9922 - Pharmacotherapy Exam 2

Diabetes Mellitus (DM) pathophysiology

chronic metabolic disorders characterized by:


1. hyperglycemia
2. altered fat and protein metabolism caused by defects in insulin secretion or insulin action (sensitivity)

Insulin

secreted by the beta cells of the islets of langherhans

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reduce BG in response to high blood sugar:


1. increase cellular uptake of glucose
2. increase glycogen formation
3. reduce gluconeogenesis
4. reduce glycogenolysis
5. increase fat storage/reduce fat breakdown
6. increase protein formation

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structure includes prepro insulin, pro insulin, insulin, and C-peptide

Insulin secretion

basal: absence of stimuli

bolus: response to glucose (eaten)

a. biphasic secretion:


1. first phase: quick and peaks after 5-10 minutes
2. second phase: delayed and persists for length of stimulus

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In healthy individuals, normal insulin secretion in composed of bolus insulin needs and basal insulin needs. Eating results in the first phase bolus insulin secretion followed by the second phase for the remainder of the meal. Each time an individual eats throughout the day they experience a bolus insulin secretion. In the background, individuals’s have basal insulin needs . Throughout the day the body is secreting a baseline quantity of insulin to maintain this need. In individuals who require insulin (T1 and some T2) insulin therapy is programmed to mimic normal insulin secretion.

Type I diabetes

autoimmune condition that results in the destruction of pancreatic beta cells

! absolute insulin deficiency

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symptoms: increased urination, thirst, fatigue, and weight loss also nausea, vomiting and diarrhea

Type 2 Diabetes

marked by an initial increase in insulin requirements and beta cell production followed by an increasing rise in insulin resistance and decreased beta cell function

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The body can not produce sufficient enough insulin for cellular need = insulin resistance

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cause: visceral fat (beer belly), physical inactivity, poor diet, older age, increased CV risk

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symptoms:


1. frequent urination
2. hungry/thirsty
3. fatigue
4. blurry vision
5. bruises and slow healing wounds
6. diabetic neuropathy
7. dry itchy skin

counter-regulatory hormones

help maintain glucose homeostasis


1. glucagon: secreted from pancreatic alpha cells, stimulate hepatic glucose production = increased BG
2. epinephrine: gluconeogenesis,, symptoms of hypoglycemia
3. cortisol and growth hormone

Monitoring goals for DM

fasting BG = no fodd/drink for 8-12 hours

pre-prandial: 80-130 mg/dL

post-prandial: goal < 180

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A1C: average BG from the past 2-3 months

! normal: 4.5-5.7%

ADA goal: < 7% (avg. BG 154)

!BG increases by \~30 point per percent

Hypoglycemia

level 1: < 70

level 2: < 54

level 3: severe cognitive impairment, assistance required

! 15 g simple sugar (4oz juice, 4 sugar tablets, or 1 oz. honey)

! glucagon, frosting, or honey if unconscious

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if BG still < 60 or symptoms persist after 15-20 minutes repeat

Insulin dosing

dosed in units/mL SQ

! Regular can also be dosed IV

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U-100 is the most common

Rapid acting insulin

onset: 15-20 minutes

peak: 1 hour

duration: 3-5 hours

place in therapy: mimics endogenous bolus secretion - prior to meals, correction doses (high BG), and used in insulin pumps

drugs:


1. lispro: humalog and lyumjev
2. aspart: novolog and fiasp
3. glulisine: apidra

!lyumjev and fiasp have quicker onset

Short-acting insulin

onset: 30-60 min

peak: 2-3 hours

duration: 5-8 hours

place in therapy: dosed IV, onset slower than rapid-acting but longer duration, dosed prior to meals as bolus, and for correction of high (account for longer onset)

drugs: U100 Regular: humulin R, novolin R, and ReliOn R

Intermediate-acting insulin

onset: 2-4 hours

peak: 4-10 hours

duration: 10-24 hours

place in therapy: dosed 2x a day basal insulin, suspension - roll, but it is cheap

drugs:


