USMLE Pharmacology II

What are the side effects of Ethylene glycol ingestion (Antifreeze)

CNS depression

Metabolic Acidosis!! (Oxalic Acid)

Nephrotoxicity from formation of Ca++ oxylate crystals... can lead to ATN

What are the side effects of Methanol, AKA wood alcohol ingestion?

Respiratory failure

Metabolic acidosis

Ocular damage*** with permanent blindness

What is the treatment for OD with either ethylene glycol or Methanol?

Fomepizole...Alcohol Dehydrogenase inhibitor.

What cofactors are required by Acetaldehyde dehydrogenase to do its job?

Thiamine

and

Folate!! This is how alcoholics get deficient in these.

Alcoholics are at increased risk for which two cancers?

Esophageal cancer

and

Signet ring cancer of the stomach

What is the MOA of disulfram?

Inhibits Acetaldehyde Dehydrogenase, leading to a buildup of Acetaldyhyde and N/V, headache, hypotension, and bad feelings

Which drugs commonly cause disulfram-like reactions?

Metronidazole*** (and almost any AZOLE) similar to FOMEPIZOLE, an inhibitor or alcohol dhse

Cefoperazone

Cefotetan

Chlorpropamide

Griseofulvin

(Aripiprazole, Omeprazole)

What is the DOC for a generalized ABSENCE seizure?

Ethosuximide...

Can also use Valproic acid

Treatment of status epilepticus if Lorazepam or Diazepam don't work?

Phenytoin or Fosphenytoin

What are the top 3 DOCs for partial seizures of general tonic-clonic seizures?

Valproic acid

Phenytoin

Carbamazepine

What is the MOA of Phenytoin?

Blocks axonal Na+ channels in their inactive state, with the M-gate open and the H-gate closed so it prolongs the time before returning to an active conformation...Prevents seizure propogation, not the start of the seizure itself.

When is Phenytoin used?

In any seizure except absence seizures.

What are important points to rememebr about Phenytoin use?

It follows Zero order kinetics

and

Is an inducer of P450, contraindicated in porphyrias

What side effects of Phenytoin are quite specific for the drug itself?

Hirsutism and Gingival hyperplasia together.

What are common side effects of Phenytoin?

CNS depression

Ca+ and Phosphate changes in blood

Megaloblastic anemia from decreased folate absorption

Aplastic anemia from high protein binding

Phenytoin is teratogenic...what does it cause?

Cleft lip and Palate commonly

What is the DOC for trigeminal neuralgia?

Carbamazepine...

What is Carbamazepine used for besides seizure treatment?

Bipolar disorder

What is the MOA of Carbamazepine?

Blocks axonal Na+ channels in their inactive state, with the M-gate open and the H-gate closed so it prolongs the time before returning to an active conformation...Prevents seizure propogation, not the start of the seizure itself.

What are the side effects of Carbamazepine that set it apart from Phenytoin?

EXFOLIATIVE DERMATITIS, aka Stevens Johnson syndrome

and

Increased ADH secretion, leading to dilutional hyponatremia and brain edema, increased IOP

What are the teratogenic effects of Carbamazepine?

Cleft lip and Palate

Spina Bifida

What is the MOA of Valproic Acid?

Similar to Phenytoin and Carbamazipine but also

Inhibits GABA transaminase, which normally degrades GABA...leads to increased GABA

ALSO

BLocks T-type Ca++ channels in the Thalamus, so is useful in ANY type of seizure.

Uses of Valproic acid?

Any seizure

Mania of bipolar

Migraine headaches

What is relevant about the effect of Valproic Acid on P450??

Unlike Phenytoin and Carbamazepine it is an INHIBITOR of P450

Side effects of Valproic acid?

Hepatotoxicity

Thrombocytopenia

PANCREATITIS***

ALOPECIA ** (opposite effect of Phenytoin)

Several BOARD relevant drugs associated with causing acute pancreatitis?

Valproic acid

Alcohol

Didanosine

Zalcitabine

Asparaginase (treatment for Leukemias)

Teratogenicity of Valproic acid?

Spina Bifida

MOA of Ethosuximide?

Blocks-T-type Ca++ channels and is used in absence seizures

Safest anticonvulsant to use in Pregnancy?

Phenobarbitol

What is the effect of Inducers of P450 on OC pills?

Decreased efficacy...Many pts on seizure meds are on OC pills to prevent pregnancy due to teratogenic risks...Use Valproic acid, an inhibitor of P450

What is the MOA of felbamate?

Blocks Na+ channels and Glutamate receptors.

What is the MOA of Lamotrigine?

Blocks Na+ channels and Glutamate receptors

What is the use of Felbamate?

Antiseizure drug

What is the use of Lamotrigine?

Antiseizure drug

Side effects of Felbamate?

Hepatotoxicity and aplastic anemia

Side effects of Lamotrigine?

Hepatotoxicity and aplastic anemia

Stevens Johnson syndrome

What is the MAC value WRT inhaled anesthetics?

The minimal alveolar anesthetic concentration needed such that 50% of pts do not respond to an assault, such as a scalpel. (like the ED50)

What are two general rules about the MAC value for Inhaled Anesthetics?

