Chapter 35: Substance Use Disorders IV: Major Drugs of Misuse Other Than Alcohol and Nicotine

Welcome to Last Minute Lecture.

This free chapter overview is designed to help students review and understand key concepts.

These summaries supplement not replaced the original textbook and may not be redistributed or resold.

For complete coverage, always consult the official text.

You know, when you first stare down a massive pharmacology review on substance use disorders, it can feel a bit like you're just memorizing, well, a very dangerous phone book.

Oh, definitely.

Just endless lists.

Right.

A long list of names, side effects, antidotes, all just crammed into your short -term memory before clinicals.

But if you look closer, there's actually a distinct, beautiful logic to it.

Yeah, there really is.

Because knowing a drug's mechanism of action, I mean, it isn't just trivia.

It's the exact roadmap for figuring out its toxicity and predicting exactly how to reverse it.

That's the perfect way to look at it.

The mechanism is the map.

If you understand the why at the receptor level, the clinical presentation and the treatment protocol just naturally fall into place.

You stop memorizing and start anticipating.

Exactly.

You can see the overdose happening at the cellular level before it even manifests fully.

Well, welcome to this deep dive, everyone.

Consider this your customized one -on -one tutoring session.

If you are an advanced practice nursing or physician assistant student, grab your mental notepad.

We are going deep today.

We really are.

Our mission today is to master the clinical reasoning behind managing the major drugs of misuse, specifically those other than alcohol and nicotine, as outlined in Chapter 35 of Len's Pharmacotherapeutics.

Yeah.

And right at the start of the chapter, Table 35 .1 gives us our framework.

It categorizes these misused drugs into six major families.

Right.

So we've got opioids, psychostimulants, depressants, psychedelics, anabolic steroids,

and a few miscellaneous agents.

And we're going to cover them in that exact order today, breaking down the mechanisms, the safety priorities, and the patient education for each one.

Let's start with the heaviest hitters, the opioids.

When we look at the classic street prototype heroin, what is happening pharmacokinetically that makes it so remarkably potent compared to like other opioids?

So it really all comes down to lipid solubility.

Heroin has incredibly high lipid solubility.

Which means it gets into the brain faster.

Way faster.

It allows it to cross the blood -brain barrier almost effortlessly.

And once it crosses into the brain, it's rapidly converted into its active form, which is actually just morphine.

Wait, really?

It just turns into morphine.

Yeah, exactly.

The route of administration dictates the pharmacokinetics though.

If a patient injects it intravenously,

that intense rush hits in just like seven to eight seconds.

Oh.

But if they smoke or snort it, the effects peak much later, usually in 10 to 15 minutes.

But obviously the opioid crisis isn't just about street heroin.

We deal with prescription medications constantly in clinicals, like oxycodone.

Right.

Specifically, the controlled release formulation, oxycontin.

Yeah.

And if a pill is designed to be slow release, I always wonder how it ends up causing such acute, massive overdoses.

Well, the danger arises from how the pill is physically manipulated.

Those tablets are formulated with a matrix that's designed to release the oxycodone steadily over an extended period.

So it's supposed to trickle into the system.

Right.

But individuals who misuse it, they don't swallow it intact.

They crush it.

They either snort the resulting powder or dissolve it in water and inject it.

And that breaks the matrix.

Completely destroys it.

The extended release mechanism is gone.

So the entire 12 or 24 -hour dose just dumps into the bloodstream immediately.

Oh, wow.

That's terrifying.

Yeah.

And for a non -tolerant user, that creates a dangerously high serum level, resulting in fatal respiratory depression almost instantly.

That brings up tolerance, actually, which is such a critical concept for clinical reasoning here.

The pathophysiology of opioid tolerance, it's not uniform across all symptoms, is it?

No, not at all.

A patient will develop tolerance to the euphoria, the respiratory depression, and the nausea.

But they don't develop tolerance to everything.

Exactly.

They do not develop tolerance to constipation or meiosis, you know, the pinpoint pupils.

