Hypothalamic and Pituitary Hormones

Three main pharmacologic uses of hypothalamic and pituitary hormones: replacement therapy for hormone deficiency states, antagonists used in overproduction states, and as diagnostic tools to identify
abnormalities
Growth hormone & prolactin → activate JAK/STAT superfamily receptors
TSH, FH, LH, ACTH → activate GPCR receptors

GH-producing cells (somatotrophs) can form secreting tumors (more commonly in adults)
Sx = acromegaly (abnormal growth of cartilage, bone tissue, skin, muscle, heart, liver, GI tract) and gigantism (if it occurs before long bone epiphyses close)
Small GH-secreting adenomas can be treated with GH antagonists: GH receptor antagonists; somatostatin analogs; or dopamine receptor agonists
Larger pituitary adenomas require surgery/radiation
Drug Description MOA Indication PK AE Fun Facts
Stimulates longitudinal Predominantly required Growth failure in pediatric pts Administer Children: Diagnosis:
bone growth during childhood & associated with: GH deficiency, chronic subcutaneously 3- Scoliosis [during rapid growth], hypothyroidism, Grow < 4cm/year
↑ Bone density adolescence renal failure, 7x/week intracranial HTN [rare], otitis media [Turner Absence of serum GH
↑ Muscle mass Effects mediated mainly by Noonan/Prader-Willi/Turner syndrome, Persists in blood syndrome pts], pancreatitis, gynecomastia, nervus response to two GH
Somatropin [in GH deficient people] IGF-1 short stature homeobox containing gene for 36h growth, diabetic syndrome [chronic use] secretogogues
(recomb. GH) ↑ GFR Activates IGF-1 via the deficiency, small for gestational age with
Differentiation of JAK/STAT signaling failure to catch up by age 2, idiopathic CYP450 inducer Adults: Contraindicated in pts
adipocytes cascade leading to up short stature in pediatric pts Peripheral edema, myalgias, arthralgias [esp hands with malignancy (cause
Anti-insulin actions regulation of GLUT-1 & 4 & wrists], carpal tunnel syndrome, proliferative tumors to grow at faster
[↓ glucose utilization & ↑ transporters GH deficiency in adults retinopathy [rare] rate) and with
lipolysis] Wasting in HIV pts cytochrome P450
↑ Immune system function Short bowel syndrome inducers

Somatrem
(GH analog)

Complex of recombinant
human IGF-1 and
recombinant human
Mecasermin
IGF-binding protein-3
(IGF-1 analog)
GH receptor antagonist
Pegvisomant Prevents dimerization of receptors (that cause
phosphorylation of JAK2)
Somatostatin analog
Action mediated by
Octreotide disulfide bridge between
cysteine residues
Dopamine agonists
Bromocriptine Inhibit prolactin and GH
Cabergoline secretion
Needs to be combined with Small number of children with growth Hypoglycemia [eat 20 min before or after admin.]
IGF-binding protein-3 to failure have IGF-1 deficiency (giving
see clinical effects GH has no effect) Intracranial HTN [rare]
Causes: Elevation of liver enzymes [asymptomatic]
-GH receptor mutation
-Develop. of neutralizing Ab to GH
Small GH secreting tumor JAK/STAT pathway block
Inhibits release of GH, TSH, Reduce symptoms of hormone 45x more potent Nausea, vomiting, steatorrhea Octreotide acetate is a
glucagon, insulin & gastrin secreting tumors [acromegaly, in ↓ GH release Constipation, gallstones & biliary sludge long-acting suspension
carcinoid, gastrinoma, etc.] (than Pain at injection site given at 4 week intervals
Localize neuroendocrine tumors somatostatin) Sinus bradycardia
Control bleeding from esophageal 2x more potent in B12 deficiency
varices (causes vasocontriction) ↓ insulin
t1/2 = 80 min
Activates post-synaptic Prolactinoma Oral or as vaginal Nausea [bromocriptine>cabergoline], HA, lightheadedness, orthostatic
dopamine receptors Acromegaly [in combination with inserts hypotension, fatigue
surgery, radiation or octreotide] Bromocriptine Psych manifestations [may co-admin with anti-depressants]
t1/2 = 7h High dose = cold-induced peripheral vasospasm
Cabergoline Chronic high dose = pulmonary infiltrates
t1/2 = 65h
Menotropins Purified FSH and LH Act through GPCR’s aiding Induce ovulation [expensive and Women: Ovarian hyperstimulation syndrome, multiple pregnancies, HA,
(hMG) in follicular development, complicated, reserved tx] depression, edema, precocious puberty
Follitropin Purified FSH ovulation and pregnancy
Urofollitropin Male infertility due to hypogonadism Men: Gynecomastia
hCG Extract or recombinant requires both FSH and LH SC or IM
Synthetic GnRH GnRH binds GPCR on Stimulation: IV/SC Stimulation: Continuous admin gives biphasic response:
gonadotrophs to modify Female infertility [uncommon] t1/2 = 4min HA, lightheadedness, nausea, agonist ‘flare’ for the first 7 days with
FSH and LH levels in blood Male infertility d/t hypothalamic flushing, hypersensitivity inhibitory action following after (receptor
hypogonadotropic hypogonadism dermatitis, rare acute down-regulation and changes in signalling
Gonadorelin Pulsatile → stimulates Diagnosis of LH responsiveness in hypersensitivity reaction, pathways)
Continuous → inhibits delayed puberty sudden pituitary apoplexy and
blindness [in pts with Contraindicated in pregnant and breast-
Suppression [more common]: gonadotropin secreting tumor] feeding women
Controlled ovarian hyperstimulation Suppression:
GnRH analogs Endometriosis, fibroids, PCOS IM/SC/ Women: menopausal symptoms,
Prostate CA nasal [nafarelin] depression, ↓ libido, pain, vaginal
More potent and longer Precocious puberty t1/2 = 3h dryness, breast atrophy,
lasting than gonadorelin Breast and ovarian CA osteoporosis
Leuprolide
Thinning of endometrial lining Men: hot flush, sweats, edema,
Nafarelin D-amino acids at position 6 gynecomastia, asthenia, ↓ libido,
Goserelin
hematocrit, bone density

Cetrorelix Competitive GnRH receptor Suppress gonadotropin production thus preventing LH surge during
Ganirelix antagonists controlled ovarian hyperstimulation
Stimulate adrenal cortex Limited use as therapeutic agents ACTH is normally secreted from pituitary in
via the MC2 receptor → ↑ (less predictable and convenient than pulses
cAMP → steroid hormone corticosteroids) Highest conc. at 6am, lowest in the evening
Corticotropin
ACTH analogs secretion Differentiate between primary and Similar to glucocorticoids Stress stimulates secretion
Cosyntropin
secondary adrenal insufficiency Cortisol suppresses release
Tx: Infantile spasm [West Syndrome]

Acts on GPCRs
Stimulates release of PG’s
and LT’s that augment
uterine contraction
Milk ejection
Oxytocin
Low dose: ↑ force and IV: initiate & augment labor t1/2 = 5min Sustained uterine contractions Contraindicated in:
frequency of contraction IM: control postpartum bleeding Do not give as [fetal distress, placental Prematurity/Fetal distress
High dose: sustained bolus → abruption or uterine rupture] Abnormal fetal presentation Cephalopelvic
contraction with weak hypotension Excess fluid retention and water disproportion
antidiuretic & pressor intoxication [activation of Uterine rupture predisposition
activity vasopressin receptors]→ seizure
and death

Atosiban Oxytocin antagonist Preterm Labor [NOT in US]

Released in response to
Vasopressin ↑ plasma tonicity or ↓ BP
Long acting synthetic
vasopressin analog with
Desmopressin minimal V1 activity
Vasopressin antagonist
Conivaptan
ADH analogs binding and DOC for Diabetes Insipidus IV/IM HA Has both antidiuretic and vasopressor
activating 2 GPCRs: [Vasopression much better than a t1/2 = 15min Nausea activities
V1 → vasoconstriction thiazide] Abdominal cramps
V2 → H2O reabsorption via Vasopressin: bleeding from esophageal IV/SC/oral/ Allergic reaction Much greater antidiuretic effect than
renal tubular cells varices and diverticula intranasally Hyponatremia and seizures can pressor effects (4000x vasopressin)
t1/2 = 1.5-2.5h
Desmopressin: Hemophilia A and von be seen with overdose
Willebrand’s disease
High affinity for V1 and V2 Approved for hyponatremia (due to
receptors elevated vasopressin)
 Clinical Applications of corticosteroids [mineralocorticoids and glucocorticoids]
Adrenocortical insufficiency Congenital Adrenal Hyperplasia Cushing’s Syndrome Primary Hyperaldosteronism
Chronic [Addison’s disease] Defects in cortisol synthesis most commonly due to 21- Bilateral adrenal hyperplasia secondary to ACTH Usually due to excessive production
Weakness, weight loss, fatigue, hypotension, hydroxylase deficiency secreting pituitary adenoma → chronic excess from adrenal adenoma
hyperpigmentation and the inability to maintain Other causes: defective CRH production in hypothalamus glucocorticoids Sx: renal loss of K+ → hypokalemia,
glucose during fasting or corticotropin production by pituitary TX: Surgery or radiation alkalosis, hypernatremia
TX (both mineral and gluco effect needed): High dose of cortisol before and after surgery DX and TX: Spironolactone
Daily hydrocortisone (increase dose in times of ↓ steroid levels → ↑ ACTH and hyperplasia of adrenal → Pt’s can experience a withdrawal syndrome;
stress) + fludrocortisone (mineralocorticoid) glands taper off accordingly
Do not use long-acting glucocorticoids or ones Increased cortisol precursors are shunted to androgen
lacking Na+ retaining activity; the negative feedback pathway Dexamethasone Suppression Test
suppresses adrenal glands (big problem in the long Cushing's syndrome: dexamethasone
run) TX: Glucocorticoids → suppress ACTH; suppresses cortisol release in individuals with
(tx initally as an acute adrenal crisis) pituitary-dependent Cushing's syndrome (not
Acute crisis → when assoc. w/ shock, infection or Once stablilised: oral hydrocortisone or released from adrenal tumors)
trauma, start treatment immediately prednisone + fludrocortisone Depressive psychiatric states
TX: high dose hydrocortisone + correction of fluid
and electrolyte abnormalities [no MC yet] Protect fetus by giving dexamethasone to mother
Admin. salt-retaining hormone after 5 days
Non-adrenal disorders treated with synthetic corticosteroids: Short term use = few serious AE (treat with short-immediate acting steroids as much as
Stimulation of lung maturation in fetus [IM steroids: dexamethasone], immunological inflammatory conditions, possible)
allergic reactions, Hodgkin’s lymphoma [prednisone], cerebral edema [dexamethasone], chemotherapy-induced Long-term use = predictable toxicity based on physiological effects
vomiting, hematologic disturbance, organ transplants, renal disorders [nephrotic syndrome], hypercalcemia,
mountain sickness, inflammatory bowel disease, idiopathic orthostatic hypotension [fludrocortisone] Adverse Effects include:
Metabolic effects [Cushing’s, diabetes, muscle wasting, osteoporosis]; peptic ulcers;
Toxicity can be minimized by: myopathy, steroids can mask clinical findings in certain disorders [especially in
Local application, low dose, tapering dose to avoid withdrawal syndrome, alternate day therapy, addition of a bacterial and mycotic infections]; nausea, dizziness, weight loss, CNS effects, glaucoma,
stress dose in pt’s with insufficiency, K+ supplementation, Ca2+ & Vitamin D supplements cataracts, Na+ and fluid retention, hypokalemia, growth retardation [children] and
adrenal suppression
Contraindications (weight risk vs. benefits):
Peptic ulcers, heart disease or HTN w/ HF, TB, varicella zoster, psychoses, osteoporosis, glaucoma
Drug Description MOA Indication AE
Spironolactone Mineralocorticoid antagonist Competes with aldosterone for its Dx and Tx of hyperaldosteronism Hyperkalemia, arrhythmia
receptor → ↓ effect peripherally Hirsutism in women Menstrual abnormalities, gynecomastia Sedation, HA, GI distress,
Diuretic skin rash
Mifepristone Glucocorticoid and progesterone antagonist receptors Inoperable ectopic ACTH syndrome
or adrenal CA
Aminoglutethimide Blocks conversion of cholesterol to Adrenal CA [supplement w/
pregnenolone reducing synthesis of all hydrocortisone or dexamethasone]
hormonally active steroids
Ketoconazole Potent & non-selective inhibitor or Cushing’s Syndrome (not first line, when tumor cannot be removed)
Synthesis inhibitors adrenal and gonadal steroid synthesis Prostate CA

Metyrapone Selective inhibitor of steroid 11- Tests of adrenal function Na+ and H2O retention [due to excess aldosterone]
hydroxylation blocking cortisol and Tx Cushing’s in pregnant women Hirsutism, dizziness, GI distress
corticosterone synthesis
 Gonadal Hormones
MOA:
Steroid hormones (oestrogens, progesterone, testosterone) bind to cytosolic receptor → conformational change (dimerization) →
hormone receptor complex travels into nucleus → modulate gene expression

Drug Description Physiologic Effects Indication PK AE Fun Facts

Synthetic: Sources: ovary, Sexual Development: Hypogonadism in females [IM long IV, IM, oral, ↑ incidence of thromboembolism Absolute contraindication:
Ethinyl estradiol adrenal gland, placenta, Growth/development of vagina, uterus and acting oestrogen preparations] transdermal, topical ↑ risk of CVD Hx of thromboembolism
Conjugated estrogen adipose fallopian tubes, breast enlargement, ↑ incidence of breast and endometrial Breast/Endometrial CA
Mestranol [aromatization] myometrial excitability, 2° sex OCP [combined with progestins] → Metabolized by cancers Pregnancy
Diethylstilbestrol (DES) characteristics in females suppress FSH & LH secretion and inhibit CYP450 Migraine, cholestasis, mood changes Liver disease
Estradiol = more Non-reproductive: ovulation (enterohepatic Nausea, breast tenderness, bloating
Estradiol potent than estrone ↓ bone resorption, prevent bone loss, circulation) 50x increase in estradiol and
Estrone and estriol closure of growth plate in long bones Post-menopausal HRT → ↓ hot flush, Combination with DES (non-steroidal estrogen agonist) estriol in pregnancy
Estriol Pro-coagulable state: osteoporosis, urogenital atrophy inducers = ↓ OCP use in preganancy = female child w/ 1000x increase in estriol =
Mestranol = prodrug ↑ Factor II, VII, IX, X, XII in higher doses efficacy infertility and vaginal cancer indicator of fetal well-being
of ethinyl estradiol (↑ ↓ AT-III, Protein C & S Prostate CA, acne, dysmenorrhea and
bioavailability, Favorable lipid profile: dysfunctional uterine bleeding
↑ half-life, ↓ FSH/LH via ↑ HDL, ↓ LDL
feed-back) Hormone levels:
↑ transport of various hormones (cortisol,
thyroxine, steroids)
↑ cholesterol in bile → gall stones
Tamoxifen Selective Estrogen Antagonist: breast Breast CA & prophyaxis for high risk Hot flush [antagonist]
Receptor Modulators Agonist: liver, endometrium, and bone patients Thrombosis [agonist]
SERMs (partial) ↑ risk of endometrial CA
Raloxifene Antagonist: breast Breast CA & prophylaxis for high risk No estrogenic effect on endometrium
Mixed MOA: Agonist: bone patients No increased risk of endometrial cancer
agonist/antagonist Prevention of postmenopausal
Toremifene
osteoporosis
Clomiphene Oestrogen antagonist in hypothalamus and Anovulatory infertility Oral Ovarian hyperstimulation → ovarian Interferes with receptor
anterior pituitary t1/2 = 5-7 days enlargement recycling effectively depleting
Blocks –ve feedback inhibition of GnRH at Fertility drug Significant protein Multiple pregnancies (10%) hypothalamic ER’s → loss of –ve
hypothalamus → ↑ pulsatile release → ↑ binding and Hot flushes, nausea, vomiting, breast feedback
FSH & LH → growth of follicle and enterohepatic tenderness, weight gain
ovulation circulation
Fulvestrant Estrogen Receptor Estrogen receptor antagonist in all tissues Breast CA in tamoxifen resistant pts IM Hot flush, HA, injection site reactions
Antagonist [SERD]
Letrozole Aromatase Inhibitors Block conversion of androgen to estrogen 2nd line treatment for breast CA following Oral Hot flush Exemestane = irreversible
Anastrozole Exemestane tamoxifen resistant ↓ Bone mineral density aromatase inhibitor

Sources: corpus Progesterone elevation = ovulation Contraception (alone/with estradiol) Oral Long term use: Medorxyprogesterone, etc →
Progesterone luteum, placenta, Required for gestation and maintenance of Hormone replacement therapy IM injection newer preps lacking of
Medroxyprogesterone testes, adrenal cortex pregnancy (pro-gestation) Suppress ovaries in the treatment of Weight gain, glucose intolerance, androgenic and antiestrogenic
Norgestrel Induces secretory changes in the dysmenorrhea & endometriosis androgenic (hirsutism, acne), anti- effects.
Norethindrone High dose → endometrium Diagnose estrogen secretion when estrogenic (blocks lipid changes), Drospirenone → spironolactone
Norgestimate suppresses FSH & LH ↓ uterine & gallbladder contractions menstruation occurs after progesterone depression, edema, ↑ HDL, used as OC anatagonize
Desogestrel leading to anovulation Decrease estrogen receptor expression administration in a patient with ↓ HTN & LDL aldosterone effects useful in
Drospirenone produce thick cervical mucus that inhibit amenorrhea acne in females
sperm entrance
Mifepristone Antiprogestin Controversial "morning after" pill → used Oral Excess bleeding Given with PGE or PGF to
Competitive inhibitor of progesterone and glucocorticoid receptors as abortifacient GI [N/V, anorexia, pain] increase myometrial contraction

