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Flashcards in Exam 5 Deck (194):
1

What is the basic structure of the epidermis and how does it affect percutaneous drug absorption?

- Stratum corneum (aka horny layer) – these are dead keratinocytes (aka corneocytes). This area of skin varies in thickness depending on the part of the body. This is the major barrier to percutaneous absorption and RLS.

- Stratum granulosum, stratum spinosum, stratum basale

2

Identify and describe the variables affecting PCA (percutaneous drug absorption).

1. Drug variables

- Concentration, lipophilicity, molecular size

2. Skin variables

- Stratum corneum thickness (RLS), cutaneous vasculature, area of absorptive surface, mucosal surface

3. Other: inflammation, ulceration, skin hydration, occlusion of medication, age

3

Identify and describe conditions that influence the choice of vehicles.

1. Body area

- Scalp and hairy areas: use lotions, gels, solutions, foams and aerosols

- Intertrigenous areas: use creams, lotions and solutions. Never ointments (water in oil emulsion)

2. Condition of skin

- If it is wet, dry it. If it is dry, wet it.

- Ointments, creams, gels for dry scaly skin. Tinctures, powders and pastes for wet oozing skin.

4

Which areas of the body are more likely to absorb higher amounts of a topical agent leading to systemic exposures/effects?

- Mucous membranes (#1), scrotum, eyelids, face

- Chest/back, arms/legs, dorsa, palmar and plantar surface, nails (#9)

5

What antibiotics are used to treat acne? How do they work?

- Erythromycin, clindamycin: inhibit protein synthesis of Propionibacterium acnes

- Metronidazole: disrupting DNA

- Sodium sulfacetamide: kills P. acnes by inhibiting folic acid biosynthesis

- Azelaic acid: reduces growth of bacteria such as P. acnes and S. epidermidis; reduces inflammation, reduces keratinization, keratolytic

6

Azelaic acid side effects

- Lightening of skin and dryness

7

Benzoyl peroxide. Clinical use, MOA

- Clinical use: non-inflammatory and inflammatory acne

- MOA: antibacterial by release oxygen (bad for anaerobes), anti-inflammatory by inhibiting neutrophils, keratolytic activity, comedolytic

8

Salicylic acid. Clinical use, MOA

- Clinical use: acne

- MOA: keratolytic, increases solubilization of stratum corneum by altering keratin and breaking H bonds, clears comedones by desquamation

9

What are the general adverse effects of using retinoid products?

- Photosensitivity and increased risk for severe sunburns

10

Tretinoin. Clinical use, MOA, adverse effects

- Clinical use: acne, photoaging

- MOA: decreases cohesiveness of follicular epithelial cells that are responsible for producing microcomedones, increase mitotic activity in follicular cells causing extrusion of comedones, reduces keratinization

- Adverse effects: photochemically unstable (apply at night) causing sunburn/sensitivity, don’t use with benzoyl peroxides which inactivates tretinoin, pruritus, erythema, xerosis, pregnancy C teratogen

11

Adapalene. Clinical use, MOA, adverse effects

- Clinical use: acne

- MOA: reduces cellular proliferation and inflammation, comedolytic

- Adverse effects: pruritus, erythema, xerosis (dry skin)

12

Isotretinoin. Clinical use, MOA, adverse effects

- Clinical use: severe acne (this is big gun drug), oral use

- MOA: suppress sebum production by inducing apoptosis in sebum producing cells of sebaceous glands

- Adverse effects: significant risk of teratogenesis, women must be on effective contraceptive 1 month prior, during and for one or more menstrual cycles following tx

13

Tazarotene. Clinical use, MOA, adverse effects

- Clinical use: psoriasis and mild/moderate acne, also decrease fine wrinkles

- MOA: decrease inflammation and epidermal hyperproliferation

- Adverse effects: teratogenic, pregnancy cat X (contraceptives must be used), photosensitivity

14

Can retinoids be used during pregnancy? Which are relatively safer?

- Preferentially not. If benefits outweigh risk, use tretinoin and adapalene, which are class C. Isotretinoin and tazarotene are category X drugs and require contraceptive use. Also avoid acitretin used for psoarisis.

15

What drugs inhibit sebaceous gland function?

- Antiandrogens, oral contraceptives and isotretinoin

16

Acitretin. Clinical use, MOA, adverse effects

- Clinical use: severe, recalcitrant psoriasis

- MOA: unknown

- Adverse effects: highly teratogenic (avoid in pregnancy), combination with etoh causes conversion in etretinate, which has a half-life greater than 3 months. Women should avoid pregnancy for 3 years after administration of this agent!

17

Calciprotriene. Clinical use, MOA, adverse effects

- Clinical use: moderate to severe psoriasis

- MOA: binds vit D receptor, inhibits proliferation of keratinocytes, reduces inflammation

- Adverse effects: slight risk of hypercalcemia and hypercalciuria

18

Corticosteroids. Clinical use, MOA, adverse effects

- Clinical use: atopic dermatitis, psoriasis +

- MOA: reduce inflammation and inhibit immune function

19

In terms of strength/potency of corticosteroids, rank the following: mometasone furoate, clobetasol propionate and hydrocortisone

- Weak = hydrocortisone

- Intermediate = mometasone furoate

- Super high = clobetasol propionate

20

Describe important considerations when administering topical corticosteroids

- Initiate lowest potency to control dz

- If large SA, tx with low to medium potency

- Low-potency on face and intertriginous areas. Potent on palms and soles.

- Avoid high dose in infants and young children other than for short-term use.

- Tachyphylaxis (diminished therapeutic effect) when high potency used daily for 2 x weeks. Can alternate days to prevent.

21

Adverse effects with topical corticosteroid use

- Topical: atrophy, acne, enhanced fungal infection, retarded wound healing, contact dermatitis, glaucoma/cataracts

- Systemic: HPA suppression, Cushing syndrome, growth retardation

22

Psoralens. How are these drugs used? Names? Uses? Adverse effects?

- Taken orally, then skin is exposed to UVA

- Methoxsalen and trioxsalen

- Uses: alopecia, cutaneous T-cell lymphoma, eczema, psoriasis

- Adverse effects: N, blistering, painful erythema, photoaging, actinic keratoses, non-melanoma skin cancer

23

Effect of histamine on nervous system, CV system, pulmonary system and immune system

- Nervous system: circadian pattern release (high day, low nigh) from hypothalamus controls release of pituitary hormones, wakefulness and appetite/satiety. In peripheral and central NS, mediates itch

- CV system: vasodilation, increased vascular permeability, increased FOC in heart and increase HR (not prominent)

- Pulmonary system: secretions, bronchoconstriction

- Immune system: immune cell adhesion, vascular permeability allowing immune cells to site of inflammation, chemotaxis of eosinophils and neutrophils, inflammatory cytokines, increase antigen presentation from APC cells

24

Describe H1 and H2 receptors in terms of where each is found and receptor signaling

1. H1: SM cells, vascular endothelial cells, CNS neurons, peripheral sensory nerves. From pharmacology point of view, agents that block these function to block allergic cascade.