1. NPH (protamine): humulin N, novolin N, ReliOn novolin N
2. U-500 regular insulin: Humulin R U-500

! higher concentration allows its duration to mimic intermediate insulins

! basal insulin

Long-acting insulin

glargine


1. Lantus, basaglar, and semglee
2. mimic basal insulin secretion
3. dosed QD
4. no peak'
5. acidic environment - burn
6. 100units

detemir


1. levemir
2. duration is dose dependent
3. mimic basal insulin secretion

Ultralong-acting insulin

degludec


1. tresiba
2. U100 and 200
3. peakless
4. once daily insulin - basal

concentrated glargine (U300)


1. toujeo and max
2. peakless
3. once daily - basal

mixed insulin

x/y: x% NPH (intermediate) + y% R (short): humulin, novolin, and reliOn/novolin

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humalog/novolog mix x/y: x%LPS/APS (depending) (intermediate) + y% lispro/aspart depending (rapid)

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! protamine mimics NPH, added to rapid-acting to lengthen action and improve stability

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BID before meals, R/S for breakfast and dinner and intermediate for lunch and dinner

Insulin education

1. storage: initially in fridge, once opened keep room temp.
2. change needles EVERY time
3. rotate site - abdomen, arm, thigh, butt

! lipohypertrophy (dents)
4. when to inject
5. how to inject
6. hypoglycemia - sign, symptoms, and treatment

insulin ADR

1. hypoglycemia


2. hypokalemia
3. fluid retention
4. weight gain
5. allergy
6. lipodystrophy: lipoatrophy/hypertrophy

hypoglycemia signs and symptoms

1. Adrenergic: NE is released in response to low = anxiety, shakiness, dizziness, and palpitations


1. sweating, hunger, paresthesias (pins and needles)
2. CNS: behavioral changes, confusion, headache, shallow respiration, coma, convulsions, and death

hypoglycemia causes

1. mismatched insulin and carbs
2. hypoglycemia unawareness
3. alcohol
4. increased activity

glucagon therapy

for severe lows - unconscious


1. baqsimi: nasal
2. gvoke: pre-filled pen
3. glucagon kit/GlucaGen: fill self

Adjunct DM therapy

Remember T1D DO NOT produce insulin. They are 100% required to be on insulin

! with age T1D can develop T2D tendencies (i.e insulin resistance or reduced insulin sensitivity). In this case T1D may benefit from adjunct therapies used by T2D

Metformin

first line of treatment - if a pt can be on it they should be

MoA: does not effect pancreatic beta cells


1. reduce hepatic glucose production
2. reduce absorption of glucose in the intestines
3. increase insulin sensitivity

class: biguanide

Brand: glucophage, glumetza, fortamet, and riomet

ADR:


1. abdominal discomfort - most common diarrhea, also bloating and upset stomach


1. avoid by taking with food and titrating dose
2. weight loss
3. lactic acidosis - check kidney function (does not cause kidney dysfunction)
4. B12 deficiency

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generic and inexpensive

takes effect in \~2 weeks

TZD

Add on therapy

MoA


1. bind to PPAR gamma receptors found in muscle, liver, and fat
2. alter protein transcription
3. increase insulin sensitivity in muscle, fat, and liver
4. increase glucose transporter expression
5. reduce hepatic glucose production

ADR


1. fluid retention


1. start at low dose and avoid max dose
2. refractory to diuretics
3. increase when combined with insulin
4. avoid if have heart failure
2. fracture
3. weight gain

drug: pioglitazone - actos

full effect in \~3 months

sulfonylureas

add on therapy

MoA: secratogogue


1. bind to pancreatic beta cells
2. prevent efflux of potassium ions resulting in depolarization
3. voltage gated calcium channels open
4. insulin is secreted

flogs the pancreas

ADR:


1. hypoglycemia
2. weight gain

potential renal dysfunction

Drugs:


1. glimepiride - amaryl
2. glipizide - glucotrol
3. glyburide - micronase

Meglitinide

secratogogue

Therapy: prandial blood glucose

MoA: bolus sulfonylurea - same MoA

! 1/2 life of 1 hour

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Drugs: Repaglinide - Prandin