Testosterone Sythetic androgens = Testosterone: Hypogonadism Transdermal Buccal Over-masculinization Excess use → feminization due
Methyltestosterone 17alkyl derivatives Wolffian Duct, spermatogenesis, bone ↑ bone density in osteoporosis SC implant In women: hirsutism, suppression of to feedback inhibition and
Oxandrolone Stanozolol with ↑ anabolic effects formation & muscle growth, genitalia ↑ muscle mass [+ N balance] IM menses, acne, clitoral enlargement conversion of exogenous
Fluoxymesterone DHT = more potent growth, libido, deepening of voice Some cases of aplastic anemia BPH, hepatic adenomas testosterone into estrogen
Nandrolone than testosterone and DHT: Cholestatic jaundice
Oxymetholone androstenedione External genitalia differentiation, prostate, Illicit use in athletics Aggression and dependency
(adrenal gland) male pattern baldness, acne, facial/body Premature closure of epiphysis
hair
Danazol Synthetic androgen derivative Endometriosis Inhibits CYP450 Hepatitis Modified testosterone →
Partial agonist of progestin & glucocorticoid receptors Fibrocystic change in the breast gonadal steroid Abnormal LFT and drug interaction masculinization/hirsutism
synthesis d/t P450 interaction
Flutamide Bicalutamide Androgen receptor Used for androgen-receptor-positive Primarily used in conjunction with GnRH analogs
Nilutamide blockers cancers [eg. leuprolide] to reduce initial tumor flare ups of prostate
carcinoma
Finasteride Dutasteride 5α reductase inhibitor Block conversion of testosterone to DHT BPH Oral Gynecomastia Combo TX = 5α reduct. inhib +
Male pattern baldness Impotence α1 antagonists [for BPH]
Ketoconazole Steroid synthesis Inhibits CYP450 Advanced prostate CA resistant to other Oral Drug interaction with other steroids
inhibitor 1st line drugs (not 1st line) due to CYP450 inhibition
Leuprolide Gonadorelin GnRH analogs Continuous dose causes a reversible
Nafarelin medical castration

Spironolactone Anti-androgen action Spirinolactone = blocks aldosterone and competes androgen receptors; used in hirsutism Hormone therapy component
Cyproterone Cypoterone = progesteronal effect suppresses LH and FSH; used in hirsutism and to ↓ excessive sexual drive in men for M→F transsexuals

Drug Description
Peptide hormone secreted by the
posterior pituitary → milk ejection
in lactating women
Oxytocin Uterus becomes more sensitive to
Oxytocics [Uterine Stimulants]
Drugs acting on the Uterus
Mechanism
Activates Gq → … ↑ Ca2+ →
MLCK → myometrial contraction
↑ PG synthesis which further
stimulates contraction of uterus

oxytocin during 2nd half of

pregnancy
Partial α-agonist & some 5-HT (serotonin) receptors
Ergonovine Sensitivity of uterus to ergo alkaloids increases dramatically during
Methylergonovine pregnancy
Carboprost PGF2α analog
tromethamine
Synthetic preparation of PGE2 Adminstered to promote
Dinoprostone cervical ripening in women
with unfavourable cervixes
PGE1 analog Stimulate uterine contractions
Misoprostol

Preterm birth [< 37w] is the leading cause of neonatal mortality. Managed with bed rest, tocolytics and glucocorticoids [< 34w
achieve maximal effect → decrease NRDS, intracranial bleeding, and mortality. There is no first line tocolytic; agents below are
Drug Description Mechanism
Uncouples excitation-contraction in myometrium through inhibition
Magnesium sulfate of cellular action potentials [opposes Ca2+]
Similar efficacy to terbutaline with better tolerance
Tocolytics [Uterine Relaxants]

NSAID Inhibit PG synthesis [which

stimulate uterine contraction]
Indomethacin

Ca2+ channel blocker Inhibits contractility

Nifedipine Effective and safe ↓ Ca2+ → ↓ MLCK

Atosiban Competitive oxytocin receptor antagonist

Activates Gs → ↑ cAMP → ↑ PKA → phosphorylates SmMLCK →
SmMLCK has ↓ affinity for Ca2+/calmodulin complex → myosin is
Terbutaline not phosphorylated → smooth muscle relaxation
[β2 agonist]
Phased out and replaced by Mg2+ sulfate due to AE
rugs acting on the Uterus
Indication
DOC for induction of labor IV [slow]
Augment dysfunctional labor IM
1st line in management of
post-partum hemorrhage (due
to uterine atony)
2nd line for post-partum
hemorrhage when oxytocin is
ineffective [or use both]
h bed rest, tocolytics and glucocorticoids [< 34w]; tocolytics delay delivery for 48 hours so glucocorticoids can
There is no first line tocolytic; agents below are all commonly used
Indication
Most popular/primary
tocolytic agent
Delay preterm labor
More successful prolongation of
preterm pregnancy (compared
to others)
Not available in US
Injectable terbutaline needs to
be limited to max. 72 hours
Oral terbutaline should not be
used to treat preterm labor
PK Adverse Effects Contraindications
Excessive stimulation: fetal distress, placental
abruption, uterine rupture
Activate vasopressin receptors → fluid
retention, hyponatremia, seizures and death
Ripening agent should be used before oxytocin in
women w/ unfavourable cervixes
IM HTN, HA, seizure, N/V, Angina, MI, pregnancy,
chest pain CVA, ischemic attack,
HTN
IM
Vaginal Tachysystole This alone initiates
insert or Fever labour in many
cervical gel Chills women, and obviates
Intravaginal Vomiting need for oxytocin
/oral/ Diarrhea
sublingual
PK Adverse Effects Contraindications
Crosses Monitor mother for:
placenta Respiratory depression
Cardiac arrest
Crosses Oligohydramnios d/t ↓ Not recommended after
placenta in fetal renal blood flow 32 weeks because AE
[if used > 48h] are more common
Premature closure of
ductus arteriosus
Maternal tachycardia,
palpitations, flushing,
nausea, HA, dizziness
Black box Palpitation, tremor, N/V, anxiety, chest pain,
warning dyspnea, hyperglycemia, hypokalemia,
[2011] hypotension, pulmonary edema, cardiac
insufficiency, arrhythmias, MI, maternal death
 Thyroid and Anti-thyroid Drugs
Function of thyroid gland = take up iodine and convert it into thyroid hormones
Iodine is covalently bound to tyrosine residues in thyroglobulin molecules via thyroperoxidase (TPO is responsible for oxidation, organification, and iodide coupling reactions of MIT and
DIT; MIT + DIT = T3, DIT + DIT = T4)
Reverse triiodothyronine (rT3) = isomer of T3, derived from T4 by deiodinase, blocks action of T3 (source: stressful conditions)
Physiological effects of thyroxine: ↑ BMR via Na+/K+ ATPase (↑ RR, ↑ body temp, ↑ O2 consumption), ↑ sympathetic activity β effects (↑ CO, ↑ HR), promotes CNS development, bone growth
(with GH), ↑ gluconeogenesis/glycogenolysis/lyposis, LDL expression (↑ in hyperthyroidism, ↓ in hypo)
Pharmacokinetics of thyroid hormones: most circulating T3 is formed from deiodination of T4 in peripheral tissues, liver, and kidney;
5'-deiodinase enzyme is also present in pituitary gland, brain and brown fat- some T3 is released from thyroid
Thyroxin-binding protein (TBG) = transport protein for T3 and T4; ↓ TBG in hepatic failure and ↑ TBG in pregnancy and OCP
Normal thyroid gland produces >90% T4 and 10% T3; T3 = 10x more potent than T4; only free forms of T3/T4 are active
Pituitary gland is regulated by hypohalamus (TRH) → thyroid gland is under control of pituitary gland (TSH) → negative feedback from T3 and T4
MOA: signalling mechanism via TRH (IP3 mediated) → TSH (cAMP mediated) → T3 and T4 binds with intracellular receptors in nucleus → proteins synthesized depending on tissues
Hypothyrodism = ↑ TSH, ↓ total T4, ↓ free T4, ↓ T3 in blood (primary = Hashimoto's thyroiditis, radiation exposure, iodine deficiency, lithium, amiodarone;
secondary = ↓ TSH from pituiatary due to radiation, surgery, tumor; tertiary = ↓ TRH production from hypothalamus)
Sx = lethargy, weight gain, cold intolerance, constipation, hair loss, carpel tunnel syndrome, poor memory, intectual deterioration, hoarse voice, puffy face, waxy skin, eyebrow hair loss,
bradycardia, delayed relaxation DTRs, Queen Anne's sign (thinning of hair in lateral third of eye brow)
Cretinism = mentally retarded, short stature child with protruding umbilicus, pot belly, pale & puffy face, protruding tongue
Causes = lack of dietary iodine, defect in T4 synthesis, developmental failure of thyroid
Hyperthyroidism = ↓ TSH, ↑ total T4, ↑ free T4, ↑ T3 in blood; causes = Graves disase, toxic multinodular goiter, toxic adenoma, molar pregnany, postpartum thyrotoxicosis, post-viral
thyroiditis
Sx = weight loss, heat intolerance, nervousness, palpitation, bowel infrequency, insomnia, abnormal menses
Thyroid storm = life threatening medical emergency associated with extreme effects of hyperthyroidism; caused by illness, surgery, thyrotoxicosis
β-blockers manage CVS tachycardia/HTN; propylthiouracil, IV sodium iodine, and glucocorticoids inhibit peripheral conversion of T4 → T3

Drug Description MOA Effects PK AE Fun Facts

Thyroxine [T4] Levothyroxine (T4) = longer t1/2 TRH [IP3] → TSH [cAMP] → T3/T4 [nuclear Used in treatment of: Enzyme induction Tremors, tachycardia, arrhythmias, heat T3 & T4 circulate bound to
Triiodothyronine [T3] T4 is converted to T3 in target tissues receptor] → altered gene expression Cretinism (due to thyroid hormone synthesis enzyme (P450) can ↑ intolerance TBG → ↓ in hepatic failure; ↑ by
such as liver, kidneys, etc defect) metabolism of T3 Overdose = hyperthyroidism Sx pregnancy and estrogen intake
Liothyronine (T3) = short t1/2 Adult hypothyroidism (myxedema) and T4 Pts w/ longstanding hypothyroidism = Only free forms are active
T3 is 10x more potent than T4 highly sensitive to TX (monitor elderly)
Propylthiouracil Thioamides Inhibit TPO → block iodination of TG and DOC for thyroid storm = PTU b/c it also inhibit 5’- Oral Rash and arthralgia, agranulocytosis, Goitrogens: thioamides,
Methimazole Slow onset of action because they do inhibit coupling reactions (prevent MIT deiodinase, decreasing the conversion of T4 → T3 Meth = 1x/day aplastic anemia, hepatotoxicity, cabbage + cassava (contain
not inhibit preformed T4/T3 and DIT to form T4/T3) PTU is reserved for pts intolerant to methimazole/not fit PTU = 3x/day hypoprothrombinemia, vasculitis thiocyanate), imatinib,
for surgery/131-I (RAI)/used in 1st trimester Serious AE less common with methimazole, sunitinib (TKRI),
but it is a teratogen (aplasia cutis aminogltethimide,
congenita) sulfonylureas
Iodine High levels of iodide paradoxically inhibit thyroid hormone synthesis Decrease vascularity and size of the thyroid → useful Available as Chronic iodide intoxication (iodism), Preparations available:
Iodide salts Wolff- Chaikoff effect [last for only 2 weeks] = ↓ organification and proteolytic preoperatively for easy thyroid excision preparations anaphylactoid reaction (angioedema), 1. Lugol’s solution
release via brief TPO inhibition Used in conjunction with PTU and β-blockers in swelling of larynx/eyelids, brassy taste, (iodine + potassium iodide)
Can result in multinodular goiter if large doses are continued thyrotoxic crisis burning of teeth & gums, ↑ size of parotid 2. Saturated solution of
[Jod-Basedow phenomenon] and maxillary gland potassium iodide
Radioactive iodine is taken up and Toxic β-rays damage tissue Tx of hyperthyroidism and Grave’s disease that is Contraindicated in pregnancy and nursing Dosing is very difficult - may
131 sequestered in the thyroid Does not cause CA refractory to other therapy mothers develop hypothyroidism
I
Only medical therapy that causes
permanent reduction of activity
β-blockers - useful in controllong nervousness, palpitation, fatigue, weight loss, Propranolol (nonspec) prevents conversion T4 → T3 Partial agonists Alternatives to β-blockers in thyroid storm Inhibit conversion of T4 →
Propranolol heat intolerance, and tremors associated with hyperthyroidism, short-term are not used for pts with asthma = CCB, diltiazem, or T3: corticosteroids,
Esmolol (short acting) is used to control intraoperative
Esmolol management in pregnancy, preoperatively, and thyroid storm verapamil propranolol, amiodarone
thyroid storm
Diatrizoate Radiocontrast media Suppresses conversion of T4 to T3 (5'- Rapidly reduces T3 concentration in thyrotoxicosis Oral May also inhibit hormone
Iohexol deoiodinase) in peripheral tissues Oral/IV release from thyroid gland
Perchlorate Inhibit concentration of iodine in the Competitively inhibits the Aplastic anemia
Thiocyanate gland by blocking transportation Na-I-symporter
Pertechnetate
Glucocorticoids Inhibit peripheral conversion of T4 to T3; PTU and NaI can also block conversion of T4 to T3
IFN Provoke autoimmune or destructive
IL-2 inflammatory thyroiditis inducing
Amiodarone hypothyroidism Antiarrhythmic agent Structural similarity to thyroxine
Lithium Inhibits hormone release and thyroid enlargement
 Bone Mineral Homeostasis
Moderate decline in Mg = enhance in PTH secretion, severe decline = decrease in PTH secretion
Common causes of ↓ Mg: chronic diarrhea, diueretics and alcohol abuse, chronic PPI and aminoglycoside use
Fibroblast growth factor-23: produced by osteoblasts and osteoblasts; inhibits calcitriol production and phosphate reabsorption in kidney
[↓ serum PO4, ↓ Ca2+ and PO4 absorption by intestines, ↑ PO4 excretion by kidneys]
Drug Description MOA Effects AE Fun Facts
Recombinant PTH analog ↑ Osteoblast and osteoclast activity via High levels: subperiosteal bone resorption May cause transient Denosumab: RANKL inhibitor preventing
Useful in the treatment of ligand RANKL [TNF cytokine] Low dose given intermittently/pulsatile (SC): hypercalcemia and osteoclast differentiation and function that
Teriparatide osteoporosis PTH acts by coupling Gs receptors to ↑ stimulates bone formation hypercalciuria can also be used to treat osteoporosis [but
Significant intervention for cAMP in bone and renal tubular cells Used for < 2y due to ↑ risk carries an increased risk for infection]
restoring normal bone loss of osteosarcoma
Calcitriol → 2° hyper- Vit D acts by activating steroid nuclear Other Vit D supplements are used in osteoporosis, Chronic overdose: Deficiency causes rickets in children: Type 1→
Cholecalciferol (D3) parathyroidism (↑ PTH, receptors chronic renal failure, nutritional rickets (d/t inadequate Hypercalcemia defective 1α-hydroxylase
Ergocalciferol (D2) ↓ serum Ca2+) in pt’s with dietary intake) & chronic liver disease. Cholecalciferol Hyperphosphatemia [↓calcitriol → ↓Ca and ↓PO4]
chronic renal & liver disease
Calcitriol Doxercalciferol & ergocalciferol are added to calcium supplements & Type 2 → defective Vit D receptor
Calcipotriol → topical psoriasis
Paricalcitol Calcipotriol dairy products OR osteomalacia in adults
treatment
Binds dietary phosphate and Prevents hyperphosphatemia in pt’s with chronic Does not alter calcium, aluminum or bicarb
Sevelamer
prevents its absorption renal failure
Oral: Ca carbonate, Ca citrate or IV calcium gluconate is used for treatment of IM: necrosis, abscess
Calcium Salts Ca lactate hypocalcemic tetany and to counteract overdose of Mg formation
IV: Ca gluconate used in eclampsia IV: thromobophlebitis
Peptide hormone Antagonizes PTH inhibiting Approved for tx of osteoporosis and has been shown to Salmon calcitonin = longer t1/2 and greater potency
Calcitonin
Injection or nasal spray osteoclastic bone resorption increase bone mass and reduce spine fractures
Estrogens (effective in Tamoxifen: antagonist in breast, Useful in preventing tx of osteoporosis in post- Thromboembolism
preventing bone loss) agonist in bone and uterus menopausal women (given as hormonal replacement Migraine
Tamoxifen
Raloxifene: antagonist in breast, therapy) Increased risk for breast
Raloxifene
SERMs = selective estrogen agonist on bone (no estrogenic effect and endometrial CA
receptor modulators on endometrium) Hot flushes
Bisphosphonates Inhibit osteoclastic activity via ↓ Tx of osteoporosis, malignancy associated Erosive esophagitis Chronic use of etidronate & pamidronate may
Oral bioavailability < 10%, so farnesyl pyrophosphate synthesis hypercalcemia (Paget’s disease of the bone) (irritation of lining) result in bone malformation ↓ osteoblastic
Etidronate Alendronate they are given IV through disruption of the mevalonate Alendronate = DOC for glucocorticoid-induced Etidronate (<12 months): activity
Pamidronate pathway ↓ osteoblast H+ ATPase osteoporosis osteomalacia,
Risedronate Causes ↑ in bone mineral density in post-menopausal osteonecrosis of jaw, Paget's disease = due to latent viral infection,
(alongside HRT) fractures associated with chr. 5 & 6
Activates calcium-sensing receptors Tx of secondary hyperparathyroidism in chronic Nausea
Cinacalcet in the parathyroid → ↓ PTH synthesis renal disease & hyperparathyrdoisim in pts with Hypocalcemia
and release parathyroid carcinoma
Glucocorticoids May cause osteoporosis [along with lithium , heparin, anastrazole, and alcohol]
Fluoride Chronic exposure causes new bone synthes which is denser but brittle
Gallium nitrate Inhibits bone resorptionm useful in cancer-related hypercalcemia Nephrotoxic
Cytotoxic anti-CA drug for hypercalcemia Thrombocytopenia
Plicamycin (Mithracin)
Hepatic/renal toxicity
Thiazides Increase Ca2+ reabsorption and reduce risk of Ca2+ stones
Drugs causing osteoporosis: corticosteroids, heparin, lithium, anastrozole, alcohol
Drugs causing osteomalacia: phenytoin, etidronate (>12 months use)
Drugs preventing calcium excretion: thiazide diuretics (↓ excretion of calcium by ↑ reabsorption; useful in prevention of renal stones, HTN in osteoporosis pt)
Hypercalcemia: usually asymptomatic, but severe cases present with “stones, bones, groans and psychiatric moans”
→ treatment includes: furosemide (+ saline infusion), bisphosphonates, calcitonin, and parathyroidectomy (if pt is symptomatic)
Osteoporosis: affects thin built, postmenopausal women (Caucasians & Asian), low bone mineral density & bone mass; hip, vertebral compression fractures and h/o steroid use/smoking
→ treatment: stop smoking/alcohol/corticosteroid use, HRT (in symptomatic perimenopausal period), calcium & vit D supplementation, bisphosphonates, SERMs, teriparatide
 Anti-diabetic Drugs
Type 1 (absolute deficiency of insulin)
Autoimmune attack on the pancreatic β-cells (Sx appear when 80-90% of β-cells are destroyed).
Hallmarks: elevated blood glucose and ketone bodies
Tx: involves subcutaneous injections of exogenous insulin to control hyperglycemia and avoid ketoacidosis
Type 2 (most common form)
A combination of peripheral insulin resistance and dysfunctional β-cells
Early stage: hyperinsulinemia - peripheral resistance and increased liver production of glucose make insulin levels
inadequate to normalise plasma glucose levels
Late: β-cells fatigue → insulin production fails → hyperglycaemia
Metabolic alterations are milder than those of type 1 diabetes, insulin secretion is enough to restrain ketogenesis
Hallmarks: hyperglycaemia but no ketone bodies
Tx: typically involves non-insulin hypoglycemic agents; insulin is not needed for survival, but may be needed to achieve
optimum health
Heterogenous group of disorders characterized by an elevation of fasting blood glucose or a deficiency of insulin
Insulin Secretion
Stimulation → glucose (most important), A.A, GI hormones (incretins)
Oral glucose stimulates incretin → enhance insulin secretion → higher insulin plasma concentration compared to IV glucose (the
Incretin Effect)
MOA: Glucose enters via GLUT-2 → glycolysis → ATP → closes ATP sensitive K+ channel → less K+ leaves the cell →
depolarisation → opening Ca2+ channel → trigger exocytosis of insulin and C-peptide
Peripheral: Acts on GLUT-4 → metabolic actions, cell growth and differentiation via glycolysis, FA synthesis, TAG storage, AA
uptake into muscle