- Receptor: Gq – PLC, IP3 and Ca

2. H2: gastric parietal cells, cardiac muscle, CNS neurons. From pharmacology point of view, agents that block these lea to decrease in gastric acid secretion.

- Receptor: Gs – AC = increase cAMP

25

Describe mechanisms of histamine release from mast cells

- Cytologic release: membrane damage, high levels of drugs such as phenothiazines and opioids

- Non-cytologic release: immune response requiring previous sensitization, non-immunologic response from basic polypeptides such as substance P/wasp venom, OR morphine, codeine, contrast, some antibiotics

26

Identify and describe the differences and mechanistic explanations for the differences bw 1st and 2nd generation H1 antihistamines

- 1st gen: dirty drug and inhibit more than just H1 (which they do effectively), including ACH muscarinic, alpha-1, serotonin. These are sedating typically, cross BBB

- 2nd gen: clinical use, non-sedating, don’t cross BBB as these have reduced lipophilicity

27

Identify which antihistamines are 1st or 2nd generation. Use?

- 1st generation: allergies, N/V, motion sickness, sedative, sleep aid, extrapyramidal sx associated with antipsych drugs, cough, common cold
o Chlorpheniramine: sedating, primarily for allergic rhinitis, other allergic
o Diphenhydramine (Benadryl): allergic rhinitis, allergic conjunctivitis, urticaria, cough suppressant, relief of motion sickness, sedative
o Pyrilamine: sedative
o Hydroxyzine: sedative, antiemetic, sedative, mild anxiolytic, skin allergies
o Meclizine: motion sickness, vertigo
 Promethazine: motion sickness, antiemetic

- 2nd generation: see above for use, non-sedating so not used for sedative, sleep aid purposes
o Fexofenadine (Allegra)
o Loratidine (Claritin)
o Desloratadine (Clarinex)
o Levocetirizine (Xyzal)
o Cetirizine (Zyrtec)
o Azelastine (Atelin): intranasal and opthalmic

28

Chlorpheniramine. Clinical use

- 1st generation H1 anti-histamine

- Use: allergic rhinitis, other allergic conditions

29

Diphenhydramine. Clinical use

- 1st generation H1 anti-histamine

- Use: allergic rhinitis, allergic conjunctivitis, urticaria, cough suppressant, relief of motion sickness; sometimes to reduce extrapyramidal rxns of antipsychotics; parenterally for acute dystonic rxns to antipsychotics

30

Pyrilamine. Clinical use

- ? allergies – doesn’t really specify

31

Hydroxyzine. Clinical use

- Use: antiemetic, sedative, mild anxiolytic, skin allergies

32

Meclizine. Clinical use

- Use: motion sickness and vertigo

33

Promethazine. Clinical use

- Use: anti-motion sickness, antiemetic, local anesthetic effects by changing Na channels in excitable membranes

34

Cyproheptadine. Clinical use

- Allergies?, sometimes used to tx serotonin syndrome

35

What antihistamines have the strongest:
a. Anticholinergic actions
b. Sedative actions
c. Anti-emetic
d. Anti-motion sickness actions
e. Anti-serotonin receptor effects
f. Anti-Alpha-adrenergic receptor effect

a. Diphenhydramine, promethazine

b. Diphenhydramine, promethazine, hydroxyzine

c. Diphenhydramine, promethazine, hydroxyzine, meclizine

d. Is this the same as c. above

e. Cyproheptadine

f. Promethazine

36

What are the drug interactions with 1st gen H1 antihistamines?

- MAOIs

- Additive sedative effects with opioids, etoh and other sedatives

- Additive anti-cholinergic effects

- Accidental or intentional overdose with diphenhydramine

- Max dose daily of 300 mg: toxicity = extreme drowsiness, delirium coma, respiratory depression, sinus tachy, QT prolongation, ventricular arrhythmias

37

Azelastine. Clinical use, MOA

- 2nd generation H1 receptor antagonist

- Intranasal and opthlamic for allergies

- MOA: H1 receptor antagonist, also inhibits mast cell histamine release

38

Adverse effects of 2nd generation H1 anti-histamines

- Less sedating than 1st generation. Levo- and cetirizine are relatively more sedating than others.

39

Cromolyn and nedocromil. Clinical use, MOA

- Use: nasal spray or eye drops to tx allergic rhinitis and allergic conjunctivitis (also prophylaxis)

- MOA: ? inhibition of chloride channels in cell membranes, stabilized mast cells inhibiting degranulation

40

Omalizumab. Clinical use, MOA

- Use: tx of asthma, chronic urticaria

- MOA: recombinant humanized monoclonal ab binds to IgE

41

Doxepin. Clinical use, MOA

- Use: tx of chronic urticaria

- MOA: inhibits both H1 and H2 receptors

42

Ketotifen. Clinical use, MOA

- Use: opthalmic preparation for allergic conjunctivitis

- MOA: H1 antihistamine with additional mast cell and basophil stabilizing properties

43

What is the role of the hypothalamus (part of HPA axis) in the release of adrenal hormones? (how does it receive signals/ what does it release?)

Receive signals induced by diurnal rhythms and emotional stress from higher order CNS and associated stressors (ie: fever, inflammation, hypotension, and hypoglycemia).

Release Corticotropin-releasing hormone (CRH)

44

What is the role of the anterior pituitary (part of HPA axis) in the release of adrenal hormones? (how does it receive signals/what does it release?)

CRH activates GPCRs on the corticotropic cells of the anterior pituitary.

Rapid secretion of ACTH

Slower increase in synthesis of ACTH

45

What is the role of the adrenal cortex (part of HPA axis) in the release of adrenal hormones?

ACTH activates receptors on the adrenal cortical cells which results in steroidogenic enzyme expression and the synthesis of cortical steroids.

ACTH stimulates production or cortisol and adrenal androgens

46

What regulates aldosterone production?

Angiotensin II and blood K+

47

How do cortisol/glucocorticoids affect the HPA axis?

Negative feedback by binding glucocorticoid receptor in the cytoplasm of corticotroph cells in the anterior pituitary and CRH-secreting neurons in the hypothalamus

GRs translocate to the nucleus where they are bound by cortisol where they can significantly inhibit the synthesis of ACTH and CRH

48

What is the effect of administration of high levels of glucocorticoids?

Inhibited synthesis of ACTH and CRH results in cortical atrophy and a decrease in the ability of the adrenal cortex to produce cortisol

49

What is the effect of rapid withdrawal from high levels of glucocorticoids?

