What is the drug of choice for long term management of primary and secondary hypothyroidism?

What is the mechanism of action of this drug?

What special directions should be given to a patient regarding when to take this drug and/or other thyorid medications? Why?

Levothyroxine (LT4)

Synthetic T4, providing a steady source of T3 similar to what is seen after normal T4 secretion.

Take on an empty stomach to make sure absorption is maximal.

Name a synthetic form of T₃. What are the disadvantages of using this drug?

What is an appropriate use of this drug?

Liothyronine (LT₃)

Shorter halflife (multiple dosing)

More costly

Higher hormonal activity enhances cardiotoxicity

Short-term TSH suppression.

What drugs accelerate the metabolism of T4 in the liver?

What must be done for such a patient?

Phenytoin (gran mal seizure med.)

Carbamazepine (seizure med.)

rifampin (antibiotic)

amiodarone (SSRI antidepressant)

Increase the thyroid drug dosage.

A 24 year old female who is on thyroid medication and oral contraceptives complains of diarrhea and excessive thirst. Even though she keeps her air conditioning on 70 degrees or lower all of the time, she complains that she feels "hot all of the time" and constantly feels sweaty.

She feels like her thyroid medication is the problem and wants to drop the medication.  What should you tell her?

The exogenous androgens from her birth control patch are causing her TBG levels to be lower than normal, increasing free thyroid hormone in the blood.  Her thyroid medication dosage is thus probably too high with her contraceptive use.

Give her a lower dose of thyroid medication and tell her to come back for a higher dosage if she comes off of the birth control.

Which patient will generally need a higher dosage of T4 in replacement therapy?

A patient who had surgery, removing the thyroid gland

A patient with Hashimoto's thyroiditis

Why?

The surgical patient will need about a 20% higher dose.

The Hashimoto patient may have functioning lobes of thyroid gland which can still contribute thyroid hormone.

When a hypothyroid patient is treated, how long does it usually take before tests show a NORMAL TSH level?

What is the halflife of TSH?

4-6 weeks

1 week

What are two antithyroid medications that can be used for a hyperthyroid patient, and how should they be administered?

How long does their effect take?

propylthiouracil (PTU)

Methamazole (Tapazole)

Start with a low drug dosage and slowly titrate upward, trying to find the lowest effective dosage.

Slowly inhibit multiple steps in thyroid hormone synthesis, and take 2 to 8 weeks to have an effect.

What is one main difference in the mechanism of the two antithyroid medications? What effect does this have?

What do they do similarly?

PTU, unlike methamiazole, blocks the conversion of T4 to T3 in peripheral tissues.

The effect of this is a quicker reduction in active thyroid medication and faster remediation of symptoms.

Both inhibit the coupling step of thyroid hormone precursors.

Which of the antithyroid drugs is the drug of choice for the general population, and which is more suitable for pregnant women?

What are the reasons?

Methamiazole

PTU

Methamiazole has fewer side effects, has better patient compliance (1-2 times per day vs 3-4 times per day), and costs less.

The inhibition of T4 to T3 in PTU is beneficial for pregnant women and those with severe thyrotoxicosis (less T3 to fetus due to increased protein binding). Also, methamiazole has been shown to cause aplasia cutis.

What is the main concern regarding the adverse effects of antithyroid medication?

What are the other 2 toxicities?

Agranulocytosis; decreased WBC count

reversible hypothyroidism, Liver failure

What antithyroid medication blocks the final step of thyroid synthesis, preventing its release from the thyroid gland?

When might this drug be useful, and what are its disadvantages?

What is a consequence of long term treatment?

Potassium Iodide (possibly blocks thyroglobulin proteolysis)

Short-term management of a thyroid storm and preoperative surgery.

May delay thioamide treatment or radioactive treatment due to an increase in intrathyroid hormone levels.  Also, may cross the placenta and cause a fetal goiter.

Gland escapes block in 2-8 weeks; short term usefulness only.

Small goiter size

MILD elevation of thyroid hormone levels

The Somogyi phenomenon is the bodies response to low blood glucose by causing a rapid increase in blood glucose; usually occurring at night. Typically occurs after excessive insulin administration.

The dawn phenomenon is due to the "morning hormones" such as cortisol that cause an increased level of glucose in the body that cannot be controlled by the ineffective insulin in diabetics.  Usually due to the waning effects of insulin.

What are the fastest acting insulins?

How does each work?