Insulin receptor: consists of two covalently linked heterodimers (each contains an α and β subunit)
α subunit: extracellular, contains recognition site for insulin
β subunit: spans the membrane and contains tyrosine kinase
When insulin binds to α subunit, TK is activated in the β subunit
This leads to phosphorulation of tyrosine residues on the β subunits and of cytoplasmic proteins
Insulin analogs Human insulin preparation
Mimic physiological insulin profiles more closely Mimic physiological insulin
than human insulin preparations Given > 30 mins before a meal
Given just before a meal Produced by recombinant DNA technology using strains of E. coli or
Improved glycaemic control and decreased risk of yeast
hypoglycemia
Drug Description PK Indication AE Fun Facts
Lispro LAG: Rapid acting insulin SC, IV Standard administration is SC via Hypoglycemia Drug interactions:
Aspart analogs 15m prior to meal Lasts disposable needles/syringes, pens and → tremor and palpitations Hypoglycemia →
Glulisine → Do not form hexamers up to 5h and usually pumps ↓ risk with rapid acting insulin EtOH → decreases gluconeogenesis [messes with NAD/NADH ratio]
(hexamers slow down given w/ a longer β-blockers → mask sx. + ↓ gluconeogenesis & glycogenolysis
absorption of insulin) acting insulin Goal: replace basal insulin as well as Management: Salicylates → enhance β cell sensitivity to glucose; weak peripheral insulin like action
Mimics prandial release of prandial insulin Mild- conscious pt → juice, or any
insulin sugar containing beverage or food Hyperglycemia
Regimens: Severe unconsciour or stupor → IV Due to anti-insulin action at peripheral tissues
Regular insulin Short acting SC 30m before meal IV
Basal-Bolus : Long acting once a day glucose infusion Epinephrine, glucocorticoids, atypical antipsychotics, HIV protease inhibitors
Soluble crystalline zinc insulin in emergencies Lasts 5-
(glargine/detemir) plus a short acting Severe (No IV available) → glucagon Phenytoin, Clonidine & CCB’s → ↓ insulin secretion directly
8h
pre-meal (lipro, aspart or glulisine) SC or IM Diuretics deplete K+ which inhibits insulin secretion indirectly
Used in managing hospital pt’s
Pump therapy: predetermined amounts
DOC in pregnant pt’s
delivered to mimic normal insulin secretion Allergic reaction [rare]
(lipro, aspart or glulisine) → protein contaminants
Lipodystrophy [rare]
Hospitalised Patients → at injection site
Neutral protamine Intermediate acting SC Oral antidiabetic agents should be
Hagedon (NPH) Lasts 18-24h discontinued and replaced w/ insulin Inhaled:
Basal control Cloudy solution Cough, throat pain, hypoglycemia,
Also called Usually given with Protomine added IV infusion (regular human inslin) : pulmonary function should be
Isophane insulin rapid/short acting insulin for Pts w/ ketoacidosis, during pre-operative monitored
meal-time control period, during labor and delivery, intensive Contraindications: Asthma, COPD,
care situations smokers
Glargine Long acting SC
Detemir Glargine: precipitates in SC Lasts > 24h Inhaled (dry powder of human insulin):
tissue (pH 7.4) → forms a Peaks 12-15 mins and declines in 3 hours,
depot, slow dissolution has AE, pulmonary function should be
monitored
 Non-insulin Antidiabetic Agents - Oral hypoglycaemics
Drug Description MOA Effects AE Fun Facts
1st gen: Sulfonylureas Bind SUR1 subunit → block Chlopropamide - long t1/2 Mostly seen w/ 1st gen Glyburide, glipizide, and glimepiride
Chlorpropamide ATP sensitive K+ channel in β- Glipizide - short t1/2 Hyperemic flush when alcohol is consumed SIADH → more potent with less AE and therefore has
Effective at reducing fasting cell membrane → stimulate [chlorpropamide] replaced the 1st gen
2nd gen: plasma glucose and HbA1c insulin release (Pancreas) Hypoglycemia [especially in the elderly & in 20-30%
Glyburide Glipizide of Glyburide users]
Glimepiride Weight gain

Repaglinide Meglitinides Same as sulfonylurea, but less Rapid onset and short duration Hypoglycemia [esp. Repaglinide] Must be taken before each meal
Nateglinide effective in reducing FPG and Post prandial glucose regulators Weight gain If the meal is missed the drug must be omitted
HbA1c Rapidly absorbed and rapidly cleared Indicated in pt’s with sulfur allergies
Not sulfur containing
Metformin Biguanide AMPK mediates: Improved glycemic control → slight decline in serum Mainly GI: N/V/D, anorexia DOC in type 2 DM
DOC: type 2 DM ↓ gluconeogenesis by insulin Decreased B12 absorption Reduces macrovascular events in type 2 DM
reducing expression of Reduces plasma TAG by 15-20% Lactic acidosis (small risk, contraindicated in Can be used alone or in combination w/
Does not cause insulin enzymes (Liver) Decreases body weight conditions that can lead to hypoxia) sulfonylureas, Tzds and/or insulin
secretion or hypoglycemia ↑ glucose utilization in the
muscle and liver Contraindicated in pt’s with renal or hepatic disease
or alcoholism (leads to hypoxia, increases risk of
lactic acidosis)
Pioglitazone Thiazolidinediones [TZDs] PPAR-γ agonist with Decrease insulin resistance by promoting uptake and Fluid retention and edema Slow onset and activity shows over weeks to months
Rosiglitazone intracellular receptors found in utilization of glucose in adipose tissue May exacerbate CHF → contraindicated in pt’s with
Less effective than muscle, fat & liver class III or IV heart failure Compared with rosiglitazone, pioglitazone is assoc.
sulfonylureas or metformin Weight gain w/ significant improvements in lipid profile : HDL,
in reducing FPG and HbA1c TG, LDL size and concentration
FDA requires hepatotoxicity monitoring (due to
hepatoxicity due to troglitazone)

Acarbose α-glucosidase inhibitors Competitive intestinal Reduce postprandial digestion of starch and Mainly GI: flatulencem diarrhoea, abdominal pain. Not very effective
Miglitol (brush border enzyme to enzyme inhibitor → ↓ disaccharides Contraindicated in IBS or any intestinal condition Tend to be used an adjuncts due to its modest effect
breakdown starch absorption of glucose from the ↓ postprandial hyperglycemia and hyperinsulinemia worsened by gas and distension on FPG control
derivatives) gut
Acarbose → reversible liver enzyme elevation [use
Evokes a modest drop in with caution in pt’s with hepatic disease]
FPG and HbA1c levels → monitor LFT’s periodically
 Non-insulin Anti-diabetic agents - New agents
Drug Description MOA Effects AE Fun Facts
Exenatide GLP-1 analog [glucagon like Incretins are released from gut Enhances glucose dependent insulin secretion and ↓ GI: N/V/D Derived from salivary gland of the Gila monster
polypeptide]- full agonist, a → ↑ insulin secretion postprandial glucagon release Acute pancreatitis
type of incretin Slows gastric emptying, Injectable
Resistant to dipeptidyl Decreases appetite Should not be used in patients with gastroparesis
Used in combination with peptidase IV [DPP-IV - Stimulates β-cell proliferation
other agents enzyme that breaks down Approved to improve glycemic control in adults with
incretin] type 2 diabetes

Sitagliptin Selective inhibitor of DPP- Increases circulating GLP-1 and insulin levels Pancreatitis Given orally
IV Approved to improve glycemic control in adults with Hypersensitivity (including Steven-johnson
type 2 diabetes syndrome)
Pramlintide Synthetic amylin analog Inhibits food intake, gastric emptying and glucagon Injectable
secretion
Amylin is a peptide normally Adjunct to insulin
co-secreted with insulin
from pancreatic
β-cells

Colesevelam Bile acid sequestrant Unclear Tx of type II DM Oral

Adjunct

Canagliflozin SGLT-2 inhibitors ↓ glucose reabsorption in ↑ glucose excretion and ↓ bood glucose levels Increased incidence of genitourinary infections Oral
proximal tubule by sodium SGLT-2 = responsible for most glucose reabsorption Osmotic diuresis → volume depletion, ↑serum Adjunct
glucose transporters (SGLTs), creatinine levels, hyperkalemiam hypermagnesium
lose more glucose into urine hypophosphatemia, hypotension

Contraindicated in patients w/ GFR <45 ml/min

Glucagon Main goal is to increase plasma glucose… can be used in severe hypoglycemia, radiology of the bowel [relaxes intestine] and as an antidote for β-blocker overdose, Glucagon C-peptide test (test for residual B cells function in
diabetes)
American diabetes association Guidelines for Diabetes Type 2
Initial therapy Dual therapy Triple therapy
1st agent: Metformin (preferred first agent) If monotherapy doesn’t achieve HbA1c goal in over 3 months, the next step is to If Dual therapy fails to achieve target - Add a third agent
add a second agent
Started if lifestyle intervention did not achieve Hb1Ac goals Third agent: oral agent
Monotherapy can reduce Hb1Ac ~ 1% Second agents: Oral agent, exenatide or insulin
Many patients will eventually need to be transitioned to insulin, and should be favoured
Patients with Hb1Ac >9.0% should be started with a combination of two non- The higher the Hb1Ac, the more likely insulin will be required when Hb1Ac is >8.5%
insulin agents or with insulin itself Therapy is expected to reduce Hb1Ac by an additional ~1%

Transition to insulin therapy Insulin Co-morbidities

Start: Low dose w/ single injection of basal insulin and the dose is then
uptitrated
Basal insulin: NPH, glargine, detemir
If significant post-prandial glucose exercisions → Add prandial insulin
therapy w/ shorter-acting insulins
Prandial insulin therapy → Lispro, aspart, glulisine
Insulin is the most effective of diabetes medications in
lowering glycaemia → can decrease any elevated Hb1Ac to or
close to therapeutic goal
There is no celing effect and large doses of insulin may be
necessary to overcome insulin resistance in tyoe 2 diabetes
(than type 1)
Used as initial therapy when: Significant hyperglycaemic sx,
ketonuria, Hb1Ac >10%, random glucose >300mg
CVD:
Hypertension : ACE inhibitor or ARB
Dyslipidemia: Statins (regardless of lipid levels) for pts w/ overt CVD or >40 but have more than 1 risk
factor for CVD
Antiplatelet agents: Aspirin for patients with type 1 or type 2 diabetes at increased CV risk
Nephropathy: ACE-I or ARB for pts with albinuria without HTN, reduces risk of kidney failure
Distal symmetric polyneuropathy: amitriptyline, pregabalin, gabapentin, duloxetine, venlafaxine, valproate
and opioids
Gastroparesis: Metoclopramide or erthromycin (prokinetic agents to improve gastro sx)
Erectile dysfunction: Phosphodiesterase type 5 inhibitors
Most diabetic foot infections: Empiric antibiotic therapy targeted at aerobic gram+ve cocci especially staph
is common as the infection tends to be polymicrobial
 Antidepressants
Major depression: MAO
Depressive episodes charactized by depressed or sad mood, pessimistic worry, diminshed interest in normal activities Mitochondrial "safety valve" that normally inactivates excess NE, DA, 5HT which may leak out of the synaptic vesicles in a
Can also occur secondary to hypothyroidism, parkinson disease and inflammatory conditions neuron at rest

The Monoamine hypothesis: MAO-A → preferentially metabolises NE, 5HT

Depression may be due to lowered monoamine NT at brain synapses MAO-A & MAO-B → metabolises dopamine and tyramine.
Tx: Restore monoamine levels or actions to normality [Dopamine, NE, serotonin] Antidepressants effects of MAO-I acts on MOA-A
Monoamine depletion = depression, monoamine preservation = mood elevation
5HT reuptake blockers: Eg. TCA's, SSRI, SARI's
Pharmacologic actions of both MOA-I’s and TCA’s are immediate, but clinical effects Lead to stimulation of All 5HT receptors
take weeks suggesting that the drugs trigger long term changes 5HT1A receptors stimulated in raphe → help depression
5HT2 receptors stimulated in forebrain and spinal cord → a gitation, anxiety or sexual dysfunction
Depression may be linked to a deficiency in signal transduction → deficient response in target neurons
Antidepressant discontinuation syndrome:
Antidepressants → 2-4 weeks for any improvement and 6-8 weeks for substantial benefit Abrupt discontinuation of antidepressants
Most common mechanism = inhibition of serotonin transporter (SERT), the norepinephrine transporter (NET), or both Most often seen in association with SSRI discontinuation (most commonly prescribed) and drugs with short half-lives
(paroxetine or venlafaxine), compared to long half-lives (fluoxetine)
Sx (varies): anxiety, irritability, tearfulness, diziness, HA, lethargy, flu-like sx, electric shock sensations, insomnia, GI
effects N/V/D

Clinical indications
Depression: Smoking cessation:
SSRI's = DOC for initial tx for most pts with depression & anxiety disorders [ease of use, tolerability, safety in overdose] Bupropion is approved
Atypical antipsychotics - used as adjunct for major depression when response to antidepressant agents is inadequate
Eating disorders:
Anxiety: Antidepressants are helpful for bulima, but not for anorexia
SSRI's = first choice for most types of disorders [GAD, SAD, PTSD, PD, OCD]
Bupropion = less effective than other antidepressants for tx of anxiety Premenstrual dysphoric disorder:
SSRI's are benficial
Chronic pain:
TCA's and SNRI's are used for neuropathic and other pain conditions Warnings and Precautions:
Drugs that block NE and 5HT reuptake are often useful for pain disorders A MDE may be the inital presentation of Bipolar disorder and therefore patients need to be screened
SSRI's are NOT effective Tx with an antidepressant alone may precipitate mania in patients with bipolar disorder

Description MOA Indication AE Fun Facts

Inhibit mitochondrial MOA Used in refractory cases of depression Orthostatic hypotension, blurred vision, dry mouth, drowsiness, dysuria, constipation
MAO-I → increased NE, DA, & 5HT release and due to toxicity & food/drug interactions
Isocarboxaid
Hydrazine derivatives activation of receptors Serotonin syndrome:
Phenelzine
Selegiline → transdermal patch for Combination of MAOI (irreversible agent is most toxic ) w/ a 5HT agent
Phenelizine, isocarboxazid, Parkinson, antidepression; better tolerated Eg SSRI’s, SNRI’s, TCA’s or meperidine
tranyclypromine → binds irreversibly and safer and unlikely to cause tyramine- MOA: overstimulation of 5HT1A and 5HT2 receptors
and non-selectively to MAO-A and MAO- induces hypertensive crisis Sx: hyperthermia, rigidity and myoclonus
B
MAO-I's Cheese Reaction:
Tranylcypromine Non-hydrazines Selegiline → MAO-B inhibitor but at Excess tyramine potentiates catecholamine release
Selegiline high doses is a MAO-A inhibitor [can also be seen with other sympathomimetics eg OTC drugs pseudoephedrine & phenylpropanolamine]
Eg: aged cheese, red wine, soy products, chicken liver
MOA: tyramine is normally inactivated by MAO in gut
Sx: HTN, tachycardia, arrhythmia, seizures, & stroke
TX: Phentolamine or prazosin (anti-adrenergics)
 Block SERT and NET → increased MAO Neuropathic and other pain conditions Block fast Na channels in heart (most common cause of death): Block: α- adrenergic, muscarinic, histamine
conc. in the synaptic cleft Cardiac overstimulation, decreased cardiac conduction → arrhythmia [like receptors and cardiac fast sodium channels
quinidine] which can be reversed with NaHCO3 [also gastric lavage] → AE
Amitriptyline Clomipramine - more selective for
Clomipramine TCA’s SERT Muscuranic block: blurred vision, xerostomia, urine retention, Narrow therapeutic index
Desipramine constipation, and aggravation of glaucoma → monitor suicidal pt’s
Desipramine and nortryptyline - more α- adrenergic block: Orthostatic hypotension and reflex tachycardia
Imipramine selective for NET Histamine (H1) block: Sedation and weight gain
Nortriptyline Other: Sexual effects, especially with clomipramine

Selective for SERT with little activity at DOC for treatment of depression and Nausea, GI upset and diarrhea; Do not see the same AE’s that are apparent in
M, α, & H1 anxiety disorders Weight gain [esp. with paroxetine] TCA’s
Diminished sexual function and desire (↑ serotonergic tone at the level of
Citalopram Uses: OCD, panic disorder, GAD, PTSD, the spinal cord and above) Overdose may cause seizure, but fatalities are
Escitalopram social anxiety disorder, very rare
Sertraline SSRI’s premenstrual dysphoric disorder Fluoxetine/Paroxetine both inhibit CYP2D6
Fluoxetine [fluoxetine & sertraline], bulimia, Fluvoxamine inhibits CYP1A2, CYP2C19, and CYP3A4 Not effective in treating chronic pain or
Fluvoxamine premature ejaculation Citalopram, Escitalopram and sertraline → little drug interactions anorexia
Paroxetine
Fluoxetine: bulimia; bipolar All have potential to cause serotonin syndrome when combined with Avoid fluoxetine/paroxetine due to multiple
MAO-I’s or other serotonergic drugs drug interactions