Hypocortisolism which can lead to morbidity and mortality

50

What is the MOA of glucocorticoids?

Bind to the glucocorticoid receptor in the cytoplasm which causes the receptor/glucocorticoid to move to the nucleus and bind DNA to affect gene transcription

51

What are the metabolic effects of glucocorticoids?

up plasma glucose, up liver gluconeogenesis, up protein synthesis, up breakdown of muscle into amino acids, up lipolysis, anti-insulin in peripheral tissues (not brain and heart)

52

How do glucocorticoids regulate Epi and NE functions?

up glycogen synthesis, up glycogenolysis by epi/NE, up epi/NE receptor expression, up enzymes that convert NE = epi

53

How do glucocorticoids regulate the immune/inflammatory systems?

inc inflammation by inhibiting prostaglandins, thromboxane, and leukotriene production by inhibiting phospholipase A2

inc circulating eosinophil, basophil, and lymphocyte counts, inhibits recruitment of neutrophils/macrophages to inflammatory site

dec permeability and dilation of capillaries (Reduces edema)

54

What are the uses for glucocorticoids?

1. Anti-inflammatory: Asthma, hypersensitivity states, autoimmune/inflammatory states, prevent GVHD, in neoplastic disease in combination with cytotoxic drugs

2. Replacement therapy for patients with adrenal failure (Addison’s disease)

3. Stimulation of lung maturation when labors starts prior to 34 weeks

55

Side effects with less than 2 weeks use of glucocorticoids

Insomnia, hypomania, acute peptic ulcers (not usually major side effects)

56

Side effects of more than 2 weeks use of glucocorticoids

1. Iatrogenic Cushing’s Syndrome

2. Metabolic: hyperglycemia, truncal obesity, retarded somatic growth, increased protein catabolism, severe myopathy, osteoporosis

3. Masking of clinical symptoms of bacterial infections

4. Increased intraocular pressure (glaucoma) -common

5. Sodium ad fluid retention (mineralocorticoid effect)

6. Elevated BP

7. HPA axis suppression –may take up to 12 months to return to normal after cessation of therapy

57

What drugs interact with glucocorticoids?

Barbiturates, carbamazepine, rifampin, estrogens, androgens, cyclosporin, NSAIDs, hypoglycemic meds, BP meds, and glaucoma meds, K+ depleting diuretics

58

Are the effects of glucocorticoids increased or decreased with co-administration of barbiturates?

Decreased because barbiturates induce activity of P450s

59

Are the effects of glucocorticoids increased or decreased with co-administration of carbamazepine?

Decreased because carbamazepine induces P450s

60

Are the effects of glucocorticoids increased or decreased with co-administration of Estrogens?

Increased because estrogens compete for the bindings sites of P450s –decreases metabolism of glucocorticoids

61

Are the effects of glucocorticoids increased or decreased with co-administration of Androgens?

Increased because androgens compete for the bindings sites of P450s –decreases metabolism of glucocorticoids

62

Are the effects of glucocorticoids increased or decreased with co-administration of Rifampin?

Decreased because rifampin induces P450s

63

Are the effects of glucocorticoids increased or decreased with co-administration of cyclosporin?

Increased because cyclosporin competes for the bindings sites of P450s –decreases metabolism of glucocorticoids

64

What is the risk of combining NSAIDs with glucocorticoids?

Increased risk of stomach ulcers

65

What is the risk of combining diuretics and glucocorticoids?

K+ depleting diuretics and glucocorticoids can both cause K+ loss

66

What is the risk of using glucocorticoids with hypoglycemic, BP, and glaucoma meds??

Decreased effectiveness of these meds when used with glucocorticoids

67

Which glucocorticoids are pro-drugs?

Cortisone and Prednisone

68

How are cortisone and prednisone metabolized into active agents?

They require and 11-OH group to activate GR (glucocorticoid receptor)

Hydroxylation by 11 β-hydroxylase (11 β-HSD1)

Mostly in the liver, but also in adipose, skin, CNS, and placenta

69

What is the duration of action, relative anti-inflammatory potency (effect), and salt-retaining potency of cortisol?

Short acting (1-12 hours)

relative anti-inflammatory: 1

salt-retaining potency: 1

70

What is the duration of action, relative anti-inflammatory potency (effect), and salt-retaining potency of Prednisone?

Intermediate acting (12-36 hours)

Relative anti-inflammatory: 4

Salt-retaining potency: 0.8 (synthetic so can’t bind MR –thus basically no salt retention)

71

What is the duration of action, relative anti-inflammatory potency (effect), and salt-retaining potency of Dexamethasone?

Long acting (36-55 hrs)

Relative anti-inflammatory: 30

Salt-retaining potency: 0 (also synthetic so can’t bind MR)

72

What is the duration of action, relative anti-inflammatory potency (effect), and salt-retaining potency of Fludrocortisone?

Short acting (1-12 hrs)

Relative anti-inflammatory: 10

Salt-retaining potency: 125 –mineralocorticoid

73

What is the result of inhibition of 17-α-hydroxylase?

Prevents formation of cortisol pathway (does not affect aldosterone pathway)

74

What does 11-β-hydroxylase type I do?

Type I: Converts 11-deoxycortisol  cortisol (inactive cortisone to active cortisol)

75

What does 11-β-hydroxylase type II do?

-Converts active cortisol into inactive cortisone (in mineralocorticoid responsive tissues –kidney)

-saturated with elevated cortisol levels  activate MR (aldosterone) Na+/H2O retention, hypokalemia and HTN

76

What is the MOA and uses for Ketoconazole?

MOA: inhibit 17-α-hydroxylase (also 11-β-hydroxylase at high levels)

Use: treat Cushing’s syndrome

77

What is the MOA and uses for Metyrapone?

MOA: Inhibits 11-β-hydroxylase

Uses: diagnostic to evaluate ACTH production

-off label treatment of Cushing’s

78

What is the MOA and uses for Mifepristone?

MOA: GR antagonist

Uses: anti-progestin effects used to terminate pregnancy

-higher doses- GC receptor antagonist

-treat inoperable patients with ectopic ACTH secretion or adrenal carcinoma

79

What are some causes of Cushing’s syndrome?

Chronic glucocorticoid therapy

Pituitary tumor that causes hypersecretion of ACTH

Ectopic hypersecretion of ACTH by non-pituitary tumors

Adrenal tumor that hypersecretes cortisol

80

What are the symptoms of Cushing’s syndrome?

HTN, deposition of fat in upper abdomen and thorax (buffalo hump), round face (moon face), decreased wound healing, muscle wasting, emotional problems, increased susceptibility of infection, hyperglycemia, etc.