So their pupils will always constrict and their gut will always slow down no matter how long they've been using.

Right.

But because tolerance to respiratory depression develops in parallel with tolerance to euphoria,

the user doesn't stop breathing simply because they took a higher dose to achieve a high.

Oh, I see.

So what actually causes the fatal overdoses then?

The fatal risk comes when they misjudge the dose or mix the opioid with a general central nervous system depressant like alcohol.

Or, very commonly, they relapse after a period of abstinence.

Because their tolerance reset.

Exactly.

During abstinence, their tolerance drops right back to baseline.

If they relapse and inject their previous normal dose, well, it is now a lethal dose.

Which leads us straight to the classic toxicity triad.

If you see respiratory depression, coma, and pinpoint pupils, you are immediately thinking opioid overdose.

Every single time.

And the treatment is naloxone administered via Narcan nasal spray or the Zimhi pre -filled syringe.

But, I mean, there's a massive clinical pitfall here regarding the dosing framework.

Huge pitfall.

It feels like a lot of people think you just give the Narpan, the patient wakes up, and the emergency is totally over.

Yeah.

And that is a very dangerous assumption.

Naloxone has a very short half -life compared to most opioids.

So it wears off too fast.

Exactly.

It rapidly reverses the poisoning by kicking the opioid off the mu receptors.

But the naloxone will wear off long before the opioid is actually cleared from the patient's system.

Wait, so they just go right back to sleep?

They do.

You have to continually monitor the patient and re -administer naloxone every few hours until the opioid concentrations drop to nontoxic levels.

That's a crucial monitoring parameter.

Definitely.

Failing to repeat that dose can result in a patient who is sitting up and talking a few minutes ago, slipping right back into a fatal coma once the first dose wears off.

So assuming we get them through the acute overdose, we have to look at long -term management.

Table 35 .2 breaks this down.

We essentially have three categories of maintenance medications, right?

Yes.

We have pure agonists, agonist antagonists, and pure antagonists.

Let's start with the agonist methadone.

It substitutes for the misused opioid to prevent withdrawal, but prescribing it comes with a major black box warning.

It does.

Methadone can cause life -threatening QT prolongation on an ECG as well as severe respiratory depression.

Which is why you can't just get it at a normal pharmacy for addiction.

Right.

Because of its long half -life, complex pharmacokinetics, and high misuse liability, its non -algesic use for addiction maintenance is strictly restricted to SAMHSA -certified opioid treatment programs.

Then we have buprenorphine, the agonist antagonist.

It's a partial agonist at mu receptors, meaning it suppresses cravings but has a built -in sealing effect on respiratory depression, which makes it much safer.

Yes.

And it's also a full antagonist at kappa receptors.

But the specific formulation called suboxone, where buprenorphine is combined with naloxone, I mean, it's brilliant.

It acts like a chemical booby trap.

That's a great way to put it.

It actively discourages intravenous misuse.

How does the booby trap actually work?

Well, if the patient takes the suboxone film sublingually, as prescribed, the naloxone component is barely absorbed due to the route.

It does nothing.

Because it just gets swallowed and metabolized.

Exactly.

But if the patient tries to dissolve and inject it intravenously to get a rush, the naloxone becomes fully bioavailable and instantly precipitates a severe withdrawal syndrome.

Wow.

Instant regret.

Truly.

And lastly, for maintenance, we have the pure antagonist, naltrexone.

It blocks euphoria entirely.

But patient education is paramount there.

Oh, absolutely.

If you give naltrexone to someone who still has opioids in their system, you will throw them straight into an agonizing withdrawal.

They must be completely detoxified first.

That makes sense.

Now, as we look beyond traditional opioids, clinicians also have to be aware of emerging unregulated substitutes.

A major one right now is kratom.

Yeah, kratom's a big issue.

You see, it's sold everywhere now.

Gas stations, smoke shops.

People use it to self -medicate for pain or to ease their own opioid withdrawal, assuming it's safe because, well, it's an herbal supplement.

But it's really not benign.