Inhibit reuptake by blocking SERT and Depression that is refractory to SSRI’s (2nd Fewer CYP450 interaction compared to SSRI’s Differ from TCA's by their lack blockade of H1,
NET choice drugs) M & α1 receptors

Venlafaxine: potent 5HT uptake Duloxetine: diabetic neuropathy and

Venlafaxine SNRI’s inhibitor with activity at NET in higher fibromyalgia
Duloxetine conc. [and very weak DA reuptake
inhib]
Duloxetine: equal affinity [blocks
both] at all doses
↓ NE and DA reuptake Smoking cessation Seizures can be seen with overdose Lacks 5HT activity so there is no sexual
↑ NE and DA release dysfunction
Bupropion NDRI Given for depression when trying to avoid
sexual dysfunction
Combination of 5HT reuptake inhibitor Not very popular in use for depression Nefazodone - associated with hepatotoxicity [no longer used]
[weak] with 5HT2 antagonist [strong]
Trazodone - extremely sedating and Trazodone also blocks α1 and H1 receptors and may cause priapism
This blocks undesired side effects of commonly used as a hypnotic (used as anti-
Nefazodone
SARI’s 5HT2 stimulation in forebrain insominiac)
Trazodone
(agitation, anxiety) and spinal cord
(sexual dysfunction)

Central presynaptic α2 receptor Noradrenergic & specific serotonergic H1 antagonism is associated with sedation and weight gain
antagonist → increased NE and 5HT antidepressants
release
May be useful if agitation or insomnia is
Mirtazapine NASSA 5HT2 & 5HT3 antagonist prominient
H1 antagonist
 Drugs for Bipolar Disorder
Drug MOA Indication AE Fun Facts
Inositol depletion theory: inhibits polyphosphatase and Prophylaxis for manic-depressive pt’s and Narrow therapeutic window [death at concentration of 3-5mM]
monophosphatase, blocking the regeneration of inositol treatment of manic episodes
Neurotoxicity → confusion, motor impairment, coma, & convulsions
↓ PIP2 signalling cascade [Gq] → ↓ central adrenergic, Contraindicated in pregnant & nursing Other: seizure, ataxia and aphasia, weight gain, hypothyroidism, edema,
muscarinic, & 5HT neurotransmission mother → cardiac anomalies dermatitis, alcopecia, leukocytosis
Category D
Inositol cannot cross BBB Nephrogenic diabetes insipidus - amiloride should be given or thiazides
Lithium inhibits inositol synthesis in CNS neurons and NSAIDS
Lithium Lithium inhibits central adrenergic, muscarinic, and Tremor - alleviated with propanolol or atenolol
serotonergic neurotransmission
Inhibition is uncompetitive → only neurons with active Acute intoxication: vomiting, profuse diarrhea, coarse tremor, ataxia, Serum lithium, thyroid and renal function
receptors are affected coma and convulsions must be monitored regularly

Renal clearance reduced by:

Thiazide, NSAIDS, ACE-I, ARB's (increase levels of lithium)

Alternatives to Lithium
Valproate and carbamazepine: Atypical antipsycotics:
Widely used; can be used as an adjunct with a lower lithium dose. Olanzapine and aripiprazole are used in maintenance treatment
Liver function and CBC monitored when taking valproic acid Quetiapine, risperidone, & ziprasidone are used in mania or mixed episodes
CBC monitored when taking carbamazepine Olanzapine + fluoxetine is used in the treatment of depression associated with bipolar;
Lamotrigine (antiepileptic) is used for maintenance treatment
 Antipsychotics [aka: neuroleptic]
Schizophrenia: The DA pathways in the brain:
Chronic psychotic disorder characterised by disturbed behaviour, thinking, emotions and perceptions
Sx: positive, negative and cognitive Mesolimbic : Midbrain → limbic system, role in emotional behaviours
Blockage of D2 receptors mediate the antipsycotic effects or antipsychotic drugs
Positive symptoms: reflect an excess of normal functions Nigrostriatal: Substantia nigra → basal ganglia, role in motor movement
[hallucinations, delusions, thought disorder, perceptual disturbances, incongruous mood, increased motor function] Blockade of D2 can lead to extrapyramidal sx
Linked to overactivity of DA neurons in the mesolimbic dopamine pathway [other DA pathways: nigrostriatal, mesocortical, and Mesocortical: Midbrain → prefrontal cortex
tuberoinfundibular] Blockade of D2 may cause or worsen negative and cognitive sx
Tuberoinfundibular: Hypothalamus → ant. pituitary; inhibit prolactin secretion
Negative: reflect diminution or loss of normal functions Blockade may cause galactorrhea
[blunted affect, poverty of speech, diminished motivation, social withdrawal]

Cognitive: deficits in memory and cognitive control of behaviour

Negative and cognitive symptoms linked to hypoactivity of the mesocortical pathway

Drug Description MOA Actions AE

Classical antipsychotics Efficacy correlates with ability to block D2 in the mesolimbic Antipsychotic actions: Extrapyramidal reactions
pathway Reduce hallucinations and agitation Assoc. with high D2 potency eg. haloperidol and fluphenazine
Calming effect Less likely to occur with conventional agents - chlorpromazine or thioridazine [strong anti-
High potency: Do not depress intellectual fxn cholinergic activity and low D2 potency]
Fluphenazine, thiothixene, and haloperidol → more likely to Minimal motor incoordination Atypical antipsychotic drugs have low potential for causing EPRs
produce EPRs Action begins in < 24h
Parkonsinism
Low potency: Antiemetic by blocking D2 in the chemoreceptor Sx: Tremor, rigidity, bradykinesia
Chlorpromazine & thioridazine → more likely to produce sedation trigger zone of the medulla Tx: benztropine, trihexyphenidyl, with amantadine, or diphenhydramine [H1 blocker with anti-
Fluphenazine
(H1 block) and postural hypotension (a-1 block) but less likely to [exceptions: thioridazine & aripiprazole] M effects]
Thiothixene
produce EPRs Never use Levodopa in these patients (activates D2 receptors)
Haloperidol
Completely metabolized and do not interfere with
Chlorpromazine
other drug metabolism Akathisia
Thioridazine
Inability to sit still (restless leg syndrome)
Antimuscarinic effects may be useful in relation to Tx: ↓ dose or change drug; clonazepam or propranolol may also be added
EPRs
Acute dystonia
Autonomic effects: Tx: benztropine, trihexyphenidyl or diphenhydramine
Orthostatic hypotension and impaired ejaculation
[due to α1 blockade] Tardive Dyskinesia
Agranulocytosis → due to clozapine [RBC counts are Choreoathetosis [usually seen in the mouth and appears late]
mandatory] May be irreversible [due to DA receptor upregulation with chronic use]
Atypical antipsychotics Higher affinity for other receptors than D2 Prolactinemia (women), infertility/impotence (men) Tx: discontinue or ↓ dose of drug; eliminate all central anticholinergics [TCA’s]; diazepam may
[less likely with atypicals] be helpful and clozapine is recommended for pts with TD, but need anti-psychotics
Dual antagonism: Clozapine (prototype): D1, D4, 5HT2, M & α-adrenergic but also a Weight gain [clozapine and olanzapine]
5HT2A + D2 receptors D2 blocker → type 2 DM, HTN, ↑ hyperlipidemia Neuroleptic Malignant Syndrome:
Clozapine More effective at tx of –ve sx. Cardiotoxicity: thioridazine causes high incidence of Rigidity, tremor, hyperthermia, altered mental status, autonomic instability, elevated WBC and
Risperidone Less likely to cause EPRs [especially clozapine Risperidone: Blocks 5HT2 more than D2 QTc and T-wave changes (rarely ventricular CK, myoglobinemia (potential nephrotoxicity)
Paliperidone and quetiapine], tardive dyskinesia and an arrhythmias, sudden death) Tx: dantrolene or bromocriptine may be helpful
Olanzapine increase in prolactin Ziprasidone also can prolong QTc
Quetiapine
Sedation: due to central H1 block (low potency antipsychotics)
Ziprasidone Paliperidone: active metabolite of risperidone Ocular complications (seeing brown/ yellow): Seizures: Chlorpromazine & clozapine
Aripiprazole
Chlorpromazine → corneal & lens deposits
Aripiprazole: partial agonist at D2 and 5HT1A Thioridazine → retinal deposits
but a 5HT2A antagonist

Antipsychotics: Uses
Psychiatric indications: Drug choice: atypicals are preferred
Schizophrenia (DOC) Benefit for –ve symptoms and cognition
Bipolar disorder Decreased risk of EPR’s and tardive dyskinesia
Tourette’s - suppression of tics Lesser increase in prolactin levels
Major depression - adjuncts to antidepressants in tx resistant MDD
Psychotic depression (depression with psychosis) - in combination with antidepressants Risperidone is the most prescribed antipsychotic in the US;
Austism - treatment of associated irritability Clozapine is reserved for refractory cases due to potential for agranulocytosis
Alzheimer’s dementia - control of disturbed behaviour
Clozapine is a pregnancy category B while all others are category C;
Non-psychotic: Atypicals have a greater risk of hyperglycemia and weight gain in pregnancy
Nausea and vomiting (anti-emetic)
Neurolept-anesthesia - droperidol in combination with fentanyl
 Sedative-Hypnotic Drugs
Sedatives: Sedative-hypnotics:
Should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions Graded dose-dependent depression of CNS function [which varies between drugs]
The degree of CNS depression caused by a sedative should be the minimum consistent with therapeutic efficacy Older drugs → linear dose response curve (no ceiling)
Benzodiazepines → non-linear curve = safer
Hypnotic drugs: Increase in dose above the needed hypnosis → general state
A hypnotic drug should produce drowsiness and encourage the onset of anesthesia
and maintenance of a state of sleep that resembles the natural state of sleep At still higher doses → depress respiratory and vasomotor
[as much as possible] centres in medulla → coma and death
Involve more pronounced depression of the CNS than sedation
Can be achieved with most sedative drugs by increasing the dose 2 GABA molecules bind between the α & B subunits normally

Drug Description MOA Actions / Uses PK/PD AE

Short acting (3-8h): Benzodiazepines Bind to GABAA receptors in Agonists: Absorption and distribution: Drowsiness
Oxazepam neuronal membranes Positive allosteric modulators Lipophilic Confusion
Triazolam most widely used, much [pentameric Cl-channel - major Exert anxiolytic & anticonvulsant effects Rapidly and completely absorbed after oral admin Ataxia
safer than barbiturates inhibitory neurotransmitter] Distributed throughout body Cognitive impairment
Interm. acting Inverse agonist (close channel):
(10-20h): Benzodiazepines bind between α Negative allosteric modulators Duration of action: Paradoxical adverse psychological effects which are dose
Alprazolam and ɣ subunit (benzo receptors-α Cause anxiety and seizures Half-life determines therapeutic usefulness [short, related and rare: anxiety, irritability, histility, rage,
Lorazepam BZ1 and BZ2) Not clinically useful, used experimentally intermediate, long] paronia, depression, and suicidal idealation
Temazepam
Allosteric enhancement of GABA Main action: Metabolites: Dependence [pyschological and physical]
Long acting (1-3d): effects → ↑ frequency of opening Muscle relaxant Most undergo phase 1 reactions by CYP3A4 → get Abrupt withdrawal can cause withdrawal symptoms -
Diazepam & ↓ EC50 [left shift] Anesthesia (adjunct) conjugated and excreted confusion, anxiety, agitation, restlessness, insomnia,
Flurazepam Reduction of anxiety (short term) Desmethyldiazepam → active metabolite with t1/2 > 40h tension
Sedative and hypnotic actions → further metabolised to oxazepam (also active)
Midazolam Skeletal mm spasm [MS & cerebral palsy]
Clonazepam Larazepam, oxazepam & temazepam → are not
Seizure - clonazepam conjugated by P450 system (skip phase I - used in
Status epilepticus - lorazepam & diazepam patients with liver failure/cirrhosis)
Drug [EtOH] withdrawal- doazepam & oxazepam
Sleep disorders - flurazepam, temazepam, Flurazepam → oxidized by liver enzymes to active
triazolam metabolites with half-lives of 30-100h

Flumazenil Benzodiazepines Blocks effects of benzodiazepines Only benzodiazepine receptor antagonist available Rapid onset & short duration of action due to rapid hepatic May precipitate withdrawal in physiologically dependent
antagonist for clinical use clearance pts
(frequent administration may be necessary to reverse long-
Reverse CNS depression or overdose acting benzos) May cause seizures (if used to control seizures)
Hastens recovery after procedures
Phenobarbital Barbiturates Bind GABAA at a different site Dose dependent sedation: Enzyme induction → CYP450 Respiratory depression [especially in people with
Pentobarbital than benzos → ↑ duration of Low doses: sedation pulmonary insufficiency]
Thiopental Replaced by benzos as opening Higher doses: hypnosis → anesthesia → coma → Contraindicated in pt’s with porphyria due to Supresses hypoxic and chemoreceptor response → death
sedative-hypnotics death [thus any degree of CNS depression is increased porphyrin synthesis (most common COD)
[induce tolerance, drug- Also blocks glutamate and possible depending on the dose]
metabolizing enzymes, sodium channels → full surgical Pain: may worsen perception
physical dependence, anesthesia and pronounced Thiopental → ultra short acting used to induce Dependence: severe withdrawal syndrome
severe withdrawal, central depressant due to anesthesia Poisoning: severe respiratory/central CV depression
coma] multiple sites of action Cardiovascular collapse with rapid injection
Phenobarbital → long-term management of tonic- CNS depression
clonic seizures, status epilepticus and Paradoxical excitement
eclampsia; Hypersensitivity
Hangover

Zolpidem Non-benzodiazepine Only act on BZ-1 subtype of Hypnotic - short duration of action Short half life = 1.5 - 3.5h Minimal muscle relaxing and anticonvulsant effects
benzodiazepine benzodiazepine receptors Indicated for short-term insomnia tx (lack of BZ-2 effect)
receptor agonists characterized by difficulties with sleep Little or no tolerance
(NBBRAs) initiation Low incidence of AE
Zaleplon Indicated for short-term treatment of insomnia Rapid onset and very short duration of action
"Z drugs' Elimination half life = 1h
Eszopicline (S)-Enantiomer [pharm. active] of zopiclone Half-life = 6 hours
Approved for treatment of insomnia
Decreases sleep latency and improves sleep
maintenance
Buspirone 5HT1A partial agonist No hypnotic, anticonvulsant or Management of anxiety disorders Onset: 2-3 weeks Less psychomotor impairment than benzos
muscle relaxant properties No interaction with EtOH, benzos, or other sedatives
Only anxiolytic MOA may be analgous to antidepressants No rebound anxiety or withdrawal when abruptly
stopped
No dependence

Ramelteon Melatonin receptor Agonist at MT1 and MT2 Tx of insomnia characterized by difficulty falling
agonist melatonin receptors asleep
Hydroxyzine Antihistamine Antiemetic and anxiolytic activity Symptomatic relief of anxiety

Propranolol Beta blocker Performance anxiety Lipophilic

Clonidine Modifies autonomic expression of anxiety Sedating effect
Diphenhydramine OTC antihistamines Mild situational insomnia
Doxylamine
 Parkinson Drugs
Parkinson’s Disease: Dopamine synthesis:
Resting tremor, muscle rigidity, bradykinesia, and impaired postural balance; due to loss of dopaminergic innervation to the Tyrosine is transported by system L across the BBB in a Na+ independent manner
striatum (70% loss before sx appear) DA is synthesized from tyrosine with the rate limiting enzyme being tyrosine hydroxylase
DOPA decarboxylase turns over so rapidly that DOPA levels in the brain are negligible under normal conditions
D1 → increase adenylyl cyclase (excitatory) [therefore it is possible to enhance DA formation by providing the enzyme with increased amount of substrates]
D2 → decrease adenylyl cyclase and Ca2+ conductance while increasing K+ conductance (inhibitory)
Choice of treatment:
Benefits of antiparkinsonism is due to D2 stimulation, but D1 stimulation may also be required for maximal benefit Levodopa + carbidopa is the best tx
Dopaminergic neurons from the substantia nigra normally inhibit the GABAergic output from the striatum, whereas cholinergic DA agonsit are the next most effective drugs
neurons stimulate it Addition of a COMT or MAO-B inhibitor to levodopa can reduce motor fluctuations on patients with advanced
In Parkinson's disease, there is destruction of the neurons of the nigrostriatal pathway responsible for secreting dopamine in the disease
striatum (this resultsi n loss of control of muscle movement) Antimuscuranics can be useful addition to levodopa for control of tremor and drooling

Therapy is aimed at restoring the DA in the basal ganglia and antagonizing the excitatory effect of cholinergic neurons →
reestablishing the correct DA/ACh balance

Drug Description MOA Actions / Uses AE PK Fun Facts

Levoratomy Crosses the BBB and gets converted to Sinemet = carbidopa + levodopa in a fixed Much of the drug is Rapid absorption from SI Useful in early disease → there is
stereoisomer of dopa dopamine by dopa decarboxylase proportion (1:10 or 1:4) decarboxylated to DA enough residual DA neurons for the
peripherally → nausea, vomiting, Food delays appearance of levodopa use of Levodopa
Metabolic precursor of Restores dopamine levels in Relief is only symptomatic → only lasts arrhythmia, hypotension in plasma
DA and NE extrapyramidal centers while drug is present in the body Late disease (3rd -5th decade) →
MOA-I → can precipitate Certain A.A can compete with the Lower number of neurons therefore
Does not stop Combined with carbidopa Wearing off rxn’s → end of dose akinesia hypertensive crisis drug for absorption from gut and less effect from use of Levodopa
progression of disease, (decarboxylase inhibitor) → does not (fluctuations related to timing of levodopa) transport into brain
but can ↓ mortality cross BBB, inhibits peripheral conversion Should not be given to psychotic Need to monitor cardiac pt’s for
Levodopa of levodopa On-Off phenomenon → fluctuations in pts (exacerbate sx) Vitamin B6 → cofactor for dopa possible arrhythmias
response that are unrelated to timing; pt’s decarboxylase increases peripheral
with severe off-periods who are Contraindicated in angle closure metabolism Anti-psychotic drugs may produce
unresponsive to other measures may glaucoma parkinsonian syndrome (blockade of
benefit from SC apomorphine D2 receptors)