81

In pituitary hypersecretion of ACTH, will CRH and ACTH be increased or decreased? What will be the result of the high dose dexamethasone suppression test?

dec CRH
inc ACTH
Suppression test: 50% reduction in cortisol

82

In an adrenal adenoma, will CRH and ACTH be increased or decreased? What will be the result of the high dose dexamethasone suppression test?

dec CRH
dec ACTH
Suppression test: no reduction in cortisol

83

In ectopic ACTH production, will CRH and ACTH be increased or decreased? What will be the result of the high dose dexamethasone suppression test?

dec CRH
inc ACTH
Suppression test: no reduction in cortisol

84

What are some affects that lead to asthma symptoms?

Airway smooth muscle cells proliferate and undergo hypertrophy
Inflammation causes vascular endothelial cells to become leaky

85

What glucocorticoids are inhaled and used as asthma treatment?

Fluticasone, budesonide, mometasone, triamcinolone -often mixed with corticosteroids

86

What is the effect of inhaled glucocorticoids?

Reduce vascular endothelial leaking

Reduce growth of ASMs (airway smooth muscle cells)

Reduce adhesion molecules in airway epithelial cells

Results in increased epithelial integrity

87

What are the effects/interactions between corticosteroid and β-2 receptor agonists?

Corticosteroid: inc β-2 receptor expression and prevent desensitization of β-2 receptors

Β-2 agonist: inc nuclear translocation of GRs and inc binding of GRs to GREs on genes

88

Not an objective: What is the cause of Addison’s disease? What are the symptoms/consequences? How do we treat it?

Cause: autoimmune/ TB = deficiency in cortisol, aldosterone, and androgens

Symptoms: hypotension –can be fatal

Treatment: oral cortisol and Fludrocortisone

89

Rank cortisol Prednisone, dexamethasone, and fludrocortisone in duration of action, relative anti-inflammatory potency, and salt retaining potency. Shortest/lowest to highest

Rank cortisol Prednisone, dexamethasone, and fludrocortisone in duration of action, relative anti-inflammatory potency, and salt retaining potency. Shortest/lowest to highest

Duration of Action: Cortisol/fludrocortisone – Prednisone –dexamethasone

Anti-inflammatory potency: Cortisol – Prednisone – Fludrocortisone – Dexamethasone

Salt retaining potency: Dexamethasone – Prednisone – Cortisol – Fludrocortisone

90

Know the 2 cell theory (steps of steroidogenesis)

- Theca cell: turns cholesterol into testosterone/androstenedione

○ Controlled by LH

- Granulosa cell: turns testosterone/androstenedione into estrone/estradiol

○ Controlled by FSH

91

Know how steroidogenesis affects HPA axis

- Estrogen & progesterone regulate gonadotropin release with both negative & positive feedback

○ Positive feedback: induces ovulation, day 14

- Progesterone
○ Increases LH/FSH amplitude from pituitary

○ Decreased GnRH frequency from hypothalamus

- Estrogen
○ Both increases and decreases amplitude of LH/FSH from pituitary

92

Know how steroidogenesis affects HPA axis

- Estrogen & progesterone regulate gonadotropin release with both negative & positive feedback

○ Positive feedback: induces ovulation, day 14

- Progesterone
○ Increases LH/FSH amplitude from pituitary

○ Decreased GnRH frequency from hypothalamus

- Estrogen
○ Both increases and decreases amplitude of LH/FSH from pituitary

93

Know how estrogen and progesterone affect HPG axis, endometrium, metabolism, development, menstrual cycle, uterine smooth muscle and cervical glands

- Estrogen
○ Endometrial proliferation

○ Lipids: decreases LDL & increases HDL/TGs

○ Bone: decreases resorption

○ Liver: increases plasma proteins

○ Blood: increased coag factors, decreased antithrombin

- Progesterone
○ Endometrial differentiation, prepare for implantation

○ Lipids: increase LDL, increase fat deposition

○ Glucose: increase fasting levels

○ Key regulator of luteal phase of menstrual cycle

○ Uterine smooth muscle: decrease contractions, decrease PG production, maintain relaxin secretion

○ Cervical glands: increase mucous viscosity (birth control method)

- Both
○ HPG: feedback regulation of steroidogenesis, ovulation

○ Development of ovaries, fallopians, uterus, vagina, breasts

94

Know which are the natural and synthetic estrogens

- Natural, steroidal: estradiol, estrone, estriol

- Synthetic, steroidal: ethinyl estradiol, mestranol

- Synthetic, nonsteroidal: diethylstilbestrol (not used anymore)

95

Know important difference between synthetic vs. natural

- Synthetic have increased half life

- Ethinyl group decreases 1st pass effect (bulky group)

96

Know the 4 important estrogen preparations and the differences

- Conjugated equine estrogens (Premarin)
○ Natural, water soluble

- Ethinyl estradiol
○ Synthetic steroid estrogen

- Mestranol
○ Synthetic steroid estrogen

- Diethylstilbestrol (DES)
○ First synthetic nonsteroidal estrogen
○ Not used today

97

Know pharmacological uses of estrogen & rationale (4)

- Hypogonadism
○ Promotes sex organ development

- HRT (hormone replacement therapy)
○ Post-menopausal: maintains bone density (decreases bone resorption); suppresses
hot flashes, suppresses urogenital atrophy

- Contraception
○ Negative feedback pressure on HPG axis

○ Inhibits ovulation

- Acne tx
○ Inhibits steroidogenesis

○ Increases liver plasma proteins (increased SHBG, decreased free testosterone)

98

Know the risks and benefits of estrogen IN THE CONTEXT OF HRT

- Increased risk of CAD, stroke, PE & invasive breast cancer (after 4-5 yrs of use)

- Decreased risk of colorectal cancer & hip fracture

99

Know AEs of estrogen

- Breast tenderness

- Endometrial hyperplasia
○ Can be countered with progesterone

- Coagulation (due to decreased antithrombin & increased factors)

- Nausea

- Migraine

- Cholestasis (due to changes in cholesterol:bile salt ratio & canaliculi)

- Bloating

- Cancer (next slide)

100

Explain connection of estrogen to cancer

- HRT estrogen monotherapy = increased risk of endometrial cancer

- HRT combo therapy = increased risk of invasive breast CA, likely due to progestin > estrogen

- Contraceptive therapy = reduced risk of ovarian & endometrial cancer

- Mechanism: trophic effects of hormones + ROS production during metabolism

101

Know the important progestins & uses

- MPA (medroxyprogesterone)
○ HRT - combined with estrogen

○ Long acting contraceptive - Depo-Provera

- Norethindrone
○ Contraception - combo or progestin only

○ 19-nortestosterone derivative

- Norgestrel
○ Contraception - combo or progestin only

○ 19-nortestosterone derivative

102

Know pharmacological uses of progestins & rationale (4)