The more lipid soluble the anesthetic, the lower the MAC and the Greater the Potency

MAC values are additive

MAC values are lower in the elderly and in the present of sedative hypnotics

Why is Nitrous Oxide beneficial as an inducer of anesthesia?

It has a low Blood gas ratio, which means it most lipid soluble and easily enters the brain...Problem is it is not as potent...MAC value is high

In what pt population is Nitrous oxide contraindicated?

Pregnancy, can cause spontaneous abortions.

Important point to remember about Nitrous Oxide?

Rapid onset and recovery

it is NOT metabolized! Inhaled and exhaled...

This unfortunately can lead to diffusional hypoxia as it replaces part of the partial pressure of O2

What is important to remember about Halothanes and other Halogenated hydrocarcons?

Can cause malignant hyperthermia!

Hepatitis!

Cardiac arrhythmias, as they sensitize the heart to catecholamines

What is true about halothane and other halogenated hydrocarbons WRT the MAC and Blood Gas ratio?

Low MAC meaning they are quite potent.

Higher B:G ratio meaning they take longer to work, but they are longer lasting.

What is important to remember about Halothane WRT toxicity?

CUMULATIVE hepatotoxicity

What is Thiopental used for?

It is a barbituate used for induction...It is highly lipid soluble and has a rapid onset plus is short acting due to rapid redistribution.

Is there an antidote for Thiopental OD?

NO

What drug ' LOOKS LIKE MILK?'

Propofol...

Benefits of Propofol on anesthesia protocol?

Used for induction and maintenance anesthesia PLUS

Is a strong Antiemetic**

Why is Fentanyl beneficial in Anesthetic protocols?

Because it is an anesthetic (makes the patient non-responsive) AND is an analgesic...prevents pain.

What type of receptors does Ketamine work on?

NMDA--it is a receptor antagonist

What is Ketamine used for in the clinical setting?

It is a dissociative anesthetic used for induction... Pt may feel out of body experiences or have hallucinations

What is typical of Ketamine use in anesthesia for patients to report?

Vivid nightmares or hallucinations the night after using it.

What pt population is Ketamine particularly useful for?

Elderly patients needing anesthesia, who also have poor CV function! It is cardiostimulatory

Who is Ketamine Contraindicated for?

Pts with increased intracranial pressure/ neurotrauma.

Bonus point about Ketamine?

Can be used when we need to set compound fractures or dressing burns in Children, as the patient does not need to be fully put out.

Local anesthetics are weak bases! What type of environment must be present in order for them to be absorbed by the body?

High pH so they are not protonated...

Sometimes need to alkalinize the environment.

What form must local anesthetics be in in order to elicit their response?

The ionized form...needs a low pH which the metabolic activity of cells provides.

What is the target of Local Anesthetics?

The inactivated Na+ channel with the M gate open and the H gate closed. They block them.

What is important to remember about the metabolism of Local Anesthetic ESTERS?

They are degraded by tissue esterases, which are genetically determined and we can have slow and fast metabolizers... Slow metabolizers may suffer general anesthesia

What is important to remember about the metabolism of Local Anesthetic Amidases?

They are metabolized by the liver...need a good liver function for this.

How do you tell which Local Anesthetics are Esters or Amides?

If the name has an extra 'I" in it before the 'CAINE' it is an amIde... Like LIdocaine, BupIvacaine, MepIvicaine...

Esters do not have this... procaine, cocaine, benzocaine

Which types of nerve fibers are most sensitive to the effects of Local Anesthetics?

Small diameter fibers where the relative concentration of drug can climb rapidly

And

In rapidly firing neurons, which will provide a large pool of inactivated Na+ channels.

Type B and C (C being dull pain) are affected fastest, followed by type A delta, sharp aching pain.

What are the side effects of Local Anesthetics?

Can cause Neurotoxicity and CV toxicity if not properly 'localized' esp with vasoconstrictors.

What is meant by a Tetrodotoxin sensitive ion channel?

Means that it is a VOLTAGE gated ion channel.. Means the same thing to Physiologists

What is the MOA of Tetrodotoxin and Saxitoxin?

Inhibit the entry of Na+ though an activated Na+ channel... Type 1A.

The Nm receptor at the neuromuscular junction has 5 subunits, 2 alpha, 1 beta, 1 gamma and 1 delta... Where does ACh normally bind?

The Alpha subunits! Two molecules of Ach are needed to open the channel.

How many 'Curare' or Tubucurare molecules are needed at any one time to prevent the opening of an acetylcholine channel in the NMJ?

JUST 1! Stupid Board question...since 2 ACh molecules must bind to open the channel, just 1 curare molecule can prevent this.

What is the prototypical nondepolarizing NM blocker?

D-Tubocurarine

How is nondepolarizing neuromuscular blockade reversed?

AChE Inhibitors to increase the ACh levels enough to displace the blocker.

What type of drug is Atracurium?

A nondepolarizing skeletal muscle blocker

What are two important BOARD points to remember about Atracurium?

It is safe to use in hepatic or renal impairment as it is not metabolized by these organs

AND

It is spontaneously inactivated to LAUDANOSINE, which is known to cause seizures?