Lispro and aspart

Lispro switches the posistions of 2 amino acids, reducing insulin binding with other insulin molecules and increasing the monomer form.

Aspart has a negative charge (aspartamine) that also favors the monomer form.

7% H1C=170mg/dl blood glucose levels.

Each % point=35mg/dl of average blood glucose.

Normal=4-6%

– Glyburide

– Glipizide

– Glimepride

Hypoglycemia

Mild weight gain

– Repaglinide (Prandin; approved in 1998)

– Nateglinide (Starlix; approved in 2000)

They inhibit ATP-sensitive K+ channels, allowing for a larger release of insulin from beta cells in the pancreas.

What are the actions and effects of metformin?

What is the cheif contraindication?

• *Decreases hepatic glucose production (GNEO)

• Increases insulin sensitivity

• Decreases bl. Tg and FFA

• Weight loss

Has nothing to do with insulin secretion, thus the risk of hypoglycemia is not there. Usually first line in treating T2DM

Renal insufficiency

– Pioglitazone (Actos)

– Rosiglitazone (Avandia)

Act on muscle and fat by binding to the PPAR gamma receptors and increasing insulin sensitivity.

Also act on bones to increase osteoclast activity.  Can cause osteoporosis.

A1C -1-2%

Decreased insulin resistance

Low cost with lots of benefits

Adherence is tough...

1.5-2.5

Replaces indogenous insulin

Insulin receptor

No dosage limit, and improves the lipid profile.

Injections, hard to self monitor, hypoglycemia and weight gain.

Not very expensive.

1.5

Stimulates insulin secretion from the pancreas

Sulfonylurea receptor (SUR) of beta cells

Relatively few side effects

Weight gain and hypoglycemia

Not very expensive

1-1.5

Stimulate pancreatic insulin secretion

Inhibit the K+ ATP channel

Has a short duration of action

Can cause weight gain and requires frequent dosing (3x/d)

Can be expensive

Decreases liver gluconeogenesis and increases insulin sensitivity.

HDAC

Weight neutral and may improve the lipid profile.

GI side effects and lactic acidosis

Not very expensive

0.5-1.4

Decrease insulin resistance and decreased hepatic glucose production

PPAR gamma

Improves lipid profile

Fluid retention and weight gain.

very expensive!

0.5-0.8

Slows the digestion of carbohydrates

alpha glucosidase

Weight neutrial and no risk of hypoglycemia

GI symptoms and requires frequent dosing (3x/d)

not very expensive

0.5-1.0

Slows gastric emptying, decreases postpranial glucagon secretion, and increased saiety

amylin receptor

Weight loss

Injections, frequent dosage (3x/d), and frequent GI effects

not very expensive

0.5-1.0

Stimulate pancreatic insulin especially in the acute phase, inhibit glucagon secretion, and slow gastric emptying.

GLP-1 receptor

Weight loss

Requires injections, frequent GI effects, and usage is limited.

Very expensive!

0.5-0.7

Inhibits the degredation of incretins (GLP-1)

DPP-4 enzyme

Weight neutrial

Limited experience

Very expensive!

What is the most common type of adult seizure?

What about in children?

Complex partial seizures

Absence seizures

Focal with minimal spread of abnormal

discharge

normal consciousness and awareness are

maintained

Describe the characteristics of a complex partial seizure.

What area of the brain is mostly affected?

Local onset, then spreads

 Impaired consciousness

 Clinical manifestations vary with site of origin and

degree of spread

– Presence and nature of aura

– Automatisms

– Other motor activity

 Temporal Lobe Epilepsy most common

 Begins focally, with or without focal neurological

symptoms

 Variable symmetry, intensity, and duration of tonic

(stiffening) and clonic (jerking) phases

 Typical duration up to 1-2 minutes

Postictal confusion, somnolence, with or without

transient focal deficit

absence (petit mal) seizures

myoclonic seizures

atonic seizures

Tonic-clonic (grand mal) seizures

What is the most common cause of epilepsy?

What is the most common KIND of epilepsy?

Idiopathic

Complex partial seizures

What are the two ways that seizures are generated?

What neurotransmitters are responsible for each?