Ergot DA agonists D2 agonist Often combined with levodopa GI & cardiovascular effects Little response in pt’s who do not Contraindications:
2nd line treatment Dyskinesia, mental disturbance respond to levodopa Patients with a history of psychotic
Bromocriptine
Don’t need neurons they can activate the illness or MI
receptors directly Ergot agonists: Avoided in patients with peripheral
Non-ergot DA agonists Well tolerated, better AE profile Painless digital vasospasm Rotigotine: once-daily transdermal vascular disease or peptic ulceration
2nd line treatment Pulmonary infiltrates, pleural & patch
Pramipexole
Initial treatment esp. in younger pt’s (older retroperitoneal fibrosis,
Ropinirole erythromelalgia
pts are more vulnerable to the adverse
cognitive effects of DA agonist)
Rotigotine Non-ergot agonist:
Uncontrollable somnolence
Non- Ergot DA Rescue therapy for tx of "off" episodes of Emetogenic → pretreat with Subcutaneous
akinesia in patients on dopaminergic trimethobenzamide
therapy
Apomorphine
QT prolongation, dyskinesias,
drowsiness, sweating, hypotension
 MAO inhibitors Irreversible and selective MAO-B Mainly used as an adjunct to levodopa Metabolites (methamphetamine Rasagiline may be used as
inhibitors (allows dose to be reduced) and amphetamine) may cause monotherapy early in disease or as
Deprenyl Reduces motor insomnia if taken late in the day adjuvant treatment with levodopa in
(Selegiline) fluctuations in pt’s with Retards breakdown of DA and enhances Has little potential for causing a (Selegiline only) advanced disease
advanced disease levodopa effect hypertensive crisis
Rasagiline

COMT inhibitors Decrease metabolism of levodopa Tolcapone → CNS and periphery Fulminating hepatic necrosis is Inhibition of dopa decarboxylase causes compensatory activation of COMT
Decrease plasma 3-O- methyldopa Entacapone → periphery associated with tolcapone pathway → ↑ plasma levels of 3-O -methyldopa → competes with levodopa for
Reduces motor Increase uptake of levodopa an active carrier → transport across the BBB and intestinal mucosa
fluctuations in pt’s with ↑ dopamine in the CNS Entacapone is preferred because it
advanced disease lacks hepatotoxicity

Tolcapone
Entacapone

Antiviral drug with Increases synthesis, release or re- Restlessness, agitation, confusion, hallucinations Use with caution in pt’s with history of
antiparkinsonian uptake of DA from surviving neurons High doses: acute toxic psychosis seizures or heart failure
actions Peripheral edema [responds to diuretics]
Amantadine Less efficacious than levodopa Livedo reticularis → mottled purple discoloration of the skin in a lace like pattern
Tolerance develops more readily, but has [resolves when drug is discontinued]
fewer AE

Antimuscarinics Adjuvant therapy Improve tremor, drooling and rigidity, but Mood changes, xerostomia, pupil dilation, confusion, hallucination, urinary Cannot be used in pt’s with glaucoma,
Benztropine have little effect on bradykinesia retention and dry mouth BPH or pyloric stenosis
Trihexyphenidyl
 Anti-Epileptics
Epilepsy: Chronic disorder characterised by recurrent seizures; seizure: finite episode of brain dysfunction resulting from abnormal neuronal discharge Mechanism:
A decrease in inhibitory synaptic activity or an increase in excitatory activity might
Partial seizures: can identify a "seizure focus" trigger a seizure
Simple = no LOC, often there is abnormal activity of a single limb or muscle group
Complex = LOC does occur, motor dysfunction may involve chewing movements, diarrhea, urination GABA = inhibitory (agonists inhibit seizures while antagonist trigger them)
Partial with secondarily generalised tonic-clonic seizures = partial seizure evolves with LOC and spreads to involve the thalamus Glutamate = excitatory (agonists trigger seizures)

Generalized seizures (grand mal): no evidence of localised onset, may be convulsive or nonconvulsive and associated with immediate LOC Drug MOA:
Tonic-clonic seizures Blockade of voltage gated-ion channels (older drugs, most)
Absence seizure (petit mal) = brief, abrupt & self-limiting LOC with the patient staring and blinking rapidly [3Hz spike & wave pattern on EEG] Modulation of synpatic transmission (newer drugs)
Drug Description MOA Indication AE
Phenytoin Block voltage gated Na+ ↓ Na+ influx into the glutamatergic Partial and secondarily Tonic-clonic seizures (can use all) Induce cytochrome P450
Carbamazepine channels neuron → ↓ transmission of Carbamazepine, Oxcarbazepine, Levetiracetam, Zonisamide, Phenytoin, Carbamazepine, phenobarbital & phenytoin. Oxcarbazepine is a weak inducer
Lamotrigine Glutamate Valproate, Lamotrigine, Topiramate, Phenobarbital
Zonisamide Phenytoin
May contribute to the effects of Generalized Tonic-clonic seizures Diplopia, ataxia, gingival hyperplasia, course facial features, hirsutism
phenobarbital, valproate, topiramate Carbamazepine, Oxcarbazepine, Valproate, Lamotrigine, Phenytoin, Zero order elimination.
Topiramate Rash, Steven-Johnson syndrome

Absence seizures: Carbamazepine

DOC: Ethosuximide and Valproate Aplastic anemia, agranulocutosis,
Ethosuximide Block T-type Ca2+ Absence seizures involve oscillatory With Tonic-clonic or Atypical: Valproate Rash, Steven-Johnson syndrome
Valproate channels neuronal activity between thalamus Lamotrigine is probably effective
and cortex (goverened by the T-type Valproate
calcium channels) Myoclonic Seizures Inhibits CYP450 (thus metabolism of several drugs and its own metabolism)
DOC: Valproate Hepatotoxic
These drugs inhibit this current and Adjunct: Levetiracetam
are effective in absence seizures Topiramate is also used Rash & Steven-Johnson syndrome
Phenytoin, carbamazepine, phenobarbital
Atonic seizures (often refractory to all drugs) Lamotrigine = black box warning (discontinue drug at first sign of rash)
Benzo’s Enhance GABA Direct action on GABA receptors → ↑ Valproate and laotrigine may be beneficial
Barbiturates transmission post- Cl- influx Felbamate is 3rd line because of adverse effects Phenobarbital
Topiramate synaptically Sedation, drowsiness, rash, Steven-Johnson syndrome
Febrile convulsions: Tolerance dependance
< 15 mins: Supportive therapy only Cognitive impairment, hyperactivity
> 15 mins: IV or rectal solution of Diazepam P450 inducer

Status epilepticus: Primidone

Tiagabine Enhance GABA Tiagabine → inhibits reuptake of Similar to its metabolite phenobarbital
Vigabatrin Gabapentin transmission GABA Start with one drug and
Pregabalin presynaptically then use other drugs if the Vigabatrin
Vigabatrin → ↓ degradation of GABA seizures are refractory Visual field loss, confusion and psychosis
by inhibiting GABA
aminotransferase Felbamate
Aplastic anemia, hepatotoxicity
Gabapentin/pregabalin → increase
GABA release Overdose Toxicity:
Phenobarbital Block glutamate Block glutamate receptors → Antiseizure drugs are rarely lethal
Topiramate postsynaptically decreased Na+ influx Drug-induced seizure (other convulsive Emergencies) Most AE is respiratory depression
Diazepam, lorazepam, or phenobarbital Treatment is supportive
Stimulants should not be used
Break-through seizures:
Seizures experienced by epileptic patients who are on anti-epileptic Pregnancy & Teratogenicity
therapy All are teratogenic, there is an increase risk for congenital malformations in infants
Diazepam rectal gel is approved for this (Valproate = worst)
Gabapentin Pregabalin Block glutamate Block presynaptic voltage gated Prophylatic use of folic acid is recomended
presynaptically Ca2+ channels → ↓ influx → decrease Discontinuing Anti-epileptic
glutamate release If seizure free for 3-5 years, should be slow Newborn Hemmorrhagic disease
Benzodiazepines and barbituates should be discontinued very Enzyme inducing antiepileptic drugs may increase degradation of Vitamin K
gradually to avoid withdrawl seizures This causes bleeding in the infant and therefore Vit K supplementation is recommended
If on comb of drugs, drugs should be withdrawn 1 at a time in the final month of pregnancy

Levetiracetam Reduce glutamate Binds to a synaptic vesicle Other uses: Non-pharmocological approaches:
presynaptically glycoprotein 2A (SV2A) Carbamazepine: Neuropathic pain, bipolar disorder About 1/3 of patients with epilepsy continue to have seizures on medication
Gabapentin: Neuropathic pain 1) Surgery - excise the focal area of seizures
This may affect release of glutamate Lamotrigine: Bipolar disorder 2) Ketogenic diets - 4 parts fat, one part protein and carbohydrate
and GABA Pregabalin: Neuropathic pain 3) Vagal nerve stimulation
Topiramate: Migraine
Valproate: Bipolar disorder, migraine
Primidone: First line for essential tremor (also propanolol)
 Drugs of Abuse
Abuse: excessive self-administration of any substance for nonmedical purposes [some drugs of abuse do not lead to addiction… alter perception without reward and euphoria i.e. hallucinogens]
Addiction: 1 or more of the following behaviors: impaired control over drug use, compulsive use, continued use despite harm, craving
Physical dependence: state of adaptation manifested by specific withdrawal syndrome [produced abrupt cessation, rapid dose reduction or administration of an antagonist]
Withdrawal syndrome: physiologic and behavioral changes directly related to sudden cessation or reduction in use of a psychoactive drug to which the body has become adapted
Tolerance: state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more drug’s effects over time [may develop at different rates for different effects]
Physical dependence & tolerance are normal responses to persistent use of certain medications
As a general rule, all addictive drugs activate the mesolimbic dopamine system
CNS depressants
Drug MOA Description Treatment
Classified as a depressant Influences several cellular Heavy EtOH consumption → tolerance and physical dependence Withdrawal TX of withdrawal:
[produces sedation and sleep] functions: = tremor, nausea, vomiting, sweating, agitation, & anxiety followed by Diazepam & chlordiazepoxide = preferred agents d/t long t1/2
Initial effects of EtOH are GABA, glycine, NMDA, and 5HT- hallucinations and seizures (24-48h) (rebound withdrawal sx less likely, smoother)
perceived as stimulation due to 3 receptors Delirium tremens [formication] after 48-72h with 5-15% mortality Lorazepam & oxazepam = preferred in elderly/liver failure
suppression of the inhibitory Kir3/GIRK channels (intermediate acting, not as dependent on hepatic metabolism
systems Adenosine reuptake as other benzodiazepines)
Ethanol TX of addiction:
Disulfiram → inhibits aldehyde dehydrogenase
Naltrexone → oral opioid antagonist; reduces cravings
Acamprosate → NMDA antagonist; prevents relapse
Topiramate → facilitates GABA function, antagonizes glutamate
receptors, may reduce cravings
[not FDA approved]
Can cause physical dependence Withdrawal = tremors, anxiety, perceptual disturbances, dysphoria, Delirium, TX of withdrawal:
Addiction is rare psychosis, seizures (syndrome can be life-threatening due to If pt is on a short-acting drug, they are switched to a long-acting
Benzodiazepines
cardiovascular collapse) drug (diazepam is the most used agent)
Then dose is gradually reduced
Barbiturates Clinical use is declining Similar abuse problems as benzodiazepines
Psychostimulants
Drug MOA Description Treatment
Caffeine (most widely consumed) Block presynaptic adenosine Tolerance develops rapidly 100-200mg (1-2 cups coffee): ↓ fatigue, ↑ mental alertness
Theophylline receptors → increased NE Withdrawal → fatigue and sedation; addiction is rare 1.5g (12-15 cups of coffee): anxiety tremors
Methylxanthines
Theobromine release (since activation of Caffeine is not listed in the category of addicting stimulants Spinal cord is stimulated only by very high doses (2-5g)
receptors inhibits NE release)
D/t abuse potential, classified as Inhibits DA, NE, & 5HT reuptake CNS: No treatment for withdrawal
Schedule II drug by DEA Prolongation of DA effects in the Stimulates cortex and brainstem, ↑ mental awareness, paranoia [after Many antidepressants and DA agonists have been tested for
limbic system = intense euphoria repeated use], tremor and convulsions followed by respiratory and treating addiction but there is no clear efficacy
vasomotor depression [at high doses]
Cocaine Sympathetic nervous system:
NE → adrenergic stimulation [tachycardia, HTN, mydriasis, diaphoresis]
Withdrawal = dysphoria, depression, sleepiness, fatigue, bradycardia…
generally mild and TX is not required

↑ release of catecholamines Similar behavioral effects to cocaine due to the release of DA Tolerance and withdrawal are common
Weak MAO inhibition Increases alertness; decreases fatigue and appetite; insomnia Tolerance can be marked
Amphetamines Schedule II Possible direct Psychosis and convulsions [high doses] Antidepressants can be used to treat withdrawal
catecholaminergic agonists in Clinical use: ADD and narcolepsy [amphetamine and methylphenidate] Abstinence syndrome can occur open withdrawal
the brain Sx = ↑ appetite, sleepiness, exhaustion, mental depression
 Nicotine
Drug MOA Description Treatment
nd
2 to nicotine as most wide used Full agonist at nicotine receptor Rewarding effect → nicotine receptors on dopaminergic neurons in the Withdrawal is mild → irritability, sleeplessness
CNS stimulant ventral tegmental area; causes release of dopamine Among the most addictive drugs
2nd to EtOH as most abused One Low dose → ganglion stimulation; high dose → ganglion blockade Euphoria Nicotine replacement therapy [gum, patch, etc.]
Nicotine and relaxation; improves attention, learning, problem solving and reaction Sustained release bupropion
of the most addictive dr
→ relapse is common time; appetite suppressant Varenicline → partial nicotinic agonist in the CNS
High dose: central respiratory paralysis and hypotension

Drug MOA Description Treatment

All opioids induce strong tolerance and dependence Detox with opioid agonists → illicit drug is replaced by a long
Addiction produces behavioral disruptions and is incompatible with a acting opioid and the dose is slowly reduced
productive life DOC → methadone or buprenorphine
Withdrawal [unpleasant, but not life-threatening] → dysphoria, lacrimation, Detox with adrenergic agonists → central acting α2 blockers
Heroin Morphine
rhinorrhea, yawning such as clonidine and lofexidine inhibit the noradrenergic
Codeine Oxycodone
storm responsible for many symptoms
Meperidine Fentanyl
Detox with opioid antagonists → naltrexone [high affinity for μ
opioid receptor, can be used after detox for patients with high
motivation to remain opiod-free, but will not satisfy craving or
relieve withdrawal sx]
Marijuana
Drug MOA Description Treatment
Cannabis smoke contains 61 CB1 & CB2 are Gi receptors CB1 Produces a euphoria followed by drowsiness and relaxation Dronabinol → therapeutic THC used for anorexia/weight loss
different cannabinoids = brain Affects short term memory and mental activity associated with AIDS; nausea and vomiting with cancer
∆9-tetrahydrocannabinol (THC) CB2 = immune cells Impairs highly skilled motor activity chemotherapy [2nd line]
Marijuana produces most effects Appetite stimulant, xerostomia, visual hallucinations, delusions,
enhancement of sensory activities
High doses can cause toxic psychosis
Frequent use → tolerance and mild physical dependence
Psychedelic Agents
Drug MOA Description Treatment
Affect thought, perception, and 5HT-2 agonist actions mediate Pts present with combination of somatic and psychomimetic sx Does not cause addiction; no withdrawal syndrome
LSD
mood hallucinations Somatic sx d/t sympathomimetic effects [mydriasis, HTN, tachycardia, “Bad trips” may require medical attention
Mescaline Psilocybin
Don't cause marked psychomotor increased body temperature, flushing, sweating, tremors, piloerection] Diazepam is effective in treating severe agitation
stimulation or depression Dissociative anesthetic Causes cholinergic and anticholingeric effects No specific antidote for PCP
Non-competitive NMDA Has actions at nicotinic and opioid receptors Extreme violent psychotic behaviour requires sedation with
Phencyclidine antagonist Clinical manifestations = violent/bizarre behaviour, psychosis, nystagmus parenteral benzodiazepines
PCP, ‘Angel dust’ Blocks reuptake of NE and DA (important diagnostic clue), tachycardia, HTN, diaphoresis, miosis, Seizures should be treated with benzodiazepines
anesthesia, analgesia
Causes release of biogenic Fosters feelings of empathy and intimacy without impairing intellectual
MDMA amines capacities
'Ecstasy' Strongly ↑ 5HT conc. in the Withdrawal → depression that can last several weeks
synaptic cleft Produces degeneration of 5HT neurons in rats
Inhalants
Drug MOA Description Treatment
Nitrous Oxide Produces euphoria → analgesia → Usually taken as 35% N20 mixed with O2
loss of consciousness 100% N2O can cause asphyxia and death
Volatile organic Gasoline, paint thinner, lighter Produce sense of exhilaration and light-headedness Implicated in cancer, cardiotoxicity, neuropathies, and
solvents fluid, glue, degreasers, etc. Toxicity depends of properties of individual solvents hepatotoxicity
Organic nitrates Not addictive Amyl nitrate and butyl nitrate are used to enhance erection
Anabolic steroids Increase muscle size in body builders
 General Anesthetics
The state of "general anesthesia" includes: analgesia, amnesia, LOC, suppression of reflexes and skeletal muscle relaxation
No single dug can achieve all desired goals → balanced anesthesia: several drugs used in combination to produce anesthetic state
Inhalation agents do not have rapid onset [usually anesthetized with an IV agent]; halogenated hydrocarbons are not good analgesics; neuromuscular blockers → surgical paralysis
Inhaled Anesthetics
Gases: N2O; Volatile Halogenated hydrocarbons: Halothane, Enflurane, Isoflurane, Desflurane, Sevoflurane, Methoxyflurane;
Used for maintenance of anesthesia after administration of an IV agent
Common Features Mechanism of action Potency Meyer-Overton Correlation Pharmacokinetics
Increase perfusion of the brain Direct interaction with ligand gated ion Minimum alveolar conc. [MAC]: Potency can predict liposolubility Anesthesia requires transfer of agent from
Cause bronchodilation channels → positive modulation of GABA Conc. that results in immobility in 50% of patients when alveolar air → blood → brain
Decrease minute ventilation and glycine receptors & inhibition of exposed to a noxious stimuli [such as a surgical incision] The oil:gas partition coefficient (λ) is a
nicotinic receptors good measure of solubility This rate is dependent on:
Potency correlates with liposolubility Expressed as % of the alveolar gas mixture [inversely related to → As λ increases, MAC and onset of drug Solubility
potency] decreases Concentration in inspired air
Rate of onset inversely correlates with Adjuncts to Anesthetics → Low for potent anesthetics Pulmonary ventilation rate
blood solubility Benzo’s → anxiolytic + amnesia Opioids → → Large for less potent agents Partition coefficient is the ratio of Pulmonary blood flow
analgesia Neuromuscular blockers concentrations of a compound in two A-V concentration gradient
Recovery is due to redistribution from the Antiemetics → ↓ aspiration MAC values are additive different solvents [i.e. air and blood]
brain Antimuscarinics → amnesia, ↓ Methoxyflurane is the most potent
salivation/secretions; ↓ bradycardia ↑ potency correlates with slow onset Methoxyflurane → λ = 960
Potency of an anesthetic increases as
liposolubility increases