It is composed of two primary alkaloids, mitraginine and 7 -hydroxymetraginine.

And they work on the opioid receptors.

They do.

It interacts directly with opioid receptors in the brain.

At low doses, it produces a stimulant effect, increasing alertness.

Like coffee?

Kind of, yeah.

But at high doses, it produces classic opioid effects like euphoria, sedation, and analgesia.

And it's not federally regulated right now.

No.

But clinicians need to know the DEA is actively considering making it a scheduler hazard.

There are over 40 reported deaths, usually when kratom is mixed with other drugs or prescription medications.

Good to know.

Well, we've been talking a lot about opioids, but let's shift to general CNS depressants that work entirely outside the opioid receptor system,

specifically the barbiturates.

A completely different mechanism.

Yeah.

And when I look at the pharmacodynamics of barbiturate tolerance,

it is uniquely terrifying compared to opioids.

It really is.

With barbiturates, tolerance develops significantly to the subjective euphoric effects.

The patient needs more and more of the drug to feel anything.

Okay.

But what about the respiratory depression?

That's the scary part.

Little to no tolerance develops to the respiratory depression.

Wait.

So the lethal dose stays exactly the same while the patient requires higher and higher doses just to feel the effects.

That's a terrifying trap.

It is a trap.

That narrowing therapeutic index is why barbiturate overdoses are so common.

It's like walking out on a flank that just keeps getting thinner.

And withdrawal is dangerous too, right?

Yes.

Withdrawal can be fatal.

To safely ease a patient through barbiturate withdrawal, clinicians must substitute a long -acting barbiturate like phenobarbital and execute a very slow control taper.

Compare that to benzodiazepines, which are schedule four drugs.

They are vastly safer.

Vastly.

An overdose on oral benzos alone is rarely lethal unless the patient combines them with another CNS depressant like alcohol.

Plus, we actually have a specific reversal agent for them, right?

Flumazenil.

Yes.

Flumazenil.

Knowing the receptor mechanism really dictates the entire safety profile.

Absolutely.

Well, we've spent all this time talking about drugs that depress the central nervous system to the point of fatal respiratory arrest.

Let's flip the script.

Let's do it.

What happens when a drug hijacks the brain in the exact opposite direction, overdriving the heart instead of stopping the lungs?

Let's look at the psychostimulants, starting with cocaine.

Okay, so the primary mechanism of cocaine is the inhibition of neuronal reuptake of dopamine in the brain's reward circuit.

So it just leaves the dopamine floating around in the synapse?

Exactly.

By blocking that reuptake pump, dopamine accumulates in the synaptic space, leading to intense stimulation.

And once again, the route of administration drastically alters the pharmacokinetics here.

If a patient snorts cocaine intranasally, absorption across the nasal mucosa is relatively slow.

You get a slower rise in serum levels.

But if they smoke crack cocaine?

Then the absorption in the lungs is massive and immediate.

You get a virtually instantaneous explosive euphoria, followed by a rapid severe dysphoric crash.

And that agonizing crash is what drives the user to binge repeatedly, right?

Right.

And that binging frequently leads to acute toxicity, which presents as a massive sympathetic nervous system overdrive.

Like heart issues?

Severe cardiac issues,

ventricular dysrhythmias, and coronary artery spasm, leading to angina or a full myocardial infarction.

So clinical reasoning for treatment here, it's entirely symptomatic.

We administer intravenous diazepam to suppress anxiety and prevent seizures,

nitroproside to manage severe hypertension, and aspirin to reduce the risk of Yes, but here is where the mechanism is literally life or death.

The text explicitly warns against using beta blockers alone.

Which is crazy, because if a patient comes in with a racing heart and chest pain, my first instinct as a clinician might be to reach for a beta blocker to slow that heart down.

And that instinct could kill them.

Why?

Because cocaine causes massive vasoconstriction by stimulating alpha -1 antinergic receptors, while simultaneously stimulating beta -2 receptors, which actually promote some compensatory vasodilation in the coronary arteries.