- Contraception
○ Affects HPG axis

○ Increases cervical mucous viscosity

- HRT
○ Decreased risk of endometrial hyperplasia caused by estrogens

- Dysmenorrhea
○ Decreases endometrial mass and prostaglandin production (decreases contractions)

- Endometriosis
○ Decreases endometrial proliferation by stimulating differentiation

103

What is the result of endometrium in presence of estrogen unchallenged by progestins

- Continued endometrial growth (lack of differentiation)

104

What is the result of endometrium in presence of estrogen AND progestins

- Impaired endometrial growth

105

Know AEs of progestins

- Breakthrough bleeding

- Impaired glucose tolerance (due to increased fasting glucose)

- Hirsutism (19-nor)

- Acne (19-nor)

- Lipid metabolism (due to increased LDL/decreased HDL - opposite effects as estrogen)

106

Know types of hormone birth control, hormones contained (combo or solo), and treatment duration

- Oral pill: Combo or progestins alone, monthly, quarterly or yearly

- Injectable: Combo or progestins alone, monthly or quarterly

- Implantable: Progestins alone, q 3 yrs

- IUD: Progestins alone, q 5 yrs

- Transdermal: Combo, monthly

- Vaginal ring: Combo, monthly

107

Know MOA of hormone birth control

- Suppress LH & FSH surge (suppress ovulation)

- Alter cervical mucus

- Alter endometrium

108

Know postcoital birth control options

- Levlen: Combo (ethinyl estradiol & levonorgestrel)

- Plan-B: Levonorgestrel (progestin only)

109

Know efficacy of emergency contraceptions

- Combined: 25% failure rate

- Progestin only: 12% failure rate

- They are equally efficacious in preventing pregnancy but differ in preventing ovulation

110

Know AEs of hormone contraceptives

- Mild: nausea, mastalgia, breakthrough bleeding (estrogen), edema, HA, withdrawal bleed failure, serum protein changes

- Moderate: breakthrough bleeding (progestin), weight gain, increased skin pigmentation, acne, hirsutism, vaginal infections, amenorrhea

- Severe: thromboembolic disease, MI, CVA, GI disorders (cholestasis), depression, cancer

111

Know non-contraceptive benefits of hormone birth control

- Reduced risk of ovarian & endometrial cancer

- Reduction in dysmenorrhea, endometriosis

- Decreased incidence of ectopic pregnancy

- Decreased incidence of benign breast disease

- Increase Hg concentrations

- Suppressed acne and hirsutism

112

Know contraindications to hormone birth control

- Known or suspected breast cancer or cancer of female reproductive tract

- Thromboembolic disorders

- Liver disease

- Hx of MI/CAD/Hyperlipidemia

- Smokers 35 yo+

113

Know interactions of hormone birth control with other drugs

- HIV agents, anticonvulsants, St. John's wart induce hormone metabolism

- Antibiotics lower effectiveness of contraceptives (due to disrupted gut flora)

114

Know class, MOA, use and AE of Clomiphene

- Class/MOA: estrogen receptor partial agonist (blocks estrogen negative feedback to increase LH/FSH)

- Use: fertility drug

- AE: multiple births, hot flashes

115

Know the basic MOA of agonists, partial agonists and SERMs

- Agonists: binding of endogenous estrogen results in high level of suppression in pituitary due to negative feedback

- Partial agonist: net response of partial agonist in presence of agonist is a reduced physiological effect, for example less negative feedback so less pituitary suppression (=more LH/FSH released)

- SERMs: MOA can be as either an agonist, partial agonist or antagonist

116

Know how to treat a women with infertility caused by impaired gonadotropin release, without directly stimulating the receptor

- Dose with a partial agonist (such as clomiphene) to decrease the net negative feedback

- Remove drug just prior to day 14 so the pituitary will respond to the positive feedback with a surge in LH/FSH

117

Know tissue specific effects of SERM use (bone, endometrium, pituitary, breast)

- Bone: suppresses resorption (SERM acting as agonist)

- Endometrium: proliferation (SERM acting as partial agonist)

- Pituitary: hot flashes (SERM acting as antagonist)

- Breast: inhibit proliferation (SERM acting as antagonist)

118

Know class, MOA, use and AE of Tamoxifen

- Class: selective estrogen receptor modulators (SERMs)

- MOA:

○ Agonist - bone (pro: stops bone b/d)

○ Partial agonist - endometrium (con: proliferation --> endometrial cancer)

○ Antagonist - breast/HPG axis

- Use: ER+ breast CA (!!)

- AE: hot flashes, endometrial cancer

119

Know class, MOA, use and AE of Raloxifene

- Class: selective estrogen receptor modulators (SERMs)

- MOA:

○ Agonist - bone

○ Partial agonist ???

○ Antagonist - breast/uterus/HPG axis

- Use: cancer, postmenopausal bone loss

- AE: hot flashes

120

Compare side effects of estrogen and SERMs

- SERM example is Tamoxifen

- Both INCREASE: uterine bleeding, risk of endometrial cancer, venous thrombosis, prevention of postmenopausal bone loss, and favorable pattern of serum lipids

○ Estrogen increase is 2-3x that of tamoxifen

- OPPOSITE effects on hot flashes and risk of breast cancer

○ Estrogen decreases hot flashes and increases risk of breast cancer

○ Tamoxifen increases hot flashes and decreases risk of breast cancer

121

Know class, MOA, use and AE of Danazol

- Class: estrogen inhibitors

- MOA: inhibit gonadal function (vague - not directly targeting estrogen receptor)

- Use: endometriosis, breast fibrocystic disease

- AE: weight gain, edema, oily skin, acne, hirsutism, hot flashes

122

Know class, MOA, use and AE of Anastrozole & Letrozole

- Class: estrogen inhibitors

- MOA: aromatase inhibitors

- Use: breast cancer

- AE: GI, hot flashes, lethargy

123

Know class, MOA, use and dosing of Mifepristone

- Class: anti-progesterone

- MOA: progesterone receptor antagonist

- Use: abortifacient

- Dosing: less than 7 wks gestation - first use mifepristone & then follow with misoprostol 48 hrs later

124

Know class, MOA, use and dosing of Ulipristal

- Class: anti-progesterone

- MOA: progesterone receptor partial agonist

- Use: emergency contraceptive

- Dosing: longer acting, up to 5 days after intercourse

125

Know MOA of anti-progesterones (4)

- Inhibit progesterone receptors (progesterone would decrease contractions)

- Increase uterine contractions

○ Works through both endometrium and uterine smooth muscle

○ Progesterone decreases prostaglandins; anti-progesterones increase prostaglandins, resulting in contractions

- Shed lining of uterus

- Opens cervix

126

What are the positive and negative regulators of insulin release

- Includes hormones, substrates and neuronal regulation

- Positive regulation: glucose, amino acids, incretins, epinephrine/B2-adrenergic stimulation, vagus stimulation