Solubility in blood
λ defines the relative solubility of an
anesthetic in the blood compared to air
Low blood solubility → quick rise in
arterial tension [i.e. partial pressure]
High solubility → slow rise in tension
… inverse relationship
Low λ → faster onset of anesthesia
Nitrous oxide has the lowest λ and hence
the fastest onset Methoxyflurane has the
slowest onset
Ventilation Rate
Increase in ventilation rate increases rate
of induction
Rate of rise of arterial tension is directly
dependent on both rate and depth of
ventilation
Magnitude of effect depends on λ
→ increasing ventilation with a highly
soluble anesthetic i.e. halothane will
significantly increase arterial tension
Pulmonary Blood Flow Elimination Cardiovascular effects
↑ pulmonary blood flow (↑ cardiac output) will ↓ the rate of rise Reverse of uptake Most inhaled anesthetics depress normal
in arterial tension Agents with a low solubility recover in a
cardiac contractility → ↓ MAP
similar manner as induction, Halothane and enflurane ↓ MAP by
Increased blood flow exposes a larger volume of blood to the independent of duration of admin. myocardial depression with little effect on PVR
anesthetic [↑ capacity] Isoflurane, desflurane, sevoflurane
Nitrous oxide has a very quick recovery(vasodilators) better choices for pts with
impaired myocardial fx
A-V concentration gradient High solubility → recovery depends on Halothane sensitizes the myocardium to
Difference between concentration of anesthetic in arterial and duration of administration [due to catecholamines which may precipitate
venous blood accumulation in fat, etc.] ventricular arrhythmias (effect is less marked
Methoxyflurane has a slower recovery for isoflurane, sevoflurane, desflurane)
Reflects the solubility of anesthetic in the tissues
Uptake by tissues → slower onset

Inhaled Anesthetics
Toxicity Malignant Hyperthermia CNS effects Respiratory effects
Halothane → hepatotoxicity Potentially fatal genetic disorder of skeletal muscle [autosomal ↑ cerebral blood flow → ↑ ICP → Volatine anesthetics = bronchodilators
[no specific Tx, may need transplant] dominant] exacerbate problems in pt’s with brain Isoflurane and desflurane are pungent; not
Methoxyflurane → nephrotoxicity due to fluoride release during metabolism Major COD due to anesthesia tumor or head injury suitable in pts with bronchospasm
Halothane, sevoflurane, NO are nonpungent
Malignant hyperthermia mechanism: Triggered by: Nitrous oxide increases flow the least →
↑ Ca2+ → sustained contraction + heat generation → ↑ CO2 & ↓ ATP → switch to Volatile anesthetics [halothane], depolarizing muscle relaxer has low anesthetic potency, but has Volatile anesthetics are respiratory
anaerobic metabolism → lactic acidosis & muscle death → hyperkalemia & [succinylcholine] marked analgesic and amnesic action depressants
myoglobinuria Symptoms: tachycardia, HTN rigidity, hyperthermia, Isoflurane and enflurane are the most
hyperkalemia, acidosis Enflurane at high conc. → tonic-clonic depressant
Susceptibility can be determined using the caffeine-halothane contracture test movements N2O is the least depressant
[most reliable test, muscle sample removed from thigh, response to halathone and Altered control of Ca2+ release from SR → defective ryanodine
caffeine assessed] receptor [RYR1] = unregulated release of calcium from the SR Misc N2O Effects
↑ Ca2+ conc causes sustained muscle contraction which
Hematotoxicity - prolonged exposure to N2O decreases methionine synthase generates heat, accelerated levels of aerobic met. produces CO2
activity and causes megaloblastic anemia and deplete O2 and ATP, switch to anaerobic met. worsens
acidosis with production of lactate, energy stores get depleted,
Potential occupational hazard for staff working in poorly ventilated dental operating muscle fibers die leading to hyperkalemia and myoglobinuria
suits
Tx: Dantrolene [blocks Ca2+ release from SR + other measures
anaerobic metabolism → lactic acidosis & muscle death → hyperkalemia &
myoglobinuria
Susceptibility can be determined using the caffeine-halothane contracture test
[most reliable test, muscle sample removed from thigh, response to halathone and
caffeine assessed]
Hematotoxicity - prolonged exposure to N2O decreases methionine synthase
activity and causes megaloblastic anemia
Potential occupational hazard for staff working in poorly ventilated dental operating
suits
[succinylcholine]
Symptoms: tachycardia, HTN rigidity, hyperthermia,
hyperkalemia, acidosis
Altered control of Ca2+ release from SR → defective ryanodine
receptor [RYR1] = unregulated release of calcium from the SR
↑ Ca2+ conc causes sustained muscle contraction which N2O exchanges with nitrogen in air-containing body cavities… it enters faster than
generates heat, accelerated levels of aerobic met. produces CO2 nitrogen escapes → ↑ volume and/or pressure of cavity
and deplete O2 and ATP, switch to anaerobic met. worsens
acidosis with production of lactate, energy stores get depleted,
Avoid N20 in:
muscle fibers die leading to hyperkalemia and myoglobinuria Pneumothorax, middle ear obstruction Air embolus, bowel obstruction
Intraocular air bubble
Tx: Dantrolene [blocks Ca2+ release from SR + other measures Pulmonary bulla, intracranial air
to ↓ body temp. and restor electrolyte/acid-base balance
Prolonged N2O exposure decreases methionine synthase activity → megaloblastic anemia

IV Anesthetics
Used alone or with other drugs to: achieve anesthesia, as components of balanced anesthesia, or to sedate pts in ICUs who must be mechanically ventilated for long periods
IV anesthetics include: barbiturates, propofol, ketamine, etomidate
Barbiturates Propofol Etomidate Ketamine Adjuvant drugs
Ultrasort acting: Most popular IV anesthetic Primarily used for anesthetic induction of pts at high risk of Only IV anesthetic that posses both Provide additional effects that are desirable
hypotension analgesic properties & CV stimulation during surgery
Thiopental and methohexital Used for induction and maintenance of
Used for induction of anesthesia and for anesthesia Causes minimal CVS and respiratory depression AE: Benzodiazepines
short surgical procedures No analgesic effects ↑ cerebral blood flow, O2 consumption & For their anxiolytic and anterograde amnesic
Produces no analgesia; rapid hepatic ICP. Produces dissociative anesthesia properties
Effects terminated by redistribution from metabolism AE: [blocks NMDA] → catatonia, amnesia,
brain to other tissues, but hepatic Anti-emetic → ↓ post-op vomiting Reduces ICP analgesia, +/- LOC Opiods - for analgesia
metabolism is required for their Associated with nausea/vomiting
elimination from the body AE: May inhibit steroidogenesis, with decreased plasma levels of "Emergence phenomenon": Neuromuscular blockers
Potent respiratory depressant, reduces hydrocortisone disorientation, illusions, vivid dreams To achieve muscle relaxation
(VRG: brain, liver, kidneys; MG: muscle, ICP, causes hypotension through Neuroleptic-Opioid Combinations [Tx: diazepam, midazolam, propofol]
skin; FG: fat) decreased PVR; Potent opioid analgesic [fentanyl] + neuroleptic [droperidol] Antiemetics [ondansetron]
Greater –ve inotropic effect than other IV = neurolept analgesia Prevent possible aspiration of stomach
AE: agents contents
Decrease ICP, do not produce analgesia, Can be converted to neurolept anesthesia with admin. of 65%
may cause hyperalgesia, may cause apnea, Fospropofol = prodrug converted to N2O in O2 Antimuscurinics [scopolamine]
coughing, hest wall spasm, laryngospasm, propofol in vivo For its amnesic effects, to prevent salivation
bronchospasm (concern for asthmatic pts) and bronchial secretions, to protect the heart
from bradycardia caused by inhalation agents
and neuromuscular blockers
 Local Anesthetics
Actions Pharmacokinetics
Block nerve conduction of sensoty impulses from the Vasoconstrictors keep drug at nerve, prolong period of anesthesia by ↓ blood flow and ↓ systemic absorption [usually epinephrine is often contained in the local
periphery to the CNS anesthetic preparaion]
Abolish sensation (and in higher concentrations As a consequence neuronal uptake ↑ and systemic toxic effects ↓
motor activity) in a limited area of the body without In spinal anesthesia, epinephrine acts on α2 [↓ release of substance P]
producing unconsciousness AE = delayed wound healing, tissue edema, necrosis
Cocaine constricts BV's by potentiating action of NE [prevents its own absorption]
Chemistry Pharmacodynamics
Consist of lipophilic group [aromatic ring] + intermediate chain [ester/amide] + ionizable group MOA:
[tertiary amine] Block voltage-gated sodium channels
Ester links [as in procaine] = more prone to hydrolysis than amide link = shorter duration of action Bind to receptors near intracellular end of channel
Local anesthetics = weak bases with pK values around 8.0 – 9.0 [therefore the larger fraction in the body and block the channel
fluids at physiologic pH will be the cationic form] Sufficient concentrations of a local anesthetic applied
Cationic form = most active form at the receptor site to a nerve fiber abolish action potentials
Uncharged form = important for penetration of biologic membranes.

Metabolism and excretion Structure-activity characteristics Clinical pharmacology

Ester-linked local anesthetics are metabolized by tissue Liposolubility correlates with both potency and Choice of local anesthetics for a specific procedure is based on the duration of action required
& plasma esterases (pseudocholinesterases) duration of action; ↑ liposolubility = ↑ toxicity • Procaine and chloroprocaine = short-acting
Amide-linked local anesthetics degraded by liver pKa correlates with speed of onset of action: the • Lidocaine, mepivacaine, and prilocaine = intermediate-acting.
microsomal cytochrome P450 closer pKa is to body pH, the faster the onset • Tetracaine, bupivacaine, etidocaine and ropivacaine = long-acting

Toxicity: CNS Toxicity: PNS Toxicity: CVS Systemic adverse effects

Stimulation = restlessness and tremor that
may proceed to clonic convulsions
CNS stimulation is followed by CNS depression
Death is usually due to respiratory failure
More serious toxic reactions = due to
convulsions from excessive blood levels
When large doses must be given, premedication
with a benzodiazepine provides significant
prophylaxis against seizures
Toxicity: Allergic reactions
Ester type local anesthetics → metabolised to
p-aminobenzoic acid derivatives [responsible for
allergic reactions in a small % of population]
Amides ( extra I in the name) are not metabolized to
PABA [allergic reactions are rare]
At excessively high concentrations, all local anesthetics Block sodium channels and thus depress cardiac
can be toxic to nerve tissue
Toxicity: Blood
Large doses of prilocaine during regional
anesthesia = accumulation of the
metabolite o-toluidine [oxidizing agent
capable of converting hemoglobin to
methemoglobin]
Drug interactions
Procaine is hydrolyzed in vivo to produce PABA, which
inhibits the action of sulfonamides
Large doses should not be administered to patients
taking sulfonamide drugs
pacemaker activity, excitability and conduction
With the exception of cocaine they also depress
strength of cardiac contraction and cause arteriolar
dilation → hypotension
Cocaine may cause vasoconstriction and
hypertension; also cardiac arrhythmias
Bupivacaine = cardiotoxic than other local
anesthetics
Inhibition of THF synthesis by sulfonamides
 Skeletal Muscle Relaxants
Neuromuscular blockers
Used as adjuvants during surgical procedures and in ICUs to cause paralysis Drugs that enhance neuromuscular blockade: inhaled anesthetics, aminoglycosides, tetracyclines
Two types: Non-depolarizing blockers [antagonists], depolarizing blockers [agonists] Several diseases can ↓ or ↑ neuromuscular blockade caused by nondepolarizing muscular relaxants:
Non-depolarizing blockers - classified according to chemical structure Myasthenia gravis ↑ blockade of non-depolarizing muscle relaxants
Benzylisoquinolines: tubocuranine, atracurium, cisaracurium, mivacurium Advanced age also prolongs blockade, due to decreased drug clearance
Ammonio steroids: pancuronium, rocuronium, vecuronium Patients with severe burns or UMN disease are resistant to non-depolarizing muscle relaxants (due to
Depolarizing blockers - succinylcholine [2 acetylcholine molecules linked end-to-end] proliferation of extrajunctional receptors)

PK: contain quaternary ammonium compounds, highly polar & poorly soluble in liquid, inactive when Reversal of nondepolarizing neuromuscular blockade: neostigmine or edrophonium are given upon
given PO [given IV/IM only], poor penetration of membranes → don't cross BBB/enter cells completion of surgical procedure
Indications: Surgery, control ventilation, Tx of convulsions, prevent trauma during ECT Atropine or glycopyrrolate are used concomitantly to prevent bradycardia

Drug Description MOA AE Metabolism

All nondepolarizing blockers are competitive antagonists Drugs excreted by the kidney have longer t 1/2 & duration of action
Action can be overcome by increasing ACh in the synapse Drugs eliminated by the liver have shorter t 1/2 & duration of action
[neostigmine or edrophonium]
Tubocurarine
[prototype] First cause motor weakness, followed by flaccid paralysis
Some benzylisoquinolines may cause
hypotension due to histamine release and
ganglionic blockade
Inactivated by hydrolysis by non-specific plasma esterases and by a
Histamine release [tubocuranine,
spontaneous reaction
mivacurium, atracurium] → administer
Atracurium No ↑ in t1/2 with renal failure
Non-depolarizing blockers [antagonists]

antihistamine before NMJ blocker

Metabolized to laudanosine, which causes seizures and hypotension
Ganglion blockade
Stereoisomer of atracurium but forms much less laudanosine
Tubocurarine block nicotonic receptors of
Also causes less histamine release
Cisatracurium autonomic ganglia and adrenal medulla →
Largely replaced by atracurium in clinical practice
hypotension and tachycardia

Only non-depolarizing blocker classified as short-acting

Hydrolysis by plasma butyrylcholinesterase (primary mechanism for
Mivacurium inactivation)
Not dependent on liver/kidney

Pancuronium

Some ammonio steriods may produce Has most rapid onset among non-depolarizing blockers
moderate tachycardia due to blockade of Can be used as alternative to succinylcholine for rapid sequence intubation
Rocuronium cardiac M2 receptors (may lead to
arrhythmias)

Vecuronium
 Depolarizing [agonist]
Two ACh linked together
Rapid onset [<1 minute]
Short duration of action
Depolarizing blocker [agonist]
[5-10 minutes]
No CNS effects d/t inability
to penetrate BBB
Succinylcholine
Used to facilitate
endotracheal intubation
during induction of
anesthesia; also used during
ECT
Used to reduce spasticity in a variety of neurologic conditions
Drugs for chornic spasm: drugs that act in the CNS, drugs that act on the skeletal muscle
Drugs for acute spasm: centrally acting drugs; prototype = cyclobenzaprine
Drug Description
Diazepam Act in the CNS
Baclofen Tx of chronic spasm
Tizanidine
Dantrolene Act on skeletal muscle
Botulinum toxin Tx of chronic spasm
Cyclobenzaprine Tx of acute spasm
Activate nicotinic receptors & Bradycardia [due to M2 activation] Extremely short duration of action (5-10 Contraindications: (because they
depolarizes NMJ → Prevention: thiopental, atropine, ganglion minutes) due to hydrolysis by lead to hyperkalemia)
fasciculations → not blockers, or non-depolarizing muscle butyrylcholinesterase [BChE] Hx of malignant hyperthermia, hx
metabolized effectively by relaxants of skeletal muscle myopathies
AchE → membrane remains Histamine release [slight] Polymorphisms of BChE: Major burns
depolarized and unresponsive Muscle pain NMJ blockage by succinylcholine and Multiple trauma
to subsequent impulses → Hyperkalemia due to loss of tissue K+ mivacurium may be prolonged in pts with Denervation of skeletal muscle
flaccid paralysis during depolarization → ↑ risk with burns abnormal BChE [rare] UMN injury
or muscle trauma; may lead to cardiac TX: mechanical ventilation until muscle
AE due to activation of all arrest or circulatory collapse function returns to normal
autonomic cholinoceptors: ↑ Intraocular pressure due to extraoc.
nicotonic receptors in muscle contractions
sympathetic and ↑ Intragastric pressure [may cause
parasympathetic ganglia, emesis and aspiration]
muscarinic receptors in the Malignant hyperthermia
heart when combined with halogenated
anesthetic [Tx: dantrolene]
Spasmolytic Drugs
MOA
Facilitates action of GABA at GABAA receptors
GABA agonist at GABAB receptors
α2 agonist
Interferes with Ca2+ release by binding to ryanodine receptor in SR of skeletal muscle
Increased application in tx of more generalized spastic disorders [e.g. cerebral palsy]
Used for relief of acute muscle spasm caused by local trauma or strain
Act primarly at the level of the brainstem (centrally acting)
Structually related to the TCAs
Strong antimuscuranic side effects
 Adrenocorticosteroids
Zona glomerulosa - secretes mineralocorticoids, mainly aldosterone; principally salt-retaining activity
Zona fasciculata - secretes glucocorticoids, mainly cortisol; effects on intermediary metabolism and immune function
Zona reticularis - secretes androgens; steroids with androgenic and estrogenic activity
Adrenal medulla - chromaffin cells secerte epinephrine and norepinephrine
All 3 pathways are linked together so enzyme deficiencies in one pathway can lead to accumulation of products in another pathway

Drug MOA Description PK Fun Facts

Cortisol Binds to a Cortisol: Short duration of action Dexamethasone
(Hydrocortisone) cytoplasmic receptor 95% of hormonal activity is due to cortisol Diffuses poorly across skin suppression test used to
forming a complex Diffuses well across mucus membranes diagnose central Cushing
Synthetic: that enters the Gluconeogenesis [and glycogen synthesis to maintain hepatic glycogen availability] → ↑ serum glucose Some salt retaining effects disease
Prednisone nucleus and alters → ↑ insulin which allows glucose to enter muscle cells
Methylprednisolone gene regulation Metabolic Effects → goal is to maintain brain glucose: Synthetics: (better at Pk) High dose dex :
Dexamethasone (GRE) producing a Stimulates lipolysis → redistribution of fat & ↑ release of FAs & glycerol Rapid and complete oral absorption Suppress cortisol release
Beclomethasone tissue specific Protein catabolism & release of A.A Long half-lives from pituitary adenomas
Triamcinolone response Catabolic effects in lymphoid & connective tissue, muscle, skin and peripheral fat → wasting at high Reduced salt retaining effects but not from adrenal
concentrations tumours
Usually takes Prednisone:
several days for Major long term effects: Prodrug that gets converted to active Depressive psychiatric
response to be seen Osteoporosis prednisolone [both can be given IV] states
(same goes for AE) Growth retardation in children
Glucocorticoids