Oh, I see.

So if you give a pure beta blocker.

You block those beta -2 vasodilators.

You leave the alpha -1 vasoconstriction completely unopposed.

And the arteries just clamp down even harder.

Exactly.

Severely compromising perfusion and dramatically worsening the myocardial infarction.

That is a vital clinical pearl.

Wow.

So with opioids, we have maintenance drugs like methadone.

Do we have anything comparable for cocaine?

Currently, no.

There are no FDA -approved maintenance medications for cocaine use disorder.

Psychosocial therapy remains the cornerstone.

Are there any future treatments in the pipeline?

There is fascinating research underway.

Scientists are testing an anti -cocaine vaccine.

In mice, adding a peptide called Mastaparin -7 or M7 showed increased antibody secretion that literally binds to cocaine in the blood and blocks it from ever penetrating the blood -brain barrier.

That's incredible.

And there is also promising data showing that disulfiram, the drug traditionally used for alcohol, can reduce cocaine use when combined with cognitive behavioral therapy.

Let's look at another major stimulant, methamphetamine.

It operates a bit differently

Instead of just blocking the reuptake of dopamine, methamphetamine actively increases the release of norepinephrine and dopamine from the nerve terminal.

So it's actively pushing more out.

Exactly.

And the clinical adverse effects are profound.

You frequently see meth -induced psychosis, which presents almost exactly like paranoid schizophrenia.

How do we treat that?

Clinically, this can be treated with an antipsychotic like haloperidol.

You also see extreme cardiovascular strain, which, unlike with cocaine, can be managed with a mixed alpha and beta blocker like labetalol.

Because labetalol blocks both the constrictors and the heart rate stimulator safely.

Right.

You avoid that unopposed alpha issue.

We also see the physical hallmark of meth mouth, right?

That severe tooth decay caused by reduced salivation, chronic teeth grinding, and poor hygiene.

Yes.

For overall treatment, note the Matrix Model, which is a comprehensive cognitive behavioral therapy framework.

Now, structurally related to meth are the synthetic cathinones, better known as bath salts.

They are derived from the naturally occurring cat plant.

For years, they were heavily marketed online as legal highs, but the effects are devastating.

Like extreme paranoia.

Severe paranoia, delirium, extreme aggression, and physical dangers like acute renal failure and death.

Their schedule I now banned across all 50 states.

Let's move on to segment four, the most widely used federally illicit drug in the country, marijuana or cannabis sativa.

Let's break down the actual mechanism of action.

Okay.

So the major psychoactive component is THC.

It activates specific cannabinoid receptors located throughout the brain.

But the downstream effect on the reward circuit is what's really fascinating here.

It is.

In animal studies, administering intravenous THC causes a surge of dopamine release.

However, if you first give the rat naloxone, the opioid blocker, the THC no longer triggers that dopamine release.

Wait, really?

So THC doesn't trigger dopamine directly.

It works by first causing the release of endogenous opioids in the brain, which then trigger the dopamine.

Yep.

It's a wild connection between systems.

That is amazing.

Let's talk pharmacokinetics because route is everything here, just like with the other drugs.

Think of smoked marijuana as a direct flight.

Absorption from the large surface area of the lungs is fast.

About 60 % of the THC is absorbed directly into the blood, peaking in 10 to 20 minutes.

Fast onset,

but oral ingestion.

That's a connecting flight with a very long layover.

Because of the liver.

Exactly.

When ingested orally, practically all the THC is absorbed from the GI tract, but it is immediately routed to the liver where it undergoes extensive first pass metabolism.

So how much actually makes it to the brain?

Only 6 to 20 % survives to reach systemic circulation.

Because of this massive hepatic filtration, oral doses must be 3 to 10 times higher than smoke doses to produce equivalent effects.

And the effects take way longer to kick in, right?

Oh yeah.

The onset can be delayed by up to 12 hours.

That delay is a huge risk factor for toxicity.

The patient eats a brownie, feels nothing after an hour, assumes it didn't work, and eats three more.