Any pt coming off of skeletal muscle relaxants that experiences seizures, think of this.

What type of drug is Mivacurium?

A nondepolarizing NM blocker

What is important to remember about Mivacurium?

It has a very short duration of action

EXCEPT

That it is metabolized by cholinesterases, of which we have slow and fast metabolizers. If someone is a slow metabolizer, this drug will NOT have a short duration of action.

What type of drug is Succinylcholine?

A DEPOLARIZING noncompetitive NM blocker

What are the two phases of Succinylcholine effects?

Phase I the depolarization phase leading to fasciculations and contraction...Eventually leads to flaccid paralysis.

Phase II the desensitization phase! Constant stimulation leads to lack of response...causes paralysis.

What is the only way Succinylcholine can be reversed?

Via hydrolysis using pseudocholinesterases! Again, the problem is that there are slow and fast metabolizers and if you are slow, the drug is there to stay.

Cautions for Succinylcholine?

Prolonged paralysis if slow metabolizer

Hyperkalemia can worsen depolarization

Malignant Hyperthermia

What receptors are mutated in 50% of patients who suffer malignant hyperthermia from succinylcholine?

Ryanodine receptor mutation (AD)

Normally seen in SR and control levels of Ca++ in the SR....This mutation leads to increased Ca++ storage.

What is the 'antidote' for malignant hyperthermia caused by Succinylcholine?

Dantrolene! Prevents release of Ca++ from the SR

Outline the process of Maliganant Hyperthermia?

Depolarization of muscles in the body from Succinylcholine leads to increased contraction and need for ATP

This leads to an increase in the ETC, leading to increased acidosis and HEAT!

When the heat gets high enough, the SANS kicks in to increase sweating an decrease heat but leads to increased HR, Palpitations, arrhythmias and HTN

What is the drug used to treat respiratory depression induced by Morphine?

NALOXONE!

Do NOT give O2 as the Mu receptors have knocked out the central respiratory control center in the Medulla that causes respiration in high CO2 states. Now the only reason the pt is breathing is because of the low O2 sensed by the carotid body

Morphine should be avoided in patients with head trauma because....

It can cause histamine release, and this would lead to vasodilation and can make a intracranial bleed worse!

What is the only drug that is more highly active after Glucuronidation in the liver than it is beforehand?

Morphine! This drug is highly active, and esp in the presence of a pt with renal dysfunction it might not be adequately cleared, leading to toxicity.

What is the only Opioid drug that will NOT result in pinpoint pupils?

Meperidine! (AKA Pethidine) It is antimuscarinic, which will lead to mydriasis

Also leads to NO SPASM of GI/GU

What is important to remember about the metabolism of Meperidine?!

It is metabolized to NORmeperidine, which is an SSRI! This can precipitate Serotonin Syndrome, leading to seizures.

Primary use of Methadone??

Maintenance of opiate addiction, as it acts slower.

What is important to remember about Codeine?

Weak Mu agonist that causes analgesia...

Also is a cough suppressant

What is the relevance of Buprenorphine WRT BOARD questions?

It is a partial Mu agonist! If a pts is on Heroin and you give them Buprenorphine it can precipitate a state of withdrawal by blocking the effect of the full agonist!

What type of drug is Nalbuphine?

A mixed opioid agonist-antagonist that mostly activates kappa receptors... Leads to spinal anesthesia and DYSPHORIA.

Act as Mu antagonists that can precipitate the withdrawal

What type of drug is Pentazocine?

A mixed opioid agonist-antagonist that mostly activates kappa receptors... Leads to spinal anesthesia and DYSPHORIA.

Act as Mu antagonists that can precipitate the withdrawal

What is the use of Naltrexone?

Given PO, used to decrease craving in alcohl and opiate addiction***!

What is the use of the drug Methylnaltrexone?

Treatment of opioid induced constipation

(Opiate antagonist)

Triad of Opiate use?

Pinpoint pupils

Respiratory depression

Coma

What are the two side effects of Opiates that patients to not become tolerant to?

Miosis and Constipation

What is BOARD tested about Opiate tolerance?

The tolerance is NOT mediated by receptor downregulation or desensitization but that cells are managing to RAISE cAMP levels, the opposite of the action of the Mu receptors, which work using Gi receptors. Pharmacodynamic.

What type of drug is Loperamide and what is it used for?

It is an opiate, but is not absorbed and has none of the effects of other opiates...

Used to treat diarrhea

What type of drug is Dextromethorphan and what is it used for?

It is an opiate drug, used to suppress cough

What non-opiate drug can be used to treat Opioid withdrawal??

Clonidine! It is an alpha 2 agonist, which when it is stimulated by NE it decreases NE release from the presynaptic nerve terminal...

NE is increased in Opiate withdrawal because originally it was acting on Gi receptors to decrease NE, but now with the Opioid removed NE is again released and receptors have been upregulated.

What type of drug is Pergolide?

DA agonist

What is the effect of Dopamine on the Mesolimbic-Mesocortical tracts?

(VTA) DA stimulation here leads to reinforcement and addiction, as it causes pleasure.