Beclomethasone: Given to mother to reduce

Greatest release Immunosuppressive effects (effects on leukocytes): Short t1/2 and penetrates airway mucosa [low risk of neonatal RDS
around 6am ↑ neutrophils ( ↑ influx into blood and ↓ migration from BVs) systemic toxicity]
↓ lymphocytes (T and B cells), monocytes, EOS, basophils concentration in the blood (movement from
vascular bed to lymphoid tissue) Oral: All
Vasoconstriction [through blockade of mast cell degranulation] - decreased histamine release and Aerosol: Beclomethasone & Triamcinolone
capillary permeability IM: Triamicinolone
IV,IM: Dexamethosone, hydrocortisone,
Anti-inflammatory effects (major use) methylprednisolone, prednisolone
Activation of annexin 1 → inhibition PLA2 → ↓ AA → ↓ PG Topical: Beclomethasone, dexamethasone,
↓ NF-κB → ↓ COX-2 synthesis hydrocorticosone, triamcinolone
Induction of MAPK phosphatase I (inhibit MAPK activation of pro-inflam signalling pathway)
“Smallest dose for shortest duration”
Other:
↑ ICP (large doses, increased CSF production)
Suppress release of ACTH, GH, TSH and LH: chronic use
Peptic ulcers: stimulation of gastric acid, suppression of immune response to H. pylori
CNS effects [behavioural changes like insomnia, euphoria, depression]
↑ platelets and RBC’s
Impairs renal function
Development of fetal lungs (production of surfactant)
Mineralocorticoids

Similar to Major effect of activation is the aldosterone receptor →

glucocorticoid drug- ↑ expression of Na+/K+ ATPase & ↑ expression of ENaC
receptor complex
Natural Mineralocorticoid = Aldosterone (most important) → Major role as salt-retaining hormone
Aldosterone Bind to Regulated by CRH, ACTH and renin-angiotensin system
Fludrocortisone mineralocorticoid Promote Na+ reabsorption from renal tubule & K+ and H+ excretion → Control bodys’ water volume &
receptor electrolyte concentrations (Na+ & K+)

Fludrocortisone: synthetic, most commonly precribed salt retaining hormone (DOC)

 Drugs for Anxiety
Anxiety:
A normal response to stressful or fearful circumstances
Allows an individual to adapt to or manage the stressful/threatening situation
Excessive anxiety causes irrational thinking or behaviour and impairs a persons functioning

One of the most frequent mental disorders encountered by clinicians

Untreated disorders may result in increased healthcare use, morbidity, and mortality and poorer quality of life

Disorder Treatment Fun Facts

Generalized anxiety disorder
Antidepressants = DOC
Venlafaxine and SSRI’s are preferred [better safety and tolerability]
Benzodiazepines
Used for acute treatment as an adjuvant during initiation of SSRI therapy (since
antidepressants take 2-4 weeks to kick in)
They can then be tapered off while SSRI is is continued, or to improve sleep
Not 1st line b/c of pschyological and physiologic dependance
Antidepressants:
Reduce the psychic sx with a modest effect on autonomic and somatic sx
Onset usually takes 2 – 4 weeks
Replaced benzo’s due to: better AE profile, no risk for dependency and efficacy
in common comorbid conditions [i.e. PD, OCD, SAD, and depression]

Buspirone [2nd line]:

No abuse potential or withdrawal reaction; does not potentiate alcohol or sedative
hypnotic effects; onset in 2 – 4 weeks Other alternatives: hydroxyzine and pregabalin

Panic disorder SSRI’s = DOC Benzo’s:

Used concomittantly with antidepressants especially early in tx or as
TCA or MAO-I may be effective when an SSRI is not monotherapy to acutely reduce panic sx
Not preferred for long term treatment, but may be used when pt’s fail several
antidepressant trials

Alprazolam [benzo] may cause rebound anxiety between doses and has been
associated with a withdrawal syndrome including seizures

Social anxiety disorder SSRI’s = DOC due to tolerability and efficacy Onset may take 8 – 12 weeks

Obsessive-compulsive disorder Clomipramine, fluoxetine, fluvoxamine, paroxetine, and sertraline are all No difference in efficacy between clomipramine and SSRI’s; but SSRI’s have a
approved better side effect profile
SSRI have a better side effect profile
For highly anxious pt’s → adding benzo or antipsychotic may be beneficial

PTSD SSRI’s = DOC Other antidepressants [venlafaxine, MAO-I, TCA’s] can also be effective but have
Sertraline and paroxetine are approved for acute tx of PTSD less favorable side effect profiles
Sertaline for long term management of PTSD

Performance anxiety Propranolol and nadolol or other β-blockers = DOC High lipophilicity but use is limited by adverse effects such as hypotension
 Contraceptives
Most common goal = prevention of pregnancy; other goals = menstrual cycle regulation, reduction of premenstrual symptoms and treatment of acne
OCP = most widely used form but daily admin = disadvantage; inconsistent use of oral contraceptives may increase failure rate
Two major approaches to prevent pregnancy:
1. Preventing ovulation - supressing LH/FSH release by preventing fluctuations in estrogen levels (provide pt with stable estrogen levels)
2. Impairing implanatation - by maintaining elevated progesterone levels (provide pt with stable elevated progestin)
Combined oral contraceptives = combination of estrogen and progestin Estrogen = ethinyl estradiol or mestranol [a prodrug of ethinyl estriol]
Available in monophasic, biphasic, and triphasic preps (all have similar efficacy in preventing pregnancy) Progestins: Most have some androgenic activity
Most common = "low-dose" - contains 35 μg of ethinyl estradiol or less Levonorgestrel and norgestrel → highest
(low hormone content has decreased AE but more likely result in contraceptie failure if doses are missed) Norethindrone [2nd gen] → low
Most formulations have 21 hormonally active pills, followed by 7 placebo pills to allow withdrawal from bleeding (this facilitates constent daily Desogestrel and norgestimate [3rd gen]→ lowest
pill intake) Drospirenone → anti-androgenic
Extended-cycle formulations increase the number of hormone-containing pills to 84 days followed by 7 day placebo phase (this results in 4
menstrual cycles per year)
Continuous combination regimens provide hormone-containing pills for 21 days, then very-low-dose estrogen and progestin for additonal 4-
7 days
Drug Class Description Mechanism PK Adverse Effects Contraindications
Fixed dose in each Suppress FSH and LH → prevents 21 active + 7 placebo Nausea, bloating, Pregancy, thromboembolic disease, stroke, CAD, breast
active pill ovulation [most common] breakthrough bleeding CA, estrogen dependent CA, hepatic tumors or liver
Monophasic Progestin thickens cervical mucus Extended cycle: 84 active + 7 [improve by 3rd cycle], HA, disease, abnormal uterine bleeding, heavy smoking over
preventing sperm penetration; impairs placebo → 4 periods a year migraine and CVA, depression, age 35

Combined Oral Variable proportions of implantation by inducing changes in the Continuous regimens: 21 active insulin resistance, hirsutism, Minor: history of migraine disorder, HTN, diabetes,

Contraceptives one or both hormones endometrium + 4L7 very low dose → NO oily skin, acne [from uterine fibroids, breast feeding, smoking at any age
Biphasic periods progestin], melasma [dark skin Rifampin and other CYP450 inducers increase
Oral Hormonal

[Estrogen + in each pill to mimic

the menstrual cycle ↓ risk of endometrial and ovarian CA, dis-colouration], amenorrhea, metabolism of estrogen
Progestin] regulation of menstruation, relieve Broad spectrum ABx [especially Rifampin] reduce
dys-lipidemia, CVD → ↑
Reduces the monthly benign breast disease, prevent ovarian production of PF VII, X & intestinal flora and interrupt enterohepatic circulation
progestin dose cysts, ↓ risk of PID, and improve acne fibrinogen of estrogen and decreasing efficacy of OCP’s
Triphasic control

Slightly less effective Blocks ovulation in 60-80% of cycles, but Not widely used in the US Unscheduled bleeding and NO risk of thromboembolism
than combined OCP highly efficacious → spotting are common
Norethindrone Progestin-only ↓ dysmenorrhea, thickening of cervical mucus and
Norgestrel Pills menstrual blood loss, endometrial alterations that impair
PMS symptoms implantation
The Patch Transdermal patch that contains both ethinyl estradiol and a progestin
The Ring Transvaginal delivery of ethinyl estradiol and a progestin
Hormonal
Non-Oral

Depo-Provera, progestin-only injectiable contraceptive IM injections every 3 months Menstrual irregularities

Progestin Injection Contains depot medroxyprogesterone acetate [DMPA] Weight gain
Extremely effective Significant loss of bone mineral density [Black Box]
Progestin Implant Contains a progestin Placed under the skin in upper arm Effective for 3y Irregular menstrual bleeding
Intrauterine Systems Polyethylene body Levonorgestrel releasing Effective for 5y
Emergency post-coital contraception
Hormonal: Plan B, Next Choice - first tablet of levonorgestrel taken within 72 hours of intercourse and second tablet followed 12 hours later
AE = nausea and vomiting; no prescription needed if over age 17
Ella contains ulipristal acetate = selective progesterone receptor modulator → inhibits or delays ovulation
Single tablet taken within 5 days after intercourse, available only by prescription, AE similar to levonorgestrel
Other high dose norgestrel or levonorgestrel formulations can be used (most effective within 72 hours)
Non Hormonal: copper IUD inserted within 5 days of intercourse
 End of life care
Common physical symptoms at end of life Of all people who die, only <10% die suddenly/unexpectedly Opioids
Anorexia/cachexia: Palliative care = relieving or soothing the sx of a disease or disorder Oral admin is preferred in terminal disorders
Management: non-pharmalogical, corticosteroids (eg. Dexamethasone), cannabinoids (eg. Dronabinol) without effecting a cure There is NO maximum dose of a pure opioid agonist
Conditions that cause poor intake (eg. Oral candidiasis, gastritis) should be treated Care does not end until the family have been supported with their grief Always give "around the clock"
reactions AE: nausea, sedation, constipation, respiratory depression
Confusion: 90-90% excreted renally
Causes: drugs, hypoxia, intrinsic CNS disorders, etc Liver conjugates codeine, morphine, oxycodone, and hydromorphine
Simple causes of confusion & agitation should be sought and managed: urinary retention (urinary catherization), sleep deprivation, poorly Pain control into glucoronides
controlled pain, anxiety (benzodiazepines), severe terminal agitation (barbiturates) 1/2 of pts dying of cancer have severe pain Some of their metabolites remain active as analgesics
Only 1/2 of these pts receive receive reliable pain relief
Constipation: A lot of misconceptions about pain relief lead to sig. underdosing Opioids not recommended:
Causes: drugs (opioids, Ca2+ channel blockers, anticholinergics), decreased mobility, dehydration, autonomic dysfunction, etc All pain can be relieved by an appropriately potent drug at the Meperidine: routine dosing leads to accumulation of metabolite
If left unmanaged can lead to considerable pt distress (eg. abdominal pain, bloating, N/V, fecal impaction) right dosage normeperidine (no analgesic properties but sig. AE)
Management: stimulant laxatives (eg. Casanthranol, Senna), osmotic laxatives (eg. Lactulose, sorbitol), detergent laxatives (stool softeners eg. Mixed opioid-antagonists (eg. butorphanol, nalbuphine) should not
Docusate), prokinetic agents, lubricant stimulants, large-volume enemas be used alongside pure opioid agonist
WHO 3-Step Ladder
Depression: Opioid induced constipation:
Management: psychologic support, antidepressants for persistent, clinically sig. depression, anxiety & insomnia (sedating TCA), Should always be expectedol
withdrawn/vegetative signs (methylphenidate) Tolerance may develop very slowly (if at all)
Prophylactic laxatives help prevent fecal impaction
Diarrhea: Detergent stool softeners (docusate) not sufficient alone (stimulant is
Causes: infections GI bleeding, malabsorption, medications, obstruction, also required)
overflow incontinence, stress etc
Persistent diarrhea can lead to dehydration, malabsorption, fatigue, hemorrhoids, Opioid induced nausea/vomiting:
perianal skin breakdown Experienced by many pts
Management: establish normal bowel habits, avoid gas-forming foods, increase bulk Tolerance develops within few days
Treat with antiemetics (eg. metoclopramide)
Dyspnea:
Causes: anxiety, airway obstruction, bronchospasm, hypoxemia, pulmonary edema, thick secretions, etc
Managment: oxygen, opioids (DOC = morphine), anxiolytics Breakthrough dosing
Breakthrough pain = transitory flares of pain Corticosteroids
Fatigue/weakness: Consider using immediate-release prep of same opiod used for routine Commonly used in advanced illness:
Management: discontinue medications that are no longer appropriate and may make fatigue worse (eg, antihypertensives, diuretics), optimize dosing, ~5-15% of 24h dose Acute nerve compression
fluid & electrolyte intake, not easy to treat pharmacologically - some options are: corticosteroids (eg, dexamethasone), psychostimulants (eg Offer every 1h (orally), every 30min (SC, IM) and every Increased intracranial pressure
methylphenidate) 10-15min (IV) Bone pain
Visceral pain
Fluid/edema: Anorexia
Some pts develop relative hypotension, tachycardia & reduced urine output Dependence
Nausea
At end of life no amount of IV fluids and salt will Tolerance = normal physiological phenomenon in which increasing Depressed mood
return intravascular volume to normal return intravascular volume to normal doses are required to produce the same effect

Insomnia: Physiologic/pharmacologic dependence = normal physiological Bone pain management

Management: avoid caffeine, avoid staying in bed when awake, excess alcohol use, avoid overstimulation before sleep phenomenon in which a withdrawal syndrome occurs when an opioid Opioids = mainstay of treatment
Pharmacological interventions include: antihistamines (eg, diphenhydramine), benzodiazepines (eg, lorazepam), neuroleptics (eg, is abruptly discontinued or an opiod antagonist is admin. Second line drugs: NSAIDs, corticosteroids, calcitonin
chlorpromazine)
Psychological dependence & addition = pattern of drug use Neuropathic pain management
Nausea/vomiting: characterized by continued craving for an opioid which manifest as Burning tingling pain: TCAs [amitriptyline, imipramine], gabapentin
Management: dopamine antagonists (eg, metoclopramide), histamine antagonists (eg, meclizine, diphenhydramine), anticholinergics (eg, compulsive drug-seeking behaviour leading to an overwhelming Shooting stabbing pain: gabapentin, carbamazepine, valproate
scopolamine), serotonin antagonists (eg, ondansetron, granisetron), antacids, cytoprotective agents involvement in the use & procurement of the drug Complex pain: combinations may be required [oral antiarrhythmics, α2
agonists, NMDA receptor antagonists, corticosteroids, etc]
Pressure ulcers:
Management: hygiene, protection (thin hydrocolloid dressings), supports. avoid iodine-containing products, charcoal-impregnated dressings,
superficial infections (topical metronidazole or silver sulfadiazine)
Adjuvant analgesics
Stress:
Further improve pain control
Management: compassion, information, counseling, psychotherapy
May also be primary analgesics
Can be added at any step in WHO ladder
Grief:
Normal process that usually begins before an anticipated death [denial, fears about loss of control, suffering, an uncertain future, loss of self]

Drug MOA
Uncoupling of oxidative phosphorylation →
↓ ATP → ↑ O2 consumption, CO2 production & heat
generation and hyperpyrexia
↑ demand for glucose peripherally → glycogenolysis,
gluconeogenesis, lipolysis and
β-oxidation
↑ β-oxidation → elevated ketones
Inhibit TCA cycle → ↑ pyruvate and lactate
Aspirin
Impair renal function → ↑ sulfuric acid and
phosphoric acid in blood and ↑ renal excretion of
bicarbonate
Metabolic acidosis is mainly due to increased
production of endogenous acids rather than the
salicylate itself (saliculates are weak acids with
minor effect on serum pH)
Toxicity
Early respiratory alkalosis (central stimulation of
respiratory centres results in hyperventilation)
followed by anion gap metabolic acidosis
(accumulation of acids) → mixed respiratory alkalosis
and metabolic acidosis
Acute ingestion
Mild intox → 150-200mg
Vomiting , hyperpnea, tinnitus , lethargy, mixed
respiratory alkalosis
Severe: seizure, coma, hyperthermia, hypoglycemia,
pulmonary edema
Death caused by respiratory failure and CV collapse
Chronic intoxication
confused elderly person, higher mortality and morbifity
rates. cerebral and pulmonary edema more common
Toxicology
Treatment
1. Emergency and Supportive care
2. Enhancing elimination of salicylates:
Moderate intoxication - IV sodium
bicarbonate to alkalinize urine and
promote salicylate excretion
Severe intoxication - hemodialysis
Air pollutants:
CO
[carbon monoxide]
Drug Toxicity Treatment
Colourless, odorless, tasteless, non-irritating cas Hyperbaric O2 100%
produced by incomplete combustion of any carbon-
containing material Administer oxygen in the highest possible
concentration (100%)
Sources of CO exposure include combustion of With room air at 1 atm, the elimation half-life of
carbonaceous fuels: petrol, natural gas, etc CO is 320 minutes, but with 100% O2, it is
about 20 minutes
CO forms carboxyhemoglobin (HbCO) and ↓ O2
transport in blood
Shifts Hb to the relaxed conformation causing free
heme sites to bind O2 with high affinity
Results in inability of affected Hb to released O2 to
the tissues
→ HA, confusion, loss of visual acuity, tachypnea,
tachycardia, coma

High doses (>10g) → glucoronidation and sulfation
patways become saturated → ↑ NAPQI formed →
body's glutathione stores become depleted →
unconjugated NAPQI damage the liver → hepatic
encephalopathy
Acetaminophen
Acute ingestion (>200mg) Vigorous supportive therapy when Disinhibition, lethargy, ataxia, stupor, coma Intoxication due to acute ingestion of ethanol is
Potentially hepatotoxic intoxication is severe. Hypoglycemia; anion gap metabolic acidosis managed by maintenance of vital signs and
prevention of aspiration after vomiting
High doses: Gastric lavage should be performed in all
Renal failure (metabolite produced in kidney), lactic cases Correction of electrolyte balance may be
acidosis, severe liver damage required
Antidote = N-acetylcysteine - supplies
Acute alcohol ingestion is not a risk factor for cysteine as a precursor for increased Ethanol Thiamine given before admistering glucose to
heptotoxicity glutathione production, and directly protect against Wernicke-Korsakoff
Chronic alocholism - increased risk of hepatotoxicity detoxifies NAPQI syndrome

