferation

- Methotrexate: see above