- Negative regulation: NE/a2-adrenergic stimulation, amylin

127

Explain how glucose trigger calcium dependent insulin release

- Glucose enters B cell, results in increase in ATP

- Increased ATP:ADP ratio causes ATP sensitive K channel to close

○ Result = depolarization

- Depolarization stimulates voltage dependent Ca2+ channel to open

- Intracellular calcium triggers secretory granules to release insulin

128

What is GLUT4 function & tissue location

- Muscle, adipose tissue

- Insulin mediated uptake of glucose

129

What are insulin's actions on cellular targets

- Functions in adipose tissue, liver & muscle

- Stimulates glucose --> FAs --> TGs

- Stimulates glucose ---> TGs

- Stimulates glucose --> glycogen

- Stimulates glucose --> protein

- Stimulates AA --> protein

- Inhibits AA --> glucose

- Inhibits TGs --> FAs --> proteins

130

What are the characteristics of type 1 and type 2 DM?

- Type 1

○ Type 1a = immune-mediated; Type 1b = idiopathic

○ B-cell destruction leads to absolute insulin deficiency

○ Genetic predisposition; Immune mediated; Idiopathic

- Type 2: insulin resistance followed by insulin production

○ Insulin resistance and insulin secretory defect

○ Genetic predisposition; obesity; nutrition; physical activity

131

What is gestational diabetes and what are the cause & long term effect?

- Onset of glucose intolerance in 2nd or 3rd trimester


- Returns to normal glucose tolerance immediately post-delivery

- 40% of the women are diagnosed with gestational diabetes will develop DM in 10 yrs

- Progesterone produces glucose intolerance

132

What are signs & symptoms of T1DM & T2DM?

- Type I

○ Polyuria/nocturnal enuresis

○ Thirst

○ Blurred vision

○ Weight loss/polyphagia

○ Weakness/dizziness

○ Paresthesias

○ Level of consciousness

- Type II

○ Initially asymptomatic

○ Infections

○ Neuropathy

○ Classic severe insulin deficiency signs

○ Obesity & metabolic syndrome

133

What are the fasting plasma glucose levels in a normal person compared to diabetic, pre-diabetic or gestational diabetic pt?

- Normal FPG: or= 110-125

- Diabetes FPG: >or= 126

- Gestational DM FPG: >or=96

134

What are the types of insulin? Give examples, key features and kinetics (duration).

- Rapid acting

○ Insulin lispro/aspart/glulisine, inhaled insulin

○ 3-5 hrs duration

○ Amino acid alteration in C-terminal tail of B peptide prevents insulin complex
formation

- Short acting

○ Regular insulin

○ Forms complexes; identical to endogenous insulin

○ 4-12 hrs

- Intermediate-acting

○ NPH

○ 10-20 hrs

○ Protamine-insulin complex

- Long-acting

○ 12-20 or 22-24 hrs

○ Glargine: Amino acid substitutions result in formation of precipitate at more neutral pH

○ Detemir: myristic acid added

135

Which type of insulin would you use after a meal? For basal levels? For overnight?

- Meal: rapid acting (insulin lispro, insulin aspart, etc.)

- Basal levels: long acting (glargine, detemir)

- Overnight: intermediate or short acting (regular insulin, NPH)

136

What are AEs of insulin therapy?

- Hypoglycemia: insulin therapy too effective

- Hypersensitivity: immune response to noninsulin protein contaminants (Rare)

- Resistance: anti-insulin antibodies (Rare)

- Lipohypertrophy: fat deposition at injection site

- Lipoatrophy: fat loss at injection site

137

What is the most common complication of insulin? Symptoms? Tx?

- Hypoglycemia

- Symptoms from ANS: tachy, sweating, tremors, nausea, hunger

- Neuroglycopenic sx: irritability, confusion, HA, speech difficulty, blurred vision, tiredness

- Tx: glucose or glucagon

138

Can glucagon be taken orally?

- No, it's a peptide - must inject

139

MOA of glucagon?

- Catabolism of stored glycogen

140

AEs of glucagon?

- Very safe, N/V

141

Give the class, MOA, AEs and key points of Metformin.

- Oral antidiabetic agents for T2DM

- Class: biguanides

- MOA: not well understood, maybe decrease hepatic glucose output, increase peripheral
glucose utilization, activation of AMPK

- AE: GI disturbances (metallic taste - compliance issues) & vitamin B12 deficiency

- Key points: 1st line agent, does not produce hypoglycemia! (euglycemic)

142

Give the class/generation, MOA, AEs and key points of Glipizide, Glimepiride, Glyburide, repaglinide, nateglinide

- Oral antidiabetic agents for T2DM

- Class: Sulfonylureas & Meglitinides

- 1st generation: tolbutamide, chlorpropamide, tolazamide

- 2nd generation: glimepiride, glipizide, glyburide

- MOA: inhibit ATP-sensitive K channel of B cell, resulting in insulin release

- AE: HYPOGLYCEMIA, weight gain (less with 2nd generation)

143

Give the class, MOA, AEs and key points of Acarbose, Miglitol

- Oral antidiabetic agents for T2DM

- Class: glucosidase inhibitors

- MOA: inhibit brush border glucosidase enzyme and subsequent glucose absorption - inhibits complete carb digestion

- AE: GI (diarrhea, pain, flatulence, unabsorbed carbs - do NOT give to pts with other GI conditions like IBS/IBD/lactose)

- Key points: take with meal, hypoglycemia is rare

144

Give the class, MOA, AEs and key points of Pioglitazone, Rosiglitazone

- Oral antidiabetics for T2DM

- Class: thiazolidinediones

- MOA: increase expression of GLUT4 at transcriptional level --> increased peripheral sensitivity

- AE: peripheral edema, weight gain, HEPATOTOXICITY, bone fx, hypoglycemia, CARDIOVASCULAR

○ Avoid in pts with liver disease

145

Give the class, MOA, AEs and key points of pramlintide

- Class: amylinomimetic

- MOA: inhibit glucagon release, inhibit gastric emptying, anoretic effect

- AE: N/V/anorexia, delayed drug absorption

- Key points: synthetic peptide - must be injected

- Target = liver

146

Give the class, MOA, AEs and key points of exenatide, liraglutide

- Class: Incretins

- MOA: potentiate insulin secretion, inhibit glucagon release, inhibit gastric emptying, anorectic effect

- AE: N/V/D/HYPOGLYCEMIA, acute PANCREATITIS, delayed drug absorption

- Key points: synthetic peptide, must be injected

- Target = B cell

147

Give the class, MOA, AEs and key points of Sitagliptin, Saxagliptin, and Linagliptin

- Class: DPP (dipeptidyl peptidase inhibitors)

- MOA: inhibit incretin degradation

- AE (know these!): nasopharyngitis, URI, HA, acute pancreatitis, hemorrhagic or necrotizing pancreatitis

- Target = DPP

148

Define gene-by-environment phenotype

- Drug responses are a complex interplay between environment and genetic factors. Many factors influence genetic constitution and expression therefore altering drug responses. Eg. Pharmacomicrobiomics.