Liver transplant required for patients with IV dextrose is standard

fulminant hepatic failure

Usual dose: Euphoria, wakefulness Acidification of urine with NH4Cl Formic acid (metabolite) → acidosis, retinal EtOH (to saturate alcohol DH and reduce
(ammonium chloride) damage, basal ganglia injury, blindness, GI production of formic acid)
Higher dose: agitation, acute psychosis, Htn, Methanol distress, resp. depression, coma Fomepizole [inhibits alcohol DH]
Amphetamine
tachycardia, mydraisis, seizure and muscular For HTN: Phentolamine or nitroprusside Bicarb (for the metabolic acidosis)
MDMA
hyperactivity may cause hyperthermia and For tachyarrhythmias: Propranolol or Found in: paint solvents, wiper fluid, etc. Hemodialysis
Cocaine
rhabdomyolysis esmolol Metabolised to: EtOH
Pseudoephedrine
Hyperthermia → brain damage, hypotension, For seizures: IV benzo’s Glycoaldehyde → GI disturbance Fomepizole inhibits alcohol dehydrogenase
Ephedrine
coagulopathy, renal failure For very high body temperatures: Glycolic acid → Acidosis and renal tubular damage
Phenylpropanol-
neuromuscular paralysis Ethylene Glycol (AKI) IV bicarb for the metabolic acidosis
amine
Oxalate → Ca2+ oxalate nephrolithiasis Hemodialysis

Found in anti-freeze
Anticholinergics: Anticholinergic syndrome: Physostigmine (crosses BBB) Phosphorylation of AchE [ageing] High dose atropine
Antihistamines Skin flushing "red as a beet" → do not give to pt’s with TCA overdose as
TCA’s Hyperthermia "hot as a hare" it may aggravate cardiotoxicity [heart Insecticides: DUMBBELLSS: diarrhea, urination, miosis, Pralidoxime (2-PAM) - splits phosphate-
Antipsychotics Dry mucous membrane "dry as a bone" block/asystole] bradycardia, bronchoconstriction, emesis, enzyme bond and acts as cholinesterase
Anti-spasmodics Blurred vision and dilated pupils "blind as a bat" AChE inhibitors lacrimation, salivation, sweating regenerator if given before ageining occurs
Skeletal muscle Confusion and delirium "mat as a hatter" For agitated patient: benzo’s, Organophosphate [unable to enter CNS]
relaxants antipsychotics [eg. Haloperidol] CNS effects: agitation, confusion, seizures
Respiratory paralysis (most COD) For convulsion: diazepam or thiopental
Block both β1 & 2 at high doses Bradycardia and hypotension are most common Agents to raise BP and HR such as beta Insecticides: Carbamoylation of AchE active site Atropine
agonist and atropine are ineffective
Propranolol = most toxic β blocker: Propanolol overdose: seizures and cardiac conduction AChE inhibitors Effects are shorter than organophosphates Pralidoxime is not generally used since
Blocks Na+ channels → cardiac conduction block IV Glucagon → increases cAMP in cardiac Carbamates inhibition is spontaneously reversible
β-blockers
Lipophilic→ crosses BBB → seizures and coma cells without using β receptor
Propranolol One of the most frequently used rodenticides Vitamin K1 restores production of clotting
Partial agonists [Pindolol] → tachycardia and HTN
Warfarin factors (peak effect 24 hours)
(Rat poison) Hemorrhage Fresh frozen plasma or fresh whole blood

Block the L-type Ca2+ channels responsible for
myocardial contractility, vascular smooth muscle
contractility, conducting and pacemaker cells
Ca2+ channel
blocker
Also have CVS effects:
Peripheral artrial vasodilation,
-ve chonotropy, dromotropy, ionotropy
Ca2+ given IV (for the -ve ionotropy, less High affinity for Fe3+ in heme of cytochrome Cyanide antidote kit
effective for nodal block/peripheral vascular a,a3 [cytochrome oxidase] in mitochondria and Provides large pool of ferric iron (Fe3+) to
collapse) compete for cyanide
prevents O2 from serving as final electron acceptor
→ cellular respiration is inhibited Contains: amyl nitrate pearls, sodium nitrite,
Glucagon and Epi → increase BP with sodium thiosulfate
refractory hypotension, also increase heart Lactic acidsos and cytotoxic hypoxia Amyl nitrite is given by inhalation with IV
rate CNS stimulation, hyperpnea, HA, hypoxic sodium nitrite → oxidises Hb to form
convulsions, and death due to resp. arrest methemoglobin → meth Hb competes with
Fumigant:
cytochrome oxidase for cyanide →
Active ingredient in Cyanokit: cyanmethemoglobin is formed and
Cyanide
Hydroxocobalamin (B12 precurosr)→ reacts with cytochrome oxidase is restored
Cyanide to yield Enzyme rhodanese (transsulfurase) converts
cyanocobalamin → excreted in urine cyanide to thiocyanate → nontoxic
 CNS stimulation, hyperpnea, HA, hypoxic sodium nitrite → oxidises Hb to form
convulsions, and death due to resp. arrest methemoglobin → meth Hb competes with
Fumigant:
cytochrome oxidase for cyanide →
Inhibition of NE and 5HT reuptake Tachycardia, mild HTN and seizures For quinidine-like effects → NaHCO3 Active ingredient in Cyanokit: cyanmethemoglobin is formed and
Cyanide
Anticholinergic action Sedation, coma, peripheral anticholingeric effects (sodium bicarbonate) Hydroxocobalamin (B12 precurosr)→ reacts with cytochrome oxidase is restored
Cyanide to yield Enzyme rhodanese (transsulfurase) converts
α-adrenergic blockers Hypotension NOT physostigmine because it can aggravate cyanocobalamin → excreted in urine cyanide to thiocyanate → nontoxic
TCA’s Quinidine-like blockade of fast Na+ QRS widening, slowed conduction and depressed cardiac cardiotoxicity, resulting in heart block or Advantage = methemoglobin is not produced Sodium thiosulfate accelerates deotixification
channels in the heart] contractility asystole by promoting this reaction
Inhibit voltage-gated K+ channels QT prolongation Thiocyanate that is formed is excreted
Norepinephrine for hypotension Methylene blue used to reverse meth Hb

Severe HTN when foods containing tyramine are
consumed [cheese and wine] or drugs
[phenylpropanolamine or ephedrine]
MAO-I’s
Altered mental status with hyperthermia, myoclonic
jerking, muscle rigidity
Serotonergic syndrome (with coadministration of
serotonergic agent)
Excess stimulation of 5HT2A and 5HT1A receptors
Serotonin syndrome: Cyproheptadine
(5HT2 receptor agonist)
Rigidity, seizures, agitation → benzo's
For HTN → phentolamine or labetalol
Lead
Heavy metals inactivate enzymes and disrupt
membranes by reacting with functional groups [-
OH, -SH, -NH2]
Damage to hematopoietic tissues, liver, nervous
system, kidneys, GI, repro system
Usually due to tetaethyl lead or tetramethyl lead Succimer (oral), dimercaprol (IM), unithiol
(antiknock gasoline additives)
Absorbed through skin and lungs → CNS
hallucinations, irritability, convulsions, coma
For seizures: Diazepam
For cerebral edema: Mannitol,
dexamethasone
Chelating agent (two or more electronegative
groups that form complexes with heavy metals):
(IV/oral), edetate calcium disodium
(continuous infusion), penicillamine,
deforoxamine

Blocks delta-aminolevulinate dehydratase and

Neuroleptic malignant syndrome:
Lead pipe muscle rigidity, hyperthermia, metabolic
acidosis, and confusion.
Due to blockade of dopamine receptors by numerous
xeobiotics, including antipsychotic agents and
metoclopramide
May also rarely follow acute withdrawal of DA agonists
Anti-psychotics
(eg. stopping L-dopa, bromocriptine, or tolcapone)
1. Discontinue all antipsychotics
2. Supportive therapy
- physical cooling for hyperthermia
- benzos for agitation
3. Pharmacological therapy
Bromocriptine = preferred treatment
Dantrolene most beneficial when profound
rigidity present
Arsenic
Bromocriptine + dantrolene for moderate to
severe NMS
If temperatures > 40 degrees Celsius,
neuromuscular paralysis and aggressive
external cooling should be done
ferrochelatase in heme synthesis →
↓ Hb and cytochromes (anemia)
Toxicity: Organic As < As5+ < As3+ < AsH3
Trivalent arsenicals → react with -SH groups and
inhibit many enzymes (PDH complex is very
sensitive)
Pentavalent arsenicals → uncouple oxidative
phosphorylation
Arsine gas → hemolysis by depleting glutathione in
RBC
Severe vomiting, diarrhea, rice water stools,
capillary damage, dehydration, shock, anemia
Sweet garlicky odor on breath
Hemolysis, hemoglobinuria, and renal failure
Skin changes, alopecia, BM suppression, CA
Acute inorganic arsenic management:
Chelation with dimercaprol IM (1st line),
Unithiol IV (best one but not avail. in US)
Once hemodynamically stable → parenteral
chelation can be changed to either oral
succimer or oral unithiol
Succimer → DOC for subacute and chronic
inorganic arsenic toxicity
Arsine Gas poisoning:
No tx for arsine gas poisoning IV hydration and
if needed osmotic diuresis with manitol Sodium
bicarbonate → induce urinary alkalinization to
prevent heme pigment nephropathy
<24 hours - Dimercaprol
>24 hours - Unithiol or succimer

Mild,/mod overdose: Naloxone 3 forms: mercury vapor (elemental mercury), Acute (usually elemental):
Lethargy , small pupils, low BP and pulse rate Nalmefene salts of mercury, and organic mercurials - Oral/IV Unithiol, IM Dimercaprol, or oral
toxicity sx. depends on form Succimer
Opioids Higher dose: Mercury → reacts with -SH groups to inhibit
Coma, respiratory depression, apnea, sudden death enzymes and alter cell membranes Chronic:
Unithiol and Succimer
Acute: N-acetylcysteine
Hypoglycemia IV dextrose and octreotide
Elemental (inhalation): chest pain, dyspnea,
nausea, vomiting, renal damage, gastroenteritis and Dimercaprol is not advocated in tx of chronic
Diazoxide = alternative to octreotide, but
Mercury CNS damage poisning due to redistribution of mercury to CNS
octreotide is DOC [safety, efficacy]
Mercuric chloride: hemorrhagic gastroenteritis
followed by renal failure Succimer, unithiol, and N-acetyl-L-cysteine may
Sulfonylurea’s increase body clearance of methylmercury
Meglitinides Chronic:
Inhalation: tremor, neuropsychiatric disturbance,
gingivostomatitis
Acrodynia (mainly in children): painful erythema
of extremities and can be associated with HTN,
diaphoresis, insomnia
Depends if it is acute or chronic Severe: Tachyarrhythmias and hypotension → Not an environmental poison Deferoxamine (chelator of choice)
Seizures, hypotension and ventricular arrhythmias propanolol or esmolol
Acute intoxication: Acute toxicity seen exclusively in young kids that Activated charcoal (high effective adsorbent for
GI → vomiting, abdominal pain, diarrhea Chronic: Seizures → benzos and barbituates ingested iron tablets most toxins) is ineffective because it does not
Theophylline Iron
Metabolic → ↓ K+, ↓ PO4, ↓/↑ Ca2+, ↑ glucose and Cardiac dysrthymias, seizures (more common), minimal Vomiting, GI bleeding, lethargy, gray cyanosis bind iron
metabolic acidosis GI effects followed by GI necrosis, pneumonitis, jaundice,
Musculoskeletal → coarse tremor seizure, coma
Neurological→ anxiety; CV → tachycardia

Echinacea
Flavonoids, polyacetylenes and caffeonyl conjugates = active elements
from leaves and roots of Echinacea
Effects: Known to ↑ phagocytosis, activate NK cells,
↓ IL6/8 and anti-inflammatory properties via ↓ COX
Freshly pressed juice ingestion –within 24hr of onset:
↑ immune function, ↓ duration & intensity of common
cold symptoms
AE: Unpleasant taste, GI symptoms, HA & dizziness.
Ginseng
Ginsenosides = active components
CNS effects: ↑ levels of Ach, 5HT, NE & DA
Effects: improves mental & physical performance. Possible value in
type 2 DM and some immunomodulating effects
AE: mastalgia, vaginal bleeding – estrogenic effects
Methylxanthine found in ginseng could cause insomnia, anxiety,
nervousness and HTN
Drug interactions with anticoagulants, hypoglycemic,
antihypertensive, and psychiatric medications
Coenzyme Q10 (ubiquinone)
Serves as a cofactor for mitochondrial electron transport. Its reduced
form, ubiquinol, functions as antioxidant
Effects: it is associated with small degree of ↓ in BP (systolic &
diastolic). Used in Rx CHF, acute MI & CAD; slows progression of
early PD and migraine attacks
HMG-CoA reductase, required for the synthesis of Coenzyme Q10,
inhibition by certain statin drugs could lead to myopathy
AE: GI symptoms. Rarely rash, irritability, ↓warfarin
effects, thrombocytopenia, headache and dizziness
Kava
Roots used to produce a drink with sedative properties
Primarily consumed to relax without disrupting mental clarity
Active ingredients = kavalactones
Root of the plant used in treating short-term social anxiety
Safety concerns have been raised over liver toxicity largely due to the
use of stems and leaves
Heavy use leads to malnutrition, weight loss, liver damage (causing
elevated serum γ–glutamyl transferase and HDL levels), renal
dysfunction, rashes, hematological abnormalities
Botanical medications and nutritional supplements
Ephedra
Contain ephedrine and pseudoephedrine
Effects: Active constituents are indirectly acting sympathomimetics;
release NE from nerve endings
Used in the Rx of bronchitis, asthma and CNS stimulant
Promoted for weight loss and ↑ athletic feats
AE: insomnia, dizziness, anorexia, palpitation,
tachycardia, flushing, & urinary retention
↑doses: ↑BP, cardiac arrhythmias, and toxic psychosis.
Contraindicated in cardiac arrhythmias (stress on CVS),
hyperthyroidism, CHF, HTN, glaucoma, pregnancy, DM,
bulimia, & anxiety states.
Milk thistle
Silymarin (flavonolignans)
Effects: ↓ lipid peroxidation, scavenges free radicals, ↑ superoxide
dismutase, ↓ LT formation, ↑ hepatic RNA polymerase activity
Use: Cytoprotective effect against hepatic injury by alcohol,
acetaminophen and Amanita mushroom poisoning
No significant drug interaction or side effects except rarely loose stools
Glucosamine
Nitrogen containing sugar, major component of glycosaminoglycans,
which is an important ingredient of
connective tissues such as cartilage
Effects: it is primarily used for Rx of OA
(osteoarthritis); ↓ pain associated with OA
AE: Allergy, GI symptoms of diarrhea and nausea. ↑INR
in patients with warfarin –bruising & GIT bleeding risks
Garlic
Primary constituent is organic thiosulfinate
Forms into allicin from alliin by stomach acid
Effects: Allicin ↓ hepatic HMG-CoA (hydroxymethylglutaryl
coenzyme A). Somewhat ↓ platelet aggregation (via TxA↓), ↑NO (nitric
oxide), fibrinolytic, antimicrobial and ↓ carcinogenic activation
↓ Cholesterol, BP with reduction in plaque formation
AE: allergic reaction, hypotension and nausea may occur.
Anticoagulants and antiplatelet drugs may produce drug interactions
Breath, body odor & contact dermatitis.
St. John's Wort
Hypericin & hyperforin = active ingredients
Effects: Hyperforin ↓ serotonergic reuptake (similar to SSRI &
TCA); chronic use cause down regulation of adrenoreceptors and up-
regulation of 5HT receptors
Use: in the Rx of mild to moderate depression. Photoactivated
“Hypericin” may have some antiviral and anticancer effects
AE: mild GI disturbances & photosenstivity
It interacts with patients receiving MAOI, SSRI and with h/o of bipolar
or psychotic disorder
It induces cytochrome P450 → ↓ effectiveness of OCs, cyclosporine,
digoxin, protease inhibitors, and warfarin
Melatonin
Melatonin = N-acetyl-5-methoxytryptamine (a 5HT derivative
produced by pineal gland)
"The hormone of darkness” - release matches with darkness
Studied for the treatment of cancer, immune disorders, CVS diseases,
depression, seasonal affective disorder (SAD), circadian rhythm sleep
disorders and sexual dysfunction
Effects: melatonin improves sleep onset, duration and quality,
helps jet lag, and an alternate drug for insomnia
Led to development of Ramelteon (MT1 & 2 agonist)
AE: sedation, following-day drowsiness
↓ mid-cycle surge of luteinizing hormone (LH); Chronic use
↓ sperm quality; contraindicated in pregnancy, lactation.
↓ Prothrombin time
Ginko
Flavone glycosides & terpenoids are active constituents
Effects: shows antioxidant, free radical-scavenging effects and ↑
NO formation
Exhibits ↓ blood viscosity, ↑ vasodilation and changes in
neurotransmitters –↑ muscarinic, ↓ β-adrenoceptors
Use: in the Rx of intermittent claudication, cerebral insufficiency,
dementia/cognitive impairment, and pretreatment in CABG → ↓
oxidative stress.
AE: epileptogenic → avoid in patients with h/o epilepsy.
It is associated with insomnia, HA, anxiety; GI disturbances
May produce drug interaction with anticoagulant &
antiplatelet drugs (due to its antiplatelet action)
Saw Palmetto
Active constituents photosterols, aliphatic alcohols, polyprenes,
and flavonoids
Effects: ↓ 5 α-reductase and antagonistic effects at androgen
receptors (Finasteride → ↓ DHT)
Use: in the treatment of BPH; have shown some improvement in
urinary flow & urologic function.
AE: GI distress & pain; ↓libido, HTN, and headache
Black Cohosh (Actaea racemosa)
Native to eastern North America.
Extracts from these plant materials are thought to possess
analgesic, sedative and anti-inflammatory properties
Black cohosh preparations of tinctures or tablets of dried
materials are used chiefly to treat symptoms associated with
menopause and premenstrual tension
Recent research suggests that these physiological effects may be
due to black cohosh compounds that bind and activate serotonin
receptors
Side effects: include dizziness, headaches, and seizures
Nausea, vomiting and diarrhea
Liver damage has been reported