Excitation (too much)

– Ionic—inward Na+, Ca++ currents

– Neurotransmitter—glutamate, aspartate

 Inhibition (too little)

– Ionic—inward CI-, outward K+ currents

– Neurotransmitter—GABA

Benzodiazapines

Barbituates

Gabapentin

Tiagabine

Vigabatrin (not in USA)

Phentoyn, carbamazepine

oxcarbazepine (also blocks K⁺ channels)

Zonisamide (also blocks T-type calcium channels)

Absence seizures are caused by oscillations

between thalamus and cortex that are generated

in thalamus by T-type (transient) Ca2+ currents

Ethosuximide is a specific blocker of T-type

currents and is highly effective in treating

absence seizures

Phenytoin and carbamazapine

Phenytoin

If first line medications for partial seizures fail, what drugs can be used?

Why isn't it a first line treatment?

Phenobarbital and primidone

More pronounced CNS sedation.

oxycarbazepine

Gabapentin

5 attacks fulfilling the criteria below:

1. Headache lasting 4-72 hours.

2. Two of the following

Unilateral

Moderate or severe

Aggrevated by routine activity

Pulsating

3. 1 of the following

Nausea and/or vomiting

photo and phonophobia

4. None of the above contributed to another condition.

 Normal

1. Prodrome-hightened sensitivity to light, sound and smell.  yawning (tiredness) and fluid retention.

2. Aura

3. Headache-phobia to light, noise, and smell.  Anorexia and fluid retention.

4.Resolution-Vomiting/deep sleep

5. Recovery- limited food tolerance, tiredness, diuresis.

6. Normal

With a long history of migranes, what area of the brain shows changes?

What is this area responsible for?''

What actually occurs, what determines the amount of damage, and what does this predispose the patient to?

the preaquiductal gray matter (PAG)

Center of the decending analgesic neuronal network.

Iron deposition to free radical injury and past bleeding. Headache severity and history; not the patient's age.  Predisposes the patient to further migranes.

Which drug used in the treatment of migranes has the lowest rate of relapse and the highest rate of having no migranes post-treatment?

What is a common side effect, and when should it be given?

Almotriptan

Often can cause nausea and vomiting.  Should be given before the onset of a migrane.

Tremor

Rigidity

Akinesia and bradykinesia

Postural instability

TRAP

In parkinson's disease treatment, what is given alongside Levodopa and why is this done?

How is the effect of this adjuvant therapy accomplished?

Carbidopa; minimizes side effects.

Does this by minimizing the conversion of L-dopa to norepinephrine in systemic circulation; NOT across the BBB.

Inhibits Dopamine recapture.

livedo reticularis

What drug increases the synthesis of dopamine?

Which 3 drugs increase the release of dopamine?

Which 3 drugs inhibit the reuptake of dopamine?

Which 3 drugs inhibit MAO-B?

Which 2 drugs inhibit COMT?

What 2 drug classes are dopamine agonists?

Levodopa

Amantadine

Selegiline

Nicotine

Amantadine

Selegiline

Brasofensine

Selegiline

Lazabemide

Resagiline

Entacapone

Tolcapone

Ergot derivative

non-ergot derivatives

What acetylcholinesterase inhibitors can be used in the treatment of Alzheimers?

What NMDA receptor antagonist can be used?

What special characteristic of these agents is key to their efficacy?

Donepezil (Aricept)

Rivastigmine (Exelon)

Galantamine (Reminyl)

Memantine (Namenda)

Must be able to cross the BBB.

This class of immunosuppressant drug inhibits the activation and action of immune cells.

What is an example of this class?

corticosteroids

Prednisone

These immunosupressant drugs elicit the specific inhibition of the immune response.  Inhibit T helper cell activation and production of IL-2 by either binding to a receptor or by binding to an intracelluar protein (calcineurin).

Cyclosporin (Sandimmune)

FK-506  (Tacrolimus)

Rapamycin (very similar to FK-506)

What is the MHC responsible for "distinguishing self from non-self"?

What do all helper T cells express?

MHC-I

CD-4

What was used to immunize against TB

Low-dose aspirin (81 mg up to 300 mg/day)

has efficacious anti-platelet activity.

Intermediate dose: Antipyretic and analgesic

doses of aspirin (300 – 2400 mg/day)

High dose: (2400 – 4000 mg/day) - antiinflammatory

Which NSAID should be used in children?

Which should NOT?

Acetominophen

Asprin

Gold

Methotrexate

TNF-blocking agents Infliximab (Remicade) and Etanercept (Enbrel)

Colchicine

NSAIDS

Uricosuric agents: Probenicid and Sulfinpyrazone

Allopurinol

When might the primary treatment of primary gout be switched for NSAIDS?

What NSAID is a good replacement?

PT cannot tolerate side effects.

Indomethacin