It happens all the time.

What are the major adverse effects clinicians need to monitor for with chronic use?

We see a motivational syndrome characterized by apathy, poor grooming, and disinterest in goals.

We see chronic respiratory effects like bronchitis, and a potential risk for lung cancer if smoked.

And reproductive issues.

Yes, like decreased spermitogenesis in men.

And most concerning, long -term heavy use is associated with altered brain structure, specifically reduced volumes in the hippocampus and amygdala.

And then there's the incredibly bizarre cannabinoid hyperemesis syndrome, or CHS.

It's a pattern of severe, cyclic nausea and vomiting, diagnosed specifically in chronic marijuana users.

And oddly, it's often temporarily relieved by taking scalding hot showers.

Which is a complete paradox, because marijuana is so famous for being prescribed to treat nausea.

It is.

Speaking of therapeutic applications, Table 35 .3 and Box 35 .1 cover this.

We do have FDA -approved uses.

Right, like dronabinol and nabolone, which are synthetic THCs approved for chemotherapy -induced emesis and AIDS anorexia.

We also have Epidiolex, a purified CBD -based drug for severe childhood seizures and Lennox -Gastaut and Travit syndromes.

And in Canada, they utilize Dabixtamol, or Sativex, for MS neuropathic pain.

I always struggle with the drug interactions here, though.

Specifically those CYP450 enzyme pathways in the liver.

Think of the CYP450 enzyme pathways, like a metabolic assembly line in a factory.

THC is processed and broken down by the CYP2C9 and CYP3A4 assembly lines.

Okay, I'm following.

If a patient takes a medication that is an inhibitor of CYP3A4, like the antifungal ketoconazole, it's like the assembly line workers going on strike.

So the THC isn't broken down.

Right, it piles up, increasing the P concentrations and side effects.

Conversely, an inducer like a Phampin forces the assembly line to work overtime, rapidly clearing the THC and reducing its levels.

And crucially, THC itself acts as an inhibitor on the CYP2C9 assembly line.

Yes, which is a massive red flag if your patient is taking warfarin, the blood thinner.

Because warfarin relies on that exact pathway for elimination, right?

Exactly.

The THC will slow down warfarin's clearance, causing the blood thinner to accumulate and sharply spiking their bleeding risk.

It is not just a benign plan.

It is a highly active pharmacological compound with very real metabolic consequences.

I mean, Box 35 .1 mentions ongoing clinical trials .gov research, comparing marijuana to oxycodone for pain relief, its effects in pregnancy, and everyday memory.

It's an active area of study.

And we also need to briefly warn clinicians about synthetic cannabis.

These are Schedule I lab -made chemicals sprayed onto herbs.

And they're much more dangerous than natural THC.

Incredibly dangerous.

They cause fluorid psychosis, catatonia, and severe cardiovascular toxicity that natural cannabis simply does not produce.

Moving on to Segment 5, we enter the realm of drugs that profoundly alter perception, the psychedelics.

These drugs bring on thought patterns and sensory distortions usually restricted to dreams.

But while the patient is fully awake...

LSD is our prototype here.

It exerts its primary effects by activating serotonin 2 receptors in the brain.

But we need to differentiate an LSD trip from a true idiopathic psychotic break, right?

Doesn't perfectly mimic schizophrenia.

No, it doesn't.

With LSD, tolerance develops incredibly fast, often within just three or four days of consecutive daily use.

But there's no physical withdrawal.

That's the critical difference.

Abrupt withdrawal is not associated with any physical abstinence syndrome.

No physical dependence.

So if a patient presents in the emergency department having a terrifying bad trip, how do you manage that toxicity?

The treatment is primarily psychological and supportive.

You just talk them down in a quiet, safe environment.

If they were in severe panic, you could administer a mild anti -anxiety agent like diazepam.

But no antipsychotics.

Here is the crucial clinical warning.

You might be tempted to give a potent antipsychotic to stop the hallucinations.

But the text explicitly warns that neuroleptics like haloperidol can actually worsen the panic and exacerbate the negative experience.