ADR:


1. hypoglycemia
2. dizziness

take 15-30 minutes before meal - skip if not eating

alpha glucosidase inhibitors

adjunct/rarely given

MoA: inhibit alpha glucosidase in SI - delay breakdown and systemic absorption of carbs

ADR: GI upset - start low and titrate

Drugs: acarbose (precose_ and miglitol (glyset)

give with first bite of food

GLP-1 and GIP

secreted from the L cells of the GI tract

! GIP is glucose-dependent

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1. stimulate glucose-dependent insulin release
2. decrease inappropriate glucagon secretion
3. slow gastric emptying
4. improve satiety

GLP-1 agonists

first or second line - barriers = cost and availability

MoA: synthetic GLP analog

Drugs


1. exenatide


1. byetta - QD, most ADR
2. bcose - weekly
2. liraglutide - victoza, daily
3. semaglutide


1. ozempic - weekly
2. rybelsus - oral daily 30-60 minutes before meal
4. dulaglutide - trulicity, weekly

ADR


1. nausea
2. reduced appetite
3. weight loss
4. constipation or diarrhea
5. vomiting
6. pancreatitis

! reduces mortality and death from CV disease

tirzepatide

mounjaro

GLP-1/GIP agonist

same effect but greater as GLP-1 agonist - more expensive

best at weight reduction and second to insulin for lowering A1C

DPP4 inhibitors

add on therapy - not as effective as GLP-1 agonists, expensive

MoA: inhibit DPP4 which is responsible for breaking down GLP-1 and GIP - prolong GLP-1 and GIP effects


1. stimulate glucose-dependent insulin secretion
2. suppress inappropriate glucagon secretion

ADR


1. headache
2. URI
3. pancreatitis

drugs


1. linagliptin - tradgenta
2. saxagliptin - onglyza
3. sitagliptin - januvia

SGLT2 inhibitors

add on therapy: 1st or 2nd - expensive

MoA: block reabsorption of glucose in the proximal tubule of the kidney increasing glucose excretion

! reduce renal threshold for glucose

drugs:


1. canagliflozin - invokana
2. dapagliflozin - farxiga
3. empagliflozin - jardiance

ADR


1. genital yeast infection
2. UTI
3. increased urination
4. reduced BP
5. orthostatic hypotension
6. weight loss

thyroid hormone

functions:


1. stimulate cellular O2 consumption
2. regulate carb and and lipid metabolism
3. is involved in normal growth and maturation

effect virtually all cells

produced by the thyroid gland in response to TSH released from the anterior pituitary (TRH from hypothalamus)

T4 is the major circulating form but T3 is the metabolically active form (formed in the periphery)

more bound TH than free

T3 binds to nuclear receptors to regulate transcription

TH synthesis

1. inorganic iodide enters thyroid follicles and is oxidized by thyroid peroxidase
2. oxidized iodide is covalently bound to tyrosine residues of thyroglobulin to form MIT and DIT (organification)
3. MIT and DIT combine to form T4 and T3

hypothyroidism

! deficiency in TH

Types:


1. primary: thyroid gland issue - more common
2. secondary: hypothalamic-pituitary issue

causes:


1. hashimotos


1. most common
2. genetic predisposition
3. circulation thyroid antibodies destroy thyroid cells
2. gland destructions


1. radioactive iodide treatment
2. surgery
3. dietary iodine deficiency
4. drug-induced


1. amiodarone (both hypo/hyperthyroidism)
2. lithium
3. excess anti-thyroid drugs

wolff-chaikoff effect

baseline iodine status: normal

giving iodine causes hypothyroidism

jod-basedow phenomenon

baseline iodine status: low

giving iodine causes hyperthyroidism

clinical features of hypothyroidism

1. fatigue
2. weight gain
3. dry, coarse, yellowing skin
4. cold intolerance
5. delayed reflexes
6. memory impairment
7. constipation
8. depression
9. heavy menses
10. infertility

non-toxic goiter

enlarged goiter not associated with overproduction of TH

! caused by iodine deficiency or high levels of circulating TSH

diagnosis of hypothyroidism

1. history
2. labs


1. 0.5-4.5 mIU/L or 0.3-3.0 mIU/L
2. primary: high TSH low T4/T3
3. secondary: low TSH, T4, T3
4. subclinical: elevated TSH normal/near normal T3 and T4