149

Define monogenic vs multigenic drug responses

- Monogenic: variation in sgl gene causing difference in specific drug response

- Multigenic: variations in multiple genes causing difference in a specific drug response

150

Define allele, polymorphism, SNP. Furthermore, define synonymous SNP vs non-synonymous SNP and explain result of each change.

- Allele: one of a number of alternate forms of a gene. Individual has 2 alleles of a gene. Within the population, there can be many alleles of a particular gene.

- Polymorphism: difference in DNA code that occurs in more than 1% of the population. This is different to a mutation in that they occur in less than 1% of the population.

- SNP: single nucleotide polymorphism. Difference in DNA code of 1 nucleotide that occurs in more than 1% of the population.

a. Synonymous: Base pair change = no change in AA substitution. Result: may be decreased transcript stability or alternative splicing = changed protein expression and function.

b. Non-synonymous: Base pair change = change in AA substitution. Result: change in protein structure, stability, substrate affinity, stop codon introduction etc.

151

Define indel. What are CNVs?

- Insertion (in) or deletion (del) of genetic material.

- CNVs = copy number variations. Refer to either complete deletion or duplication of a particular gene = gain or loss of function.

152

Compare and contrast cosmopolitan vs population polymorphisms?

- Cosmopolitan: polymorphisms common across all ethnic or racial groups

- Population: polymorphisms that differ between ethnic or racial groups

153

Define pharmacogenetic train. Define the steps of the phenotype-to-genotype approach when it comes to understanding drug-gene interactions. What are the advantages and disadvantages between a candidate gene approach and a genome-wide approach?

- Start by directly measure pharmacogenetic trait (Any measurable trait associated with a drug enzyme activity, drug levels in bodily fluids, drug metabolite in bodily fluids or physiologic response to a drug).

- Group outliers and normal responders

- Genotype individuals from each group to determine differences in DNA sequence using

a. Candidate gene approach: knowledge of specific gene or cellular mechanism. More focused approach, not looking for needle in haystack potentially. Wrong gene might however be studied.

b. Genome-wide approach: no knowledge of specific gene or cellular mechanism. This is unbiased and you are not using confirmation bias etc. Disadvantage is identification of variants that don’t contribute to the response observed. Too much information here.

154

Compare and contrast the 3 pharmacogenetic phenotypes

1. Pharmacokinetic: effect of polymorphism in a gene (s) that changes what the body does to a drug, which is absorption, distribution, metabolism, elimination.

2. Pharmacodynamic: effect of polymorphism in a gene (s) that changes what the drug does to the body, ie. through changes in target receptor / enzymes, which can impair or enhance drug response.

3. Indirect: effects of polymorphism in a gene (s) that does not interact with the drug (pharmacokinetically or pharmacodynamically).

155

Drugs affected by polymorphisms in CYP2D6 gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: CYP2D6. Role: hepatic metabolism of drugs.

- Drugs: tamoxifen, codeine, paroxetine (SSRI)

- Pharmacokinetic phenotype

- Phenotypes: ultrametabolizers (UM), extensive metabolizers (EM), intermediate metabolizers (IM) and poor metabolizers (PM).

- Tamoxifen (ER pos breast CA tx): metabolites of this drug inhibit ER. If CYP2D6 metabolism effective, then use drug for tx. If not, consider alternative tx such as aromatase inhibitors.

- Codeine: requires CYP2D6 to metabolize into active morphine. Be careful of excessive side effects in UM and inadequate analgesia in PM.

- Paroxetine: CYP2D6 metabolizes drug into less active component. Selective alternate tx for those who are UM. Lower dose in those who are PM.

156

Drugs affected by polymorphisms in CYP2C19 gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: CYP2C19. Role: metabolism of drug.

- Drugs: clopidrogel, omeprazole and lansoprazole (PPIs)

- Pharmacokinetic phenotype

- Clopidrogel: CYP2C19 activates clopidrogel. Based on whether individual is normal metabolizer, intermediate or poor metabolizer, dose will need to be altered. Consider higher dosing or even alternative therapy for poor metabolizers.

- PPIs: CYP2C19 deactivates PPIs. Poor metabolizers have more drug available – meaning more therapeutic and / or worse side effects.

157

Drugs affected by polymorphisms in CYP2C9 gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: CYP2C9. Role: metabolism of drug.

- Drug: warfarin

- Pharmacokinetic phenotype

- Warfarin: CYP2C9 deactivates warfarin. Wild type allele = *1 (CYP2C9 *1). Reduced function alleles = *2 and *3 that metabolize warfarin slowly = more risk for bleeding. Lower dose in patients with these alleles.

158

Drugs affected by polymorphisms in VKORC1 gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: VKORC1. Role: enzyme that converts vit K epoxide into vit K.

- Drug: warfarin

- Pharmacodynamic phenotype

- Warfarin: this drug blocks VKORC1 preventing production of Vit K, which activates clotting factors. VKORC1-AA has lowest activity, producing lowest amount of vit K. Give low amounts of warfarin in this group to achieve therapeutic effect.

159

Drugs affected by polymorphisms in DPD gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: DPD (dihydropyrimidine DH). Role: inactivates 5-FU

- Drug: 5-FU

- Pharmacokinetic phenotype

- 5-FU: DPD inactivate 5-FU reducing toxicity. Polymorphism in DPD can lead to reduced/non-functionality = higher toxicity from 5-FU such as bone marrow suppression.

160

Drugs affected by polymorphisms in TYMS (TS) gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: TYMS (thymidylate synthetase). Involved in DNA synthesis.

- Drug: 5-FU

- Pharmacodynamic phenotype

- 5-FU: metabolite of 5-FU (FdUMP) inactivates TYMS leading to DNA damage through decrease in dTTP levels causing cell death. Know: Insertion polymorphism can lead to decreased or increased TS activity. Decreased TS activity = individuals with good antitumor response to 5-FU. Increased TS activity = individuals with poor antitumor response to 5-FU.

161

Drugs affected by polymorphisms in TPMT gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: TPMT.

- Drug: 6-MP

- Pharmacokinetic phenotype

- 6-MP: TPMT inactivates 6-MP (drug used to tx ALL by incorporating into DNA). When TPMT is very active, 6-MP cleared quicker, drug ineffective. When TPMT has polymorphism leading to decreased / no activity, drug is more toxic.