Oh wow.

Clinicians also must educate patients about HPPD, right?

Hallucinogen Persisting Perception Disorder.

Yes, those are flashbacks.

Distressing visual disturbances that can spontaneously occur months or even years after the drug has completely left their system.

We also see other psychedelics like salvia, which is unique because it's a kappa -opioid receptor activator.

When smoked, it's intensely fast but very brief.

And then the dissociative drugs, PCP and ketamine.

Right.

Both PCP and ketamine operate as antagonists at the NMDA receptors.

They distort sight and sound and produce a profound feeling of detachment.

Which is the perfect bridge to dextromethorphin or DXM.

This absolutely blows my mind because DXM is the active ingredient in standard, over -the -counter cough syrup.

Yep.

At normal therapeutic doses, DXM safely suppresses the cough reflex.

But if an individual intentionally takes 5 to 10 times the normal dose, its major metabolite, dextorphin, builds up.

And what does that do?

It blocks NMDA receptors in the exact same way as PCP and ketamine.

It causes profound dissociation and severe hallucinations.

The major clinical warning here has to be co -toxicity, though.

Misusers often drink entire bottles of combination cough syrup.

And those syrups are usually loaded with acetaminophen.

So while they are chasing a dissociative high, they are simultaneously ingesting a massive toxic overdose of acetaminophen, which frequently leads to irreversible fatal liver failure.

Exactly.

Another highly utilized drug in this category is MDMA, known as ecstasy or MOLLE.

It possesses both stimulant and psychedelic properties.

By blocking serotonin reuptake, right?

Blocking reuptake and actively promoting the massive release of serotonin, dopamine, and norepinephrine.

The major safety priorities for MDMA are twofold.

First, neurotoxicity.

It can irreversibly damage serotonergic neurons, leading to permanent memory impairment.

Second, deadly hyperthermia.

Yes.

It can cause dangerous spikes in body temperature, severe dehydration, and rhabdomyolysis.

The rapid breakdown of muscle tissue.

The clinical treatment for this severe hyperthermia is aggressive, including rapid cooling, hydration, and administering dantrolene.

Because dantrolene works directly to relax skeletal muscles, which stops the heat generation from muscle rigidity and helps prevent that fatal kidney failure.

Which brings us to our final category, the inhalants.

Unique just because of their route of administration?

Divided into two groups, anesthetics and organic solvents.

Anesthetics, like nitrous oxide, produce an alcohol -like euphoria.

But the solvents are the really scary ones.

Organic solvents, toluene, gasoline, paint thinner.

When administered via bagging or huffing, they hit the brain instantly.

They can cause sudden death due to fatal cardiac dysrhythmias or severe vagal nerve stimulation that simply stops the heart.

We have covered a massive amount of clinical ground today.

We really have.

But if we synthesize everything, the overarching clinical framework is clear.

Understanding the exact mechanism of a drug is your ultimate tool.

Whether it's an NMDA antagonist like PCP, a dopamine reuptake inhibitor like cocaine, or a CYP450 inhibitor like THC.

Knowing that underlying mechanism is the only reliable way to anticipate toxicities, select the correct antidotes, and educate your patients safely.

I want to leave you with a final thought to mull over as you head into your clinical rotations.

We've seen so many paradoxes of pharmacology today.

Think about how a drug like marijuana can be therapeutically prescribed to treat severe nausea yet chronically cause cannabinoid hyperemesis syndrome.

It's a wild contradiction.

Or how standard over -the -counter cough syrup, when pushed to its metabolic limit, operates on the exact same brain receptors as horse tranquilizers.

It just goes to show you that the line between a healing medicine and a deadly toxin isn't drawn by morality or legality.

It is entirely dependent on dose and mechanism.

A profoundly true statement for any clinician to remember.

Thank you so much for joining us for this deep dive.

From the Last Minute Lecture Team, we wish you the absolute best of luck on your clinical journey.

Keep asking why and keep looking for the mechanism.