Dosing for hypothyroidism

1\.6 mcg/kg/day

1 mg = 1000 mcg

hypothyroid drugs

levothyroxine: Synthroid

liothyronine: cytomel

desiccated thyroid: armour thyroid

levothyroxine counseling

1. before breakfast
2. no antacid/vitamin within 2 hours
3. product and color
4. effects seen in 2-4 weeks
5. follow-up with doctor in 6-8 weeks then yearly
6. life-long therapy
7. minimal ADR

hypothyroidism and pregnancy

levothyroxine is safe for use while pregnant

hypothyroidism is dangerous for both mother and baby if left untreated

myxedema coma

end-stage-hypothyroidism if left untreated

features:


1. hypothermia
2. exaggerated hypothyroidism symptoms
3. delirium/coma

high dose IV levothyroxine and corticosteroids and treatment of underlying disorders

hyperthyroidism causes

1. toxic diffuse goiter (Basedow and Grave’s disease)
2. toxic nodular/multinodular goiter
3. excess iodine replacement (Jod Basedow phenomenon)
4. excess TSH
5. drug-induced (amiodarone)
6. excess thyroid ingestion

grave’s disease

most common cause of hyperthyroidism

! production of thyroid receptor antibody which acts like TSH

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characteristics:


1. hyperthyroid symptoms
2. diffuse goiter

specific to graves disease:


1. opthalmopathy - exopthalmos
2. dermatopathy - orange peel skin especially present on tibia
3. acropachy - thickening/clubbing of fingers and toes

features of hyperthyroidism

hypermetabolic state


1. nervousness
2. irritation
3. palpitations
4. tachycardia
5. tremor
6. heat intolerance
7. weight loss
8. insomnia
9. increased bowel movements
10. reduced menses
11. emotional lability
12. vision changes (photophobia/diplopia)

diagnosis of hyperthyroidism

1. history
2. labs - TSH

treatment of hyperthyroidism

1. surgery
2. radioactive iodine
3. anti-thyroid drugs

hyperthyroidism - surgery

reasons to choose surgery:


1. compelling morbidities (cancer)
2. compressive symptoms
3. pregnant and other therapies did not work

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downsides:


1. expensive
2. complications
3. potential for parathyroid damage

radioactive iodine (RAI)

preferred treatment

thyroid replacement drugs required 2 months after treatment

antithyroid therapy - thioamides

can be used as primary therapy - often used as adjunct therapy to surgery or radioactive iodine

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methimazole is often preferred drug unless:


1. hypersensitivity (allergy)
2. pregnancy
3. thyroid storm

in which case PTU is preferred - quicker onset

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MOA:


1. block organification and coupling of MIT and DIT to form T3 and T4
2. PTU also prevents peripheral conversion of T4 to T3

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ADR:


1. methimazole: GI upset
2. ptu: bitter taste
3. rash
4. arthralgias
5. hepatitis
6. agranulocytosis

antithyroid therapy - iodides

1. preferred treatment for Grave’s disease
2. before surgery or after RAI
3. quicker
4. exacerbate hyperthyroidism in individual’s in iodine deficient areas (Jod Basedow phenomenon)

MOA:


1. acutely block the synthesis and release of TH via the Wolff-Chaikoff effect
2. reduce size and vascularity of the thyroid gland

ADR:


1. rash
2. drug fever
3. metallic taste
4. burning sensation in mouth
5. rhinitis

Beta blockers - hyperthyroidism

used for symptoms management - palpitations, tremor, anxiety

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clinical use


1. adjunct therapy before surgery, RAI, or while waiting for thioamides to work
2. thyroid storm

propranolol is preferred - non-selectivity = better clinical results

pregnancy and hyperthyroidism

grave’s disease is the most common

sumptoms:


1. failure to gain weight
2. tachycardia

complications:


1. thyroid storm
2. spontaneous abortion or premature labor
3. child developing hyperthyroidism

Thyroid storm

life threatening condition that is marked by


1. high fever
2. tachycardia
3. tachypnea
4. dehydration
5. delirium
6. coma

that lasts for \~72 hours and is often precipitated by infection or trauma. It has a mortality rate of 20%

menopause

permanent cessation of menstrual periods and loss of follicular activity

! amenorrhea for 1 + year + symptoms

reduced number of ovarian follicles, reduces estrogen and progesterone, and increased FSH and LH

consequence of menopause

Breast: estrogen promotes breast cell production →breast cancer

Bone: estrogen inhibits osteoclast activity

Liver: estrogen


1. reduces LDL, and increases HDL
2. increases triglycerides
3. increase coagulation factors (clots)

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with menopause you are reducing your risk of breast cancer but increasing risk of osteoporosis

in estrogen therapy you are increasing risk of breast cancer, clot formation, and triglyceride formation

short term menopause symptoms

vasomotor:


1. hot flashes/night sweats
2. headaches
3. palpitations
4. insomnia

genitourinary:


1. vaginal pain, dryness, itching, and burning
2. dyspareunia - painful intercourse
3. urinary frequency/urgency, dysuria - increase risk of UTI

other:


1. fatigue
2. reduced libido
3. anxiety, irritability, and depression
4. cognitive difficulties
5. backache/stiffness

long term menopause consequences

osteoporosis

cardiovascular disease (includes coronary artery disease)

menopause goals of therapy

1. relieve symptoms - pharm and nonpharm
2. improve QoL
3. minimize AE

moderate-severe menopause treatment

vasomotor: non-hormonal - reduce severity and frequency of hot flashes


1. SSRI/SNRI
2. gabapentin - antiseizure
3. clonidine - antihypertensive

genitourinary and vasomotor: hormonal


1. estrogen therapy
2. estrogen/progesterone therapy

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systemic: VM and UG - oral, transdermal, patch, gel, and spray (oral and transdermal are equally effective)

local: UG ONLY - vaginal cream, ring, and tablet

oral drugs

pros: increase HDL and reduce LDL, relatively cheap

cons: increase risk of VTE/stroke, increase TG, and reduce libido

transdermal drugs

pros: avoids 1st pass metabolism, reduced risks

cons: more expensive, adhesive sensitivities

systemic HT contraindications

1. VTE
2. ischemic stroke
3. breast cancer
4. MI
5. endometrial cancer
6. sever, acute liver disease
7. pregnancy

warnings:


1. gallbladder disease
2. hypertriglyceridemia

HT AE

Estrogen and Progesterone


1. vaginal bleeding
2. breast tenderness
3. nausea
4. weight gain
5. edema
6. headaches
7. mood changes

progesterone only


1. acne
2. hirsutism
3. bloating
4. depression

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start with low dose, give drug 6 months before switching, transdermal = less SE

systemic HT patient monitoring

efficacy


1. initial response: 2-3 weeks
2. maintenance: every 6 months
3. symptoms - severity and frequency
4. QoL

safety


1. self breast exams
2. bleeding
3. BP

systemic HT provider monitoring

1. BP
2. cholesterol
3. mammogram
4. CVD risk
5. thyroid function
6. pelvic exam
7. bone density scan

local HT monitoring

efficacy: symptoms - severity and efficacy

safety: AE


1. vaginal bleeding
2. yeast infections
3. breast tenderness

estrogens

1. start with lowest dose
2. shortest duration possible to achieve patient goals
3. partially metabolized by CYP3A4

progesterones

1. given in combination with estrogen to lower risk of endometrial cancer
2. if the patient has a uterus estrogen MUST be given with progesterone (EPT)


1. given at least 10-14 day per month

PS and urination

ACh binds to muscarinic receptors causing detrusor contraction and sphincter relaxation

voluntary control occurs at the external sphincter

Sympathetic and urination

NE binds to alpha 1 and beta 3 receptors causing detrusor relaxation and sphincter contraction

Risk factors for incontinence

females:


1. childbirth
2. menopause
3. obesity

males:


1. obesity
2. BPH

Types of UI

Important to determine type to ensure proper treatment


1. urge


1. most common
2. overactive detrusor muscle - constant activation of M2 and M3 receptors translates into feelings of urgency
2. stress


1. weak urethral sphincter + sudden increase in intra-abdominal pressure
3. overflow


1. full bladder and difficulty voiding (blockage) results in small accidents (BPH)
4. functional


1. social/cognitive/physical impairment
5. mixed


1. multiple types

non-pharm treatment of UI

1. reduce caffeine intake
2. reduce alcohol consumption
3. smoking cessation
4. moderate fluid intake
5. weight reduction
6. exercise
7. kegels
8. absorbent products
9. bladder training
10. surgery
11. catheters

anti-muscarinics for UI

antagonize M1 and M3 receptors

! M3 is preferred over M1 due to location

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MoA: relax bladder wall


1. reduce number of uninhibited bladder contractions


1. reduce urgency
2. increase bladder capacity

ADR:


1. major reason for non-adherence
2. ER and M3 reduce ADR
3. can’t see, pee, spit, or shit

anti-muscarinic UI drugs

1. oxybutynin (ditropan)


1. highest ADR
2. topical patch and gel reduce ADR
2. tolterodine (detrol and detrol LA)


1. high ADR
3. solifenacin (vesicare)


1. slightly M3 selective
4. Darifenacin (enablex)


1. highly M3 selective
5. trospium (spectra)


1. non-selective: low CNS absorption
2. take on empty stomach
6. fesoterodine (toviaz)


1. M3 selective
2. prodrug (tolterodine is active form)

Beta 3 agonist - UI

Moa: relax bladder muscle and increase bladder capacity by agonizing beta 3 receptors

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same efficacy as antimuscarinics - reduces dry mouth

ADR: hypertension

Drugs: brand only (expensive)


1. mirabegron - myrbetriq
2. vibegran - gemtesa

other UI drugs

1. topical estrogen for menopausal women (kegels preferred)
2. duloxetine (SNRI)

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Counseling for UI

1. monitoring


1. number of incontinent episodes
2. adverse effects
2. anticholinergics can cause cognitive problems in the elderly and increase fall risk
3. OTC interactions


1. sleeping meds
2. allergy meds
4. constipation can worsen UI - anti-muscarinics cause constipation


1. stool softener or change drug

BPH pathophysiology

androgens are converted to DHT by 5-alpha-reductase

DHT has greater affinity for intraprostate androgen receptors

patho isn’t fully understood but thought to do with prostatic exposure to DHT over a lifetime

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manifestations:


1. asymptomatic
2. voiding symptoms: obstruction


1. straining, dribbling, and hesitancy
3. storage symptoms: overly sensitive M3 receptors


1. frequency, urgency, and incontinence

BPH therapy

non-pharm


1. behavioral modifications
2. surgery

pharm


1. alpha 1 antagonists
2. 5-alpha-reductase inhibitors
3. PDE-5 inhibitors
4. anti-muscarinics

alpha-1 antagonists - BPH

1st line of therapy

MoA: alpha blockade leads to smooth muscle relaxation in the internal urethral sphincter

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uroselective drugs


1. tamsulosin - flomax
2. alfuzosin - uroxatral
3. silodozin - rataflo

less uroselective


1. doxasozin - cardura
2. terosozin - hytrin

ADR


1. hypotension (less uroselective more so, tamsulosin least)
2. sexual dysfunction - ejaculatory
3. headaches, dizziness, and nasal congestion

administration


1. at bedtime to avoid postural hypotension
2. titrate - not tamsulosin
3. life-time therapy

monitoring


1. AE
2. urinary frequency - especially at night

interactions


1. PDE5 inhibitors - hypotension, less risk with tamsulosin

5-alpha-reductase inhibitor - BPH

MoA: prevents the conversion of testosterone to DHT and reduce prostate size

1st/2nd line treatment

drugs:


1. finasteride: proscar
2. dutasteride: avodart

AE:


1. sexual dysfunction: ED and decreased libido
2. reduce risk of prostate cancer

administration


1. can be used indefinitely
2. titration not needed

monitoring


1. AE
2. efficacy

counseling points


1. can take 6-12 months to see a difference
2. avoid which trying to conceive - teratogenic

PDE5 and BPH

MoA: relaxation of the prostate and the detrusor muscle

2nd line therapy unless patient has concomitant ED

drug: low dose QD tadalafil (cialis)

AE:


1. hypotension
2. flushing
3. nausea
4. headaches

counseling: interactions with nitrates and alpha blocker (severe hypotension)

Anti-muscarinics and BPH

use in patients with storing symptoms - avoid in patients with voiding symptoms

M3 reduce AE

OTC that exacerbate BPH

1. decongestants - pseudoephedrine
2. antimuscarinics - diphenhydramine
3. diuretics - caffeine and alcohol

erection pathophysiology

1. arousal
2. PS stimulation to the penis
3. increased NO
4. smooth muscle relaxation
5. arterial dilation and expansion of sinusoidal spaces
6. increased blood flow and reduces blood outflow
7. increased intracavernosal pressure and penis rigidity
8. erection

NO and erection

NO stimulates guanylate cyclase to convert GTP into cGMP

cGMP phosphorylates calcium and potassium channels

phosphorylation causes calcium channels to close = reduces intracellular calcium levels and potassium channels to open (hyperpolarization)

leads to vasodilation and erection

Prostaglandin E1 and erection

prostaglandin E1 stimulates adenylate cyclase to convert ATP into cAMP

cAMP phosphorylates calcium and potassium channels

phosphorylated calcium channels close reducing intracellular calcium levels and phosphorylated potassium channels open causing hyperpolarization leading to vasodilation and an erection

PDE5 inhibitors MoA

inhibits the breakdown of cGMP prolonging the effect of an erection

PDE5 inhibitor drugs

duration is roughly 4-6 hours except cialis

dose reduction:


1. men over 65 years
2. renal/hepatic impairment
3. AE
4. drug interactions

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drugs:


1. sildenafil (viagra)


1. dosed 1 hour before intercourse
2. fatty meals delay onset
2. vardenafil (levitra and staxyn)


1. dosed 1 hour before intercourse
2. fatty meals delay onset
3. staxyn is an orally disintegrating tablet
3. avanafil (stendra)


1. 15-30 minutes before intercourse
4. tadalafil (cialis)


1. “weekender” - 36 hour duration
2. take 30 minutes before intercourse

PDE5 inhibitors AE

1. hypotension
2. flushing
3. headaches
4. nasal congestion
5. vision changes - blue tinted vision and vision loss
6. hearing loss
7. dyspepsia
8. priapism: erection lasting longer than 4 hours

PDE5 inhibitor contraindications

absolute: nitrates

warningsL alpha-1 blockers

grapefruit

anti-fungals

PDE5 inhibitor counseling

1. requires stimulation
2. max 1 time per day
3. must try 5-8 times before adjusting dose or saying it doesn’t work
4. avoid excessive alcohol consumption


1. drowsiness
2. hypotension
3. worsen ED symptoms

prostaglandin E1

Alprostadil


1. intercavernosa injection


1. Caverject, impulse, Edex
2. max once daily up to 3 times a week
3. duration 30-60 minutes
4. inject on 1 side
5. AE: bruising, fibrosis, pain, bleeding, and priapism
2. intraurethral


1. muse
2. max 2x in 24 hours
3. AE: urethral burning, itching, and warmth, pain, priapism, partner urethral burning and itching if condom is not used
4. do not use with pregnant partner

testosterone boxed warning

1. secondary exposure to women and children
2. increased cardiovascular events
3. increased risk of breast cancer in long-term testosterone use

testosterone SE

1. increased BPH
2. sleep apnea
3. acne
4. breast growth
5. weight gain
6. increased hematocrit
7. mood swings
8. liver toxicity

testosterone

schedule 111

restore testosterone levels to 300-1000 ng/dL

stimulates NO synthase

injected in glute