162

Drugs affected by polymorphisms in SLCO1B1 gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: SLCO1B1. Role: uptake of simvastatin into liver leading to metabolism/breakdown.

- Drug: simvastatin

- Pharmacokinetic phenotype

- Simvastatin: simvastatin is metabolized in liver. Requires solute carrier organic anion transporter 1B1 for uptake. T/T genotype is normal transport. C/C genotype is low transport linked to high statin-induce myopathy side effect.

163

Drugs affected by polymorphisms in ERalpha gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: ERalpha. Role: estrogen receptor.

- Drug: estrogen as HRT

- Pharmacodynamic phenotype

- Estrogen: homozygotes for less common allele have greater increase in HDL levels following HRT, which is a good effect. Note: normal physiologic response of E is to increase HDL and lower LDL.

164

Drugs affected by polymorphisms in ADRB2 gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: ADRB2. Role: bronchodilator via beta-2 receptor agonist action.

- Drug: albuterol

- Pharmacodynamic phenotype

- Albuterol: homozygotes for Arg polymorphisms have reduction in PEF during tx with albuterol than compared with placebo tx group. Response is diminished. Avoid albuterol tx in this group. Note: passive smoking augments this effect.

165

Drugs affected by polymorphisms in HLA-B gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: HLA-B*57:01. Role: presents peptides to immune cells.

- Drug: abacavir

- Indirect pharmacogenetic phenotype

- Abacavir: this is a reverse transcriptase inhibitor drug used to tx HIV. Individuals with the above polymorphism have a high risk for Steven-Johnson hypersensitivity reaction. Must do testing for this allele.

166

Drugs affected by polymorphisms in IL-28B gene? How? Does the polymorphism affect it in a pharmacodynamic, pharmacokinetic or indirect way?

- Gene: IL-28B

- Drug: IFN-alpha

- Indirect pharmacogenetic phenotype

- IFN-alpha: used to tx HCV infections. In those without polymorphism (CC homozygote), tx is more effective than in those with it (CT or TT).

167

What genes encode proteins that affect pharmacokinetics? For what drugs?

- CYP2D6: tamoxifen, codeine, paroxetine

- CYP2C19: clopidrogel, omeprazole, lansoprazole

- CYP2C9: warfarin

- DPD: 5-FU

- TPMT: 6-MP

- SLCO1B1: simvastatin

168

What genes encode proteins that affect pharmacodynamics? For what drugs?

- VKORC1: warfarin

- TYMS: 5-FU

- TPMT: 6-MP

- ERalpha: estrogen

- ADRB2: albuterol

169

What genes encode proteins that affect drug responses indirectly? For what drugs?

- HLA-B: abacavir

- IL-28B: IFN-alpha

- Also noted: Factor V and PT mutations increased risk of VTE when used with OCPs; absence of certain alleles of APOE gene correlate with better therapeutic success of tacrine tx in AD.

170

Definition and scope of study of toxicology and use by clinicians

- Toxic substances and their detection, effects, properties and regulation

171

Primary determinant (and others) of toxicity in human poisoning

- Dose of substance/drug

- Time of exposure to substance/drug

172

Understand meaning of ED50, LD50 and Therapeutic index for toxicology. How is TI calculated?

- ED50: effective dose

- LD50: lethal dose

- TI = LD50/ED50. Larger the number, safer the drug

173

Drugs to induce emesis after overdose. Contraindications?

- Apomorphine

- Syrup of Ipecac

- Contraindications: petroleum hydrocarbon solvent (causes chemical pneumonitis), caustic acid/alkali agent (causes rupture)

174

Activated charcoal use

- Binds organic toxicants which prevent absorption

175

Antidote to organophosphate (Ach inhibitors) poisoning

- Pralidoxime (2PAM) treats poisoning + atropine to block muscarinic effects of PSNS

176

Antidote to cyanide poisoning

- Amyl nitrite, sodium nitrite and sodium thiosulfate + o2

177

Antidote to botulinum toxin

- Trivalent anti-toxin (type A, B and E: equine derived ab’s)

178

Antidote to heavy metals

- Chelators such as BAL, EDTA, DMSA, DMPS, calcium EDTA, deferoxamine

179

Antidote to arsenic, mercury or lead poisoning

- DMSA, succimer

180

Antidote to ethylene glycol, methanol, isopropyl alcohol

- Ethanol: binds alcohol DH and prevents conversion of these substances into toxic forms

- Fomepizole (antizole): blocks etoh DH = drug of choice

- Also hemodialysis

181

Tx of CO intoxication. Distinct sign of severe CO poisoning

- Hyperbaric o2 chamber

- Sign: cherry red lips and gums

182

Antidote to warfarin overdose

- Vit K (phytonadione) or if severe: PT complex or FFP

183

Antidote to opioid overdose

- Naloxone: duration of action ~45 mins

- Follow up w/Naltrexone: 24-72 hr duration of action

184

Cause and tx of methemoglobinemia

- Cause: heme iron in Fe3+ (ferric) state unable to transport o2. Caused by exposure to many chemicals including nitrites, sulfa etc.

- Tx: methylene blue: causes a direct chemical reduction of methemoglobinemia back to Hb

185

Antidote for benzodiazepine overdose

- Flumazenil – flute mace nail

186

Antidote for acetaminophen

- N-AcetylCysteine: restores glutathione

187

Antidote for cocaine-induce dysrhythmia

- Lidocaine

188

Sympathomimetic toxidrome. Symptoms, drugs?

o Mydriasis, HTN, tremor, hyperthermia

o Drugs: cocaine, amphetamines, PCP

189

Sedative/hypnotic toxidrome. Symptoms, drugs?

o Coma, decreased respiration, miosis/mydriasis, HoTN

o Drugs: etoh, barbiturates, benzodiazepines

190

Opioid/Opiate toxidrome. Symptoms, drugs?

o Coma (decreased consciousness), respiratory depression, pinpoint pupils (miosis) = opiate triad

o Drugs: opiates, morphine, codeine, oxycodone, hydrocodone, propoxyphene

191

Anticholinergic toxidrome. Symptoms, drugs?

o Agitation, mydriasis, hot, dry, mad, red and blind

o Drugs: anticholinergics, antidepressants

192

Cholinergic toxidrome. Symptoms, drugs?

o Pinpoint pupils (miosis), SLUDGE: salivation, lacrimation, urination, diaphoresis, GI upset, emesis; bradycardia

o Drugs: organophosphates, nicotine

193

TCA toxidrome. Symptoms, drugs?

o Coma, agitation, dysrhythmia, convulsions, HoTN

o Drugs: TCAs

194

Salicylate toxidrome. Symptoms, drugs?

o Respirations up or down, diaphoresis, tinnitus, agitation, alkalosis (early), acidosis (late), hyperpyrexia

o Drugs: ASA